International MPN News, Science & Opinion

Six Clinics — The Index Project

mpnclinic

The MPNclinic Index

302 answers to 141 questions

In the past year,  in six historic MPN Clinics,   nine of the world’s foremost MPN specialists assembled.  In these clinics, these world renowned specialist provided 302 answers to 141 questions posted by patients, caregivers and healthcare providers.

Taken together, this rich treasure of information is 88 pages long, 41,818 words. As an unintended result of its sheer volume, precious information vital to all of us has been buried in a mountain of data.

The solution is to make it all accessible by providing (1) a searchable single document pulling it all together and (2) an index.

The index  is a work in progress, created by highlighting 88 terms and the questions (listed by number)  in which those terms appear. The results are only partial…but it’s a start.

 With your help,  we can make the wisdom and counsel buried in this document easily available to patients, caregivers and healthcare professions.

The Index Project

 We need more terms to be indexed.

We need a breakdown of topics into sub-topics.

We need volunteers to do this… and while it can be time-consuming, it’s also fun in a  geeky parlor game way and y vitally important to our MPN community.  You can volunteer to index one or more questions or send in candidates terms we should add to the index. ourMPNforum@gmail.com

Meantime, now that we have all the clinics assembled in a single document you can search the file using the Control F function. (Hold down the Control key while pressing F as in Find, type your search item in the pop-up box and hit return.)

The Doctors

Dr. Richard Silver Weill-Cornell

Dr. Richard Silver
Weill-Cornell

Dr. Srdan Verstovsek
MD Anderson

Dr. Ruben Mesa
Mayo Clinic

Dr. Claire Harrison
Guy’s & St. Thomas;

Dr. Attilio Orazi
Weill-Cornell

Dr. Ross Levine
Sloan Kettering

Dr. Jason R. Gotlib,
Stanford

Dr. Hans Carl Hasselbalch, Roskilde, Dk.

Dr. Hans Carl Hasselbalch, Roskilde, DK.

(Questions? MPNclinic@gmail.com)

Jason Gotlib =JG Claire Harrison= CH Hans Hasselbalch= HH Ross Levine=RL John Mascarenhas= JM Attilio Orazi= AO Ruben Mesa=RM Richard Silver=RS Srdan Verstovsek= SV

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September, 2012: 1-26– October, 2012:27-61   November, 2012: 63-95–  January, 2013: 98-118 – February 119-133, 2013 – March, 2013: 134-141

MPNclinic is a forum for MPN patients, caregivers and healthcare providers. Responses from doctors are informative and educational, not intended to replace or modify medical advice offered by a patient’s physician.

The Index

 Subject  References are to Numbered Questions
Anagrelide 3,7,8,21,29,54,98,104.126
anemia 16,17,24,51,60,61,66,67,83,,85,109,121,125,127,137,138,140
anti-depressant .6,111.
aspirin 2,5,6,7,14,15,28,34,41,44,53,58,69,70,77,82,87,89,92,93,98,103,104,110,125,126,130,134,139,
BCR/ABL .25.
blood 1,6,7,8,9,12,14,17,22,36,40,46,58,64,65,68,70,82,107,112,127,131,137,141,
blood cells 7,8,9,24,31,35,42,60,61,66,67,69,75,78,101,102,133,134,138,
blood test 10,20.27,29,34,37,47,49,56,63,83,85,88,93,106,115,119,123,126,129,140,
bone marrow 1,6,15,16,17,20,25,26,36,51,55,61,66,77,79,81,85,93,101,113,119,125,137,138,
bone marrow biopsy 7,
bone pain 15,22,31,50,57,66,76,129,134,
CBC 9,24,25,58,71,80,84,88,93,104,106, (see add’l after 133)
Children 20,32,49,80,90,114,
clinical trial 14,21,27,30,33,36,61,66,76,108,111,117,119,120,139,140
CYT387 .140.
cytogenetics 16,25,36,58,113,106,
cytokines .6.141
diet 29,33,42,121,122,
essential thrombocythemia 3,8,29,29,53,69,73,75,81,85,92,134,136.
ET 1,3,5,6,7,8,10,15,16,20,28,29,32,34,53,56,73,81,85,87,92,94,98,104,113,128,130,131,134,136,
ET to MF progression 3,73,77,81,114,118,
exercise 28,29,99,121,122,138,
fatigue 6,7,50,58,62,66,67,69,71,89,93,102,112,121,125,128,138,139,
fibrosis 1,2,8,15,25,58,59,73,77,79,81,85,88,93,106,112,113,125,138,141
genetic markers .11.
genotype .11.
HC .3.
headaches 7.14.89.130.134.136.
hematocrit 714,42,46,80,87,93,102,121,122,127,130,134,138,
hemochromatosis .88.
hemoglobin 7.16.51.61.66.67.71,80,83,93,116,137,138,
hemorrhage .28.
Hydrea 10,12,14,23,29,37,39,41,44,56,58,64,65,69,75,76,77,878,98,104,110,111,117,139,
Hydroxyurea 5,6,7,12,43,69,73,75,87,93,94,110,115,119,121,123,126,127,132,134,136,137,139,
hypercellular 11,16,25,58,59,93,123,138,
interferon 1,2,4,6,8,9,12,13,14,16,19,23,24,31,39,59,65,70,77,78,84,88,93,95,98,100,104,105,110,111,116,119,122,123124,125,126,127,132,134,135,136,138,139,
interferon alpha .8.95.
JAK2 inhibitors 6,70,76,79,86,108,
Jakafi 21,23,27,29,33,38,49,55,61,79,83,84,108,109,111,116,117,119,120,137,141.
karyotype 16,25,93,106,113
leg ulcers 7,
liver 23,31,40,45,59,62,66,76,83,89,90,91,115,134,137,140,141,
Low risk MF .2.
lymphoid 5.35.
lymphoma 5,13,35,63,65,
mastocytosis 31,90,
menopause 6,53,89,
microvascular .14.
monocytosis 25,26,
mortality 29,79
myelofibrosis 1,6,8,15,16,27,29,33,37,38,49,51,55,59,66,7=,73,74,76,77,78,79,81,83,85,93,95,105,106,109,1167,118,120,123,125,127,128,129,132,134,137,138,139,140.
nattokinase 28,
night sweats 6,15,33,50,53,58,66,84,93,125,138,
P32 67,68,
Pegasys 1,2,9,14,15,16,19,23,24,29,30,45,78,84,88,89,93,95,100,109,119,121,122,123,135,139,
pegylated interferon 14,19,78,93,97,123,139
Philadephia chromosome 33,71
phlebotomy 7,8,14,17,33,41,42,43,46,47,65,67,70,71,107122,125,127,138,
platelets 5,8,9,12,14,17,21,24,28,29,31,33,34,38,47,51,58,60,66,68,69,80,81,82,83,84,85,89,92,93,94,98,104,113,124,125,126,130,131,132,133,134,139,140.
PMF 2,3,59,67,81,84,86,106,141,
polycythemia vera 7,8,17,27,41,65,68,75,78,93,99,102,107,119,123,125,127,134,138.
prefibrotic MF 3.78.128
Progession 3,14,22,29,56,59,63,73,77,78,81,84,93,95,106,114,118,122,125,127,132.
proliferative phase .1.
pruritus 8,25
PV (discussion only) 5,6,7,8,9,12,14,15,17,22,24,30,33,35,39,41,42, iron intake and   43,kidney disease with   47,64,65,68,70,71,75,77,88,93,95,99,101,102,103,107,111,114,117,118, and   Jakafi 119,121, and Pegasys 122, Peg vs HU 123,   125,127,128,130,131,132,133,134,139,
RBC 8,38,48,51,65,66,84,122, 138,140,
red blood cell count 7,61,101,
reticulum 16,58
rheumatoid arthritis 10,
ring sideroblasts 16,
SAR302503 .33,108.
sarcoidosis 13,
shortness of breath 7,
spleen 14,15,22,23,24,27,33,38,45,50,51,55,61,66,76,83,84,88,93,106,116,127,129,137,139,140,141.
splenectomy 23,33,137
symptoms 5,6,7,14,22,60,61,64,66,67,68,69,87,102,112,120,125,126,129,130,134,136,138,
Tasigna 31,
therapy 1,3,6,8,9,10,12,14,31,36,65,66,68,73,75,77,79,89,95,97,104,111,115,119,123124,127,135,136,139,140
thrombocythemia 3,8,29,53,69,73,75,81,85,92,134,136,
thrombocytopenia 17,66.
thrombocytosis 8,80,81,87,112,
Thyroid 4,6,24,66,67,69,121,135,
venesection 5,14,18,88,125,127,131,134,
Warfarin 6,89,93,136,
watch & wait 105,

   

MPNclinic — The first six sections, combined.

When is Pegasys use appropriate?

`1.J.G.,  Eastern US I have found little recently published regarding Pegasys for MF patients. What criteria are desired for this therapy?

SV: Pegasys is one of the therapeutic options for patients with MF. there are no specific criteria for its use. However, it is known that interferon (Pegasys is a long-acting form of interferon) may help particularly in earlier stage of MF, in cases where there are too many cells in blood (i.e. proliferative phase of the disease) and low grade fibrosis in the bone marrow (vs. advanced MF with low blood cell count and very significant fibrosis in the bone marrow)

CH:: PEGASYS is an exciting treatment option, it is important to remember especially for MF it is really experimental. My own view is it is likely to work better for patients with early MF. My other concerns are side effects, I don’t think the data to date are compelling enough for a patient with significant side effects to stay on this therapy. Personally I am very excited that we are recruiting into a study comparing PEGASYS with HC in ET and PV.

Myelofibrosis with good counts. Is Pegasys an option?

2.D.C., Colorado… I was diagnosed with PMF in June of 2009; I am 56 yo with no other medical problems. A BMB concluded the PMF diagnosis with moderate to markedly increased reticulin fibrosis, 40% cellular marrow with abnormal clusters of large megakaryocytes, convoluted nuclei and abundant cytoplasm, no abnormal blasts. I have been on HU and aspirin since this time with eventually taking 500 mg. of HU five times a week and 1000 mg. twice a week. My doctor has told me that he would most likely be able to get Pegasys for me but with my counts being fairly good I am not sure if I want to “rock the boat” on the small hope that Pegasys will either reverse my fibrosis or hold it off for a while. I have been battling this decision…what would your advice be? Thank you so much for being willing to answer questions….wow!

CH: You are a young patient with what appears to be low risk MF, as I tell my patients, sometimes choosing the best treatment is finding the one whose side effect profile is best suited to you and also most acceptable. You could consider a trial of PEGASYS.  If it suits you well then fine, if not you could return to HC. Both are good treatments.

SV: Of course, there are no rules that one can apply in this particular situation, and approach needs to be individualized based on detailed review of the particular patient’s situation, pros and cons of proposed change, desires of a patient, and opinion of an involved physician. Detailed medical history and review of medications would be needed to see whether use of interferon is prudent. I don’t think one can give an advice easily, without proper detailed assessment.

Long-term use of Anagrelide…what are the effects?

3.A.S., Cambs UK:..Can I ask if there are any statistics or studies on the link of long term use of anagrelide with  transformation or progression from ET to MF?

CH:  The PT-1 study suggests that there is more risk of myelofibrotic transformation from ET to MF with anagrelide than with HC. This result came from 400 patients over 3.25 years. The only other study (anahydret) was not powered to demonstrate a difference. There is an on-going study EXELs a long term observational study in Europe following ET patients receiving therapy which should help show more results.

AO: There is no convincing evidence that anagrelide favors myelofibrotic progression in cases of “true” ET diagnosed in accordance with WHO 2008. Most cases of ET in which myelofibrotic progression was described were in reality early phase PMF (prefibrotic or minimally fibrotic) from the very beginning.  No fibrogenic potential of anagrelide was shown in the preliminary results of the large ANIDRET Study https://ash.confex.com/ash/2008/webprogram/Paper11545.html.  However, irrespectively of the anagrelide issue, there is a small risk of myelofibrotic progression even in true ET which is less than 1% at ten years but 9.3% at fifteen years [see: Barbui T, et al. Survival and disease progression in essential thrombocythemia are significantly influenced by accurate morphologic diagnosis: an international study. J Clin Oncol. 2011;29:3179-84].

Link between interferon and thyroid problems

4. A.S., UK… Are any studies  or stats available on the link  of the use of Interferon with thyroid dysfunction?

CH: Thyroid dysfunction is a well-known complication of interferon use. Both over and under active thyroid conditions have been reported.

SV: interferon can cause abnormality of a thyroid function, this is known rare side effect of interferon

PV and lymphoma – what is my outlook?

5. H.K., Melbourne, Australia…I have both PV (ET -2003) and follicular lymphoma (2007).  Have no symptoms and a m in w & w as I have refused hydroxyurea & interpheron due to extreme sensitivity to chemicals. Now that I’m turning 60 I am re-evaluating. I am on aspirin and had 2 venesections last year when my ET morphed into PV. My haemocrit went through the floor after the venesections. Platelets 850. Lymphoma shows no change since first diagnosis. Extremely indolent. Have you ever heard of anyone with these 2 cancers? What prognosis is the most likely?

SV: it has been well described that patients with MPN have higher chance of having lymphoid disease. prognosis is related to the type of MPN and type of lymphoma, not to the fact that both are present at the same time. in this case it seems that both are indolent at present

CH: Sorry to hear about this. There is an association between PV and lymphoid disorders such as follicular lymphoma. I wouldn’t like to comment on your prognosis question because really I would need a lot of medical information and a proper hands on evaluation. Both diseases have good treatment options if needed.

Night sweats.

6. K.A, Rochester MN….I found out I had ET in 2004.In 2007 I started bleeding and was diagnosed with mesenteric ischemia.From then on I was put on Warfarin ,Hydroxyurea and aspirin and  haven’t had any problems except night sweats.Is there anything I can try to stop these night sweats.I go to sleep and wake up 5 – 10 minutes later sweating and then every two hours.After 6 a.m. I am pretty much ok except once in a while I get it about 9 p.m.This has gone on every night since 2004. .I get very fatigued during the day which I am sure some has to do with not getting a good night’s sleep.I would like to go back to work part time but right now that seems impossible. I would appreciate any kind of suggestions. My hemotologist is at the Mayo Clinic for this.He has suggested to me to try an anti depressant but I do not like the thought of trying that being it can cause problems sleeping, interfere with my blood thinner and cause high blood pressure which I already take meds for. I am hoping you have other suggestions to try.

RM:  Night sweats can be a problematic issue in myeloproliferative neoplasms.  We have been involved in assessing the symptoms associated with MPNs since 2007 in combination with colleagues and investigators from around the world.  Night sweats are most common in patients with myelofibrosis (or those with post-PV and post-ET myelofibrosis) but still can be present in individuals with ET or P vera.

These can vary in terms of how they affect individuals.  They can range from being a mild sensation of warmth to being drenching hot flashes at night, sometimes with enough perspiration to require individuals to change the bed linens.  These likely are a side effect of the myeloproliferation going on in the bone marrow.  We do believe that they likely are related to proteins made from the bone marrow that are circulating in the blood.  These proteins are called cytokines and can lead to a variety of the symptoms associated with the disease.

For women who have undergone menopause, we sometimes do have to distinguish these from hot flashes which can occur from the lack of estrogen.  For individuals who are recently menopausal, it can be difficult to distinguish between the two.  If women have been menopausal in the distant past, we will find that there was a cessation of their hot flashes and then a recurrence.

In terms of options for helping night sweats, this has been an area where the JAK2 inhibitors, whether approved or experimental, have been helpful.  Other medications that have been helpful have been medications that have helped to suppress the myeloproliferation going on in the bone marrow.  There has been benefit that has been experienced with interferon depending on an individual’s clinical situation and other non-MPN medications have included certain antidepressants that have been helpful.  Good therapy of night sweats should be taken into consideration in the broader program in terms of treating the MPN.

CH: Sorry to hear about these troublesome night sweats. They are likely to be associated with your disease but it is worth excluding other factors perhaps hormonal, your thyroid, or diabetes as well as perhaps female hormones for example. Night sweats sometimes respond to drugs like hydroxyurea and very good control of the blood count. If this is really troubling you and it sounds like it is I would ask to be considered perhaps for a trial with a JAK inhibitor since these agents do provide better control of symptoms like sweating. Only your haematologist can tell you if this is appropriate to be considered for you.

Leg ulcers and hydroxyurea.

7. T.A.,  Perth, Australia… I was diagnosed with ET 4 years ago and was started on lowdose aspirin and as my counts became higher I was placed on hydroxyurea which gave me leg ulcers therefore I was switched to anagrylin.  My blood counts have now dropped from 1.3m to .3 and according to the specialist I should be showing no symptoms at these levels. My problem is I still have severe itching, total exhaustion after 3 hrs trying to work,violent headaches and shortness of breath. Is this in any way normal for ET? I have just had my first bone marrow biopsy and am waiting on the results. Any info you can give me would be great.

RS: Suffice to say,  leg ulcers are a frequent complication seen with hydroxyurea, often overlooked by enthusiastic users of this drug.  It occurs in a frequency of about 15 to 20% of patients.  They also heal slowly.  Often patients are referred by uniformed hematologists to dermatologists who in general have very little idea of this being a complication of hydroxyurea so the medication is continued and various local dermatological medicaments are applied without any effect.  The only way of treating hydroxyurea ulcers is to discontinue the drug.  Healing is slow, unfortunately.  Local wound care should be applied.

SV:There are many possible causes for symptoms reported and one cannot simply say whether they are related to ET or not. Detailed medical history and review of current blood work and medications would be needed. Apparently, involved physician is trying to answer this question as the bone marrow biopsy was just done. Therefore, follow up with him is mandatory, to resolve the issue and try to provide answers.

JG   Regarding your symptoms of headaches, shortness of breath, exhaustion–
a.  Ask your doctor whether you have an elevated red blood cell count, measured by the hemoglobin/hematocrit, and whether there is a role for phlebotomy.  Some patients have an overlap between ET and polycythemia vera (PV), and if the red blood cell count is high, a phlebotomy could be helpful.
b.  What is the dose of anagrelide you are on?  Anagrelide itself can cause headaches and fatigue, and sometimes effects on the heart that could contribute to shortness of breath.
c.  Because myeloproliferative disorders can be associated with blood clots in the arteries or veins, speak to your doctor to determine whether there is any concern for blood clots that can be contributing to your symptoms..

CH: These symptoms do sound bad. My suggestion is you discuss them with your haematologist. Anagrylin may be the cause of some of them – particularly headaches, splitting the dose may help. You need a medical evaluation for shortness of breath and exhaustion. Itching may be your MPN but worth checking other causes too – is it new, what triggers it, is there an associated rash?

PV to ET – what are my options?

8. S.H., Aliso Viejo, CA… In 2002 I was diagnosed with PV based on an RBC of 21. Today my RBC runs in the 3-3.2 r ange and my platelets are elevated, at around 500+ using HU (500 mg daily with addl 500 2x wk) . My current hem/onc (not the diagnosing physician) says I’ve converted to ET. As I continue to increase HU to control platelets RBC continues to drop. Anagrelide is not an option. I tried that after a heart attack in 2004 with terrible side effects. Would appreciate any insights you have to offer.

RS: The importance of doing a bone marrow biopsy in all patients with ET has recently been stressed by Thiele and there is an excellent article on this subject by Barbui in the Journal of Clinical Oncology in 2011.  This shows that those patients who present with thrombocytosis may in fact have an early phase of primary myelofibrosis and not ET.  The difference in prognosis is significant and such patients may be candidates for different forms of treatment.  Itching is an unusual complication of essential thrombocythemia.  The distinction of early essential thrombocythemia and early polycythemia vera with pruritus is very common and can only be resolved by performing a red blood cell mass which a number of us believe is a very important adjunct to the diagnosis of patients with myeloproliferative disease.  In general, the development of myelofibrosis occurs 8 to 10 years after the diagnosis of PV in patients who do not receive specific myelosuppressive therapy.  It is for this reason that some of us believe that interferon is the drug of choice in patients with significant phlebotomy requirements from the onset.  Patients with PV who have residual hematopoietic tissue and who have fibrosis in the marrow do respond to interferon and so these patients should be considered, in my opinion, with interferon therapy i.e. in Pegasys or interferon alpha 2b

JAK2 variation and Pegasys.

9. J.S., Cincinnati… I was diagnosed with PV in 2002 and have had good control of my CBC counts with interferon in the initial years and Pegasys in recent years.  My latest round of Pegasys started in late 2007 with 135 mcg/week and was reduced to 65 mcg/week fairly evenly over that time.  My doctor has started taking JAK2 tests twice a year, based on the good results from the Verstovsek study of Pegasys.  About 9 months ago, my JAK 2 was down to 4%.  Recently, it was up to 14%.  My counts have held steady over the past couple of years, HCT 40-44, platelets 104-180, White count 3.7-4.6.  Before the most recent JAK2 results came back, we had agreed to take a break from the Pegasys to see if the good results would hold steady.  Since the test came back with the increase, my doctor has restarted the Pegasys at 100 mcg per week.

Questions: How much variation is common with JAK2 percentages?  Is a movement from 4% to 14% significant?  Is there a level that causes concern?  What is the best practice concerning Pegasys “breaks”, especially in cases where the CBC numbers are good, but he JAK2 numbers are still fluctuating/increasing? Thank you so much for offering this opportunity?

 SV: Variation in JAK2 percentage is common and one usually follows a trend in change rather than be concerned about one measurement. however, most importantly, percent does not correlate with clinical outcome so there is no reason to be concerned. usually the use of pegasys is based on a clinical need, to control blood cell count, and it is not judged on the JAK2 percentage. traditionally interferon is given continuously, at the lowest active and safe dose, to maintain response, without breaks.

CH: Great news that you are doing so well on PEGASYS, congratulations! You are asking some great questions. JAK2 percentages: We are working on this in the field and the answer is each lab is different. In my lab we only use JAK2 percentage to guide therapy after a transplant. I don’t change PEGASYS dose according to these results since I am not sure we know enough about it. There is no best practice for PEGASYS breaks in our clinic.  We increase gaps and reduce dose once we get to every 4+ weeks I consider stopping, but I discuss and consider each patient individually.

MPN and Rheumatoid Arthritis…any connection?

10. R.S., Norwalk, CT...I have ET.  I have been taking Hydrea for 2 years and my blood tests are in the normal range. I am living an active life but stopped working 2 years ago to reduce stress levels. I do get tired and sometime off balance.
Question: I have just been diagnosed with Rheumatoid Arthritis.  Is there a possible connection between these 2 diseases and/or the medications?

RL: There is no clear connection between these two diseases.  However, there is data that by different mechanisms, that JAK2 and JAK1 are involved in both diseases, and JAK inhibitors are being tested both in MPNs and in RA.  So it is possible, depending on how these trials report their results, that a single medicine might help both diseases.

CH: Sorry to hear about the rheumatoid arthritis.  To my knowledge this is unlikely to be connected with your ET.

Genetic markers…an aid to therapy?

 11. J.C., Cleveland…  My genotype for European Ethnicities is CG    JAK2 V617F-positive myeloproliferative neoplasms. Will knowing the location of the marker help in developing a treatment/cure for PRV?

CH: Yes I believe all this information will ultimately help us to find a cure but we would not base current treatment on this.

RM: The location of the marker does not help in any way now, though many of us are trying to determine how genetic markers influence risk of these diseases.  Right now this has no value in treatments being used or tested in trials

Ever higher doses of hydroxyurea

12. J.C., Cleveland… I was diagnosed in 1997, my hematologist considers my blood to be very stable however over the years the hydroxyurea has been steadily increased from 500 mg/day to 1500 mg 3x a week and 1000 4x a week. Dosage may go up to 1500 4X a week soon. Hydroxyurea is tolerable but I don’t like to keep having to increase the dosage to control the platelets. The dosage increase is because platelets spike over 400 which is not high for some but causes tingling in my arms, hands, feet and legs. Agrylin did not work, Interferon did not work. Is there any other suggestion or should I continue consuming large amounts of Hydroxyurea?

SV: If hydrea works then one sticks with therapy that does the job. Alternative therapies include chemotherapy agents that are known to increase risk of transformation to acute leukemia, so this is not advisable

CH: Provided there is no other explanation for tingling in your arms, I would continue with the current dose. There is no clear evidence that bigger doses of this drug are more harmful than smaller ones. An expert panel considered 2g per day to be a maximal dose for patients weighing less than 80 kg and 2.5g for those above this weight.

PV, sarcoidosis and now non-Hodgkins lymphoma? 

13. J.V., W. Australia Dxd with pv 2011, been on hu and interferon pretty much all that time and last week was told i had sarcoidosis, the dr told me he was 99 per cent sure i had nhl, but the last week had a fine needle biopsy and thats where this dxd came from, could this be wrong? I was reading my ct scans and pet scans and they  say in keeping with stage 3

CH: This is clearly a concern I am afraid that your case sounds complicated and sarcoidosis and NHL can show features in common. I would advise a frank conversation with your clinician.  Raise your concerns, take someone else with you to the consultation and write out your questions beforehand.

PV with high platelets, phlebotomy only?

14. .C.G., NAWhat is a platelet count to start treatment for Pv?    Is is 1mm 1.5 or 2 mm?   Is age a factor as well?   The only symptoms I am having is occasional headaches lightheaded dizzy  feeling.  I have 1 mm platelets and am 40 yrs old.  I get phlebotomys when hematocrit is 45 or higher.  Platelets are the only problem so far which have been increasing over the last few years.  Do you wait until a serious Event?  ( seizure stroke clot) before treating w Pegelated interferon

CH: Good question. We have no international agreement on a platelet count to start treatment for PV. Also, in my own practice, I would individualise this for each patient depending on other things. Have they had a clot, are there other vascular risks etc. I would also aim to treat before a serious event, not forgetting that venesection and treatments like aspirin offer protection against most events.

 RM. Perhaps as a broader interpretation of this question, I think the individual would have to discuss what are the goals of therapy for patients with P vera and how does Pegasys potentially play into those roles?  The goals of therapy with P vera have potentially both short-term and long-term goals.  In the short term, therapy of early MPNs, ET, and P vera primarily focus on trying to prevent vascular events, which are blood clots or bleeding.  This could include as well microvascular symptoms or symptoms where blood flow is impeded causing symptoms such as difficulty with headaches, complex headaches, recurrent migraines, difficulties with concentration, erythromelalgia and other difficulties.

Another goal with ET and PV would be to potentially improve the symptoms associated with the disease and a final goal and a goal that at this point does remain more theoretical would be to try to delay progression in the illness.  Pegylated interferon has been shown in single-arm phase 2 studies to help to control counts, help to improve symptoms, may help to improve or decrease the risk of blood clots or bleeding, and that is currently undergoing proof in a randomized clinical trial between Hydrea and pegylated interferon.

Finally, there is speculation and hope that Pegasys may have an impact on delaying progression of the disease, but that still needs to be proven beyond a shadow of a doubt.  The impact of phlebotomy rate and platelet count on both the initiation of Pegasys or the adjustment of the dose is a more individualized decision that should be discussed with the physician and the patient, but those are secondary considerations in terms of creating the overall plan for the patient.

MF, big spleen, no meds, need treatment.

15. D.P., North Wales…  I am a post PV myelofibrosis patient with an enlarged spleen, anaemia with a haemoglobin reading of 8.7.  I am based in North Wales, UK.  I was diagnosed with ET in 2000, PV in 2005, MF in 2010.  Up until the MF period I have had very limited symptoms and only took baby aspirin during the ET period.  Currently I take no medicines at all.
I am about to start a trial period on EPO to try and raise the haemoglobin.  Apart from the impact of the anaemia on walking uphill, general tiredness etc I have no other symptoms such as bone pain, night sweats etc.  However since my diagnosis of MF in January 2010, my condition has deteriorated and I have yet to meet a haemotologist who knows much about MPNs. Would the panel recommend the use of pegasys to try and halt this deterioration which is presumably caused by the ongoing fibrosis in the bone marrow and its impact on the spleen?  If not, what treatment would you recommend in my situation?

CH: David there are many treatments potentially available for patients with the concerns you describe; which ones to offer depend upon individual patient factors. EPO is a good choice I would say since symptoms of anaemia are the ones which seem to bother you most. Really you ought to have a proper evaluation to individualise treatment perhaps seeking a second opinion at least to set a plan.

Ring sideroblasts and Pegasys

16. S.S., Michigan… Diagnosed with ET, JAK2 positive (2008)

Pegasys 22.5 MCQ (every other week)  All counts in normal range except  WBC always below normal but function appropriately when necessary. The bone marrow is hypercellular with trilineage hematopoieses and myelofibrosis (grade 2/3 WHO 2008). Latest BMB showed that there is dyserythropoiesis with increased iron storage and occasional ring sideroblasts (<10%) in the aspirate.  No circulating blasts.

My question:  Is it unusual to see increased storage and ring sideroblasts in MPNs and could this be caused by the suppression of the bone marrow due to the Pegasys?  If it is unusual what should be done?

AO: There is limited information. You have normal hemoglobin and a low frequency of ring sideroblasts that is well below the threshold of 15% (used for suspecting an MDS, refractory anemia with ring sideroblasts type). Most likely this is nothing to be too much concerned about. Possible role for interferon. Some of the cancer patients who developed transient ring sideroblasts (>15%) in a MD Anderson study (see ref.) had indeed received interferon (alpha). So it is conceivable that the ring sideroblasts may be due to interferon treatment. If you are worried, an important test to check in occasion of your next marrow is karyotype. In addition, if there is a previous bone marrow to compare it might be useful to know the percentage of ring sideroblasts pretreatment. Reference: Ok CY, et al. Leuk Res. 2011 Dec;35(12):1605-10.

CH: This is very interesting. Ring sideroblasts are red cells with excess iron around their nuclei they look very pretty down the microscope but if there are less than 15% of them generally they are not significant. I am not aware that PEGASYS might increase the chance of seeing them or indeed extra iron in your bone marrow.  I assume this wasn’t seen previously. Difficult to give an opinion here but I would keep an eye open (?)and possibly think about getting checked out for haemochromatosis, an inherited iron loading condition.

RS: This case demonstrates the importance of the bone marrow biopsy in all patients with ET especially at diagnosis.  The World Health Organization criteria are quite specific in saying that in general, patients with ET have normal cellularity whereas in patients with early myelofibrosis, the marrow is hypercellular with evidence of increased granulopoiesis and erythropoiesis.  With early PV a definite increase in reticulum fiber may be seen.  Of course megakaryocyte morphology in the hands of experts such as ourselves can be very helpful although it is a matter of contention in certain centers in Europe.  The findings of siderocytes is troubling since this is not part and parcel of the MPD picture.  Certainly FISH tests on marrow cytogenetics should be performed at the very least.

Why can’t we donate blood?

17. S.A.Wigan, UK…   (1) Why can’t we donate blood or bone marrow? If the effect of our disorder (PV) is that we produce too many red blood cells surely this would benefit those requiring blood products?  at the same time i am having a venisection for too high a Hct there are people with single figure Hct receiving blood products.  The surplus (iron rich) blood is a consequence of the disorder and not the cause, so why does the NHS not utilise this rather than incinerate our blood, or are we misinformed and it can be transmitted via blood transfer such as blood transfusion….

CH:  Unfortunately you can’t donate blood for transfusion to other patients because you have a blood disorder. You may find that the venesected blood could be used for other purposes. For example our lab use it to check normal ranges etc.

RM.  First, as always, I am impressed by individual’s altruism in that even while facing a blood illness, with their spirit of altruism, they still wish to donate blood or marrow.  First, with marrow, there is of course concern that an individual with an MPN would potentially have the MPN present in the stem cells that would be donated in bone marrow and, on this basis, potentially impact the individual who would receive the cells.  Even if the donor was in an earlier phase of MPNs, it still could be quite problematic in terms of the recipient. So I would say, in terms of bone marrow, there is concern that it could be harmful to the recipient.

Now in terms of blood, I think the issue is more complicated.  The blood of individuals with MPNs is highly unlikely to be contagious in any way and certainly unlikely to be able to transmit the disease.  Indeed, individuals with P vera who have had phlebotomies, if this blood was given to recipients who needed a blood transfusion, the likelihood of transmitting anything harmful is probably exceedingly low.

That being said, the American Association of Blood Banks has very conservative guidelines that they follow which can include multiple years of being disqualified as a blood donor for international travel to places even such as Mexico or the UK.  So the real reason that patients can’t donate blood is primarily because of the strict guidelines the American Association of Blood Bank pursues to try to have the safest blood supply possible, even though the likelihood of harm to any recipient really is probably not a major factor.

RS: The question why phlebotomy blood cannot be used for patients in dire need because of thrombocytopenia, leukopenia or anemia is an interesting one.  For many years when I was a resident and junior attending, polycythemia vera blood was highly sought after.  Suddenly, it could no longer used therapeutically.  As I remember it, through long ago conversations, polycythemic blood was transfused to a “normal patient” who subsequently developed polycythemia vera.  Apparently, there was a law suit and the possibility of some transmissible factor in the polycythemic blood causing polycythemia in a normal patient could not be conclusively excluded.

For that reason, polycythemic blood was no longer accepted.  This is a pity, since polycythemic blood is rich in red cells, platelets and white blood cells.  The white cells are physiologically active and is one of the reasons polycythemia vera patients do not develop infections.

Refused venesection.

18. S.A., UK...I’ve been 0.001 away from target threshold Hct and despite being symptomatic the local hospital has refused venosection , requiring  unecessary conflict to get a venosection done – is there a central info base for medical people to be referred to? To be refused treatment after 13 years effective self management is both humiliating, frustrating and stressful.

CH: Sorry you have experienced this I understand it is exasperating unfortunately we do not have a central information base but perhaps find a member of the local team who listens to you best and try to arrange to see them?

Does Pegasys work?

19..A.M., Massachusetts… As someone who has used pegylated interferon (aka Pegasys) for more than two years now, I’m more than a little interested in knowing more numbers with regard to this drug. Assuming that this is medical information in addition to proprietary info, I’d like to know a bit more about what the medical community has found out with regard to its efficacy.

CH: There have been several papers showing efficiency of pegasys from French and MD Anderson groups and most recently an international consortium convened by Ruben Mesa.

JAK2+ runs in the family.

20. J.P., Michigan…  I am a 53 year old female diagnosed with JAK2+ ET about 3 years ago.  My 72 year old mother was just diagnosed with JAK2+ ET as well.  Should my 4 grown children and 8 grandchildren be tested that or wait for symptoms to appear?

RL: Although family members of MPN patients have a 3-5 fold increased risk of developing MPN, and you have a family history, I would not test your family for JAK2. I would consider routine blood counts in the adult family members. 

CH: About 1 in 8 ET patients will have an affected family member just as you do. My advice would be to raise awareness in your family and that if members have a blood test it should be checked for signs of MPN. I would not advise mass testing of your family however mainly because a normal result now would not necessarily remain normal and particularly young children often have vigorous bone marrows with high platelet counts which return to normal which can cause a lot of anxiety. So I would test in two scenarios: first if there are symptoms and second if there is a risk situation e.g., a young woman needing contraception or a planned surgery.

High platelets, on Anagrelide…

21. C.M., New Jersey.. . On Anagrelide for 5 years 4 mg a day. My platelet number is 843. No symptoms other than the high platelet number. I see a hematologist regularly. I sent a saliva sample to 23 and me. Was offered to participate in jakafi clinical trial but chose not to participate at this time. What is best treatment for me? What can I expect? How does this progress? Should I travel outside US?

 CH: The best treatment is one which is individually tailored to you and reviewed to ensure it is still the right treatment. I would think you should be aiming for a better platelet number (sub 400 as a rule) however there may be excellent reasons for being kept at the level you are currently at. I can’t see any reason at the moment to travel outside the US.

 PV, no meds, what next?

22. A.F., Lousiana…I am a 47 year old female, in excellent health,  diagnosed with polyscytemia rubra vera 3 years ago. I see my hematologist every 6 months.  My only treatment is 1 baby asprin a day.   My concerns are: What should I be looking for, physical sign and symptoms, as indicators the PV is progressing? What should I be doing to prevent progression? Where can I find simple information about this condition?

CH: Well you have found MPNforum. As a source of information there are other websites linked to that one as well. The first thing to say is your disease is unlikely to progress fast if indeed it does progress. It is important to be aware of signs of a blood clot – usually pain and swelling (not always both present). Patients who progress usually start to notice a change, usually, but not always, a drop in blood counts, perhaps a fullness where the spleen is (left upper abdomen) and increasing symptoms particularly weight loss, bone pain, sweating etc. To prevent progression and prevent thrombosis it is important to have as active and healthy a lifestyle as possible. No drug treatments have been shown to delay progression.

Liver enlarged post-splenectomy

23. J.H., WisconsinSince my splenectomy 5 years ago my liver is getting larger.  What is the best line of treatment for this?  I began Jakafi 2 weeks ago.  My hematologist is advising me to get checked out at Mayo again.  Since you are not in Rochester anymore I must see someone else.  Who would you recommend.  Since United health care has recently approved Pegasys I would like to go back on that.  I will see my hem on the 6th.  My counts are good, in fact the hemaglobin has been slightly above average for the last months, plts are normal wbc is high most likely due to nucleated reds.  I have taken diuretics since the splenectomy, but my legs are swelling more with water retention in the last month. Any advice for us?

CH: There are several different treatments for liver enlargement after splenectomy I think Jakafi is reasonable to try in this setting but there are others.  You mention interferon but hydrea and 2-CDA have also been used. If you are stable I would try Jakafi for at least 6 weeks before deciding if it works or not.  Livers respond more slowly than spleens and some patients’ spleens take longer than12 weeks to respond.  It would be important to get a proper check of the water retention.

MF – spleen shrinking, anemia increasing.

24. F.M., Ontario, CanI have had PV/MF for the past 21 years. I have been on 90 micro gm of  Pegasys for the past 3 years. My last cbc showed the white cells at 16, platelets at 350 and Hgb at 104, the lowest that it has ever been!  In the past 6 months I have increasingly been feeling chronic joint and muscle pain (in conjunction with the Hgb dropping from 127 to 104) and the Spleen changing from 23cm to 15cm. The white cells and platelets dropping very marginally.

Is it possible that my dropping Hgb is caused by the Spleen getting smaller? Is the spleen helping my struggling bone marrow make blood cells? I have not had a BMB for the past 5 years.

CH: Hello Frank it sounds as though things are going well with your spleen but less well  with your Hgb and symptoms. I would say it will be really important to get checked out for other causes of anaemia (for example iron deficiency or thyroid disease linked to the interferon) and joint/muscle pain.

A difficult case…

25.  Dr. M. G. Baltimore… A 75 year old man was referred because on a preop CBC he was found to have a WBC of 45K with a H/H of 11.4/34.3 and a platelet count of 296. On smear review he has neutrophilia with a mild left shift,  monocytosis of 13% and a rare blast. He feels absolutely well.  No fever, chills,  anorexia, pruritus.  He is active,  still working full time in an office setting.PE is completely negative.  No lymphadenopathy;  no hepatosplenomegaly. Comp met profile is unremarkable.Bone Marrow:  Markedly hypercellular  (95%.)  Atypical megakaryocytes.  Reticulin stain shows very mild increase in reticulin fibrosis. Flow cytometry: No increase in blasts.  Half of the granulocytes express CD56. Cytogenetics:  Normal karyotype. Fish for BCR/ABL is negative.  MDS FISH panel is negative. JAK2V617,  JAK2exon12 and MPL are all negative.Slides were reviewed at Hopkins Conclusion:  ” difficult case to classify.” the pathologist ruled out CMML was because there was no monocytosis in the marrow.

Any suggestions as to furthur diagnostic tests?

26. AO: The case seems to fit best CMML-1. PB and bone marrow should be reviewed to confirm monocytosis (esterase and/or CD14 helps on the bone marrow). CD56 expression in granulocytes (aberrant) and monocytes  is quite common in CMML. A small proportion of CMML with WBC  >13 x10/9/L (proliferative subtype) may have a proportion of  megs. “MPN-like”  in addition to the more common dwarf forms.  Some of these proliferative CMML may have a JAK2 mutation (rare) other may have RAS mutation.

The presence of bone marrow monocytosis can be subtle. Its identification is greatly aided by esterase and/or CD14 immunostaining. In general, if the PB monocytosis is persistent  (>3 months) this might suffice for diagnosing CMML based on PB findings. The alternative is a diagnosis of MDS/MPN, unclassifiable, a heterogeneous group of neoplasms which besides RARS-T, also includes  truly unclassifiable cases with MDS/MPN overlap features. There is no much information on how to treat MDS/MPN, unclassifiable. My guess these cases  are approached similarly to CMML, tailoring the treatment to the predominant clinical manifestation(s). 

Clinical trial for polycythemia vera…

27. Sherri Pruce, Pittsburgh… My mom was recently diagnosed with post polycythemia myelofibrosis at the Hillman Cancer Center in Pittsburgh, PA.  Her doctor recommended for us to take her to see Dr. Tefferi at the Rochester, MN Mayo Clinic.  I took her on June 14 and 15th and she had extensive blood work and a third bone marrow biopsy ….  Dr. Tefferi gave us all of the paperwork to start a clinical trial  Multiple Ascending Dose of BMS-911543. It has been three weeks since her appointment and she came home with no medicine or no help.  Enrolling into this clinical trial will require her to stay there for a month and also make monthly trips to MN from Pittsburgh, PA.

Today I found online another clinical trial for An Open Label Study of INCB039110 Administered Orally in Patients With Myelofibrosis.  The details state that there will be a location in Pittsburgh, PA but not yet recruiting.  Is there any information on this trial as to which option is better for her?  She’s been on no medicines for her prior polycythemia vera or the myelofibrosis.  her spleen is enlarged to about 25 cm and she is now transfusion dependent.  Shehas had 10 units since April 1st.  I’m trying to seek out the best care for her and not sure how long she can keep waiting with no help?

RM  In the setting of progressive polycythemia vera with enlarging spleen and transfusion dependence, this is clearly a challenging scenario in which the patient is clearly affected in a way that is concerning.  The appropriate intervention, whether it be an available current medical therapy, a clinical trial or bone marrow transplant would depend upon the individual’s age and how they are doing.  Given the complexity of the options, I do think that a face-to-face consultation with an MPN expert, but closest to your area, would be advisable in that there are really a variety of options, but based on your mother’s overall health, her age, and other diseases affecting her would impact which of these options are best chosen.

CH: Sorry to hear your mum is facing these difficulties. I am not aware of details of either of these trials but your hematologist should be able to help you with these. I think it is important to think about what the key issues are that you would seek to improve an example might be transfusion or symptoms. A balance of options could be available. You don’t mention how old your mum is but if she is fit and less than 70 a transplant might be considered too.

SV: BMS-911543 is a medication that belongs to a group of medications called JAK inhibitors. INCB039110 belongs to the same group. In November of last year one of the JAK inhibitors was approved and it is available as commercial medications to patients with myelofibrosis in the USA; it is called Jakafi or ruxolitinib. To receive Jakafi you do not need to travel anywhere, your doctor can easily prescribe it.

Nattokinase and ET?….

 28.  Marleque, Denver, Colorado… Is it safe to take Nattokinase with a diagnosis of E.T.?   It has reduced platelets in 4 weeks and has continued to do so for 3years.  At 1million, now 505

 CH: I have no experience of this agent but I do see some literature of its lack of efficacy in precventing heart disease and risk of hemorrhage when combined with aspirin. So I would avoid combining the agents and not use if you have had bleeding with regard to reducing platelets I haven’t seen this.

Essential thrombocythemia, multiple questions…?

 29. Anthony Simcoe, Sydney Australia…

…I am a 43 year old male in Sydney Australia with ET – JAK2 negative and mostly asymptomatic. By reviewing older blood tests we guess I’ve probably had it for around ten years but was definitely diagnosed with ET via a bone marrow biopsy three years ago.

It is this ten year mark that has me most concerned – reflected in my first question below.

  • What studies have been conducted to measure healthy living on mortality for patients with ET? …

CH: The short answer is no-one has measured benefit of exercise, diet and lifestyle in ET patients. However there is a wealth of info out there for “healthy” folk. So I encourage everyone to take up the mantra of healthy lifestyle.

  • What does the future hold for JAK2 negative patients in terms of new treatments?

CH: All new treatments (with possible exception of PEGASYS where there isn’t any detailed data) appear to benefit both JAK2 pos and neg patients.

  • Does the untreated platelet count have any significance? Without treatment my platelets hit around 1800 – so extremely high. With my Anagrelide treatment I am keeping them down to around 600 – 700. (I was intolerant to hydroxyuria – killed off my red cells)

CH: Untreated platelet counts over 1500 increase the risk of hemorrhage.

.In Dr Mesa’s fantastic video outlining Essential Thrombocythemia on the web he mentions that medication does not stop the “progression” of the disease. It is this progression that interests me most – do we have a clear picture of that progression? What are the milestones of the progression? How do things progress from asymptomatic patients to symptomatic and what can we learn from that transition?

CH: These are questions we are trying to answer in long term clinical trials such as PT-1, the PEGASYS trials and trials with JAK inhibitors. Sadly we do not have good understanding of these events although we are learning more.

RS:  There is no question that about 5% of the patients with ET will transform to myelofibrosis by 10 years, but the overwhelming majority of patients does not.  Thrombotic risk may be complicated by associated medical diseases such as diabetes and hypertension.  Notwithstanding the aforementioned, of the myeloproliferative disorders, ET has the best prognosis, I believe, agreed by all of us.  I do think that exercise is good for everybody as is weight control.  There is no systematic study of exercise in ET that I am aware of, but as the saying goes, “it can’t hurt.”   I do not believe that allowing the platelet count to be allowed to rise untreated to 1,800,000 is prudent.  I know there are differences of opinion regarding this.  Your intolerance to hydroxurea, as I mentioned previously, is understated in the medical literature and “killing of your red cells” by hydrea  is not uncommon.

Jakafi for PV…any alternatives?

 30. Monique…The drug costs $8600 and with medicare part D, Incyte Cares will not deal with you. My itching is so beyond the pale, that I am  beside myself. I get stabbing pain as well. Pegasys is not helping those symptoms. Medicare Part D won’t pick up enough of the cost. The clinical trials are double blind placebos which really doesn’t help me. Does anyone have suggestions for me?

SV: There are several ongoing trials with different JAK inhibitors for patients with PV and MF at our center (MD Anderson Cancer Center) in Houston, and medications are of course free for participants. Most studies are not blinded and placebo controlled. To make appointment with me (Dr. Verstovsek) one should call 713 563 2000.

What to do about aggressive mastocytosis?…

 31. Shashanna Kocinski, Australia…

I am a 63 year old female who has had systemic masto (diagnosed) for 10 years. My spleen was removed in 1997 as it had grown too large and hard but the diagnosis of SM was not made then…I had a bone marrow biopsy 2 1/2 years ago. I have a serum tryptase level of 210, significant osteoporosis and extreme amounts of mast cells in the gut.

Two years ago my hematologist put me on Tasigna and that has made a difference in symptoms but has not lowered the serum tryptase level. I have habituated or accommodated to the gut problems but the bone pain and head aches are debilitating. My Doctor is not sure if it’s aggressive or not.And finally, the question: how do I determine if it is aggressive?Is tasigna the best treatment?

CH: There are standard criteria for assessing whether systemic mastocytosis (SM) is aggressive or not, nonetheless even patients with so-called indolent disease have marked symptoms. We have not yet identified the “best” treatment for SM; tasigna is one but there are also others too if this isn’t working for you.

SV: in general, aggressive means that the disease affects organ function, vs. indolent that does not. For example, if blood cell count is abnormal and one has low platelets or low red blood cells requiring transfusion, that means that bone morrow function is not normal and that patient has aggressive mastocytosis. Similar examples can be given for liver function, GI function (if patient loses significant weight due to malabsorption, etc…There is no “best therapy” for mastocytosis but there are several possibilities, including interferon, cladribine, prednisone…

Five year old with ET…

 32. Jen Donohoe, Dublin….My 5yr old daughter was diagnosed with ET in April of this yr. i am totally in shock and devastated by this news. Also, the lack of information available on children with MPD’s. she is JAK positive, she had a bone marrow biopsy in April.  She is currently on no medication. she is doing well apart from ‘cluster migraines’. i am very happy with my daughters hematologist, she seems to really know her stuff. at the same time from doing research online, people in the mpd community have urged me to seek an ‘mpd specialist’ for my daughter. i am wondering what your advice would be, since you’s are the specialists! Even though i am happy with my daughter’s doctor, i would hate to look back and regret not seeing a specialist…

CH: You seem to have an excellent relationship with your daughter’s hematologist which is really important. I would suggest you discuss this matter with her. She has probably discussed your daughter’s case with colleagues so in effect you already have an MPD specialist.

RL:  There is little data on pediatric patients with MPNs, and even fewer experts on this rare subset. I would definitely seek out a specialist opinion, both to ensure her treatment is managed well and to keep posted on new diagnostic and therapeutic advances.

Splenectomy…or Jakafi? 

 33. Patti Cooper, West Virginia… I was diagnosed with PV in 1988 at age 28. I had gone to a diet clinic which required lab work before starting their program and was told I needed to see my doctor immediately. The diagnosis of PV was confirmed through lab tests and a BMB which showed I was Philadelphia chromosome negative. I was treated by phlebotomy to bring my HCT down to 45 and continued with phlebotomy only for approximately 16 years…. In June of 2011, my platelet count started dropping, I started having night sweats, and the spleen continued to grow. In December of 2011, I entered a clinical trial for SAR302503 …. My platelets were 50,000 at the start of the trial… After several weeks, I experienced a reduction of the spleen to 19 cm and it was no longer across the midline. Wonderful relief!! However, my platelets dropped below 25,000 in cycle 3 and I had to go on a medicine hold, then re-started the meds at 100 mg. The spleen gradually grew back to 24 cm, my platelets dropped again and in June 2012, I had to be taken off the drug as my platelets did not show a consistent recovery. At that time, I was told that my BMB done in December 2011 showed “early myelofibrosis” and it was recommended that I have a splenectomy. I am not losing weight, am not in severe pain, and have fortunately not had any complications such as clots or bleeding. I sought a second opinion from another MPN expert and he is opposed to the splenectomy due to the poor outcome he has seen with some of his patients. He recommends Jakafi 15 mg once per day, keep a close eye on platelets and raise to 15 mg twice a day if platelets will allow….

So, I’ve taken all this information to my local hematologist who has followed me since diagnosis and he feels unqualified to be the “tie-breaking” vote between two of the top experts in the country. (neither is a part of this panel of experts) Splenectomy or Jakafi? I’m very afraid of the surgery after reading about some of the potential problems associated with the surgery itself, post-surgery complications…. However, I’m a music teacher, not a doctor and don’t know what risks I may be taking if I don’t have the surgery. My doctor is also not sure how to handle low platelets during treatment with Jakafi, so I’m somewhat concerned about how this would work. I have made myself sick trying to decide what to do. Please, can you help to sort through all of this and suggest the best way to proceed??….

CH: Patti your questions are excellent and there is clinical data which should help and perhaps also a thought that you can always try the drug then think of splenectomy but not the other way around. Two studies are underway using JAKAFI in patients with blood counts exactly like yours showing (so far) that it can be used safely and effectively. So on this basis I would use drug then consider op if needed. I am also thinking you should have a consult on SCT because it seems to me that your disease shows some features which would make me consider this option in the near future. You could consult on this while taking the JAKAFI.

SV: Jakafi is a pill that is taken twice a day, not once a day. In patients with low platelets count the starting dose should be low, to offset a risk of lowering platelets and requiring platelet transfusion. Therefore, since your platelets are low at 60, one may start with 5mg twice a day for the first month, then dose is increased to 10mg twice a day during second month, if there is no major benefit and no significant decrease in platelets, and then increased to 15mg twice a day for the third month, again only if there is no benefit and no significant lowering of platelets. Hope this will help. It is much safer to take pills than undergo surgery of course

ET to Mt. Everest Base Camp…

34. Colleen Rudnisky… I am a 52 year old female diagnosed with ET two years ago.  My blood work is very consistant with my platelets being in the 800 range.  I take no medication. I quit taking aspirin because of nosebleeds( several a day)I am in good health!

I am planning a 19 day trek to the Base Camp of Mt Everest and was wondering if I should be aware of any limitations because of my high platelets.  I will be accending at a slow pace to 18,000 feet.  Two years ago I did hike to 14,000 with no trouble.  I took Diamox to help with altitude sickness. The tour company is aware of the dangers of altitude sickness and have a slow and steady pace set out for us with several acclimitasation days en route.

Is there added danger because of high platelets?  Is Diamox a good option to help prevent altitude sickness?  Any input you give would be greatly appreciated.  My hem is on holidays at the moment.

CH:Any advice needs to be premised on knowledge of all your medical history, based on what you have said – completely fit and assuming no bleeding or clotting. Then this seems fine. Please make expedition leaders and insurance companies aware of your condition too however.

SV: Diamox is good to take, yes. There is no correlation between platelet number in blood and risk of clotting, so you are fine with that too

RM: Patients with MPNs have been successfully able to pursue a variety of very active sporting activities including significant endurance events, long distance cycling events and being at a high altitude.  Factors that weigh in on the safety for these individuals depend upon their other illnesses, what difficulties the MPN has had on them in the past and how well controlled they are.  In theory, a high platelet count alone in an individual who is being appropriately managed would not necessarily be a contraindication for being at high altitude, potentially even the Everest Base Camp; however, that final decision really is best left to your treating physician who knows the full situation regarding your health, the symptoms that you have with the disease, the symptoms and issues you have had with your illness and your current therapy.  I would say in the ideal world, a normalized platelet count for such an activity would probably be best, but again that specific recommendation comes best from your physician.

MPNs and lymphoid malignancies….

 35. Karen Letts…I was diagnosed with ET in 2010. My question is:

My family history has Hodgkin’s Lymphoma in it. My maternal grandmother and her sister both had Hodgkin’s. My maternal aunt was diagnosed with “too many red blood cells” (PV?) and maternal uncle died from Leukemia. I have the JAK2 mutation. Has there been any link made between Hodgkin’s and MPNs?

CH: There is a known link (but rare) between lymphoid disorders such as Hodgkin’s disease and MPD.

SV: in patients with myeloproliferative neoplasm, there is increased incidence of lymphoid malignancies, like lymphoma. This is well established. Link between lymphoma in family members of a patient with PV, ET, or MF have not been established.

 RS:  There is an increased incidence of other malignancies in patients with myeloproliferative disorders.  The association has recently been reported in Blood.  We have seen non-Hodgkin’s disease and Hodgkin’s disease in patients’ myeloproliferative disorders.

 AO: JAK2 involving rearrangements [e.g., t(4;9)(q21;p24)] have been recently found  in cases of classical Hodgkin lymphoma but no JAK2 mutation is documented in this condition. Familiar MPNs are usually JAK2 negative. To my knowledge, no evidence for a link has been established so far

 Asymptomatic with high blasts…treatment?

36. Jaswinder Singh….This is medical oncologist – 70 yr old  with dx of cmml1 – normal cytogenetics and now low grade cytopenias. Asymptomatic has increased blasts to 24 percent. Is it unreasonable to treat with dacogen ?

SV: Very reasonable

 RS:  Clinically, it is unusual for someone to have 24% blast in the peripheral blood and also to be asymptomatic.  Personally, I would treat this patient with chemotherapy.

RM: Answer:  If I read the question correctly, it appears it is regarding transformation to CML blast phase.  CML blast phase, if it is BCR-ABL mutated, is a very challenging scenario; in particular, in an individual who is 70 years of age.  There are several questions that would need to be done in the setting of a comprehensive consultation with a hematology team as to whether an eventual bone marrow transplant would be a consideration.  Age alone would not preclude that, but on the basis of age response to the acute leukemia to other therapy, availability of a donor and the patient’s wishes would all factor in to such a decision.  There are medical treatments that have activity, potentially the tyrosine kinase inhibitors, but this would depend upon what the history had been prior to the development of CML blast phase.  There has been activity and experimental trials with a new medication, ponatinib, or one would be able to treat it with our other non-induction chemotherapy regimens such as hypomethylation therapy, decitabine or azacitidine.  Again, a very complex situation that really requires an entire team looking at the spectrum of options from available therapies, clinical trials and bone marrow transplant to come up with the best issue

Hydrea and low sodium?…

37. Freddie Rosenfield…I have myelofibrosis and my internist has diagnosed SIADH/hyponatremia.  I charted hydrea use and it seems to correlate with the low blood and urine sodium values.
Has this been noted in other patients?  If yes, is there a standard treatment?  I’ve tried water restriction which didn’t help.

CH: I am not aware of this link. I would expect a thorough work up to look for other causes of low sodium which should then guide treatments.

SV: I am not aware of the connection between hydrea and SIADH. Would follow instructions from your doctor on how to treat SIADH.

Spleen and ruxo?…

 38. Cheryl Boyd….I was diagnosed with primary myelofibrosis in1981.  I have been on differing doses of HU for 20 years.  I am also Jak-.  I have been on radiation treatments twice in the last 4 years to reduce the size of the spleen.  I had 5 treatments of radiation in May, but my WBC and RBC went to zero and my platelets to 35.  My oncologist does not think Ruxo would benefit me since I am negative.  What are your thoughts on what options I might have?  My spleen is huge and I take 500 of HU 3 days a week.  My WBC is now 1.5 and my RBC is 3 and platelets 191. …

CH: Ruxolitinib or JAKAFI works for patients regardless of whether the have the JAK2 mutation or not; based on what you have said I would consider this treatment but there may be other factors which may be affecting your doctors decision.

SV: Ruxolitinib is JAK inhibitor (not JAK2 mutation inhibitor) and benefits patients with and without JAK2 mutation to the same extent, there is no difference. According to your counts, you are excellent candidate for ruxolitinib

PV keeps progressing….

39. Dave, Florida My PV just keeps progressing.  I started out with phlebotomies, and am now on 1,000 mg Hydrea per day. I am tired of taking Chemo.  Does the disease just keep progressing until death? ( I realize it can turn into another MPN at any time)

SV: No.  Disease can be effectively controlled with hydrea, interferon or new medications in development and people live normal life 

RS:  The myeloproliferative disease group (MPD-RC) does have a protocol regarding the use of interferon in patients resistant to hydroxurea which you certainly seem to be eligible.  I suggest you contact one of the physicians in the MPD group.  You will obtain Peg-INF without charge.

Pregnant with an MPN…

40. Jennifer Olsen…Hi! I am a newly diagnosed 38 year old female.  Coincidentally, just as being diagnosed I found out I was pregnant.  I understand that I am a rare bird and there isn’t a doctor on my great team that has treated someone that like me.  With that said, I’ve been relying on others opinions and what outdated info I can find on the internet to answer my questions.  (thanks for being here to also ask!)

The two things weighing most on my mind right now are….

1) as I approach my due date (1/1/13) by OBGYN feels I need to be induced at least a week early, I would love to hear your thoughts on that.  (I delivered 11/1/04 and 5/1/09 both healthy girls w/normal delivery).

2) is there any information out there that would solidify an answer as to whether we should pay to privately bank the babies cordblood vs. donating it?  would it benefit me in any way?

CH: Congratulations. In our center we would not induce patients with MPN and pregnancy as long as prior pregnancies have been OK and the patient is healthy. I generally advise against banking cord blood specifically for MPN since we rarely do cord transplants and you are probably unlikely to need one for many many years at which point we cannot be certain about how useful the cord blood would be.

SV: What is the diagnosis?

Breast cancer, lymph node biopsy with PV?….

41. Kristy Nordaas…. My mom was diagnosed with polycythemia vera several years ago, and has treated it with phlebotomies, hydrea, & aspirin.  Now she has Stage 0 DCIS breast cancer.  I’ve seen that often it is recommended to do a lymph nodes biopsy with breast cancer surgeries.  Her surgeon and oncologist do not know much about PV, so we have not gotten clear answers on whether or not to mess with the lymph nodes.  My aunt has the same 2 diseases, but was diagnosed with PV after her breast cancer surgery.  She had a lymph node biopsy, so now she has to do her phlebotomies from her hand, which is painful.

Another concern for my mom, is that since her PV diagnosis, she has gotten pneumonia, shingles, and bronchitis (multiple times).  So it seems that her immune system is not as strong as it used to be.  What will be the effect on her immune system if lymph nodes are disturbed.  I realize that it’s important to check for the spread of cancer, but just wondering about weighing the options.

SV: Breast cancer is very serious condition and I would strongly suggest that all recommendations/suggestions by treating doctor be followed, including lymph node issue. PV is bystander that can be effectively controlled with measures already in place, and should not interfere with attention to breast cancer.

 RM: In an individual who has the need for a breast biopsy or a lymph node biopsy in the setting of breast cancer, P vera should not be a limiting factor to undergoing the appropriate diagnostic and therapeutic plan for breast cancer.  If an individual has uncontrolled PV, the physician may choose to try to rapidly normalize counts prior to an invasive procedure with phlebotomy or other anticoagulation if appropriate in the individual setting.  That being said, the urgency of an accurate diagnosis and plan in the individual with breast cancer is tantamount and will try to make the best of the PV risk while undergoing that necessary medical intervention

Iron intake and PV?….

 42. Peggy Frederick, Nutley NJ… Since primary PVers are overproducing red blood cells, our iron intake is closely monitored via ferritin levels. Many of us are extremely diligent about cutting down or eliminating red meats from our diet to reduce our intake of heme iron. We also watch how we ingest non-heme forms of iron particularly with regard to consuming it in concert with Vitamin C because we know that the combination will enhance the ability of iron to be absorbed. Are we proceeding wisely in this regard? If not, how would you recommend we adjust our nutritional intake via diet and supplements. Are there any food sources or supplements we should reduce or eliminate given our high red blood counts? Thank you

RM: Iron itself is not a stimulus for a P vera, nor is it harmful.  The challenge is that when individuals are on phlebotomy alone, phlebotomies primarily work in controlling the hematocrit in patients with P vera by inducing iron deficiency.  So, in these individuals, if we give them oral iron, it would just stimulate more red cells to be created and more phlebotomies need to be undertaken.  This is primarily in the issues of iron supplementation and iron vitamins.  The amount of iron in food, even red meat or other rich sources of iron, is still relatively modest compared to iron supplementation, so in general, I have not found that it is necessary to be overly restrictive with iron in the diet and instead just focus on individuals who are dependent upon phlebotomy alone that we try to avoid specific iron supplements that are working contrary to the goals of the phlebotomy.

Kidney disease with PV….?

 43. Jeannete Sense… Background: I’ve been a patient of my local Hematologist for 5 years, taking Hydroxyurea for a “classic” case of Polycythemia Vera. From 1989-1993 I received treatment for Minimal Lesion Disease from a local Nephrologist. I failed a year trial of prednisone and became stabilized on a year of (100 daily) cytoxin.

My kidney functioning has been declining….  What should be my focus, as I want as little intervention possible (hence the referral to the nephrologist to do the CT scan if he feels it necessary–instead of each doctor doing their own tests).

SV: The two problems should be dealt with separately and in parallel. PV apparently is treated properly with phlebotomy, aspirin and hydrea; that should not be changed. Kidney problem is under care of kidney specialist, which is fine too.

On Pegasys…with side effects.

45, Tom Weissbach…I am now in my fourth week of Pegasys at 45mg. I have an enlarged spleen 21cm and liver 19cm. My only side effect has been severe gastro discomfort with no appetite and weight loss. I have had problems like this my whole adult life, just not this severe with weight loss. I just received my old colonoscopy/endoscopy report from late 2006 and it shows gastritis and colitis with non specific chronic inflammation. I know one of the side effects of Pegasys is exacerbation of auto immune disease and colitis. Do you have any suggestions for dealing with this side effect? I really would like to continue with the Pegasys.

CH: I would look at what factors seem to spark the discomfort keep a diary including food and drink; think about dose of pegasys and discuss with your hematologist all these things and whether starting a lower dose and building up might help.

SV: 45mcg is very low dose and unfortunately, if this dose causes problems, the usual approach is to discontinue it. I am sorry.

When is phlebotomy needed?

 46. Susan Kennedy, Lexington KY I have recently read that there are different opinions about when a phlebotomy is needed.  The guidelines seem to be more flexible than in the past.  What are some of these latest  guidelines and do all countries agree on the same ones?

CH: Most countries use 0.45 as a target; some recommend a lower target if the patient is symptomatic at 0,45.

RS: We are very liberal with the use of phlebotomies.  In our own practice, we believe the hematocrit should not exceed 45% in men and 42% in women.  Our attention to this detail has made our thrombotic risk virtually zero compared to other studies recorded in other literature.  Blood is a non-Newtonian fluid.  By that I mean, viscosity increases logarithmically as the hematocrit rises.  Increases in HCT over 45 causes significant increase in viscosity.  Therefore, the hematocrit is of significant importance with respect to thrombotic risk in my opinion. Having said that, we do know the hematocrit level is not the only issue regarding tendency towards thrombosis in PV.  Certainly, platelet, white count and other vascular factors play a role.  However, controlling hematocrit is such an easy maneuver with phlebotomy, I see no reason in not paying strict attention to this detail.  Our clinical results substantiate this fact.

 Monthly phlebotomies increase blood counts? 

47, Sheridan Emery, Clayton California…66 years old,  diagnosed with PV three years ago, JAK2 negative. 8 weeks of weekly phlebotomies @500cc each.  Then every 3-4 months, now, in last 1.5 yrs. – bi-monthly – consistently with Hem between 15-17 and HCT 45-47; platelets between mid-to high 400’s except last July and again this July, 2012 – slightly over 500 mark.  I am now seeing a new Hematologist, Dr. Esther Q. Catalya at Mt. Diablo Oncology and Hematology Center  and she has “suggested” 250cc draws – monthly, as needed. She allowed me to go 2 months this May/June and I had a 500 cc draw July 11, 2012 which has left me wiped out and very pale – not so unusual, but I’m wondering if she might just be right!  Less stress…..with less withdrawal – makes sense?  BUT, my concern is having such frequent Phlebotomy Treatments – does this just exacerbate the renewal of new/more cells…..?  Also, now being watched/tested for hypercalcemia.  Would appreciate any comments.

CH:I would monitor you symptoms and try to correlate these with the size of phlebotomies I think the approach is reasonable I have used this for several patients myself. I would not be concerned about monthly phlebotomies increasing blood counts. The hypercalcaemia needs to be investigatd it is not likely to relate to your PV.

Complex case 

48. Patricia Harrison… Hello, I’m a 59 yr old lady who has had E-mail correspondence over the last year with Dr. Mesa, who has been wonderful. My question is:

I have just had #50, Venofir iron infusions over the last 4 years. I was told that because my RBC’s are so immature , they die off before the iron has anything to adhere too? Is this always going to happen to me? And am I just a complex case , as Dr. Mesa calls me? My counts dropped and my ferritin also dumped to about 4, so just walking across the room was almost too much. I was taken off my Hu for a month and given 2 infusions, which made me feel human again, and now counts have re-bounded, and started the 500 mg Hu daily again.

CH: Things are clearly very complex for you just as Prof Mesa says. It is impossible really to answer your question without a thorough face to face review of your case and all results. I am sorry

 

Jakafi, heart disease, and jet fuel…

49. Mike Masello  Boston… My name is Michael,I am 50yrs old father of 4 children…I have 20 yrs in the transportation industry. I was born in Boston Ma. and grew up right next door to Logan International Airport. There is a reason why I need to let You know where I grew up.I lost my dad(also 30yrs in transportation industry) to acute leukemia when he was 58yrs. old,he also grew up in the same area as did his parents, both died from bowel cancer, both where late 70,s.I was diagnosed with Myelofibrosis and the JAK2 mutation through a bone marrow biopsy in 2005. …and I have been on Jakafi 20mgs 2x a day since march 27 2012. Since my last visit approx 4wks ago, my blood counts where good spleen reduced 20% still have 50, some fatigue, night sweats but not as frequent and have been going through EMG testing( having pain,cramps,weakness in legs & back pain) ….I started feeling extreme tightness in right arm and chest roughly 8-10 times in the past 45days and Im getting frequent severe headachs very strange feelings.

I have a couple of questions: 1-Do MPNs cause heart disease? 2-What does JAKAFI cause? 3-Living near jet fuel,diesel fuel and other carcinogens have a major role in the breeding of MPNs and gene mutations? 4- and what can be done to stop it?.

SV: 1. No, these is separate issue in your case. 2. Jakafi may lower blood count too much in some patients; it does not cause heart problems, blood pressure issues, or any of the problems you mentioned. 3. This is presumed, yes. 4. Follow your doctor’s recommendation, you are in good hands

After SCT, how long before RBC and HG normal…?

 51. Jen Speyer… How long does it typically take for RBC and HGB to get back to normal after a Allogenic Stem Cell Transplant. Platelets and WBC are going up nicely. I’m currently at day 130.

CH:  This is very variable depending on donor and recipient factors and complications like infections etc.

RL: It can take up to a year for counts and marrow changes to normalize after a bone marrow transplant.

RM: The response to a stem cell transplant in MPNs, particularly in myelofibrosis can be delayed where we see that it can take up to a year for individuals to see resolution of the enlargement of the spleen and improvement in fibrosis.  The anemia of myelofibrosis can be slow to respond post-transplantation because aspects of healing from the transplant can also lead to anemia from the other medications, from chronic graft vs. host disease and even from delayed engraftment from the donor marrow.  I would say that this amount of time in terms of needing transfusion, it would not be uncommon that this could certainly extend into several months or even a year.  There are some individuals that have successful stem cell transplantation who never fully return to a normal hemoglobin.

On second opinions….

52.  Vicki Bazin, Victoria, Can….I would like to know how important it is to get another opinion when dealing with MPNs.

I have e/t which was diagnosed at age 47 I am now 51.  I am concerned about my e/t moving to mylofibrosis.  I understand there has been some information that perhaps e/t is early stages of m/f.

I was tested for JAK 2 in 2007 when I was diagnosed which was negative but after I received my 23 & me results they suggest that I have substantially increased odds of developing JAK 2.

I am really not to sure what all of this means.  I spoke to my haematologist about this but he really did not say to much at all. My G/P told me that I really would not get any different information so I should not bother seeing someone else.

CH: Vicki whether you have the JAK mutation or not does not effect the likely course of your disease and it is rare for patients to go from being negative to positive. If you have concerns which aren’t being addressed you could consider a second opinion.

Menopause and ETand BMB timing…?

53. Aileen Shaw, Northeast England…I was diagnosed with Essential thrombocythemia November 2010 and am Jak2 positive. It would seem that treatment is quite different here in England. My platelet count is 750,000 and stable at the moment and I take aspirin every day. I notice from contact with others in USA that it is routine to have a bone marrow biopsy taken but was told this was not necessary, is this correct. I would also like to know if ET is a form of blood cancer as I was told that it definitely wasn’t yet have seen on websites that it is so am quite confused. For the past year have also suffered from recurrent UTI infections and have been a Urology patient since last July and have been taking antibiotics every day for past 3 months and have another 4 months to continue until I return to Urology in October. A cystoscopy last September showed no abnormalities and was wondering if I’m  just unlucky or if this is a common problem with ET. I am constantly exhausted and have night sweats but this has been put down to the menopause ,is this likely.

CH: In the UK national guidelines do not mandate a BM biopsy for the diagnosis of ET provided certain criteria are met. If you are concerned about a possible mistaken diagnosis I would discuss with your hematologist. The symptoms you describe do occur with the menopause and ET so tricky question to answer are you definitely menopausal?

Peripheral neuropathy…

 54. Helen, Sussex, England…I have ET, well controlled with Anagrelide, and I should like to know what triggered the peripheral neuropathy I have in my feet now.  Plavix hasn’t helped much so is there any other treatment or research into this.

CH: Peripheral neuropathy has many causes including drugs but also diabetes, vitamin deficiency etc.; Helen this really needs a thorough medical work up I am afraid.

SCT — Decision

 55. Sue_Waite Cleveland….  am 42 years old, diagnosed with MF in February of this year. I went to the doctor, after many years, because I was feeling exhausted and had a lot of side pain. I was pretty overwhelmed at the diagnosis. My doctor was going to start me on Jakafi, but then in the last month I have been feeling great and we decided to hold off on doing any kind of meds or treatments. My counts are almost normal and my spleen was 10 cm and has shrunk to 6 and my energy is great. He believes my spleen shrunk because I had read in Jakafi info that if you were of child bearing age you had to be on some kind of birth control, so on my own, I had it prescribed. Since it increases clotting risks, my hem/onc had me stop taking it.

We have started discussing the possibility of a BMT. Deciding the right time to do it is overwhelming me. My dr. says I have to do it when I am strong enough to beat it, but also have to weigh the risks of taking on a whole other host of problems that come with it knowing I could live well with MF for a very long time. Plus, there seems to be a lot of hope in the advancement of MF treatments.

I would like another doctor’s opinion on when it is the right time to have a BM

CH:  Sue this is a big decision for you and your family it needs careful review of your disease the risk factors you have and what type of BM donor you might have all of these things impact upon decision making.

SV: Unfortunately there is no clear answer to this question. Approach to 55, (including bone marrow transplant) is individualized and depends on disease characteristics, trends in a change for worse, patients other medical problems and age, personal beliefs, etc

RM:  This is a very important but very complex question that we struggle with each day as a field and we struggle with each individual patient that we visit with.  There are many factors that we look at and the factors involved have a big impact on what is the right timing.  First, the donor.  Is there an appropriate donor?  Is it a safe donor?  The less safe the donor, the less the enthusiasm for a transplant.  Next, what is the risk with the myelofibrosis?  How problematic is it?  How likely is it to be life threatening within the next one year, two years, five years?  Typically, we think that individuals who we think are expected to live well beyond five years, a young asymptomatic myelofibrosis, the risk of undergoing a bone marrow transplant may be excessive for the risk of the disease.  Next, we look at the health of the patient.  First, their risk with the myelofibrosis – how life threatening is it; secondly, what are their other illnesses, and then finally the age of the patient; additionally, clearly the philosophical goals of the patient in terms of how aggressive they wish to be with their disease.  All of these are important factors in determining the appropriate timing for an individual and need to be considered.

How often should BMB be done?

56. Gwendolyn Wall, Hi I have ET taking plavix, hydrea and pravastatin. I was diagnosed back in 2002. My question is How often should I have a bmb done or is it unnecessary only at diagnosis

CH:  Strictly speaking a BMB is only needed at diagnosis or if the disease shows signs of progression.

SV: Bone marrow is usually repeated only if there is a significant change in blood count, and one suspects change in disease characteristics and therefore would repeat biopsy to address that possibility

Extramedullary hematopoiesis and nuclear bone scan

57, Peggy Reeve Does a nuclear bone scan show extramedullary hematopoiesis? I am having one soon and hoping it will show all the bone pain I am having which I imagine is hyperactivity

CH: Sometimes a bone scan can detect this abnormality but other tests may be needed too.

RL:  This test will not show EMH in all cases.  The diagnosis is more clinical than radiographic, though a MRI of a specific bone with pain can see EMH.

Physician: Patient consult…

 58. Dr. Anthony Ruggeri … I have a 52 yo man who presented in oct 2010 with night sweats and fevers to his PCP, CBC and CMP were drawn which were significant for platelet count of 627,000

Bone marrow biopsy revealed hypercellular marrow megakarryocytic hyperplasia and increased reticulum fibrosis normal male cytogenetics, peripheral blood negative for JAK 2.  Pt was placed on aspirin and observed by December night sweats were so bothersome it was interfering with his ability to work due to fatigue the following day.   His platelets had increased to 900,000. I then started Hydrea 500mg every other day. Pt had complete resolution of night sweats and platelets have hovered in 600-700,000k. Pt feels good. PS=0 Pt did undergo imaging of c/a/p to look for other causes of night sweats only Abnl was liver hemangioma no splenomegaly or LAD.
My question is would you advise any change in management any role for transplant, currently only other lab Abnl. Is mildly elevated LDH 291 (nl=234) WBC =6.8 hgb=13.7 plt=638.

SV: Management appears excellent. Would not suggest any change or transplant

AO: The reported presence of marrow fibrosis (degree unspecified) in conjunction with the presence of marrow hypercellularity and elevated LDH might suggest the possibility of very early PMF. You might want to consider repeating a bone marrow biopsy to precisely assess the current marrow status (e.g., cellularity, degree of fibrosis and megakaryocytic atypia). The marrow findings might be helpful in determining the need for management changes, e.g., starting peginterferon alfa-2a. The latter has been found useful in stabilizing the disease by preventing further myelofibrotic progression [Silver RT, et al. Recombinant interferon-α may retard progression of early primary myelofibrosis: a preliminary report. Blood. 2011;117:6669-72].

Anemia and HU…?

60.Gilliam Beamish…on my last visit to my hematologist he said he was worried that my hemoglobin has dropped to 10.4, he said if it drops by 1 on my next visit which will be in 8 weeks he will have to consider a different medication. what would be the best meds for me to take i am taking 500mg HU daily and 1000mg on sundays which has just been increased by one extra due to my platelets rising over 8 weeks from 220 to 406. i would appreciate as much advice as possible so i can feel informed by my next visit

CH:  Gillian it is important to check for other causes of anemia eg iron deficiency and balance out treatment benefit with side effects. This will depend then if other causes have been excluded on whether you have symptoms of anemia (like tiredness for example) and how well controlled your blood count needs to be.

What does Jakafi do?

 61. Dean Finch… I am fortunate to be able to take… Jakafi (5 mg twice daily).  My first question is … could provide an understandable explanation of what this drug really does?  I know my spleen is decreasing in size, however, my blood counts are still low and I am currently on weekly Procrit injections (50,000 units) to manage my low hemoglobin.  My second question is will this drug eventually permit my bone marrow to produce healthy red blood cells so I won’t need the Procrit any longer?

CH: The drug is a JAK1 and 2 inhibitor as such it will sometimes worsen anemia, in some patients anemia has improved. In clinical trials this generally stabilized by week 12. There is experience of using procrit and the JAK inhibitor. Clinical trials show that this drug reduces the size of spleens and improves quality of life possibly improving survival.

SV: The drug inhibits the growth of cells and therefore reduces spleen and liver size, if they are enlarged, and provides anti-inflamatory effect and therefore controls systemic symptoms like fatigue, bone aches, sweating, etc. it is unlikely to increase red blood cell count. Typically patients are on little higher dose, 10mg twice a day or more.

Signs of developing leukemia or lymphoma

63. Bonnie Evans, Georgia…When does the MPN physician request a consultation with a leukemia or lymphoma expert? What are the signs that the patient has developed leukemia or lymphoma?

RL: In most cases, the MPN expert will know what to look for if there is concern patients develop leukemia, including changes in blood counts, new infections, or changes in medication sensitivity.  They will be able to perform the needed tests, and in most cases treat the patient as needed in that case.  Lymphoma does not evolve from a MPN, and in most cases the MPN doctor will refer to a lymphoma expert.

RM: First, a transformation to lymphoma in an individual with an MPN would be an unlikely event, at least not a natural progression from earlier having an MPN.  People with MPNs clearly can develop other cancers and lymphomas are not protected from developing an illness like this, but the natural progression of the disease would be more toward an acute myeloid leukemia.  The major signs of this would be worsening blood counts and increasing blasts in the peripheral blood or in the marrow, especially to a level in the blood or marrow of over 20% blasts.

Eye disease and PV or HU

64  Bonnie Atkins …Can having PRV or taking HU affect ones eyesight or cause eye diseases?

RM: I am not aware of any direct effect that P vera or Hydrea have on eyesight.  There are individuals that have had unusual blood clotting events to the blood vessels involving the eye and this could impact vision; likewise, individuals that have had stroke related with PV could impact vision, but these are not the common occurrence

SV: Uncontrolled, high blood cell count in PV can affect blood flow in any part of the body, including in the eyes, and one may have symptoms, affecting eye sight. HU very rarely causes mucosal ulcers, and they are usualy in the oral cavity, not in the eyes. New diseases of the eye are not caused by the PV or HU.

 Elevated counts, should I consult MPN hem?

65. Allison Carroll…Short version 34 years ago at age 6 I had to have regular phlebotomy as my blood was too thick, that’s all my mum can remember they said. This lasted for a few months then my blood leveled out and no other thought was ever given to it until three months ago.

I have suffered with pain since my twenties and battled throughout to get anyone to listen to me, always being quoted I’m too young, it’s because I just had a baby, miscarriages, that I have mild osteoarthritis and a whole host of other reasons. However in 2009 after a gp change I finally got referred to a rhematologist who did extensive tests and decided I have fibromyalgia… Three months ago I had my yearly blood test due to my high blood pressure … my levels, were HCT:0.475 HGB:15.8 RBC:5.09.

My Dr at present mentioned that it sounded as if I could have PV and had it as a child but that she would just monitor my bloods and if my HGB got higher that 17 she would consider phlebotomy the same as I had as a child.

My bloods were taken again this week and were HCT:0.434 HGB:15.1 RBC:4.75 WBC:8….My question(s) is should I request to see a haematologist based on my past history as a child and the borderline FBC results, is it possible it isn’t fibromyalgia but PV causing my symptoms?

SV: Diagnosis of PV has become relative straight forward process these days. A visit to a hematologist would easily address the question and institute treatment plan, if PV has been confirmed. If not confirmed then that would eliminate any doubts. I would see the hematologist.

RM: What you describe is a complicated situation that is truly not best answered in this sort of forum.  Trying to delineate what is the correct diagnosis, how it is impacting your symptoms and how best to manage you would best be done visiting with a qualified hematologist or an MPN expert.  I advise you to speak with your friends on the list or an MPN clinic to see who in your area would be best for you to see.

RS:  There is a slight increase in the frequency of leukemia and lymphoma in patients with MPNs.  However, an experienced MPN physician can easily detect the development of these complications and therefore usually is not necessary for the patient to worry about such an event occurring undetected.  Indeed, our patients should be reminded that MPN physicians are board certified in hematology, medical oncology and internal medicine and if it is a little low grade lymphoma, they may not consider it necessary to refer a patient to a so called lymphoma or leukemia expert.  Hydrea has many side effects, but eye disease per se is not one of them.  It should be noted, however, that patients receiving interferon have reported to have a co-existent of macula degeneration.  Whether this is related to interferon or this is because macula degeneration and polycythemia vera occurs in the same age group is undetermined.  I follow the rule in the few patients who have developed macula degeneration on interferon therapy of discontinuing the interferon just to be safe.

Should I try Ruxo?

66.   Haydn Jones  I am a 59 year old male diagnosed last October with primary myelofibrosis and currently under haematology and transplant team at Leicester royal infirmary  England U K.

I am at a crisis at the moment as Prednisolone has helped maintain my blood levels but I am told I cannot be on this for much longer. I continue to lose weight and my night sweats are increasing so haemotology have concluded that I need to have a bone marrow transplant. I am due to see transplant team on the 21st August. Today at haemotology there was some question about the size of my spleen (last measured 19cms approximately 2 months ago) as this can hamper the transplant success. The haemotology doctor would like me to trial a Jak-2 inhibitor Ruxolitinib but a side effect of this drug can be anemia which could make me transfusion dependent, my transplant doctor has told me he did not want me to have too many transfusions as this could cause more complications. Investigations 06/07/2012 Haemoglobin 10.7 White cells 26.6 Neutrophils 19.9 Platelets 547

JM: Ruxolitinib is a reasonable treatment option for MF patients with splenomegaly and/or MF related symptoms. The drug was approved in the US November 2011 for the treatment of intermediate/high risk MF patients with symptomatic splenomegaly or MF related symptoms (constitutional symptoms, bone pains, fatigue, etc).  The dose limiting toxicity is thrombocytopenia and most patients will experience a reduction in hemoglobin and platelet count. The drug is generally well tolerated and headache, dizzy spells, and bruising were the most common non-hematologic adverse events noted in treated patients and were low grade events.  The COMFORT-1 (USA and Canada) and the COMFORT-2 (Europe) trials compared ruxolitinib to either placebo or best available therapy, respectively.  The ruxolitinib treated patients in both trials experienced significant reduction in spleen volume and significant improvement in symptoms. Although this drug is not curative and has not been shown to improve the bone marrow abnormalities or significantly reduce the JAK2V617F mutational burden, it has been shown to reduce markers of inflammation and improve quality of life and performance status of patients. The drug is not appropriate for patients with very low platelet counts (<50,000), and should be given at low doses (5mg twice daily) for platelets in the 50-100,000. Patients need to be followed carefully for changes in their blood counts and some patients may even require red blood cell transfusions at least initially within the first 3 months as the drug dose is adjusted. There are clinical trials that will soon open within the MPD-RC evaluating the role of ruxolitinib prior to stem cell transplant in order to reduce the spleen size and improve the performance status and hopefully this will improve engraftment and overall outcome.

Patients that have not needed RBC transfusions are less likely to develop alloantibodies (antibodies that your body make directed against donor red blood cells) that can potentially affect engraftment of the donor marrow cells. Having said this, it is not an absolute contraindication to receive RBC transfusions if clinically warranted prior to transplant and most MF patients that undergo transplant have received transfusions previously. Also highly transfused patients (>20units) begin to run the risk of developing iron overload and this may affect blood cell development and cause end organ damage (heart, pancreas, liver, thyroid) in patients. Sometimes iron chelation (medications that bind and remove iron) is employed either before or after the transplant for this reason.

In your case I would not eliminate the option of ruxolitinib even if you will ultimately go to transplant as the drug dose can be titrated to avoid incurring excessive anemia and transfusion requirements.  The possible beneficial effects of the drug beyond reducing the spleen and constitutional symptoms, may include improving your weight, energy level and endurance

SV: Use of ruxolitinib before the transplant is very good suggestion, to reduce the spleen and improve the body condition (many patients regain the weight). This is usually done for few months, and then one crosses over to the transplant (I assume you have the donor identified). Suppression of the blood cell count by ruxolitinib, if it happens (and it may happen in about 25% of patients) is easy to manage since it is dose related; therefore, one would adjust ruxolitinib dose if needed. Good luck with the transplant!

RS: Our current feelings is that patients who are symptomatic with large spleens and who are candidates for a bone marrow transplantation probably should have a course of ruxo before transplantation.  The Myeloproliferative Disease Research Group (MPD-RC is going to conduct such a study to get critical data that does not exist at the present time.  I would favor a trial of JAK2 supporting platelets with prednisone if necessary.  The data would suggest pre-treatment with ruxo may be of advantage.  This has not been shown in a controlled trial, however.  The MPD-RC will be conducting a study of this soon.

RM:The choice of trying ruxolitinib is a personal one.  Clearly, the medicine has demonstrated in myelofibrosis the benefits of improving splenomegaly in symptoms and probably prolonging survival in individuals with advanced myelofibrosis.  As an individual young enough for stem cell transplantation to be a consideration, it is a very delicate discussion of the risks and benefits of each of these options and whether one should pursue directly through transplant or use ruxolitinib prior to transplantation.  So far, there has been limited information about the use of ruxolitinib prior to transplantation and we are awaiting several clinical trials.  You are correct that the use of ruxolitinib may contribute to needing some transfusions pre-transplantation, but whether this potential negative would be offset by the benefit of reduced spleen size and entering transplant in a heartier state are difficult to say.

Timing for packed red cell transfusion in MF?

67. Jan Noble …Can you tell me if there is a “rule of thumb” when considering the appropriate timing for packed red cell transfusion for MF ?

SV: Usual guideline for red blood cell transfusion is to transfuse a patient if hemoglobin is less than 8. However, this needs to take into account a person in question. Older person or a person with heart condition may need transfusion whenever hemoglobin gets lower than 9, for example. Younger person may be fine with hemoglobin levels below 8. What this tells us is that guidelines are what guidelines are for, to follow them but to adjust practice according to a patient’s condition.

RM: As a rule of thumb, we would use in our clinic a hemoglobin of 8 g/dL or, and this is an important or, when the individual is overly symptomatic or short of breath.  So individuals between the range of 8-10 g of hemoglobin may be transfused depending upon how they are feeling.  A transfusion for a hemoglobin of over 10 g/dL would be very unlikely.

RS: There is no rule of thumb for obtaining red blood cell transfusions in PMF.  It depends whether or not a patient is symptomatic and whether or not they have adjusted to a given level of hemoglobin.  In general, patients develop symptoms when they have a hemoglobin of less than 10grams percent.

In general, we do not transfuse patients with a hemoglobin value of 10grms % or more.  Some patients will tolerate a more severe degree of anemia without requiring transfusion because they become adapted to the hemoglobin value.  This depends on the patient’s level of physical activity and other co-morbid condition.  At age 81, I would not be worried about the side effects of p32.  A long forgotten but very important one is that the PVSG showed the quality of life in patients treated with p32 was very good compared to with alternative forms of treatment in the PVSG study i.e. phlebotomy alone or chlorambucil.  Fatigue is a very general symptom, and your physician should give you a complete examination to make sure there are not some co-existent conditions which may be playing a role, for example hypothyroidism which is a very common clinical condition.  If he cannot do this, you should be referred to an internist for a complete physical examination and appropriate testing.

PV & Porphyria,  what about p32 therapy?

68. Mariel Strauss, New Mexico…I have PV and Porphyria.  I have a question about p32.  It worked well for me (could not take chemo in seven tries) and my platelets are near normal now.  But if they go over 800 Dr. Wong at Mayo says to give him a call.  Do you think it is that important to keep my platelets under 800?  I was at 1,500 and did not have a stroke, even though I am 81.  My porphyria makes taking drugs for this impossible (severe side effects including purple toe and low pulse).  I am doing much better after p32.  My feet don’t hurt as much and I took a long walk in the wind tonight in Los Alamos.

SV:  It is very difficult to comment on a management of your particular condition without knowing more details, I am sorry.

In general, patients with ET or PV above age 65 are at increased risk of blood clot due to their age (age is a risk factor, not the platelet number), and the therapy is given to decrease blood counts to normal levels. In patients that have symptoms from the disease (you mention pain in the legs) therapy is indicated to lower the count to normal level, to reduce symptoms. It seems that the doctor is using 800 platelet number as a gauge when to see you and evaluate your condition, rather than a hard number to prescribe therapy.

In general, for patients with ET and PV, one can state that elevated platelet number does not correlate with the risk of thrombosis (blood clot). In other words, having 700, 900, or 1300 platelets makes no difference when we talk about a risk of blood clot. Patients with very high platelets count, more than 1.5 or 2 million, are in fact at increased risk of bleeding; what happens when one has so many platelets is that these platelets consume proteins needed for blood coagulation, and therefore cause artificial increased risk of bleeding.

RS:  At age 81, if Dr. Wong believes that you should have p32, I would not worry about!  Quality of life with p32 is quite good, as was shown years ago by the Polycythemia Vera Study Group. 

The most awful fatigue. Any ideas?

69.  Sandara Matchett…I am a 53 year old female diagnosed with ET, slightly enlarged spleen and Jak2+. My current meds are Hydroxyurea 11 x 500 mg caps per week, Aspirin 75mg.My current counts are: Hb 14.7  WBC 7.2 Platelets 482  Neutrophils 5.2

I am not experiencing any other symptoms now that my platelets are reducing, however I am still experiencing the most awful fatigue, which I had before I went on medication 7 months ago.  I work 8.5 hours per day, 4 days a week in an office using a PC.  I do try to keep active by taking the dog for a walk.  I am not good with hills as I get out of breath very quickly, I certainly couldn’t walk and talk going up a hill.  When I get really tired, I get a look on my face as if it is haggard (not great when you are a lady who likes to take care of her appearance).  The fatigue is in danger of ruining my career, social life and any aspirations I had, etc. I am not overweight and I sleep like a baby at night, yet I wake up exhausted.

My question is, ‘Is there any medication I can take to give me more vitality’ I have tried everything else?  Please help?

SV:With excellent control of the blood cell count, one has difficulty connecting a disease and fatigue (i.e. saying that the disease is causing fatigue). Hydrea sometimes can make people more fatigued but you mention that your level of fatigue has been constant all along. One would therefore, look at other causes of the fatigue, as it seems that the disease is well controlled (number wise) and therapy is not causing harm.

RS:  You should have a thorough physical examination to exclude other conditions that may give you fatigue, such as hypothyroidism.  In general, fatigue is not a complication of essential thrombocythemia or hydroxyurea.  Of course, there are many factors that can cause fatigue which are too numerous to be listed here and that is why such co-existing illnesses should be considered.

 Early 30’s with PV…life expectancy?.

70.  FS…  I’m in my early 30’s and have been diagnosed with PV. I am a mild case and only take 81mg aspirin and phlebotomies when required to get my levels in check.

My question is, what should I expect my life expectancy to be? I’ve seen some sites say that with regular treatment I can expect a near normal life span. When I dig deeper I can see that PV can turn to many other diseases/complications if only using phlebotomy for treatment.

My main question is on the life expectancy with phlebotomy/aspirin treatment?

RL:  Most patients without other risk factors (age, history of cardiac disease, chromosomal abnormalities) can do well for a very long time on phlebotomy and aspirin.  You and your doctor need to follow your case closely to ensure things are stable for the first year or two but I would be optimistic that phlebotomy and aspirin will be helpful for a long time.  Some young patients who want to consider treatment with an agent which can put their disease into remisison discuss interferon treatment, which I would suggest you consider given your age, but no urgency to that decision.

RM: It is difficult to know what is the impact of P vera on life expectancy in 2012, particularly for the young individual given new therapies that are being developed such as interferon, JAK2 inhibitors and many others.  As we look in the past, patients with P vera, some but not all individuals have seen their P vera perhaps have an impact on how long they live compared to the normal population.  As an individual younger, it is always possible that a greater amount of time with the disease may make this change more pronounced than an individual who is closer to the end of their life when they are first diagnosed.  That being said, I am very hopeful with all of the advances in science that are being made and new therapies that, although P vera has impacted survival in the past, we are hopeful that we will be able to change that trend for the future.

RS: I do not agree that young patients should be treated with phlebotomy/aspirin only and expect the normal survival.  This relates to the fact that the disease will progress and myelofibrosis splenomegaly will develop usually in the course of 7 to 10 years ( v+).  If your phlebotomy requirement is more than 4 per year, we always start patients on PEG Intron.

The development of polycythemia in patients under the age of 50 occurred in 40% of our database population.  Under the age of 30, it accounts for 15% of our PV patients.  It is not a disease solely confined to the “older age group” and therefore treatment with chemotherapeutic drugs should never be used in younger individuals nor should patients be treated with phlebotomy only.
Jak Neg, looks like PV, could be something else?

71. Meryl Dieterich…My husband was diagnosed with PV back in April 2008.  At the time his CBC was indicative of an MPD so he had a bone marrow biopsy done & the diagnostic note said: “the blood and bone marrow findings are highly suggestive of a chronic myeloproliferative disorder, especially PV.  He is JAK2 negative but his HCT, Hemoglobin and WBC counts all run high.  He’s been treated with phlebotomies only since his dx.  He recently had another bone marrow biopsy which basically said there was no change.  He was tested for the Philadelphia mutations & tested negative for those as well as JAK2 (retested at time of bone marrow biopsy… He seems very asymptomatic except for the fatigue which I attribute to the phlebotomies.  The only other issue he has is that he has these strange lumps & bumps on his hands & forearms.  He was tested for RA & that came back negative as well. Some of these bumps are hard small ones & others are large & squishy.

Since he’s negative for almost all marking of PV, I’m wondering if something else could be going on with him. Any insight you could provide would be appreciated.

SV: Almost all, but not 100%, of patients with PV have JAKV617F mutation, and this is a mutation that doctors test for. About 3% of patients will have different mutation in the JAK2 gene, called “exon 12 JAK2 mutation”. And yet, there are occasional patient for which even this mutation testing is negative. This is why the presence of JAK2 mutation is one of the diagnostic criteria for PV (there are several, of which most but not all must be fulfilled for diagnosis to be made). In the other words, one can fulfill diagnostic criteria and not have JAK2 mutation.

It is difficult to comment on the lumps/bumps; they do not come with PV.

RM: It is true that to make a diagnosis of P vera can sometimes be a complicated situation, particularly in those individuals that do not have the JAK2 v617f mutation.  There are some individuals that will have an alternative mutation that has to be tested for specifically – the JAK2 exon 12 mutation, and there probably will remain even a small subset of individuals who lack either of these two mutations.  The changes in the bone marrow can be an important finding as well as whether or not the serum erythropoietin level is decreased or normal or increased and delineating whether P vera is the diagnosis in an individual who is JAK2 negative is probably best done with the assistance of someone who focuses on MPNs.

RS:  How many phlebotomies is he requiring per year??  Fatigue may be due to the development of iron deficiency which occurs in patients who are treated with phlebotomy only and then become symptomatic from the iron deficiency.  Have other causes of polycythemia been excluded such as high affinity hemoglobin etc?  You do not mention the serum EPO level which is important.
What are do’s and don’t post SCT?

72. Patsy Bushy… Although I have a booklet produced by Be The Match, and my doctor has told me some things, I have found out some things by accident from other SCT patients. For example, you should never clean a litter box for a pet again; you need to wear a medic alert bracelet or necklace at all times, day and night; you should wear long sleeves and slacks when outside and sun tan lotion of #50. I have been told all of these conditions are for life. Would love to have a list of “must do” and “must not do” for protection for the rest of your life, following a SCT.  Cannot find anything but bits and pieces. Had my SCT last April, and I truly am uncomfortable about the fact I have found little about the needs for the rest of my life. I have a wonderful doctor, and he has given a great deal of guidance.

SV: You point out one great need for patients like you and I hope things will improve, and information become more readily available, in near future.

RS:  Those patients with transplant services have all this information available, to them most often in a booklet form.

Does ET progress to Leukemia

73. MJM…We hear many opinions on the progression of ET – does it progress to Leukemia, Fibrosis.  Some say yes, some say no. What is the answer.

RL:  A subset of patients (1-2% per year) can progress to fibrosis or leukemia.  Most patients do not progress but this is an important reason for close follow-up.

JM: Essential thrombocythemia can progress to myelofibrosis at a rate of 10-20% over the first 10 years from diagnosis and less frequently (3%) to acute leukemia.  Many patients with ET do not ever progress to MF or acute leukemia and in fact the median survival of ET patients is essentially the same as a sex and age matched cohort

RS:  The true form of ET progressing to leukemia occurs very rarely.  Many patients treated with ET may be with one or more types of chemotherapy which may play a role in the development of acute leukemia.  We see this especially in patients with primary myelofibrosis who have been treated with a variety of chemotherapeutic agents especially hydroxyurea.  This has been known for years and was reported by Ellis J et al for the PVSG.

 RM:  Patients with ET may progress to acute leukemia or to post-ET myelofibrosis.  That being said, the rate of change to these things is probably lower in ET than in those with P vera.  The confusion arises that there is a current discussion that those who have been historically diagnosed with ET, some have a form of ET that is fairly benign and has a low likelihood of progression and others have early myelofibrosis.  It takes quite a specialized hematopathologist to help distinguish these two groups as well as a clinician.

Need Joint replacement but does MF make it pointless?

74. Terry RoncinI am a 53yr old female, primary MF. I need joint replacement in both knees and right shoulder which has given me a severe rotary cuff tear.  Is it worthwhile to try and be placed on a year’s waiting list here in Canada for joint replacement.  Or does the MF affect the bones and cartilage connecting to my joints which would in turn affect the outcome of the surgeries.

SV: One would of course like to know much more about your MF to make more informed comment. However, in general, having MF does not preclude my patients from having surgeries of this type. Quality of life is very important and I have no doubt that joint replacement has a great potential to improve your quality of life.
RM- As a relatively young individual with primary myelofibrosis, in general, we would not feel that the diagnosis of myelofibrosis would preclude you from either benefiting from a joint replacement nor make such a surgery not an option.  Clearly, this needs to be an individualized choice discussing both with your hematologist and orthopedic surgeon, but at least in my practice, would probably not preclude an individual from considering this surgery.

RS:  Does your orthopedic know you have PM?  Long bone (femur) can certainly be affected.

Treatment options for 80 year old Mom with PV

75. Mary Williams…  My 80 y/o mother was just recently dx’ed with polycythemia vera on 8/6/12.   She had a platelet count of 833 K, WBC of 11.6 K, RDW of 16.7 %.  Her Hgb was 12.8, Hct 39.2.  Her B12, iron were OK, erythpoeitin was low.  JAK 2 mutation was +.  She was placed on Hydroxyurea  500 mg twice a day.  First couple of days she had some slight nausea, diarrhea.  After one week, she experienced an itchy rash on her neck and upper chest.  She called her hematologist and she stopped the Hydrea but the next day, my mom developed swelling of her lower lip…

My mom always seems to get whatever side effects of a medication that there is.  I am concerned about what I read as the options for intolerance of hydroxyurea for her MPN.  I am thinking with this new development of not tolerating the recommended treatment for her condition, that maybe we should get a 2nd opinion from a center that deals with MPN’s on a regular basis

She was having no symptoms from the high platelet count prior to this. She really does not look like the signs of polycythemia vera that the literature describes.  I am afraid that the treatment options will just make her sick feeling and what kind of life is that.  Recommendations?

SV: In general, patients with PV above age 65 are at increased risk of blood clot due to their age (age is a risk factor), and the therapy is given to decrease blood counts to normal levels. It is not as much about having a symptom from the disease, which many patients do not, to start therapy but about the risk of having significant impairment of quality of life due to a possible blood clot (e.g. stroke). Hydrea is the first, standard, therapy for patient with PV and I hope that a lower dose (e.g. once day) might be tried to see whether your mother can tolerate it. There are other possible therapies, including some investigational therapies, for patients not tolerating hydrea. If there is any doubt about diagnosis or therapy, second opinion is good option.

RS:  According to the criteria I use for the diagnosis of PV, your mother does not have it.  It sounds more like essential thrombocythemia but not all data have been submitted.  A bone marrow could be helpful.  In any case, starting at a dose of 1,000mgs of hydrea a day in an 80 year old woman with displayed counts you reported is high in my experience.

Husband just dx w/MF, what to do?

76. Katie H…My husband was found to have Stage 3 of 3 Myelofibrosis  3 years and 5 months ago.  We initially were on Hydrea 500mg for various days over approximately 18 months and my dear Ivan seemed to be doing well, living normally, his only complaint was joint and bone pain, not taking a thing.  Then about 5 months ago and especially the last month, his conditions seems to be getting worst everyday. He has lost so much weight that actually I know for the first time what skin and bones mean.  He does not sleep and has no appetite, even his favourites he takes a few bites and is full… We found out that his spleen is enlarged and he seems to have pain where his liver is. Our GP says jaundice is now a problem….

Our specialist is Dr. Terry Frost, of Brisbane. My husband is now taking Hydrea 500mg 3 times a week for the last 6 weeks.  We are on various puffers for his coughing. I feel there must be something else we can do….Dr. Frost has mentioned trials but nothing has come of it….. We see  Dr. Frost on this Thursday…..What do we ask him?…..I am worried I am losing my Ivan, he seems to be getting worse every day and I have no idea how I can help him..

SV: Myelofibrosis is unfortunately progressive disease and I am sorry to hear about your husband’s condition deteriorating. Without knowing the details, in general, one would suggest searching for clinical trials in Australia with new medications, JAK2 inhibitors, that may help with many of the symptoms as well as with enlarged organs (they improve both). Ruxolitinib is a JAK inhibitor recently approved in the USA, Canada and Europe, perhaps it is/will be available in Australia.

RS: We are so sorry to hear that Ivan is doing badly.  The development of jaundice is not a good sign unfortunately.  It would be important to know if this condition has changed into a leukemic phase and so you should tell us what his bone marrow and peripheral blood showed.  Perhaps prednisone would be of help

Peg dosage and can it stop MF?

77. Jeremy…I am fifty-three years old and had PV for twenty plus years and was taking Hydrea for all of those years. I have recently converted to mylefibrosis. I am no longer on hydrea and my Doctor increased my aspirin to 81MG Low dose four times a day from one and stopped my Hydrea.  My Doctor has recommended PEG- treatment 45mg once a week for two weeks to start.  My question is am I starting on the right dosage of Peg-INFN and has PEG-INFN in clinical studies shown the ability to stop myelofibrosis or just PV?

RM: At this point in time, the data does seem to suggest, in P vera in particular, that the use of interferon may help delay progression to myelofibrosis.  There have been also individuals with early primary myelofibrosis, i.e. myelofibrosis with less than the most advanced grades of fibrosis and massive splenomegaly that have seemed to have some bone marrow regression to fibrosis in particular with use of the medicine.  Ongoing studies are looking at how much we can count or what is the likelihood of having this benefit with the use of interferon.

 RS: We like to start with low doses and gradually increase is tolerated.  PEG interferon can be very helpful in this kind of myelofibrosis presuming that the bone marrow shows residual hematopoietic (blood cell function).

SV: This is good plan and the dose is right. Therapy may positively affect the bone marrow and halt progression of the disease. Although there are no comparative studies done to prove that interferon therapy can stop progression of the fibrosis, and in some cases reverse it, there is enough published literature to suggest that this is indeed possible (particularly from work by Dr. Silver in NYC).

Peg studies hi-risk, any lo risk studies

78. Michael M… It appears to me that most studies done with Pegasys are on patients who are high risk. What studies, if any, have been done on Pegasys with low risk patients? If there are none, what results have you seen to date?

SV: Pegasys was studied in patients with PV, both newly diagnosed and in those with more advanced disease, and it was very effective in both in controlling blood cell count (85-95%). It was also used in patients with myelofibrosis, where it was more effective in those patients with proliferative disease than in more advanced disease, like the experience with regular interferon in the past.

RM: Up to this point in time, there is limited information on the use of pegylated interferon and individuals with low-risk P vera.  That being said, some of the benefits that we hope for in P vera [of helping delay] progression.  Maybe this is relevant with low-risk individuals.  The risk scores with polycythemia vera primarily relate to risk of blood clot or bleeding events and do not relate to the risk of progression.

RS:  Low risk patients with myelofibrosis have been treated by me and my group with interferon. [It] affects megakaryocytes and presumably its breakdown products and decreases the development of fibrosis  We believe that the treatment should be earlier than later.  Other investigators such as Hasselbalch in Denmark and Kalidjian in France also agree and published on this very same subject.  Our paper appeared in Blood June 2011.  It showed that 80% of patients with prefibrotic or intermediate one disease will benefit as manifested by improvement in blood count,  decrease in spleen size, bone marrow reversion, etc.  Of course this was a phase 2 single arm study and this data must be interpreted in that light, however, the results are most encouraging.

70 y.o. doing great on Jakai, what about a cure?

79.  Susan Hill… I am a Myelofibrosis patient who was diagnosed in 2001 at age 60 and was told this was a “ten year disease.”  I’m happy to report that Jakafi came along just in time as I was seriously ill in 2008-2010.  I participated in the Comfort I Study and was fortunate enough to receive the actual drug.  The rest is history!  Today I am an energetic, healthy grandma with a future to see my granddaughters grow up.  Other than my monthly blood transfusions, I am as normal as any other 70 year old!

My question concerns the current research efforts.  Having attended the last two MPN Patient Symposia in California, I am encouraged by the reports we heard from the researchers.   What is the current status of research toward a cure?

JM: There is a significant laboratory research effort to better understand the biological mechanisms that drive myelfibrosis. As we advance our understanding of the different gene mutations (genetic lesions) and associated protein abnormalities (epigenetic lesions) that work in concert to cause hematopoietic stem cells to transform into clonal MF cells, we can better target these cells and eliminate them. Currently, stem cell transplantation is the only therapeutic option that offers the potential for cure at a risk of transplant related mortality that is not insignificant.  The approach to transplant is being refined and improved and transplant outcomes are continuing to improve. We do not have medications that reverse the bone marrow abnormalities that characterize this disease and extend life expectancy (disease course modifying agents). Future trials will combine current experimental therapies that have shown signals of activity as mono, in myelofibrosis (e.g. JAK2 inhibitors, histone deacetylase inhibitors and immunomdulatory agents) with the hope that these combination therapy approaches will better target and remove the malignant bone marrow cells sparing normal bone marrow cells.

SV: Development of JAK inhibitors as therapy for myelofibrosis is the first building block toward finding a cure. I am very happy to hear about your excellent response. Ruxolitinib improves signs and symptoms of the disease and it seems that with that it can actually prolong life of patients with advanced myelofibrosis. It does not eliminate bone marrow fibrosis, or the malignant cells from bone marrow or blood. Efforts are underway to combine with JAK inhibitors other targeted medications, either commercial or investigational, to improve the response, perhaps to improve bone marrow fibrosis, improve blood cell count, and further extend the good quality life. This is more realistic next step, but an important step toward finding a cure

 RL:  No long-term remission and/or cure.  Please keep coming to the meetings as we keep working towards that goal. No current treatment is curative, but we are all working to identify better therapies, including combination treatments, which might allow us to work towards that goal,

RM: At this point in time, we view that ruxolitinib and other JAK2 inhibitors are giving a significant benefit to those with the disease.  We do not feel that it is a cure.  Combination studies are ongoing to see if we can greater impact the disease.  Clearly our goal is moving in the future towards a cure of the disease, but we do not yet have a medical therapy that we can say, outside that of stem cell transplantation, we could accurately call a cure.

RS: How wonderful that you feel so well, Susan!  This is great news and it encourages all of us working in the field.  We are all trying to work towards a cure.

4 yr old son, high platelets, confused dx, BMB?

80. Holly Swanson…My 4 year old son has been a fairly healthy child up until last October when he suddenly came down with acute pneumonia. Then in December he had labs drawn for the first time after he had been complaining his feet and hands hurt. He has since had persistent thrombocytosis for 10 months highest was 684,000 back in and lowest he has ever been was 487,000 (<that was a recollect draw because lab error) he has had over 6 CBC w/ differential w/platelet tests and all 6 times come back looking the same; elevated platelets slightly elevated: hematocrit, hemoglobin, RDW, eosinophils and at times monocytes….He has since had rashes all over his body that come and go for no apparent reason; his former pediatrician said he has never seen “eczema” this involved on the body but since it itches he is going to diagnose it as eczema. He had been complaining that his hands and feet hurt and they feel “funny” (that was when his platelets were in the 600,000 + range) and he will still complain about them hurting but not as often now. He has seen an hematologist at Loma Linda Childrens Hospital 2 times back in January (5min visit each) who said “he prob has a virus his platelets will come back down within normal range soon” “reactive thrombocytosis”; he sent my son back to his pediatrician for follow up with his care who has retested him 2 more times and its still elevated and doesn’t know why it’s like that and said there is nothing he can do.  No more testing is needed. … His new Pediatrician agreed and said maybe he has the Essential Thrombocytosis a Myeloproliferative Disorder… His new pediatrician said in the 37 years he’s been practicing medicine, he as never been so puzzled by one of his patients labs because even though he has thrombocytosis and other labs are only slightly elevated, they are not in any critical value ranges and all the other organ functioning tests come back completely normal. My questions are what are these doctors missing if anything? Is the next appropriate step a Bone Marrow Biopsy?

SV: I am very sorry to hear about your son’s condition and hope that involved doctors will find the answer soon. The bone marrow biopsy is reasonable next step; I do not see anything obvious that has not been done so far. Hope the answers will be coming soon from further testing, but sometimes we find no answers. 

RM: MPNs are possible in children, but there are many potential confounders and other congenital situations that can mimic MPNs in children, particularly those very young such as a 4-year-old.  I think having expert second opinions in pediatric hematology specifically would be very important to be sure that the diagnosis is both accurate and to determine the therapy.  Almost all the information that you will read in MPN clinics or on the [list serves] are really specific to adults and the use of medicines, which medicines and what are their goals will be a different discussion with children that needs to be very individualized as there is unfortunately very little information on optimal treatment of these patients if they are pediatric in age.

RS: Absolutely see a pediatric hematologist.

PreMF diagnosis, is MF inevitable?

81. Amy… Is there a difference between bone marrow scarring from ET vs MF.  My doctor indicates I have scarring of the bone marrow but has stuck with ET dx. My BMB states the following: Final Diagnosis: Chronic myleoproliferative neoplasm with mild myleofibrosis. Diagnostic Comments: The differential includes the pre-fibrotic stage of primary myleofibrosis and essential thrombocythemia.  It is difficult to differentiate between these entities at this stage as approximately 15% of PMF cases present with thrombocytosis and a minority of ET cases present with mild reticulin fibrosis …. Followed up with CAT Scan of pelvis and abdomen which came back fine.  JAK2 positive, Platelets usually 1.25 -1.32 million…  Dr. says it just means I have a pre-cursor to PMF, is pre-cursor same as inevitable

SV: Presence of bone marrow fibrosis in the bone marrow does not automatically means that one has disease Myelofibrosis. Some fibrosis can be seen in patients with ET and PV, as well as in some other bone marrow diseases. For each entity, ET, PV, and MF, there are diagnostic criteria that need to be fulfilled and I would suspect that your doctor is following them.

RM: The rate of progression for individuals with ET, even with mild fibrosis, can be quite variable and in some individuals it could take potentially many years before they would progress to overt myelofibrosis.  It is possible that new therapies may impact this rate of progression, but I would not say that it is inevitable that progression will occur.  Many factors remain.  Given your youth at the age of 46, we would tend to think that the likelihood of progressing at some point in your life is possible, but surely that might be impacted by therapies being developed.

RS:Amy raises a very important point.  Fibrosis (reticulin fibrosis) is seen in 5% of patients with ET.  This does not mean you have the disease entity “primary myelofibrosis”.  It also does not imply “scaring of the bone marrow” nor does it have the same implication.  However, an experienced hematopathologist should be able to distinguish the pre-fibrotic stage of primary myelofibrosis and true essential thrombocytosis.  We do it in more than 85% of cases.

 Omega 3 better than Aspirin?

82 . Susan Kennedy… I am taking aspirin 81mg daily for PV blood thinning.  I have recently read (Journal of the National Cancer Institute) that daily aspirin increases risks for breast and pancreatic cancer.  Also, The American Journal of Preventative Medicine states that omega 3’s naturally thin blood and are more effective without the risks of aspirin. Does anyone know anything else about this?  Do some MPN patients take omega 3’s instead of aspirin? 

SV: In PV it has been shown that taking aspirin is beneficial for patients and has therefore become standard practice to prescribe it. I am not aware of any studies in PV with omega3.

RS: Dear Susan, please do not refer to “blood thinning”.  Aspirin is used for preventing coagulation because of its effect on platelets.  It prevents them from clumping.  It does not “thin” the blood.  I am not familiar with a decrease in pancreatic cancer and such study should be read very carefully; the study you have reported, I have not read as yet.

 MF, why are some hem’s against Ruxo?

83. Tiziano Giunti… I am afflicted with myelofibrosis post PV I am using Ruxolitinib for two weeks, my spleen has already reduced and I feel much less tired than before. My hemoglobin is 14 and platelets 190 thousands (before beginning 110 thousands).I would like to know why some hematologists aren’t in favour of Ruxolitinib/Jakafi, that remains the first and only JAK2 inhibitor at our disposal.

SV: Good question but no good answer to it. Ruxolitinib is good in improving quality of life in patients with MF, and it is very good in reducing enlarged splee and liver in MF. Therefore, it is not for every patient. In those needing help, it should be tried. If it lowers significantly the blood count, the dose needs to be adjusted, otherwise in general there are no other common side effects

RM:  Ruxolitinib is a very helpful medicine in that it has impacted splenomegaly symptoms and potentially how long an individual lives with more advanced myelofibrosis.  It has been particularly helpful in those with PV myelofibrosis as these individuals tend to have less issues with ,,,,,, or low platelets with this medication.  I think it is not a question of whether someone is for or against ruxolitinib, I think it is important to have a realistic expectation of the benefits one might have with this medication and how to monitor it accordingly.  The medication is not a cure for myelofibrosis, but does seem to benefit many of the individuals who have received it.  What the level would be in earlier disease is something that still remains experimental.

RS: It is best to ask those hematologists who are not in favor of ruxolitinib.

 Compare benefits Peg and Jakafi

84. Dave Mueller…I am 52 and was diagnosed with early PMF in 1/11.  I was a bit anemic and had a large spleen of 9cm.  I began Pegasys a few months later at the suggestion of RS, and ramped up my dose to 90mcg before beginning a trial for SR Jakafi.  My spleen was measured at 15cm at this time and my decision to try Jakafi was based on my enlarging spleen.  I am now currently on 20mg Jakafi and 90mcg Pegasys.  I think I’m doing well, but other than feeling good on this combination, is there any way to tell if I am benefiting from it?

I have tracked my counts back a year before diagnosis, and they have been pretty much stable up until starting Jakafi which lowered my platelets and hgb.  My platelets are now stable at around 113k and hgb is back up to pre jakafi days at 12.2.  Most people I speak with see a lowering of counts while on Pegasys, and I can’t tell it’s made any difference.  No change the 4 months on Pegasys alone before starting Jakafi.

I know a bmb may provide some answers, but I want to wait a bit longer.  The benefits I see from Jakafi are reduction in spleen (now at 7cm) and reduction in night sweats.  What I see from Pegasys is reduction of bone and joint pain and an increase in energy.

So has this combination helped keep me stable, or would I have been stable without it?  I think my spleen would be a whole lot bigger now.  Latest CBC wbc 5.9 rbc 4.06 hgb 12.2 hct 35.5 rdw 17.6  plt 113.

RM:  At this point in time, the benefits of these two approaches are different and there is a potential that there may be some synergy to be explored in the future.  Pegasys potentially can help the control counts, help to improve symptoms sometimes and may have an impact on delaying progression of the advanced disease.  Ruxolitinib has been tried in people with more advanced disease and has helped splenomegaly symptoms and potentially survival.  The goals are slightly different with the use of these medications and needs to be discussed with your hematologist, as I would have a different expectation on timelines of benefit for both of these medicines.  As I mentioned, there will be efforts to see what a combination approach with both medicines will do in terms of helping individuals.

RS: Dear Dave: the combination of pegasys and jakafi is a very intriguing one.  A study is beginning in Europe with this combination.  It is very hard to tell how much you are benefitting from the combination without assessing the bone marrow but in general, responses to interferon in PMF take at least 6 months to a year so I won’t rush into getting another bone marrow.  The dosage seems about right.  As long as your spleen is getting smaller and or stable and you are feeling much better, I would stay on this current course

 ET with good numbers, premature for BMB?

85. Elizabeth Goldstein…   I have ET, diagnosed almost two years ago.  Right now, my blood work looks good but if my bone marrow becomes fibrotic, how long will it take to show up in myblood work?  Am I being over cautious to ask my hematologist for a bone marrow biopsy every two years (assuming blood work is still good)?  She is a good doctor and has agreed to do this but am still wondering if I’m just worrying too much.

SV: In patients with ET bone marrow biopsy is usually done as needed. This means that it is done if/when blood count shows significant change, e.g. anemia, low platelets, abnormal types of white cells, or similar. How long, and if at all, these changes will happen we do not have a way of predicting. We do not suggest bone marrow biopsy just to check whether there is any change. A presence of some fibrosis in the bone marrow does not mean that the disease has changed to Myelofibrosis; there are other factors, like those I mentioned one can see in the blood, that make up a criteria that needs to be fulfilled for Myelofibrosis to be called.

RM: A bone marrow biopsy is very helpful as a baseline in people with ET and P vera to see if there is any fibrosis, any increase in blasts, any changes in chromosomes.  If an individual is stable, the bone marrow would only need to be repeated if there was evidence of change in the disease in terms of blood counts or how the individual was feeling, but a baseline is very helpful so that if an individual does progress, we know where they started from.

RS: Dear Elizabeth, you did not tell us what your bone marrow showed initially.  If it was consistent with essential thrombocythemia, and if your blood work “looks good”, you may not need a bone marrow at this time.

PMF. Jak 2 Neg and MPL pos… what does it mean

86. Jack Pelfrey… was dx with PMF in 1998, I go to Stanford for blood draws, I feel good do not take meds.  I was told I have the MPL mutation.  I do not have the JAK2 mutation.  What does having the mutation mean to me?

SV: There is no particular clinical relevance whether a patient has JAK2 mutation, MPL mutation or no mutation.

RM:  MPL is a mutation that can function very much like mutations like JAK2.  We do not feel that there is a significant difference in how the disease behaves.  Individuals with MPL mutations will tend to respond to JAK2 inhibitors just like those who have the JAK2 v617f mutation.

RS: You have excellent hematologists in Stanford who should address this question.

ET…burning, skin sensitivity.  HU?

87. Amy Rubin ET, burning pain, back and hands.

I am a female age 60 living in SeattleWa. I was diagnosed with Essential Thrombocytosis at the age of 59 through blood work; I have a Jak 2 mutation.The  hematologists I have consulted see no need for a bone marrow biopsy.

My platelet count has been between 570-650 for the last 18 months; my counts have exceeded the normal range since 2008 but have never been over 650. Dr. Harlan is my current hematologist. For the past fifteen months I have had burning in my hands and arms which occasionally goes into my legs and back. The touch of any fabric on my inner arm or wrist will trigger even more pain so I can only be reasonably comfortable when dressed in a t-shirt and shorts.

I have had all sorts of medical tests including a complete neurological workup which showed nothing… The hematologists I have consulted think that there is only a 10% chance that the Essential Thrombocytosis is causing this pain. I am afraid to take hydroxyurea because of its potential side effects and possible connection to cancer, so am only taking a baby aspirin. Has anyone else with ET reported symptoms similar to mine? Would you advise me to try a trial of hydroxyurea to see if my symptoms abate?

SV: Symptoms from ET include those symptoms you have described, yes. If the extensive work up, you mentioned, has      not revealed any other possibility to explain the symptoms, it is reasonable to assume it is due to ET. The real answer will come, you are correct, from trying hydrea. After a couple of months the symptoms should go away. Alternatively, one may try different medications that are used for neurological conditions, for example, Paxil, Elavil, Neurontin or similar. Occasionally they may work as well

RS: All patients with a myeloproliferative disease should have a bone marrow done at diagnosis.  Of course not only to aid a proper diagnosis but establish a baseline for development of future fibrotic changes (see question 85).  I certainly will not give hydroxyurea without defining the issues as much as possible and in this regard a bone marrow biopsy would be of help.  You also did not say what your hematocrit or white blood cell count were.

Connection between Low cholesterol and MPNs

88. Matthew Hicks…I am 49yo male diagnosed with PV in august 2010, almost a year after a MI. Under care of experienced haematologist. Main symptoms at time of dx were arthritic type joint pain in wrists, knees, shoulders and aquagenic pruritis. All blood counts were elevated. Have had 3 BMBs. First showed reticulin fibrosis MF-2 but later ones show had lessened. Initially had 8 venesections. On INF – Intron A – (Pegasys not available for MPNs in Australia). Ferritin iron readings had been very low till early this year but increased significantly in 2 months. Will be checked for haemochromatosis next CBC. My question though relates to cholesterol readings. Mine have always been low and at time of dx I was 2.4 total chol (range 3.5-5.5 here in Australia) which I think is about 100? in US range ie very low. Currently 2.6 total chol. I know of some literature on connection between low chol and MPNs (Harriet Gilbert I think) and thought had read somewhere of possible unfavourable prognosis with very low chol in MPNs. Any comment on any significance of very low cholesterol?

RM: We have identified in the past that MPNs, perhaps through making the spleen more active, may help to decrease cholesterol by the spleen chewing up some of the cholesterol in the bloodstream.  It tends to lower the good and bad cholesterol, LDL, and HDL.  We do not know, in fact there is no proof, that the lowering of cholesterol by the illness is beneficial in terms of protecting from heart disease.

RS: You are right.  Harriett Gilbert was the first to note the low cholesterol values and myeloproliferative neoplasms.  She attributed this to patients who had large spleens.  Patients with PV of course have low serum irons as you did since you had phlebotomies.  Serum iron will rise in response to the use of interferon.  That is a characteristic, it does not suggest hemochromatosis at all.  You might check on your cholesterol values as your polycythemia continues to respond to interferon.  It should rise.

 Pegasys, menopause and skin issues…continue Peg?

89. Susan Ketcham…  I started Pegasys on July 28th at a dose of 90 mcg which I am still on.  My WBC is under control after rising to the low 20′, but unfortunately my platelets have been rising, presently at 745 (I stopped HU 3 weeks ago) so my doctor wants to raise my dose to 135 mcg. So far my HCT and HGB are holding at around 42 and 13 respectively.
I have had the usual side effects (mood swings, achy joints, headaches, fatigue, dizziness) which are far from fun but which I can tolerate, however I am worried about a few things.  Since I began treatment my AST which averaged 35 prior to treatment, has risen to 65, which is above normal.  My ALT, which averaged 16, has risen to 43 – still normal but just.  In addition my LD has gone from around 560 to an above normal 675.  All of my other liver enzymes remain pretty steady, but my liver, already compromised by a portal vein clot and Nodular Regenerating Hyperplasia, is obviously taking a beating from the Pegasys.
In addition, at the same time I started the Pegasys I also seemed to have started menopause with a vengeance! …. AND, finally, I am having a weird skin problem where I have little red bumps randomly appear on my arms, trunk and crotch area, that itch briefly then scab over.  …Continue Pegasys?
(Background) Other medications – Warfarin, Omeprazole, Nadolol, Cymbalta, Aspirin 81mg, Sonata PV diagnosed in 2006, but present since at least 2000, sMF diagnosed in 2010.  HU therapy for six years with fluctuating counts… Platelets that WILDLY fluctuate as much as 400 points in a ONE WEEK PERIOD. Have gone from 31 to over 1,000,000 in a ten day period – both labs repeated, both labs done at UCLA.

SV: As with any other therapy one should balance the risks and benefits of Pegasys. The best strategy in long-term therapy like this one is to engage closely with treating physician and work things out as a team. I would suggest talking to your doctor about your concerns, and listening/understanding his view on the matter. Only then the proper plan can be put in place. For example, since you mention multiple side effect (although tolerable) one may want to wait some time to see whether they will go away as the body adjust to the therapy, or will get worse on the present dose. In general, with chronic therapies there is no rush in changing the dose/schedule and one needs to be sensitive to side effects, for therapy to be given long-term and produce desired results.  

RS:  I would first check the laboratory for your platelet counts.  This cannot be due to the disease or medication.  Of course UCLA is an excellent institution.  Perhaps your blood was not done in the same lab or by a different technician or SAT before being submitted, etc.                                                                                                                         

 Two kids with mastocytomas. Need BMB for dx, risk for MPN

90.  Bonnie Nasar Two of my four children have solitary mastocyomas. We have not had bone marrow biopsies, so I do not know if it is systemic or not. My question is, what are the odds that I have 2 kids with solitary mastocyomas in the same place on their bodies and this is not considered a genetic disease? Also, is there or will there be any way to find out if it is systemic without a bone marrow biopsy? Also ( I guess I have more than one question) one of my kids showed a significantly elevated risk for developing an MPN but the other showed normal risk. Both kids are diagnosed. What does that mean?

RS: I think a geneticist would have to comment on the risk of developing a MPN in this case.

SV: Mastocytomas happen in the kids and are considered benign condition. However, depends where in the body they are, they may interfere with the function of affected organ/body part and may need to be removed. It is unusual to have two kids with it.

Systemic disease can only be diagnosed by the bone marrow biopsy. If body organ function is not affected (normal blood count, liver function, etc) then there is no need to do bone marrow biopsy. There are 2 types of systemic mastocytosis: indolent type which is present in the bone marrow but does not affect organ function (indolent in its name indicated its benign nature), and aggressive type that does affect organ function. The one that matters is aggressive type which would already be evident if blood count is abnormal, liver function abnormal, etc, as mentioned.

 Have ET…Any link between aspirin and boils

92. Jackie Donegan …   I have probable ET jak 2 negative current platelets 705 on aspirin and have recurrent boils. Is there a link?

RS: No connection between the boils and essential thrombocythemia that I am aware of.  Likewise aspirin.

SV: I don’t know of a link between aspirin and boils.

RM: Difficult to say.  There are people who have aspirin allergies.  Typically would manifest more as hives than as boils.  ET certainly can cause itching.  It certainly can cause redness in the skin called erythromelalgia, but typically not boils.  I would work with your dermatologist to look for potentially alternative causes.

 PV dx 09,converted to MF. Is Peg a good option?

93. Augusto Filho..My name is Augusto Ornelas Filho, 48 years old, and I am from Brasília, Brazil.

I was diagnosed with PV (JAK2 V617F positive) in 2005. Before treatment, I had portal vein thrombosis, inferior cava vein thrombosis (partial) and a renal vein thrombosis. It was all asymptomatic, detected during image exams….I have been taking hydroxyurea (1.000 mg/d), warfarin (7.5 mg/d), aspirin (81 mg/d) and omeprazole (20 mg/d).

I have had very good quality of life: asymptomatic disease, blood counts under control (hematocrit <= 45%; hemoglobin around 14.5 g/dL; platelets around 280.000 /µL; and leucocytes around 6.000 /µL); little splenomegaly; few phlebotomies during this period (2 or 3 each year); and no additional thrombotic event. Suddenly, I had my blood counts reduced, checked in my routine blood test of August, 2012. My hemoglobin dropped to 12.0 g/dL, my platelets to 160.000 /µL and my leucocytes to 5.000 /µL. At that time I could feel some fatigue and I started to have, sometimes, very low fever (37 °C) and night sweats.

I had a BMB September, 2012 and we could see that my disease transformed from PV to PPV MF. Now I have myelofibrosis.  The karyotype is normal, but the bone marrow fibrosis grade is MF-3

As far as I can understand, hydroxyurea is not a good option for me right now because it has no effect on the fibrosis. Maybe, Pegasys could help me with the stabilization of the bone marrow fibrosis or even with some reversion effects on it. I have read that Pegasys would be better for early MF but I don’t see any other better option for me. Even with the MF-3 grade, my bone marrow is hypercellular (95%), my CBC counts are still fine and the only constitutional symptoms that I have had are unexplained low fever and night sweats, sometimes, during the last month…Considering that splenomegaly is not my main concern right now (spleen of 19 cm, palpable at 4 or 5 cm below the left costal margin), do you think Pegasys would be a good choice for me? I didn’t have any problem with hydroxyurea but, as far as I know, it doesn’t help with the fibrosis reduction?  I imagine this is the best option for me now! I am feeling good anyway, but very worried about what direction I should take!

RM: Pegylated interferon may have a benefit for individuals with early myelofibrosis.  Clearly it is difficult to advise what would be your optimal therapy based strictly on your question, but given your youth and your time with myelofibrosis, certainly it would be a consideration that would be potentially helpful in trying to delay further progression of the disease.

SV: I think that Pegasys is very good choice for reason you have mentioned. I am very happy to see how well informed you are about your disease and therapies.

RS: Many patients with portal vein thrombosis have a “forme fruste” (hidden) of polycythemia vera.  The reason they do not have an elevated hematocrit is because the plasma volume is increased and thus a “falsely low” value for hematocrit is found.  That is a the importance of a red blood cell 51 chromium mass study which in these cases virtually always demonstrates an increased red blood cell volume which has been masked.  Hydroxyurea will not prevent the further progress of fibrosis in the bone marrow.  You have read earlier questions, patients responding to interferon.  This is the drug of choice for you in my opinion.

ET at age 39, brain aneurysm, ET related?

94. Sandra Birdsall… Was dx with ET back in 1994 at age 39 and have taken hydroxyurea ever since, with a 500 mg daily dosage effective all this time in keeping platelets in the 450 range.  3-1/2 years ago I suffered a nearly fatal brain aneurysmal hemorrhage and subsequent stroke.  I have always wondered if the ET contributed to this event–I have tested JAK2 positive.  It has been a very long road to recovery.  Any comments?

RM: In an individual with an MPN who had a stroke at an early age, we would have to be highly suspicious that the MPN could be a contributor.  There is no guarantee that the MPN is the cause as you mentioned a bleed from an aneurysm that could have been an anatomic event.  That being said, we would have to be very cautious that it could be the ET and aggressively control counts accordingly.

RS: Very hard to say.  If it were a true aneurysm and if your platelet count was very high at the time, it could have contributed in part to bleeding.

PV controlled w/PEG, need equivalet INF

95. Richard Albert… I have been turned down for PEGASYS after having used it successfully for 2 years. I have PCV for 23 years now all counts presently well controlled. I would like to continue with some kind of INTERFERON as I believe it is presently the only drug that can arrest the prgression of the disease I was taking 135ug PEGASYS What would the equivalent dose of Inteferon be? Is anyone looking at combo therapies of Interferon AND HU? When INTERFERON was the old Standard Remedy many years ago,for those who could tolerate it what was the conversion rate to AML and Myelofibrosis like.

RM: It is difficult to translate the dose of pegylated interferon and regular interferon, but similar ranges of Pegasys which would be about 90 mcg a week would typically be similar to about a million units of regular interferon three times a week.  Individuals with regular interferon typically will need between 1-3 million units three times a week whereas as you’ve seen people with Pegasys will typically need anywhere from 45 to as high as 180 mcg per week.  The goals of this therapy are twofold.  1) To try to control counts; 2) to try to delay progression.  Delaying progression may need lower levels of the medicine than the level needed to control the counts.  There are times that individuals that need higher doses of the Pegasys or regular interferon to control counts, we will consider combination therapy.

RS:  You have asked a recurring question.  There is no qualitative difference that I can find between the different types of interferon.  Only convenience and perhaps decreased side effects with PEG.  Therefore, it is perfectly safe for you to take interferon alpha 2b.  There is no exact equivalent dose of interferon.  You can start at 2m units 3 times a week that is roughly equivalent to the 135mu of Pegasys.  Interferon is not an “old standard remedy.”. We use it all the time.  We do have patients whose insurance company does not pay for PEG for reasons I do not understand.  There is no evidence that interferon of any type predisposes to the development of AML or myelofibrosis

ET with high platelets , baby aspirin enough?

98. Dx ET 25 yo, platelets at 700-800, briefly one million. Went down after pregnancies. Baby aspirin only. Hem. Turned me down for second opinion on meds. Needed?

HARRISON: In general if you are otherwise well with no complications and based on this information I would manage you with baby aspirin only.

VERSTOVSEK: The number of platelets does not corresponds to the risk of thrombosis, therefore whether the number is 700 or a million it does really matter. The risk of thrombosis is related to other factors: age over 60 or history of thrombosis make a patient at a high risk for a thrombotic event and these patients require a medication (e.g. hydrea, anagrelide or interferon) to normalize the count. Conversely younger patients without thrombotic event are low risk and need nothing more than baby aspirin.

SILVER: It would seem that no additional treatment is necessary, Charyl.

JAK+ with PV but 23andMe doesn’t catch it.

99. DNA result confusing, have PV, positive for JAK, on hi dose HU but my 23andme DNA test doesn’t show high risk for MPN. Any idea why?

MESA: :  The DNA testing by 23andMe is still exploratory.  The reports that you received have issues of risks for common diseases and dosing for current medications.  The report that one receives is not diagnostic testing for the presence or absence of an MPN.  If your doctor has diagnosed you with polycythemia vera, this I am certain is the accurate diagnosis.  What 23andMe is reporting on is that there are certain genes that are more commonly associated with a predisposition to MPNs, but one does not necessarily have to have one of those genes to actually have an MPN, so unfortunately, I fear the result you have received has caused inadvertent confusion, but the diagnosis from your doctor is correct.

CH: I think the issue is the differences between what these tests are looking at. The JAK 2 test is searching for the specific mutations found in PV, the most frequent being V617F. The 23 and me panel is essentially a fishing exercise done on saliva to look for genetic changes or even normal features that are seen more often in MPN. It isn’t a validated test essentially its a research exercise whose findings have to be examined and tested by the rest of the community. So in essence I would be confident you had PV and be interested in the 23 and me results.

SV: I am not familiar with 23andme DNA test, very sorry

LEVINE:  The 23andMe test just notes the risk of MPN, but does not mean anything if you already have an MPN. In other words, even if the test comes back low-risk, the risk is not zero, and some MPN patients will come back low-risk on their genetic profile but still develop MPN. Inherited risk factors, are just that, factors.

RS: I have no experience with 23andme DNA test per se in PV but if your JAK2 is positive, it certainly suggests that you have PV so assuming all other criteria are met for the diagnosis of this disease.

Breast feeding and Pegasys?

100. Breast feeding and Pegasys or older INTs safe for infant? Any reference to studies for my hem to review?

SV:  This is perfect question for Dick Silver

CH:  there are several reviews on this subject which are visible in medical literature. Interferon and probably pegasys are found in small quantities in breast milk. However these drugs are not absorbed well in a fully mature digestive system and so we think the risk to a baby with an immature gut is less. We support our mums to breast feed as there is clear overwhelming evidence of the benefit of breast vs bottle.

RS:  Your hem can look up the literature regarding Pegasys in chronic hepatitis regarding breast feeding or call Roche ( the pharmaceutical company).  In general, it is not wise to take any potent medication, which includes interferon, while breast feeding.

Can testosterone injections cause MPN?

101. 56 yo woman, dx w/ET maybe PV now. Had depo-testosterone injections every 16 days for about the last 15 years – for low libido. Can this cause PV or marrow failure?

RM: At this point, we know testosterone can have an impact on the number of red blood cells and cause erythrocytosis.  If an individual has a diagnosis of P-Vera or ET, we do not think that has been associated with a prior use of testosterone.  It is important that the diagnosis be confirmed, both on the appearance of the bone marrow and ideally with the presence of a definitive marker such as JAK2 to be certain that the changes in the blood counts are from an MPN and not secondary to medication.

CH: I am not aware of a link between depo-testosterone and either PV or marrow failure.

SV: Testosterone can raise red blood cell count. What the role, if any, these injections had in the disease process is not possible to say; would not cause bone marrow failure, however.

RS:  Insufficient evidence to comment.

High hematocrit. A result of dehydration?

102. 15 yo son being tested for PV based on his HCT and symptoms (fatigue, rosy cheeks, etc.).  Now normal counts. JAK neg. Could high counts have resulted from dehydration?

RM:  The diagnosis of polycythemia vera clearly requires more than just a high hematocrit in symptoms at this point in time, and with normal counts in JAK2 being negative, it is certainly possible that your son does not have polycythemia vera.  That being said, it clearly needs to be a case evaluated by an MPN expert to be certain whether there is or is not an illness, but from what you describe it does seem possible that the increase in the hemocrit was a temporary finding and not a sign of an MPN.

CH: High counts could have resulted from dehydrated or the testosterone surge at this point in a young man’s growth.

SV: Unlikely. Happy he is doing well now and no disease is present.

RS:  We have repeatedly pointed out that, for more than 50 years it has been known that a single hematocrit cannot determine whether or not blood volume (the number of red cells) is truly increased.

PV with bleeding. Stop aspirin?

103. I’m 64, PV diagnosed in 2006, JAK2 positive, on phlebotomies and 81 mg aspirin. Endoscopy showed small intestine bleeding due to aspirin. Stop aspirin? Alternative?

RM: Best not to answer in a forum such as this a very specific question as to whether or not you should stop or start a medicine such as aspirin given that there are a lot of complexities that a physician has to consider in this regard.  I would answer that in generalities, if an individual has had bleeding from an ulcer or from the intestine, it does give us greater pause for the use of aspirin and certainly needs to be discussed with your doctor whether that is necessary.

CH: Usually under these circumstances I would switch to aspirin and a proton pump inhibitor once the bleeding has healed or depending on the severity of symptoms and need for aspirin to an alternative agent like Plavix.

SV:  I would agree to stop aspirin and try alternative, not to risk significant bleeding through GI track.

RS:  One might try Plavix.

GOTLIB: This is a discussion with your GI doctor and hematologist, particularly as it relates to the severity of the bleeding.  One or both doctors may provide recommendations about temporarily holding the aspirin or reducing its frequency.  Other anti-platelets may be considered but may not provide any more safety margin compared to aspirin.

My platelets up.   Time to worry?

104.  ET…My platelets were at 1050 every time my FBC (CBC) was taken. On 75mg of aspirin. In the last seven weeks platelets jumped to 1466.Should I worry?

RM: The platelet count at which we are concerned in ET depends on many things, including an individual’s age, other medical problems, symptoms and whether or not there is any predisposition to bleeding.  A platelet count rise to 1466 could be a consideration for therapy to reduce the platelet count, but needs to be done so with careful consideration by your physician looking at all of these other issues.

CH: Platelet counts can vary due to underlying factors, for example cold, etc. I would see what the next reading is. Watch out for bleeding (usually minor bruising) as this is more frequent with higher counts. This may mean you are coming close to needing to make a decision about additional treatment.

SV: The number of platelets does not corresponds to the risk of thrombosis, therefore whether the number is 700 or a million it does really matter. The risk of thrombosis is related to other factors: age over 60 or history of thrombosis make a patient at a high risk for thrombotic event and these patients require a medication (e.g. hydrea, anagrelide or interferon) to normalize the count. Conversely younger patient without thrombotic event are low risk and need nothing more than baby aspirin. Very high platelets, 1.5 million, 2 million… may predispose a patient to bleeding (!) so close monitoring by hematologist is prudent; when platelets are that high they use up protein called Von Willebrand factor that is present in the blood and is important for coagulation; if it is low then that predisposes patients to bleeding. In that case one would stop aspirin.

RS: I would worry mostly about the laboratory doing the test.  Once cannot make a blanket statement unless more information is provided regarding co-existent risk factors to determine whether your platelet count should be lowered.

When is Watch and Wait not enough?

105. Watch and Wait–Afraid of HU and not sick enough for ruxo and panobinostat. When can you tell it’s really time to treat an MPN?

CH: Watch and wait can be an entirely appropriate strategy for many patients. The decision or recommendation to treat will be based upon the specific features of your disease type.

SV: This is something that is usually decided between a patient and physician, based on the assessment of one’s situation, prognosis, etc. there is no one parameter or test that would determine the right time to start therapy. In general ruxolitinib is indicated for patients that have symptomatic spleen, or have general symptoms from myelofibrosis.

RM: It is indeed a very difficult and complex choice when an individual should receive therapy for an MPN and which therapy should be given.  There are many factors that need to be considered and it is a complex discussion between you and an MPN expert whether or not therapy for your disease would be helpful in the setting where the disease has not been overly advanced.  There has been some information suggesting interferon may be helpful in earlier forms and phases of myelofibrosis, but this is a complex discussion that needs to occur between you and your physician.

Bone marrow biopsy vs. blood smear

106. Can odd cells be detected in CBC, or only blood smear. What does BMB uncover that blood smear can’t?

CH: Generally while odd cells can be detected in a CBC done by an analyser a blood smear evaluation will be required for their correct identification. Depending upon the type of odd cells a bone marrow biopsy is an excellent tool to evaluate bone marrow architecture and how orderly blood cell production is. All three —  CBC, smear, BMB — plus others, for example, spleen exam are needed to fully evaluate MPN patients.

ORAZI: Circulating atypical cells (e.g., immature cells such as blasts) are usually detected by manually reviewing the blood smear at the microscope, although if numerous, they might also show up in the automated CBC result. In patients with fibrotic myeloproliferative disorders (e.g., PMF, post-PV myelofibrosis), the bone marrow aspirate smear which is used to detect the presence of atypical cells in the bone marrow is often hemodiluted because of the fibrosis and frequently spotty cellularity, and thus may be non- representative of the marrow cellularity. The bone marrow biopsy offers the advantage of being able to assess such fibrotic marrow. It allows confirmation of marrow cellularity, lineage composition, determination of the degree of fibrosis and identification of eventual atypical cells (including e.g., blasts). If needed, confirmation of morphological finding can be obtained by immunohistology. A complete hematopathologic evaluation, e.g., to exclude disease progression should always include review of peripheral blood and bone marrow aspirate smears (touch preparations if bone marrow aspirate fails), bone marrow biopsy sections stained also for reticulin, flow cytometry of both peripheral blood (if atypical cell are present in the blood smear) and bone marrow aspirate. Karyotype analysis of bone marrow aspirate. If aspirate is unobtainable and peripheral blood smear shows circulating atypical cells karyotype should be done on peripheral blood. Atypical cells should always be separated out and preserved for eventual molecular genetic studies.

RS: “Odd” cells can be detected both in blood smears and in the bone marrow.  That is what makes hematology a specialty.

RM: A bone marrow biopsy gives three pieces of information that the blood smear does not – the degree of fibrosis, whether there is not an increase in the blasts and whether there are any chromosomal changes.  The peripheral blood smear gives us a sense of the appearance of the blood cells and that can give insight into the illness.  A complete blood count, which is an automated, machine-generated series of values will only give us certain information, but will not tell us information about the appearance of the blood cells or the white blood cells.

Does Red Cross use PV blood

107.  At the clinic for my PV I was told I could go to the Red Cross for my phlebotomy. Does this mean they would later use PV blood for transfusions?

CH: No, PV blood sadly cannot be used for transfusions. You would be advised to make your diagnosis clear to the Red Cross.

RM: Can you donate blood with polycythemia vera?  At this point there is nothing about polycythemia vera that we consider to be transmissible.  It is not something that by giving blood someone is going to develop by receiving that blood.  That being said, at least as of my last understanding, the American Association of Blood Banks will not accept blood from patients with polycythemia vera or having blood removed for therapeutic purposes.  They do this with the greatest abundance of caution.  Whether its necessary, I think is something that is debatable, but I think at the moment, they will not accept blood from patients with polycythemia vera.

RS: In general, PV blood is not used because of medical-legal reasons irrespective of whether the Red Cross  or any other phlebotomy center performs the test.

JG: Blood banks will not use blood from PV patients since PV is considered a chronic blood disease and has some potential to evolve into acute leukemia.

Jakafi side effect

108. After 3 weeks on Jakafi, swelling of neck, breathing constriction. Had to get off drug despite its help with my itching. Any ideas?

CH: You may have had a bad reaction to JAKAFI there is a study with SAR302503 for patients who have run into these problems – its called JAKARTA-2. Discuss with your haematologist.

SV: Have not heard about this type of side effect although I have treated several hundred patients with Jakafi so far; very sorry you experienced it.

RS: This is a complicated question.  It would depend on the rest of your clinical and laboratory status including bone marrow findings.  One cannot give a meaningful answer to this.

RM: It seems that you are describing a possible allergy to ruxolitinib or Jakafi.  If that is the case, it is probably best not to go back on the medicine if there was a true allergy.  There are times if this was after the first dose of the medication, people may with their physician’s help and under guidance have a second try to make certain that there was a true allergy.  If there is an allergy to the medication, that allergy is not likely to be present by using alternative JAK2 inhibitors.  There are several ongoing clinical trials of other JAK2 inhibitors that could be considered in the setting.  There is specifically a trial of SAR302503 in a variety of centers; a trial called JAKARTA 2 for individuals that might benefit from a JAK2 inhibitor but were not able to remain on ruxolitinib.

Stem cell transplant problems. Jakafi an option?

109. SCT age 60 for MF.Relapse at 2 & 12 yrs. Good control w/Pegasys but discontinued because GVHD. Now inflammation, erythema nodosum. Is Jakafi an option?

RM: The use of ruxolitinib after a stem cell transplant has not been extensively studied.  There is in theory a possible activity of JAK2 and JAK1 inhibition for individuals who have graft vs. host disease.  I would say that the use in your setting likely would be experimental and there is really no good information on its use in this setting yet at this time

CH: JAKAFI may be an option but your case is obviously complicated so many things also need to be considered. There is not much experience of using Jakafi in patients with GVHD.  I have had one experience which was positive. So I would discuss with your transplant expert and haematologist.

SV:  In general ruxolitinib is indicated for patients that have symptomatic spleen, or have general symptoms from myelofibrosis. I would discuss this issue with your doctor if you have either of the two.

RS: Jakafi has been used in patients post-transplant.  It may be an option.

JG: Jakaki is useful for MF-related symptomatic splenomegaly and symptoms.  The use of Jakafi in MF should be judged on a case by case basis, and more information would be needed.  For example, if your major issue was just anemia, Jafaki may not prove particularly useful in your case since it is not expected to make a large impact in this regard and could make it worse.

Worried about high dose of hydroxyurea

110. PV, 2008, 59 yo Female., After cardiac event on 1500 mg of HU, put on Plavix, Lipitor, 81 mg. of aspirin. HU seems high and is interferon an option?

CH: HU doses vary greatly between patients and may go up to 2500mg or more. Interferon may be an option but some clinicians (including myself) prefer not to use this at or around the time of a cardiac event.

RM: Fifteen hundred mg of hydroxyurea or 21 pills a week is on the high end for the medication but not a concerning dose.  I would say that the average patient with an MPN will require between 10 to 20 pills of Hydrea a week or somewhere under two pills a day to somewhere in the range of three pills a day.  Four pills a day or 2000 mg would be an uncommon dose.  Now, whether or not a change to interferon is appropriate or necessary would depend on whether the Hydrea is giving you any side effects and also how the disease is behaving.

SV: If HU is providing desired benefit without side effects, then one in general would not change it (regardless of the dose). Interferon of course is good alternative.

RS: Interferon can have adverse cardiac effects.  It depends what the cardiac event was.  This requires evaluation.

Itching!

111. 67 yo PV…desperate to relieve itching. Can’t sleep. Take Piriton 5 mg 3x/day, HU 500mg/day. Can I increase either to relieve itching?

CH: I am sorry to hear this. You need to discuss these and other ways to relieve itching such as other medications, possibly light (PUVA) therapy, etc. with your clinician. I would not exceed the maximum recommended piriton and would not increase HU. You could also discuss another antihistamine with your pharmacist.

SV: HU can be increased, but that needs to be done under supervision of your doctor, and is based on your counts. Alternative strategy is to engage in a clinical study with JAK2 inhibitor for patients with PV, that are symptomatic despite the use of HU. Ruxolitinib (jakafi) is being evaluated in such a study, for example, throughout the USA.

RM:  A JAK2 inhibitor may be helpful in this setting.  There is a clinical trial ongoing called the RELIEF Study, which is a randomized study for patients who have persistent symptoms on Hydrea being randomized between remaining on the Hydrea and changing over to a JAK2 inhibitor.  A JAK2 inhibitor may be helpful for the refractory itching.  Other things that can help itching are therapeutic UV light as well as a variety of the antidepressive drugs such as Zoloft or Paxil that have some benefit.

RS:  The best drug to relieve itching in PV is interferon. Paxil is also helpful and should be considered.

JG:  The JAK inhibtors are very good in providing relief from itching so,  if there is a center that is conducting a trial with Jakafi for PV, and  you are eligible, this is an option.  I have had success with a medicine aprepitant (brand name Emend) in controlling itching.  It is an  anti-nausea medicine for which a good literature also exists for its anti-itching (pruritis) benefits.

Familial blood cancer. I’m symptomatic.

112. 41 yo female, Mother has PV, father CML.  My plts 500-700, HCT 47-51. Fatigue, joint pain rash. Hem says unrelated to MPN. Get a second opinion?

RM: With both parents having a hematologic disorder and your counts being abnormal, I certainly would be concerned that there could be an underlying blood disorder, although it is not definitive.  One could have some erythrocytosis and thrombocytosis for alternative reasons, but I do think being 100% certain as to the cause, given your symptoms, would be wise.  It is possible that if your symptoms are from a secondary cause, that secondary cause is also responsible for the increased counts.

CH: these symtpoms could well relate to your blood count. I would say you need a thorough evaluation.

RS: Yes.

ET….a myeloid malignancy?

113. BMB showed atypical megakaryocytes. High platelets. Dx ET. No AML. Can I be sure I have no myeloid malignancy?

CH: The term atypical megakaryocytes is tricky as it covers a variety of potential diagnoses. I would take this question back to your physician or the bone marrow specialist for a second opinion. Remember that the WHO classed ET and all MPN as -neoplasms and hence by definition myeloid malignancy. Please also remember that the term malignancy covers many non-aggressive conditions which ET usually is.

AO: The morphology of the megakaryocytes provides some indication of the type of myeloid disease. Careful review of the bone marrow finding may be needed to confirm a diagnosis of ET. In ET the “atypical” features are limited to a predominance of large megakaryocytes with deeply lobulated nuclei. The bone marrow cellularity is more often within normal (age-related) limits or only mildly increased. There should not be a significant granulocytic proliferation. Moreover, to confirm ET, the presence of significant fibrosis must be excluded by performing reticulin stain (Gomori stain). The presence of an increased number of blasts in bone marrow or peripheral blood and/or the presence of specific karyotypic findings identify AML. If the report does not describes blasts and the karyotype is normal you most likely do not have AML. Is JAK2 mutation or other marker of clonality (e.g., MPL) detected in your case?

RM: The spectrum of myeloid diseases do exist on a spectrum of which ET is a myeloid malignancy, although frequently the one that is the least likely to progress to acute leukemia.  What the expectation over the prognosis is with your ET depends on many things and you should have a thoughtful discussion with your physician.

RS:  If the bone marrow does not show an overt myeloid malignancy, the chances are you do not have one.  However, far more sophisticated test are now being used such as flow cytometry, cytogenetics, special stains etc. to conclusively exclude myeloid malignancies.

Five year old is JAK+, likely to progress?

114. Five year old daughter JAK+ dx ET considering age what are chances of progressing to PV MF, AML?

CH: We know very little about these diseases in children however I have several patients diagnosed as teenagers who are now in their mid to late 40s and fine. You can hopefully take comfort in the huge advances in treatment which will benefit your daughter.

RL: This is a difficult question as ET is rare in children. Most studies suggest there is a lower, but not zero, risk of progression to PV/MF/AML. She should be followed, and treated carefully by an expert in pediatric MPNs.

Drug interactions with hydroxyurea.

115. What drugs are contraindicated while taking HU.

CH: Most drugs are fine. Be cautious with drugs which also lower the blood count such as methotrexate. If you have a specific question I would discuss with a pharmacist.

SV:  None, but one would not like to use other chemotherapy drugs in the same patient to control the disease. It has been shown that patients who were treated with HU (which is a chemotherapy agent) and with any of the other chemotherapeutic agents (e.g. busulfan, melphalan,…) had much higher risk of transformation to acute leukemia.

RS: Your hem should consult the PDR or the drug insert which accompanies hydroxyurea when delivered from the pharmacy.

Stick with interferon…or Jakafi?

116. MF 2003, Intron A was effective in raising Hg and then not. Now back on interferon w/Darbopoetin. Counts low but stable. Is this regimen effective or would Jakafi be a better option?

CH: Jakafi may be an option to be considered particularly if you have troublesome symptoms or are bothered by a large spleen. It sounds as though low counts may also be a problem in which case you would need cautious dosing with Jakafi and to be aware it may worsen this issue.

SV: In general ruxolitinib is indicated for patients that have symptomatic spleen, or have general symptoms from myelofibrosis. I would discuss this issue with your doctor if you have either of the two. Jakafi does not improve red blood cell count, in general.

RS: How effective was interferon in raising your hemoglobin and then how high?  What happened to spleen size?  Interferon can cause marrow reversion of architecture abnormalities whereas Jakafi does not

Jakafi trial for PV?

117. Is there a trial for Jakafi and PV?  And will Jakafi lower WBCs and eosinophils?

SV: Yes to both questions. There is a large multicenter study of Jakafi in PV, called RELIEF study, for patients on Hydrea that are still symptomatic from PV.

CH: There are 2 global trials for Jakafi and PV response and relief, and a separate study in the UK. These studies have very specific inclusion criteria but most relate to having tried and failed or been intolerant to HU or having persisting symptoms. We do know that Jakafi lowers WBC and in my experience eosinophils too although they may be lowered by relieving itch.

RS:   There are a number of trials at major MPN centers around the country.  At Cornell we have a number of studies besides Jakafi as do other centers.  It depends upon your location.

RM: There are two ongoing studies for Jakafi in P-Vera – the response trial and the relief trial.  These trials have very specific eligibility criteria, but would refer you to the web to look at those.  There are many individuals who might benefit from JAK2 inhibition with P-Vera, but at the moment the clinical trials are relatively narrow in their eligibility.  Ruxolitinib may lower an increase in the white count eosinophils.  Eosinophilia has not been frequently treated with ruxolitinib to this point in time so I think whether it would reduce it, I am less certain.

Cause of PV weight loss.

118. How do you know if your weight and muscle loss is from PV or a statin?

SV:  Tough question. One would need to be seen, examined, check blood tests, and similar, and then provide opinion.

CH: Very difficult to know. Timing could be a hint. An alternative is to discuss pausing the statin and see if the problem resolves.

RS: Please remember your hematologist should be an internist first and thus, careful evaluation is necessary before weight and muscle loss is ascribed to one disease or another.

RM:  It is difficult to know for certain, but we do know that, particularly in the myelofibrosis end of the spectrum, muscle loss, wasting and weight loss is associated with myelofibrosis.  If the disease is stable PV, I would take this as a possible sign of progression.  Although I think these difficulties have occurred with statins, they are not common, so I would be a bit more suspicious of the P-Vera/myelofibrosis than all the statin use.

 

 

Jakafi and PV…

119 . Will Jakafi be approved for PV in the near future? Will Jakafi lower WBCs and Eosinophil

HARRISON: PV is currently being tested in PV patients in several ongoing trials. If these are positive and certainly it seems likely then I am sure that the drug companies will file for license. Jakafi does lower white cell counts and in my experience also eosinophil counts.

VERSTOVSEK: We don’t know. Standard first line medication that is used as therapy for PV (when is necessary) is hydroxyurea. It is effective and safe in great majority of patients. However, there are patients that do not respond well to hydroxyurea or lose the response. What to do in this situation is not well established. Therefore a study for patients with PV that are refractory or resistant to hydroxyurea was done recently comparing Jakafi to “best available therapy” (this means basically that a doctor had an option to choose any among several therapeutic options). I don’t know when we will know the results. If Jakafi is shown to be superior significantly in this study over “best available therapy” in controlling signs and symptoms of PV, then Jakafi might be approved for use in PV patients refractory or resistant to hydroxyurea.

MESA:  Ruxolitinib (Jakafi) is currently in two phase III clinical trials for P-Vera in individuals that have either had inadequate benefit from hydroxyurea or have failed hydroxyurea in the past. If these trials are positive, it is highly probable that ruxolitinib will be approved for polycythemia vera. The exact wording and indication from the FDA may or may not include all patients with polycythemia vera. Polycythemia vera has been shown to lower increased white cell count in patients with P-Vera but has not been studied specifically for increased eosinophils.

SILVER:  Jakafi does lower white blood cell count and can lower  eosinophils.  Whenever the Food and Drug Administration becomes involved, one can never anticipate a given date for approval.

HASSELBALCH : If interferon-alpha2 is available this is the drug of choice in newly diagnosed patients with PV . This agent – in low-dosage – e.g., Pegasys 45 ug x 1 sc/week initially with increase to 90 ug x 1 sc/week  after 2-3 months if normal counts have not been achieved  – is safe , efficacious and associated with low-toxicity . In addition – as the only agent in MPN-treatment – IFNa-alpha2 may induce major molecular remission with low-burden JAK2V617F after (3)-5 years- (7) ( < 1 % mutated alleles ) and normalization of abnormal bone marrow architecture.  Then , IFN-alpha2 may be discontinued for several years ( 3 years the longest observation period ) still with completely normal blood counts and normal bone marrow.

Jakavi will likely have a future role in combination with IFN-alpha2 in the treatment of patients with PV – e.g., those patients  being intolerant /not responding adequately to IFN-alpha2

Husband tired, not eating well. Has Jakavi stopped working?

120. My husband with MF, in his 60’s is tired, not eating well, his tastes have changed and he seems sad. I know that Jakavi can stop working after a time and then you get off and back on. How can I tell when that is happening?

CH: Sorry to hear your husband is not so well without seeing him and knowing all the details, recent results etc it is hard to know what is going on. This could be physical but since you mention sadness there could also be a psychological element too.

SV: One would need to know more details about the patient’s current situation, spleen size, blood count, drug dose, etc… to be able to comment properly. For example, one may suggest that additional medication be added to Jakafi to bolster its effect, or bring additional benefits. Or the dose of Jakafi needs to be increased. Or one may suggest different jak2 inhibitor or other drugs in clinical trials. Hard to say…

RM: Those things you describe with your husband are concerning and definitely need to be addressed with his physician. We do get concerned when an individual is fighting a difficult disease such as myelofibrosis.  If they are having symptoms – is it completely from the illness; is there a component potentially of depression from feelings of anxiety related to the illness or a combination of both. It would be helpful to discuss these issues with your hematologist.

RS: This is a complicated clinical issue and must be judged by the person caring for your husband.

HH: To answer your question I need further  information on the duration of treatment with Jakavi , other medications etc. and in addition if your husband has exhibited a very favourable response previously with decrease in fatigue, spleen size etc . If so, and all his symptoms now emerge again on continuous unchanged dosage ( how much ? ) then you may consider that Jakavi is no longer working provided that a complication has not supervened – e.g., an  infection . My best advice is to consult your hematologist and have a talk with him on all these issues.

What’s causing fatigue…my MPN or meds? Can diet and exercise help?

121. I’m struggling with fatigue. Can diet or exercise help? Is it a result of PV or HU?

CH: Fatigue needs to be a major focus of effort in the future. Many MPN patients have fatigue sometimes this can be helped and indeed hindered by medication. Keeping a diary can help. HU can make you sleepy. I advise my patients to try taking it in the evening. I believe attention to diet and exercise may also help as well as ruling out other concerns like thyroid disease.

RM: Fatigue is a very common problem in MPNs and one that we struggle against. Diet and exercise can be potentially beneficial. It definitely can be from the disease. Medications can worsen fatigue. Hydroxyurea is not commonly a contributor of fatigue, but it is always possible. I do suggest what you discuss with your doctor is both optimizing the therapy of the PV as well as other non-medical ways to try to improve your fatigue.

RS: A nutritious diet and exercise usually help patients with fatigue although there may be limits owing to anemia, spleen size, etc.  Thus, it could be a result of the PV but not HU.  In general, I find patients who receive Pegasys have fewer symptoms when they exercise regularly.

HH: The fatigue is likely explained by PV , if the disease is not well-controlled implying normal leukocyte and platelet counts and a hematocrit < 0.42 in females and < 0.45 in males . Other diseases associated with fatigue should be excluded – eg. metabolic-endocrine diseases  such as diabetes mellitus, hyperfunction or hypofunction of the thyroid glands, hyperfunction of the parathyroid glands . In regard to HU, a subset of patients experiences fatigue during treatment with HU although it is uncertain if HU is responsible for the complaint.  Exercise is always beneficial anyway.    

Long-time PV switched to Pegasys, getting slow results. Should I continue?

122. PV for 8+ years, on HU since diagnosis. Switched to Pegasys for the past 13 mos, dosage 135 mcg. All counts down except RBC, still phlebotomies monthly. I heard it could take a year or two on Pegasys to no longer need phlebs. Should I continue what I’m doing?

CH: It sounds like things are going well though frustrating that you still need phlebotomy. It can take a while to settle or it may be that you need a slightly higher dose.

SV: It is very unusual not to respond to Pegasys at this dose (I assume it is given weekly) for such a long time. It seems that either the drug is not working or you are somehow in your diet getting excess iron.

RM: The goals of the use of Pegasys in patients with P-Vera are to try to delay progression as well as normalize counts. The optimal dose for you is something that needs to be discussed with your doctor, but in general our goal is to try to have the counts normal while hopefully obtaining some of the benefit of Pegasys in delaying disease progression.

RS:  The dose of interferon is “getting up there” and gentle exercise may elevate some side effects if you have them.  It may take a year or two for Pegasys to reduce the number of phlebotomies and, of course, it does depend on the number of phlebotomies you require to keep your hematocrit in the correct range i.e. for a man under 45%, and for a woman under 42%, as we have been saying for years.

HH: Wonderful – you are on track – your requirements for phlebotomies will likely steadily decrease further during the next 12 months . I advise you to continue treatmentlikely your dosage may be decreased thereafter but I assume that you have no side effects from PegasysI kindly refer to my answer above (119)

Pegasys vs. HU…why the difference of opinion?

123. Why disagreement on Pegasys vs. HU for PV? Why does the Mayo Clinic website not recommend Interferon and Dr. Silver does? My doctor claims Pegasys has side effects and HU is the drug of choice for PV. 49 yo female with PV, confused by this disagreement

CH: The honest truth here is we have never studied HU and Pegasys side by side so we do not know which agent is best. However such a study is now on going so we will know in the future. In my own opinion all other things being equal the medicine for a patient is the one which physically suits them best leaves them with the fewest side effects and allows them to enjoy life to the fullest extent.

SV: International panel of experts (including physicians from the Mayo Clinic) published a few years ago in a prestigious journal recommendations on , of myeloproliferative neoplasms, including therapy for PV. By consensus HU and interferon are BOTH first line therapy for PV.

RM: The current European LeukemiaNet Guidelines, to which many of us have contributed, both list pegylated interferon alpha-2a and hydroxyurea as reasonable front-line therapies for polycythemia vera. Which is the correct choice for you is something best discussed directly between you and a hematologist in that there are many issues between both of these medicines. There is currently a phase III trial for the MPD Research Consortium trying to prove beyond a shadow of a doubt which of these two is better therapy.

HH:  I cannot answer your question why the Mayo Clinic website does not recommend interferon but I can answer you why Dr Silver recommends interferon. Dr. Silver was the pioneer in IFN-research in PV in US publishing the first report in 1988 . Since then he has contributed significantly with several classical papers on interferon in MPNs . Recently Dr. Silver and his colleagues from Weill College have also shown that even patients with hypercellular myelofibrosis may benefit substantially from this treatment. A similar observation in MF-patients  has been reported by the French group (Kiladjian et. al.). Kiladjian and co-workers published for the first time  in Blood a few years ago that Pegasys was able to induce complete hematological and deep molecular remissions with a significant and rapid decline in the JAK2V617f-allele burden in a high proportion of patients. We and others have published similar observations and several reviews on interferon in MPNs have been published in recent years emphasizing that a renaissance and  a new era for treating with IFNs in MPN-patients are emerging, implying HU to be substituted by Peg-IFNs in countries where Peg-IFNs are available for treating MPN-patients. As mentioned above ( answer to 119 and 122) pegylated interferon-alpha2 (PegIFNalpha2a = Pegasys  PegIFNalpha2b = PegIntron) is the drug of choice for the treatment of ET , PV and hypercellular myelofibrosis.  A large number of trials  have convincingly shown that IFN-alpha2 is the drug of choice for treating ET and PV patients with IFN , normalizing blood counts within the first few months in most patients although the need for phlebotomies may continue for 1-2 years but on a declining curve. Concomitantly, enlarged spleens normalize. In Denmark we have used IFN-alpha2 routinely for the last 15 years  and in other European countries – eg Sweden, Norway, France and Austria – several centres are using interferon instead of HU as well in younger patients due to the concern in regard to the potential of HU to elicit /promote myelodysplasia , acute myeloid leukemia and possibly also skin cancer. HU will not elicit cancer after short exposure ( e.g., 3 years) but there is increasing concern that HU may elicit the above mentioned myeloid cancers after long-term exposure ( about 10 % after 10 years , 15 % after 15 years and 20 % after 20 years ). Accordingly, in February 2012 we launched in DK a multicenter study treating all newly diagnosed patients with ET, PV or hypercellular MF with the 2 peg-IFNs – randomising patients between Pegasys or PegIntron in those < 60 years and in those > 60 years we have added a third arm – HU. The aims of our study are to compare the safety, efficacy and toxicity profiles of low-dose Peg-IFNs – Pegasys ( 45 ug x 1 sc/week)  and PegIntron (30 ug x 1 sc/week) – since no such studies have been performed in MPN-patients. In addition, Quality of Life (QoL) is currently assessed by a Danish  internet-based design to capture all disease-related symptoms and side effects of treatment as early as possible. Biologic studies are implemented to answer important questions on gene signatures and other molecular studies  of those patients obtaining good responses versus those not responding adequately to treatment with IFN . Likewise we hope to obtain a predictive signature of patients developing side effects to IFNs giving us the opportunity to select accurately the patient population that benefits most on IFN.

As you may understand, I do not  agree with your doctor when saying  that IFN has side effects to such a degree that it disqualifies treatment in favour of HU. When being used in too high a dosage IFNs have certainly side effects –all MPN-physicians remember the initial very high CML-dosages which indeed were toxic. But on low-dose IFN as described above by the large majority tolerates IFN very well.

MPN patients…at higher risk for other cancers?

124. I read that  research suggests elevated platelets provide the fuel for tumor growth. Tumors activate platelets and platelets in turn fuel tumor growth. Are MPN patients subject to higher risks of cancer? Should platelet levels be normalized?

CH: I am not aware of any evidence linking platelet levels in MPN to cancer. Lowering of platelets is done to protect against blood clotting and bleeding events.

SV: It is well documented that patients with MPN have somewhat higher risk of cancer. We do not why but we do know that it is not connected with platelet number.

RS: A recent article in the New England Journal of Medicine suggested that patients with ovarian cancer may have tumor growth accelerated by increased platelet counts.  Patients with MPNs are subject to a slight but definite increase in the rate of cancer.  In general, platelet counts should be normalized, but mainly for thrombotic reasons.  Remember that some of the drugs used in the treatment of myeloproliferative diseases are carcinogenic.

HH: A very interesting question. You refer among other things to studies showing that patients with e.g., lung cancer and ovarian cancer and high platelet counts have an inferior prognosis and also to several experimental studies showing that platelets enhance tumor aggressiveness and invasiveness ( metastatic potential ) . This research on the interaction between platelets and tumor growth is indeed of utmost significance in the context of MPNs . We are studying  this particular issue in upcoming research projects in DK as well. If this interplay between tumor growth and platelets is further substantiated and confirmed – already several papers being published –  this association may be an additional argument for normalizing elevated platelet counts in MPN-patients and for early intervention with interferon-alpha2 at the time of diagnosis. To this end, MPN-patients have an increased risk of second cancer – shown recently in Danish and Italian epidemiological studies. It is tempting to speculate if the increased risk of second cancer is due to an impaired “Tumor Immune Surveillance “ with qualitative and quantitative alterations in immune cells. Actually, several of these changes in immune cells may be restored by interferon treatment.

Negative effects of aspirin…

125. Can regular venesections and daily aspirin jeopardize my longevity or contribute to progression to MF in the future? 47 yo female with PV, asymptomatic.

CH: There is no clear evidence that just venesection and aspirin is worse for you in terms of progression and longevity especially when long term risks of drugs are also considered.

SV: No. This is standard therapeutic approach in young patients without history of blood clots,

RM: At this moment, there is no evidence to suggest that regular phlebotomy or venous sections in aspirin contribute to progression toward myelofibrosis in patients with polycythemia vera. We do know that it is in the natural history of these diseases to progress, but that controlling of the counts and a baby aspirin both have been shown to be helpful.

RS: It is impossible to control patients with PV with phlebotomy only.  This was shown in studies of the PVSG and confirmed and particularly by articles by Najean years ago reporting data of French patients.   Of those patients randomized to the phlebotomy arm of the old PVSG study only 10% could continue on that management after 5 years.  Recurrent phlebotomy produces severe iron deficiency, anemia, which in and of itself  has significant side effects.  There is abundant literature in nutrition journals showing decreased cognition because of iron deficiency anemia.  It is my belief that persistence phlebotomy does lead to myelofibrosis and this is natural since such treatment does not stop the progress of the disease and in fact may increase its activity by bleeding, activation of leukocytes, platelets, etc.  Of course,  in the initial PVSG studies, there was a high rate of thrombosis in patients treated with phlebotomy-only during the first five years of treatment and thus myelo-supppressive therapy was introduced.

HH: In addition to phlebotomies and aspirin PV should be treated with IFN-alpha2 upfront at the time of diagnosis  for reasons already given above – even if you are asymptomatic since untreated the disease will steadily progress, you will be symptomatic as well – hypermetabolic symptoms as fatigue, night sweats , weight loss etc – , increasing spleen size , increasing bone marrow fibrosis and leukocyte /platelet counts. When you enter the advanced disease stage treatment with any agent – including IFN-alpha2 – is far less successful. PV is a cancer and the earlier you treat a cancer with an effective agent, having the potential to induce minimal residual disease ( = interferon-alpha2 ) the better the likely prognosis.

Platelets rising…can HU stop working?

126. ET for six years with symptoms of migraine, tingling hands, controlled by HU. Increased dosage when platelets rose. Can HU stop working?

CH: The dose of HU needs to be adjusted from time to time. However sometimes it loses the ability to control the blood counts. Under these circumstances switching medication is usually useful.

SV: Yes it can.

RM: There are a variety of issues that can impact the actual platelet count itself. Hydroxyurea typically does not stop working in terms of decreasing the platelet count, but there are other things that may be raising the platelet count further – iron deficiency amongst other difficulties. There are times hydroxyurea is giving us inadequate benefit and then alternative therapies can be considered.

RS: In patients with ET, as long as there is an effect on the platelet count, one can suppose that hydroxyurea is working.  The issue is the development of toxicity rather than ineffectiveness.  However, some years ago, I did publish a paper on the effectiveness of anagrelide in patients who did not respond to hydroxyurea in individuals with high platelet counts in chronic myeloid leukemia.  This is not the same disease as PV and other mechanisms may have been operative in that situation.

HH: Yes, resistance to HU may develop – I would ask your doctor if interferon-alpha2 is available for you. I assume that you receive treatment with aspirin as well. Your symptoms are typical “microcirculatory “ which very often vanish on aspirin ( 75 mg/day). If not symptom remission on this dosage you may increase aspirin to 150 mg or you may add a statin ( eg simvastatin 20-40 mg/day). Statins are potently anti-inflammatory and “downregulate” the tendency of white blood cells and  platelets to aggregate in the circulation . Furthermore, most recent research has shown that statins – in addition – impair MPN-cell growth, this capacity acting in synergy with JAK-inhibitors.

What’s better, phlebotomy or HU to lower hematocrit?

127. What are the trade-offs between venesection and hydroxy in lowering HCT level?

CH: Many and complex. Smoother HCT control with HU which will also lower WBC and Plts, but long term risks of drug, potential but unproven benefit (see 125) in preventing progression.

SV: The two do not compare. Venesection is standard medical intervention for all patients with PV, to keep HCT below 45, and is done periodically whenever HCT goes above 45. Hydroxyurea is provided IN ADDITION to patients with PV that are at a high risk for thrombosis (those that are older than 60 or have history of blood clot) with a goal to eliminate a need for phlebotomy (i.e. keeping HCT continuously below 45)

RM:Between phlebotomy and hydroxyurea in controlling the hematocrit in patients with polycythemia vera, in theory, phlebotomy alone has the advantage that it does not involve a medication; however, it does induce iron deficiency and iron deficiency can have symptoms. Hydroxyurea is typically viewed for individuals who have high risk of blood clotting events and may benefit patients receiving this therapy by also helping control the white count and the platelet count which may contribute to those risks.

RS: Please see above answer.  In general, hydroxyurea cannot lower the hematocrit sufficiently without supplemental phlebotomy in my experience.  Usually, I do not find ET patients developing fatigue unless they also develop anemia raising the issue of whether or not the individual really has myelofibrosis in the cellular phase, etc.  Thus,  a bone marrow examination is mandatory.  Severe fatigue therefore must be pursued with determination of spleen size,  degree of anemia, type, bone marrow, etc.

HH: Venesection is the cornerstone therapy to rapidly lower elevated HCT, which is not obtained by HU monotherapy. Venesection as monotherapy of PV is inadequate .  On maintenance therapy with HU and interferon-alpha2 you also achieve control of elevated HCT .

Fatigue and ET…related or not?

128. An MPNclinic doctor said fatigue is not generally a complication of ET. Other doctors disagree and as an ET patient with severe fatigue I couldn’t disagree more considering the impact fatigue has on my life. How account for the different opinions?

CH: Medicine is an art as well as a science. In my own experience patients with ET and other MPNs can be unlucky enough to be afflicted with severe fatigue. The challenge is beating it!

RM: We have data in several hundred patients with ET from around the world using standardized questionnaires of fatigue and symptoms. I could say without question that ET can be a contributor to fatigue. That being said, patients with ET live on a spectrum and there are some individuals who do not have fatigue; maybe that might be up to half or there are others in which fatigue can clearly be a complication.

RS: Of course, one must always consider side effects of all the medications we use and this query cannot be answered intelligently without knowing what medications you are taking.

HH: Several QoL-studies have convincingly shown that a subset of patients with “ET” is heavily burdened by fatigue. Future studies may unravel if this subset of  “ET” patients are those which suffer  “early prefibrotic myelofibrosis.”  Some of the fatigue-burdened ET patients may also have  PV – if JAK2V617f-positive – since up to 60 % of Jak2V617F-positive “ET” actually are misclassified as “ET” if  an estimation of the red cell mass (RCM) ( increased in PV patients )  is not performed at the time of diagnosis . The JAK2V617-positive ET patient may transform to PV and – accordingly – is considered as a precursor stage of PV in the biological continuum from ET over PV to the advanced myelofibrosis stage.

My doctor says new  lower leg pain not related to MF.  Can that be right?

129. Female, dx with MF in October now suffering lower leg and back aches. My hematologist says it is unrelated to MF but I have never had this before and see no other reason. Is he right?

CH: The honest answer is you could both be right. It is possible to get bone pain with MF but we should always remember there may be other causes. Have another chat with your doc!

SV: One would need to know more details about patient current situation, spleen size, blood count, etc. to be able to comment properly. Certainly bone aches can be related to MF but one needs to know patient’s clinical situation; for example, if patient has relatively good blood count, no enlargement of spleen and no other symptoms except for back pain, one would very likely suspect back pain not to be related to MF. On the other hand, if spleen is huge, patient has night sweating, weight loss, then bone aches are likely related MF.

RM: It is always difficult when one is having common symptoms – leg, back aches – as to whether or not it is related directly to the hematologic disorder, such as myelofibrosis. That being said, if there is no alternative cause, certainly myelofibrosis can cause a range of symptoms of which aches certainly could be part of it.

RS:  In my opinion, you really require a thorough re-evaluation.  Such a question is impossible to answer in a casual fashion. It is bad medicine and equally bad advice

HH:  In myelofibrosis patients with “Leg and back aches “– but also in the ET and PV –patient – increased disease activity should always be suspected . In rare cases so-called extramedullary sites may involve the nervous system by compression of nerve roots etc ( “extramedullary hematopoiesis” – the same process which explains the enlarged spleen when  immature blood cells seed the spleen – they may seed at other sites , including along the nerve roots which are being compressed giving rise to aches in the back and legs ). I advice you as soon as possible to have a talk with your doctor on these issues . I would recommend to consider  a bone marrow biopsy and a CT-scan of your back .

New ET intermediate risk patient…when should I start HU?

130. dx ET w/JAK2+ on 10/12, 54yo, platelets 761-909, aspirin only, doc classified me as intermediate risk. Headaches, itching, veins have bad valves. My hem leaves it up to me to start HU to avoid thrombotic events. Is it time to start?

CH: I would agree that based on the information provided you would be classed as intermediate risk. I wouldn’t want to make treatment advice based on this small amount of information. But I would ask are you on aspirin and does this help? Check if there are other things which could be causing your symptoms etc. The other thing to consider is a trial of treatment to see if it helps your symptoms..

HH: It is time to start treatment – if available IFN is the drug of choice for you; you have JAK2V617F- “ET” – I assume that a bone marrow biopsy has been performed . I wonder if your headaches and itching actually reflect that you have PV and not ET albeit these symptoms may also be seen in ET patients . What is the level of your hematocrit , what is your plasma –erythropoietin level ( low in PV and also lowered in many patients with JA2V617F-“ET”  ) what is your plasma ferritin – normal or low?  – if low with no  iron in the marrow you have likely PV and not ET. If your doctor has access to a red cell mass estimation this would be optimal to confirm or not the PV diagnosis.

Any correlation between ET and high blood pressure?

131. 24 yo male with ET. Platelets at 900 and told I had Essential Hypertension and put on lisinopril hydrochorothiazie. Is there any correlation between ET and high blood pressure?

CH: No correlation that I am aware of. However both increase the risk of blood clots and therefore it is important to keep the blood pressure well controlled.

SV: No.

RS: There is no correlation between ET and high blood pressure although presumably if the kidneys become involved with thrombi and impaired function, that is a possibility.

HH: Yes, a large number of ET and PV –patients suffer hypertension at the time of diagnosis – up to 50 % of PV-patients. As stressed above, it is very important to secure that you actually have ET and not PV . Many  hypertensive PV-patients achieve normalization of the blood pressure in concert with a reduction in the expanded red cell mass during repeated venesections . I wonder if you are being treated for your ET and if a diagnosis of PV has been excluded by the absence of an expanded red cell mass  etc  as mentioned above in my 130 -answer .

Allele burden…what does it mean?

132. What exactly is the Allele Burden, and what does it say about the status of our disease? I’m specifically interested in PV, but I think it also pertains to all MPNs.

CH: Allele burden is the quantity of abnormal JAK usually expressed as % of total. Broadly speaking patients with PV have higher amounts than those with ET and higher amounts may also be seen in patients who have had the disease for a long time. At present what we don’t know is what does current allele burden predict and what benefit is there in changing the allele burden.

RS: What is allele burden?  Simply, one can define this as the amount of JAK2 abnormality present in your cells.  In general, three published studies (Vannucchi, Tefferi, Silver) have shown that the higher the burden the more aggressive the disease. It has been used as a guide by some of us to determine the aggressiveness and treatment type in PV.  It is also significant to those interested in the biology of the disease since a figure more than 50% indicates that 2 alleles (genes) are involved rather than 1.

HH: The allele burden is the “molecular  index” of “tumor burden” in JAK2V617F-positive MPN-patients implying that the more tumor burden – as assessed by e.g,. the level of the leukocyte count and the degree of enlargement of the spleen, the higher the JAK2V617-allele burden.  The JAK2V617-allele burden is smallest in ET ( virtually all ET patients have an allele burden below 50 % and an allele burden above 50 % in the “ET” patients should give rise to diagnostic re-evaluation – has the patient PV or MF ? ). The JAK2V617F allele burden is highest in the advanced myelofibrosis stage ; however, declining levels of JAK2V617 may be seen in myelofibrosis and – if so – should raise suspicion of an overriding JAK2V617-negative clone which may precede leukemic transformation. During IFN-alpha2 treatment the JAK2V617F-allele burden steadily declines but the patterns of reduction in JAK2V617F are highly heterogeneous . Some patients exhibit a rapid decline from e.g,. about 80 % to 30-40 %, within a year and then a slower decrease in succeeding years: others display a slow decline with a definite decrease occurring in the second year. The mechanisms behind these heterogeneous patterns are unknown but may be related to different disease duration before diagnosis with the rapid molecular responders having a short disease duration . In addition, a heterogeneous biology may explain these discrepancies. Several patients achieve normal blood cell counts and  still may have high JAK2V617F-allele burdens.   Studies have shown that the JAK2V617 –mutation per se may be a thrombosis promoter . Furthermore, JAK2V617F per se induces genomic instability, which implies a higher risk of disease progression. For these reasons – the JAK2V617 being both a promoter of thrombosis and a promoter of genomic instability and accordingly an “inducer” and “driver” of disease progression – the optimal agent for MPN-treatment has the potential of inducing a sustained decrease in the JAK2V617F-allele burden . This agent is interferon-alpha2 . Hydroxyurea may in a subset of patients also reduce the allele burden but this decrease has no sustained molecular impact since  the allele burden rapidly increases in concert with increasing leukocyte and platelets a few days to weeks after discontinuation of HU. Finally, a large Danish epidemiological study has shown that the JAK2V617 mutation is associated with an increased cancer risk .

PV with elevated B12. Is this a problem?

133. Norwegian woman, PV 1997, JAK Neg B12 levels 3x above normal (1265) why? On phlebs only.

CH: Elevated vitamin B12 is common in PV this will not cause you a problem. It is due to activated blood cells in PV

HH: Your B12 levels are elevated due to an increased level of the B12- binding protein in the blood . This binding protein is released from your white blood cells . Accordingly, the elevated B12-level does not reflect that you have an increased amount of B12.

Considered further response, earlier questions on CBC versus blood smear 

106. Can odd cells be detected in CBC or only blood smear. What does BMB uncover that blood smear can’t?

ORAZI: The diagnosis of all myeloid neoplasms is based on a combination of clinical and laboratory findings and not only on peripheral blood results (CBC and smear review) or bone marrow biopsy. In cases of disease progression, the bone marrow examination is often the most sensitive tool to identifies blasts which are usually much more numerous in the bone marrow than the blood. In addition, tapping the bone marrow allows to perform much more effective flow cytometry, cytogenetics and eventual additional molecular tests as required in a given case. In cases in which progression is suspected, it is also important to assess cellularity and degree of fibrosis. Those assessment require bone marrow examination.

113. BMB showed atypical megakaryocytes. High platelets. Dx ET. No AML. Am I sure I have no myeloid malignancy?

MARCH 2013

Is headache an ET symptom?

134. Are there specific criteria which would indicate that persistent head pain is an ET symptom? –NR/UK

MESA:  Headaches in a variety of manifestations can be associated with ET or the MPNs.  This can range from head pain to bone pain of the skull, migraines or migraines with visual changes such as wavy lines or parts of the vision being affected.  Now that being said, headaches are a very common condition in the general public as well so I think it needs to be discussed with your doctor whether or not this is specifically from your ET but given the prevalence of headaches in ET it is certainly likely at least possibly a contributor.  Additionally, medications for MPNs can contribute to headache as well.

SILVER: Persistent head pain is a serious symptom and of course may require neurologic evaluation. Usually, persistence of head pain is seen in patients with polycythemia vera more often than essential thrombocythemia but if the platelet count is significantly elevated, this is a possibility.  Head pain is a common symptom in the general population due to stress, muscle tension etc., so not all head pain can be attributed to myeloproliferative disease per se.  It is an important symptom which however requires evaluation.

HASSELBALCH: Headache in ET and PV is not uncommon (about 40-50 %) – indeed also in myelofibrosis (about 50 %)  . In the PV patient head pain is closely associated with a raised hematocrit and accordingly being most common at the time of diagnosis or if the elevated hematocrit is not well controlled during the course of the disease ( in women always below 0.42 and in men always below 0.45 ). Otherwise , the mechanisms accounting for headache in the MPN-patients are large unknown but  they may  likely be explained by the elevated cell counts (red cells, white blood cells (WBC) and platelets in PV patients ) and white blood cells and platelets in ET and MF ). White blood cells and platelets may  “stick together” ( making cell aggregates in the small vessels and accordingly decreased delivery of oxygen to the tissues , thereby eliciting pain in the affected organ  ). Besides venesection in the PV-patient  aspirin – in addition to being a “pain killer” – may significantly improve headache for reasons given above since aspirin immediately separates cell aggregates in the circulation with ensuing improvement of blood supply.     Importantly, however , in about 30 % of ET patients with neurological symptoms ( eg. headache, dizziness, visual disturbances ) aspirin alone does alleviate the symptoms which only vanish after reduction of WBC and platelets by eg. interferon-alpha2 or hydroxyurea.

I assume that a diagnosis of PV has been definitely excluded in your case . The distinction between ET and PV may be difficult in a subset of patients , requiring  additional investigations including an estimation of the total red cell mass. Furthermore, in some patients ET may transform into a polycythemia vera and accordingly a need of phlebotomies .Finally, rarely persistent severe headache  may be elicited by a so-called “cerebral sinus thrombosis.” As in other patients your headache may of course  be elicited by non-MPN-mechanisms ( muscular, ocular etc )

HARRISON: – No not really. This can be very tricky. One helpful thing if no other cause identified is to consider whether ET treatment makes them better e.g., aspirin (sometimes need a higher dose) or sometimes also controlling the platelet count.

Do heart and thyroid issues prevent me from taking Pegasys?

135. Can I take Pegasys if I am pre-CKD, have a heart murmur and thyroid condition?  -BA/Florida

RM: Of these three the thyroid condition potentially can be the biggest red flag for concern.  The use of Pegasys has impacted the thyroid or caused hypothyroidism in some patients.  I think the nature and the severity of each of these conditions would need to be discussed with your doctor before choosing the therapy.

RS: Hypothyroidism is not an uncommon complication of interferon therapy.  It is easily corrected with supplemental thyroid.  On the other hand hyperthyroidism represents an auto-immune disorder and in general, we do not like to give patients who develop this complication, interferon.  A heart murmur and pre-CKD is not a contra-indication per se.

 CH:   You will need close monitoring of your thyroid and kidney function. Most heart conditions are fine with Pegasys but not all. A benign heart murmur should be OK but good to have it checked out.

 HH : No problem in regard to your cardiovascular disease . However, if you have an increased thyroid function ( autoimmune disorder), I would be reluctant to start treatment with IFN-alpha2.

.

Multiple issues, warfarin, what to do?

136. Multiple symptoms – Pennsylvania PV Study Patient)..

On January 7th, after 3 weeks of my husband suffering a severe, debilitating headache, we finally got to see the neurologist, who ordered an MRI, February 4. The morning of Feb 5th, they called with the results and told us to go to the hospital where he was to be directly admitted. He has Cerebral Venous Thrombosis (left transverse sinus & sigmoid sinus thrombosis, and partial thrombosis of superior saggittal sinus). He was on an IV with Heparin for 6 days, and then on Coumadin, saying he will have to take it for the rest of his life… During his hospital stay a hematologist ordered more blood tests. She was referred by the attending doctor, because his platelet level was really high….

The hematologist said that he does have the JAK2 gene mutation and diagnosed him with Essential Thrombocythemia…,and prescribed hydroxyurea, putting him on 500 mg, saying he will have to be on that drug too for the rest of his life.. He is only 43 years old, was very active, fit and healthy…and minus the headaches, has never had any medical problems.

His has neurological defects (memory, concentration, ability to multitask and figure things out, handwriting, at times his speech is slurred or words are jumbled together) I’m guessing these  are caused by the CVT? Perhaps he has had a stroke and we aren’t aware of it? … Any thoughts you have will be greatly appreciated.  Thank you all for your time   -KU/Pennsylvania

RM:  The MPNclinic which has been put together is a wonderful resource but I don’t think it is an ideal resource for second opinions for very complex situations such as the one you mentioned.  I do think that it would be beneficial for you to see someone who specializes in MPNs so that you have a thorough understanding of the disease, the options, and feel engaged as part of the process.  I see that you are from Pennsylvania and fortunately there are multiple MPN subspecialists on the East Coast and I refer you to them and the list that they maintain regarding referral of patients for those resources.

RS:  This is a very complicated case report and should really be evaluated personally in consultation with an expert in MPNs.  It is perhaps beyond the scope of the MPN Clinic.

CH:  Warfarin is notoriously difficult, especially when you first start and some patients always are unstable on warfarin. The best protection against further clots is anticoagulation and platelet lowering drugs and the best drug proven to do this in ET is hydroxyurea. Sometimes we do use other drugs and this could be discussed along with doing a BMB in the fullness of time. It may be helpful for your husband to have a full assessment of the problems he has at the momen,t which you mention, so that a recovery programme can be planned. At the same time I would take your concerns about possible other conditions and current treatment (it may help to write a list). It is always helpful to have these out in the open and fully discussed.

 HH.  Cerebral venous thrombosis (CVT) is a rare complication in MPNs but should always be considered in a patient with persistent severe headache ( please, notice case 134). Treatment for the CVT and the MPN will be carefully monitored by your hematologist; since he is only 43 years old I would prefer cytoreductive therapy with interferon-alpha2, the aims being consistently normal leukocyte and platelet counts . In addition, a bone marrow biopsy is a normal diagnostic procedure in MPNs.

Mother transfusion dependent, anemic..HU?

137. Female, 70 transfusion dependent, anemic on HU.

My Mom who is 70 now, was diagnosed with Primary Myelofibrosisin 2010. Her only symptom at that time was anemia and was treated with Procrit (10,000 units 3 times a week ) and also Revlimid for a month. Her hemoglobin levels went up and were stable until Nov 2012. We also did a JAK2 gene test and it came back negative.

Early Nov 2012, when she had a viral fever her hgb levels dropped to 4.4. Her spleen size was 15 cm according to ultrasound & 16cm in CT scan at this time. After about 4 units of blood transfusion, she was put on Procrit (10,000 units 3 times a week ) for 4- 5 weeks and has not responded to it this time around. Since then she has been transfusion dependent mostly every 2-3 weeks, since her hemoglobin levels are dropping to 6...After one of the blood transfusions she had severe abdominal pain radiating to the shoulder….She had a splenic infarct and a low grade fever.

My mom’s hematologist back in India did not refer a splenectomy and prescribed Jakafi for her spleen enlargement.  This drug is not available in India yet and so he started her on Hydroxyurea (500mg) on alternate days and also Procrit once a week. The question I have is will Hydroxyurea help her anemia? How can we make her transfusion independent. Is hypersplenism reason for her anemia? Any suggestions/help would be greatly appreciated. SV/India 

RM: The issue of anemia in patients with myelofibrosis is very complex and it originates from several reasons–the inadequate production of red blood cells from the bone marrow, the spleen holding onto too many red blood cells, medications potentially impact on the production of red cells from the marrow.  The situation you present is complex and is best discussed with a face-to-face consultation with an MPN specialist who has had a chance to review all of the materials and have a thorough discussion with you.  In general, we would not view that hydroxyurea would be a medicine that would be likely to improve anemia; it is a medicine that primarily has been used for helping to lower elevated counts and has modest benefits for improving the size of the spleen

RS: The cause of anemia is very complex and of course any chemotherapeutic drug can cause marrow suppression.  So can hypersplenism.  This is a very complicated issue that requires thorough evaluation.

CH: Very difficult to answer your questions as this issue is complex. There are many different causes for anaemia in MF.  Hydroxyurea may be helpful as may Procrit. Actually JAK inhibitors often make anaemia a little worse.

HH: Anemia in myelofibrosis is very often complex being elicited by several mechanisms , e.g., defective production in the bone marrow due to “defective  red blood cell machinery” as part of the disease per se, bone marrow fibrosis, increased “pooling and destruction of red blood cells in the enlarged spleen, increased “plasma volume “ due to the enlarged spleen ( hemodilution of red cells ), production of antibodies against red blood cells ( autoimmune hemolytic anemia)  — and not least due to deficiency in the “building stones for red cell production (iron, folic acid and vitamin B12) . I assume that test for these deficiencies have been performed and turned out to be negative.

Then, your mother has likely defective red cell production as the most significant anemia-generating mechanism although the enlarged spleen may have a major role as well.

Danazol is a semi-synthetic androgen , which may improve anemia in about 40 % of MF-patients (TBl. Danocrine /Danol 200 mg x 3 /day) . It may improve anemia within weeks but in some patients several months (up to 3-4 (5) )  may elapse before this agent works . The mechanisms of action are complex – direct stimulating effect on red cell production but also a very potent immune-modulating, anti-inflammatory effect, which actually may be the most important. Thus, Danazol likely decreases enhanced red cell destruction in the enlarged spleen as well. In patients with type II diabetes, Danazol may improve BS-regulation. Side effects are few – in women beard growth may develop but indeed rarely; some may suffer mild headache and others leg edema. The blood pressure should be carefully monitored and liver function tests as well (the latter on average monthly or every second month ).

Prednisolone is another option – again it may improve anemia in about 40 % of MF patients. In regard to EPO I assume that a plasma erytropoietin was measured before starting EPO. A value above 250 (500 ) is unlikely to be associated with a beneficial effect of EPO. On the other hand – if the EPO-level is < 250 an increase in EPO – dosage or giving Aranesp 300 ug x 1 sc/week may improve anemia. In each case the choice should be balanced against potential side effects, including increasing spleen size during EPO-administration. Also, the potential risk of thrombosis during EPO-treatment should be considered. My advice is to discuss all these possibilities with your hematologist.

Can intense exercise use up red blood cells?

 138. Impact of exercise on RBCs.

 Here is a question I have asked my oncologist/hematologist and some exercise physiologists, without getting much of an answer. My doctor is happy that I am such good shape! This pertains to exercise (cardio) and effect on bone marrow function or RBC formation.  I am now 65 (diagnosed in 1999 at age 51 with P Vera). I have had phlebotomies every 2 – 3 months (there was a period of time earlier on that I had it more often…almost weekly) to control the hematocrit. This was successful with nothing else really needed. I was always active, working as a physical therapist, walking our lab dog almost daily, and skiing, hiking etc.

My last phlebotomy was in Sept 2009. At that time, I began a membership at my local gym for all around training (cardio and strength). After this started, I never had another phlebotomy; and my hematocrit/hemoglobin has been dropping (now around 32 and 10 respectively) since.

My bone marrow biopsy (2011) has shown no blood and fibrosis. I have been fatigued, but thought it was age, my job, etc… Sometimes, I can not complete a work out (and this is not high impact or fast paced), due to being fatigued.

Here is the question: what effect, if any, does cardio exercise or strength training have in “using up” RBCs? I can understand the bone marrow not making it fast enough due to P Vera, but does the exercise cause the RBCs to be used up more readily and now is not being replaced? …I have an enlarged spleen (2x normal) but this has not grown larger in the last 2 years. Is this (exercise) something I should not participate in as much? I want to continue being active and strong but not if it is going to accelerate the progressive rate of my disease.

I have asked a few people and tried finding some correlation on-line, but have not been successful. If you could refer me to a site, or help with my understanding, I would appreciate it.  AS/California

RM: Non-extreme exercise should not have a significant impact on blood counts one way or the other.  It can impact the hydration status of an individual and may immediately appear to create an increase in the hematocrit.  In general, exercise is considered to be an excellent resource for patients with MPNs to improve their cardiovascular health as well as to improve the strength and the function of the heart and the lungs.  In general I feel people should live out their lives as best they desire in terms of exercise and function and then we as physicians try to adjust the hematocrit or medications to best support those goals.

RS:   Cardiovascular exercise and strengthening is good for all patients in moderation depending upon the illness, degree of impairment etc.  Under normal circumstances, moderate exercise should not affect the blood count.  Repeated phlebotomies will always produce iron deficiency which will certainly have effect on exercise and even cognitive function.  There have been many studies in the literature supporting these facts.  Thus, your symptoms may be due to iron deficiency anemia, a consequence of the phlebotomy, particularly since your hemoglobin is only 10gms %.  In general, drugs such as interferon allow the correction of iron deficiency and avoid phlebotomy.  This is a typical case in which phlebotomy only, in and of itself, causes symptoms and problems.

 CH:  I am not aware of a website that would help with this. There are some conditions where extreme exercise may make you more anaemic as red cells can get destroyed by the physical activity. This however is rare. It is very important that you exercise and try to stay fit. Doing this within your own limits and gradually building up is the best plan. Exercise in this way will not worsen your condition.

HH: Exercise is wonderful – it does no harm . You should continue to exercise as usual and within your “power.”  I understand that you have been treated with phlebotomies only for your polycythemia vera . During the years your spleen has steadily increased and now being enlarged twice normal. Since your need for phlebotomies has gradually decreased and now stopped you are likely in the “transitional phase “ towards myelofibrosis. You are increasingly disease burdened , including fatigue ( and perhaps also night sweats , weight loss?). I would recommend you to ask your hematologist for yet another bone marrow biopsy, since I am convinced that you have some degree of fibrosis in your bone marrow. Since you are also anemic you may have entered the disease phase – post-polycythemia vera myelofibrosis. Accordingly, a treatment option may be JAK-inhibitor ( Jakavi).  Another option might be interferon-alpha2 if you are still in the so-called “hypercellular” MF-phase with only modest bone marrow fibrosis (connective tissue in the bone marrow). As noted in another answer above it is of course important to exclude other causes of anemia (indeed also iron deficiency in addition to deficiencies of folate and vitamin B12).

Severe erythromelalgia after switching from interferon to HU.

139. Erythomelalgia and HU 

I am a 61 yo male, diagnosed PV in 1998. For the past 10 years I have been on INF and the last year on Pegasys, 135mcg. No aspirin or other regular medications. All along, I have still been needing 6-8 phlebotomies per year. Increasing Pegasys to 180 mcg makes my platelet count fall below 80 (N: 150-400). The last 2 years, an increasingly unbearable fatigue has turned into my main complaint.

My hematologist, having ruled-out myelofibrosis and with my spleen size unchanged at 15cm, advised me to stop Pegasys and to start HU. Now, after 3 months, my fatigue has very much improved. But on HU 1000mg the platelets dropped again. So now on 500mg, and waiting.

My new problem is the following: In the past 15 years I’ve had a few episodes of erythromelalgia, sometimes on both feet, sometimes on one, often times following a transatlantic flight. Pre-flight aspirin was the solution. However,  since the change from Pegasys to HU last November and despite taking now twice daily 80 mg aspirin, I have already had 3 episodes of erythromelalgia. One episode lasted more than 2 weeks and was difficult to treat even with high doses of aspirin (1500mg daily). Also, even while on the high doses, I developed erythromelalgia in the other foot.   -EC/Amsterdam

RM:  This can be a challenging complication as you have already undoubtedly learned. Aspirin is helpful for many individuals for this indication, yet as you describe, not necessarily all individuals.  You have been both on pegylated interferon as well as high doses of aspirin without success.  Obviously the next best choice of therapy is something to be discussed between you and your physician but I do feel more aggressive control of the underlying disease would be helpful.  Pegasys is a good medication and is helpful for many but has not been completely helpful for all.  If you are still having symptoms related to the proliferative nature of the disease it is possible that the addition of Hydrea that you had may be helpful, a combination of both, or if neither are helpful perhaps alternative or clinical trial medicines would be a consideration.

RS:  Unbearable fatigue may occur with doses of Pegasys as high as 180 mcg a week and so I would agree with your hematologist to discontinue it.  Erythomelalgia in general correlates with the height of the platelet count, although not always.  One should also check for evidence of peripheral vascular diseases due to other causes such as diabetes, tobacco, etc, etc.

CH:  A difficult problem. I would want to make sure this is erythromelalgia not something like gout. Then take a good look at your labs and see what is different between HU and Pegasys.

HH. You have received IFN-alpha for the last 10 years and lately Pegasys up to 180 ug x 1 sc/week. Your fatigue may be a side effect to Pegasys since a dosage of 180 ug x 1 sc/week is rather high. Alternatively, your fatigue may reflect disease progression despite Pegasys. Since your fatigue markedly diminished after discontinuation and shift to hydroxyurea (HU)we conclude that it has been IFN-related. I have no information in regard to the efficacy of IFN-alpha2 on the JAK2V617F-allele burden in your case. In many patients it steadily decreases within the first year – in others within the first 2 years and in several it will be reduced below 10 % within 3-5 years . At that time a subset of patients need no further treatment and may be observed by serial measurements of blood counts and JAK2V617F ( about thrice yearly). When the counts begin to rise IFN-alpha2 is reinstituted. Some patients may be off therapy for several years (4 years the longest observation period ) and still with a normal bone marrow.

On HU you still suffer erythromelagia and when increasing the dosage you develop lowering of the platelet count. I would like to advise you to contact your hematologist in regard to the following options :

1. Combination therapy Pegasys ( e.g., 90 ug x 1 sc/week or 135 ug x 1 sc/week ) + HU 500 mg or 1g /daily .

2. It may be OK if the platelet count drops to about 50-80 MIA/L and the leukocyte count eg 3.0-5 MIA/L.

3. Continue with aspirin 75 mg or 150 mg/day but add a statin ( e.g., simvastatin 40 mg/day). Very often adding a statin may alleviate “aspirin-refractory” erythromelalgia being explained by the fact that statins – in addition to lowering the cholesterol – also have a very potent anti-inflammatory and anti-aggregatory potential. In addition, most recently, statins have been shown to inhibit MPN cell growth.

Transfusion dependent with MF, bad numbers, splenomegaly, hepatomegaly. Options?

140.  MF, Transfusion dependent, low numbers

Since diagnosed with Myelofibrosis (8/2012) I have had 12 blood transfusions 2 injections with Aranesp, 200mg of Danazol three times a day.  Blood lab  WBC 1.2, RBC 2.2, HGB 6.3 HCT, 19.8 PLT ,70 MCV 86, FERRITIN 1239.  Prednisone 1mg daily, Vitamin B12 1mg daily.

The spleen and liver are enlarged. No changes for two months.  What needs to be done and what can I do?   Please help.  -BV/US

RM:   Again a complex situation that is not best handled through this forum to give you a precise recommendation.  The challenges you face are a difficult set of circumstances with both low platelets and anemia in the setting of myelofibrosis.  I do think visiting with an MPN specialist to best look at therapeutic options and if these options are not being helpful to consider clinical trials could be most beneficial.

RS: Anemia in patients who are transfusion dependent has multiple causes.  This is a very complicated issue and at the very least another bone marrow should be performed.  It is best to consult an MPN expert for a complete review.

CH:  There are a number of other options for managing your anaemia which should be discussed. These include drugs like lenalidomide, revlimid, thalisomide, perhaps a trial with CYT387 or consider another JAK inhibitor or removal of spleen.

HH: Please, read my answer to 137; 2 injections with Aranesp is too early to assess efficacy. I assume that you receive 300 ug x 1 sc/week . Prednisolone 1 mg  may be a misspelling ( 10 mg ?) .

You receive vitamin B12 due to a proven vitamin B12 deficiency; I assume that deficiency of folate has been excluded.

My advice is to continue treatment for additional 2-3 months; if no change at all then you discontinue Aranesp and Danazol . Prednisolone should be given in an adequate dosage – a subset of patients may benefit from Tbl Dexamethason 40 mg/day for 4 days being repeated every 28 days for 3-4 cycles. Another option might be combination therapy with Tbl. Thalidomide 50 mg + Prednisolone . This combination therapy improves anemia in about 40 % of the patienyts and your platelet count may likely increase as well (above 100).  Finally – since you have enlargement of the spleen and likely  suffering massive fatigue you may be candidate for treatment with JAK-2 inhibitor (Jakavi) .

What happens to the spleen and its contents after splenomegaly?

141.  When Jakafi shrinks a big spleen where does all that extra red, white and blue pulp in the big spleen go when in addition to doing its usual jobs it took on the extra work of making blood from a fibrotic marrow?  …to the liver?  back to the marrow? to some long forgotten embryonic marrow bone? or does it just disappear,  dissolved or swallowed up by hungry phagocytes? And another thing. What about that big spleen’s stretched capsule?   When the spleen shrinks, does the capsule become rough and wrinkled and look like my skin  –a little less than baby-smooth?-AM/Florida

ORAZI:   Ruxolitinib  may provide temporary relief of PMF-associated splenomegaly, but it is not curative in any way  due to its a lack of efficacy in reducing mutant clones or improve patient survival. Unfortunately, there are no data in relation to spleen pathology changes in patients treated with this or other type of  inhibitors. Most investigators feel that the splenic reduction effect may be secondary to a JAK2 inhibitor associated suppressive action on cytokines or other “inflammatory mediators.”

Recently, in a mouse model reduction of extramedullary hematopoiesis, the pathological hallmark of PMF was obtained with a newer small molecule inhibitor called G6.  In this particular mouse model, histopathologic examination of bone marrow and spleen were performed. They showed a convincing response with markedly decreased marrow fibrosis and reduction in the degree of splenic extramedullary hematopoiesis, both the sine qua non of PMF. For further information please read:  http://www.ncbi.nlm.nih.gov/pubmed/22796437. So the search is still on and the possibility of restoring the splenic red pulp to its previously normal state seems  a real one. Coming to your other questions, the spleen is very effective in recycling due its very high content in histiocytes/macrophages coupled with high blood flow and lymphatic drainage. Once splenomegaly decreases or disappears, the capsule will adapt due to its plasticity and capability for structural remodeling.

 

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APRIL 2013

Comments on: "Six Clinics — The Index Project" (6)

  1. Dr Silver:

    In general, the development of myelofibrosis occurs 8 to 10 years after the diagnosis of PV in patients who do not receive specific myelosuppressive therapy. It is for this reason that some of us believe that interferon is the drug of choice in patients with significant phlebotomy requirements from the onset. Patients with PV who have residual hematopoietic tissue and who have fibrosis in the marrow do respond to interferon and so these patients should be considered, in my opinion, with interferon therapy i.e. in Pegasys or interferon alpha 2b.

    SPOT ON IN MY CASE> UNFORTUNATELY I WAS NEVER OFFERED IFN AND IT WAS DISMISSED WHENEVER I BROUGHT IT UP>

  2. david l sorrell said:

    I was diagnosed with PV in about 2006. Have been through warfarin, phlebotomies, aspirin, e.t.c. Have we come any closer to concluding that agent orange is likely causal for this terrible disease? The VA states there is no proof of that and will not place it on the ‘known disease’ list.
    thank you

  3. Trudy Cuffe said:

    Cyclophosphamide is a drug my doctor is trying me on for PV read about it scares me does anybody know about its use?? Thank you

  4. Kathy Van Meter said:

    I sent an e-mail to MPNclinic@gmail.com with my question and also read all the clinic questions/answers. Very helpful!

  5. I read here to take Jakafi twice a day. After 6 weeks of being on 20mg twice a day, my Dr. told me to just take one. What should I do?

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