MPNforum Magazine

(Questions? MPNclinic@gmail.com)

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

Prior Clinics:

September, 2012– October, 2012-   November, 2012–  January, 2013 – February, 2013

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.

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.

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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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