MPNforum Magazine

The MPNclinic Patient Roundtable

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The MPNclinic is an MPN community service of MPNforum Magazine and participating physicians.  The purpose is to provide deeply experienced insights into the nature of MPNs, developing science, diagnostics, and therapeutic interventions.  The next MPNclinic Patient Roundtable will focus on Clinical Trials.   Your questions designed to explore that subject are welcome. Please send inquiries and questions for the panel  to:  MPNclinic@gmail.com.

     Zhenya Senyak, Director                                             Mary Morochnick, Patient Coordinator

 

The MPNclinic, March 2014: 

CH: Claire Harrison, Guy’s & St. Thomas’;  HH: Hans Hasselbalch, Roskilde Hospital;   RL: Ross Levine, Sloan-Kettering;   RM: Reuben Mesa, Mayo Clinic;   RS: Richard Silver, Weill-Cornell;   DS: David Steensma, Dana-Farber;   MT: Moshe Talpaz, University of Michigan;   SV: Srdan Verstovsek, M.D. Anderson

 

142

Is Pegasys safe to use after a heart attack?

SS – My husband is 39, diagnosed with PV four years ago. He’s been on hydroxyurea and phlebotomies. Two months ago he had the widow maker heart attack, blocked 95 percent. Is it safe for him to go on Pegasys interferon shots?  Thank you!

SV: I am not aware of contraindication for use of pegasys in this setting.

MT – Interferon may have multiple metabolic effects including effects on blood lipids. As it is not a critical treatment for PV, I would rather continue with Hydroxyurea.

RS –  Interferon can very rarely cause direct myocarditis and pericarditis. We have used Pegasys in patients with arteriosclerotic heart disease with the appropriate monitoring.  It seems to me that that at age 39, very strict attention should be directed towards monitoring his cholesterol problem if one exists since the risk of significant heart disease is more significant than the selection of Pegasy or not.  This is a complicated issue and requires thorough evaluation and collaboration between a knowledgeable cardiologist and hematologist. 

CH –  Usually I wait for a period of at least 3-6 months. Other issues, if present, also need to be considered, e.g. history of depression, thyroid etc.

RM– Although it is impossible to say by a written question such as this, whether interferon is an appropriate medication for your husband, I would say that this is best held as a discussion directly with his physicians.  As a general concept what things lead us to be concerned about the use of pegylated interferon is clearly individualized but the main areas of concern one has with the use of pegylated interferon would be potentially if there was significant psychiatric problems from the past, autoimmune diseases, inflammatory disorders, or any strong allergy to interferon.

HH – No problem , cardiovascular disease is  common in patients with PV and is not a contraindication for using IFN.

143    

Interferon and PV – the debate

DH- There have been a number of articles by MDs and researchers saying that Interferon, properly dosed and administered soon after PV diagnosis, can lead to “molecular remission” of PV. However, it seems that, in the U.S., anyway, most hematologists and oncologists are sticking with  the long-used phleb-and-monitor approach, turning to drug intervention only when symptoms and blood levels change.

Is early INF inappropriate for some PV patients, such as so-called low-risk patients?  Why do some doctors and researchers believe that the pro-Interferon research is still inadequate?

I believe many PV patients are in the same situation I am: Our doctors are wonderful, but they are in the phleb-and-monitor school…I feel as though I don’t have enough information to have an intelligent conversation with my hem/onc about this subject.

SV: Standard practice is to use medications (hydrea, interferon) in patients with high risk disease for thrombosis. Use of interferon in low-risk patients is open to debate and opinions differ, exactly as described in the question, due to inconclusive data. I don’t think we have a way of resolving this, unfortunately, unless we all engage in a large prospective randomized trial of interferon vs. observation in low risk patients.

RS- The issue of interferon versus phlebotomy has been addressed many times in this column and in the literature.  DB is advised to read the review of this subject by Silver, Kiladjian and Hasselbalch in Expert Reviews of Hematology (Silver RT, Kiladjian JJ, Hasselbalch HC. Interferon and the treatment of polycythemia vera, essential thrombocythemia and myelofibrosis. Expert Rev Hematol. 2013 6(1):49-58).  We believe that unopposed phlebotomy is ill-advised in the majority of patients with PV since it leaves most with the development of significant iron deficiency anemia and earlier development of myelofibrosis.  This was first noted by Najean, the famous French expert on polycythemia vera, more than 25 years ago.

CH –  I think it is a question of balancing risks and benefits. IFN is a great drug but also a drug associated with side effects and not all patients will enter a remission. So its a question of reaching a mutually agreed decision.

RM – At this point there is not conclusive proof as to which therapy should be the preferred therapy for patients with P Vera.  There are good cases to be made for interferon in some individuals; there are cases to be made for hydroxyurea, but at the current time there is a randomized trial comparing these two medicines in newly diagnosed, high risk patients with PV and ET through the MPD Research Consortium.  These data directly comparing the therapies will be very helpful to try to both judge which therapy is the best and to help to make a more convincing case for physicians, one way or the other, which medication would be best to consider.

HH – Interferon is very efficacious in ET, PV and hyperproliferative MF.  Several studies have shown that IFN normalises elevated blood counts within weeks/months . Some PV patients may still need phlebotomies after the first year but the need is steadily declining already within the first year.  If the JAK2V617F-allele burden is monitored  a decline will be recorded in most patients within the first 6-12 months albeit the molecular response may be heterogenous with a significant reduction in JAK2V617F in the second year only.

The reasons for the different molecular response patterns on IFN is unknown but among others may be explained by the duration of the disease before starting IFN or the lack of response may be explained by additional mutations or an advanced PV stage , in which IFN may “work up hill”  . In Denmark most hematologists start IFN upfront at the time of diagnosis in the large majority of patients as part of a multicenter study in which all newly diagnosed patients are randomized between Pegasys vs PegIntron ( < 60 years ) and above 60 years an additional HU- arm is included. However, off-protocol patients are also treated as early as possible with IFN at most centres.

This “early intervention concept “ is based upon several recent studies  and reviews, which argue for early treatment of a cancer to prohibit cancer progression from early stage cancer stage ( ET/PV) to the advanced cancer stage, myelofibrosis stage, when it is very difficult to revert the disease progress unless a  SCT is an option. The observations that long-term treatment with IFN in PV ( > 5-7 years ) may be associated with normalisation of the bone marrow in a subset of patients – even being sustained for up to 5 years off IFN is supportive of the early intervention concept. Thus, such a successful outcome is likely easier to obtain if treatment  with IFN is started as early as possible. If PV is treated with phlebotomies and aspirin only there is a definite risk of thrombosis  or bleeding ( due to leukocytosis and thrombocytosis ) , since leukocytosis per se is a thrombogenic factor ( also in the general population ) and the JAK2V617F mutation per se is thrombogenic as well.  

To this end without other treatment ( interferon) the clone  will steadily expand and  the JAK2V617F burden will steadily increase , inducing – in addition to an additional risk of thrombosis as outlined above –  increasing genomic instability  as well with increased risk of additional  mutations, subclone formation, resistance to treatment and ultimately myelofibrotic and leukemic transformation.

144

Post Sanofi, Jakafi not working second time around. Increase dosage?

DB – I was on Jakafi in clinical trial for 27 months mostly at 15 mg twice a day..  When my spleen started to enlarge (21 cm) and HGB wouldn’t hold when dose was increased, I dropped out of trial and was on the Sanofi trial for 6 mos until it was halted in Nov 2013.  I went back on Jakafi Dec 1st, 2013.  After 5 weeks, bone pain, mild to moderate itching & occasional night sweats are back.  Is it normal to not work very long the 2nd time around?  My HGB has been better this time, (10.9) but PLTs dropped 100,000 in 5 weeks to 120,000.  Current dose 15 mg twice a day.  When I was on 20 mg twice a day the 1st round, my HGB wouldn’t hold.  Do we dare increase it again with the PLTs dropping so quickly?  Any suggestions?  There are no open MF trials in my area at this time.

SV – Increasing the dose of adding another medication to it may help. For example, adding danazol, thalidomide or hydrea may help. We used to treat patients with a combination of agents in the past, why not now? There are also trials for patients on Jakafi, where investigational agent is added to it.

RS-  This is a complicated clinical situation and must be reviewed in detail by an expert in the use of JAKAFI of which there are many now around the country.

MT – I suspect that by now the disease is resistant to Jakafi, although we do not understand well what are the mechanisms of resistance, and whether it is a complete or partial resistance.  I am in favor of testing those escalations to see if it provides any benefit.

CH – There is data that Jakafi does work second time around, perhaps you need to consider a dose increase as you suggest.

HH– My advice is to address your questions to your hematologist – too complicated to advise you in this MPNclinic.

RM – The MPN Clinic is really not the best format to recommend specific medications or dosages.  I will say in general terms that the dose of ruxolitinib: 1) in general, we have found this to be titrated to an individual dose; 2) that it typically takes anywhere from 2-6 months for the blood counts to stabilize after the initiation of ruxolitinib.

145

Interferon holiday

RW- Many years ago, Dr. Harriet Gilbert suggested that Interferon could be discontinued for a period of time for treatment of PV. Anecdotal reports suggested that when patients needed to resume interferon, after “honeymoon” from use, a higher dose of interferon was necessary  to control disease than for original regimen.  The French, apparently, frequently take their patients off interferon, when they have gone into “remission”.

Do you recommend a holiday from interferon, when patient has been on low dose (2 million units 3X per week) for several years and counts have been stable. In other words, are their long term effects of interferon (other than depression for some users) that suggests benefit from discontinuing use. What are the long term negative side effects of low dose interferon usage.

RS- Dr. Harriet Gilbert, an old former colleague, and I discontinued interferon in patients who had been in remission for a good number of years.  However, the risk of relapse means that one will have to be phlebotomized again and re-induced into remission.  Obviously, specific recommendation can’t be made unless your case has been reviewed in detail.

SV- In our practice we would not interrupt therapy with interferon, but continue the lowest effective dose for as long as safe.

CH – In my experience the side effects of interferon are the same but less common and less intense with lower doses. In my practice I gradually reduce the dose of IFN and offer a drug holiday if the patient wants to try.

RM – Many questions remain regarding interferon, specifically around the duration of therapy, long term maintenance, and what really is the endpoint of therapy.  It is a very helpful therapy for many but whether indefinite maintenance or a holiday is helpful I would say is something that we truly do not have enough information around to know for certain.

HH– When patients have been treated for several years with IFN –about 5 years – some have achieved “minimal residual disease “ as described in my answer above (Question 143). As part of “Good Clinical Practice” in our clinic a bone marrow biopsy is performed to assess , if the bone marrow architecture has normalised  – to obtain a status on the impact of therapy. If the bone marrow has normalised or if only minor MPN-changes left IFN-treatment may be discontinued for years ( up to 5 being the longest recorded IFN-pause in our clinic ). Importantly , however, treatment may also be discontinued for long periods  ( 6-8-(12) mo in patients still displaying MPN-features in the bone marrow  and in those not having a bone marrow biopsy but have been in complete hematological remissions for several years. In such patients discontinuation of IFN  may also be followed by long periods ( holidays ) of several months off IFN

146

Post-phlebotomy scarring. Any alternative to port or ultrasound?

KP – 55 yrs old. PV JAK2 + dx 9 yrs ago.  Rx: Phlebotomy avg 6/yr, aspirin, bp meds. After yrs of phlebotomy  scarring is an issue. One place refused treatment unless I got a port, but i refused. Now I go to a place that will use ultrasound to find deeper veins but that is not always available. What are your thoughts on using ports, ultrasound, or consideration for next line of treatment?

RS –  You can try applying heat to the veins prior to phlebotomy.  I have not used ultrasound to locate veins.  Clearly, the success of phlebotomy depends on the skill of the phlebotomist.  In general, we do not like to use ports because that introduces a foreign body and there is always the risk of complications, particularly infection.  

SV – Difficulty in performing phlebotomy is sometimes considered to be an indication for starting cytoreductive therapy (hydrea, interferon), in order to eliminate a need for phlebotomy

CH –  We use the ultrasound successfully in many patients, a port could also be useful but carries its own risk. We also sometimes use drugs like IFN or HU if venesection is difficult.

RM-  The need for continued blood draws or transfusions can be very hard on the veins in the arms which are utilized.  Indeed, for this reason, a port sometimes can be a helpful consideration; however, any long term central access such as a port does carry with it risks.  There are several alternatives and I would advise you to speak with your team or seek a different team if only one option is being presented.

HH– As described above IFN is certainly an option .  If IFN is not tolerated imatinib may be another option.  Several studies have been published, the largest by Silver et al.   One of the most striking and consistent effects  of IFN in PV was a definite decline in the need of phlebotomies in some patients ,  whereas the impact upon the leukocyte and platelet counts was more unpredictable.

147

What’s the effect of anemia on PV

CI– I have both PV and Pernicious Anemia.  What effect would the anemia have on PV. My recent CBC:   RBC 4.16- HGB 14.2- HCT 41.7-MCV 100.1 At Diagnosis  Dec 2010: RBC 2.69- HGB 11.1- HCT- 31.7 MCV- 17.8

DS – With a hemoglobin of 14.2 g/dL, you are no longer considered anemic.  Perhaps at the time of initial diagnosis in 2010, you were iron deficient or there was another cause of anemia.  This is unlikely to have a significant effect on how the PV evolves.

RS-  The association of PV and pernicious anemia has been reported in literature

SV- Having hematocrit below 45 is the goal of therapy in PV. If pernicious anemia provides that, I think you should be OK if we talk only about controlling red blood cells count.

CH – If your pernicious anaemia is well treated no effect on PV.

HH -PV and other MPNs may carry an increased risk of autoimmune diseases , including pernicious anemia, which requires life-long substitution therapy with vitamin B12.

148

Are MPNs hereditary?

KG– Here is my question: Are MPNs hereditary or is a tendency towards getting them hereditary?

DS –There are familial forms of MPN, and several investigators are actively working to understand the genetic basis of these conditions.  For instance, there is an inborn genotype, JAK2 haplotype “46/1,” that is present in healthy people that slightly increases the risk of developing an MPN.  There are clearly other inborn predispositions that are less well characterized.  However, most MPN do not run in families and the vast majority of people with MPN do not have a relative with an MPN.

RS – As listed, there is no direct inheritance, but a weak link existence we are aware of in the “myeloproliferative families.”

SV -There is a predisposition for developing MPN that runs in families.

CH – You are correct that there appears to be a weak inherited risk of MPN. I think the two halves of your question mean the same thing.

RM- Most accurately some patients with myeloproliferative neoplasms do have a family history.  At this point the most accurate statement we can make is that a subset of patients with MPNs does have other afflicted family members.  We do not believe that this is the case in all individuals.  In the end there likely are two groups:  1) a group of individuals that have a familial predisposition; 2) in which the MPN truly has come out of the blue or is sporadic.  It is difficult to know the exact percentage of who falls into which group.

RL – There is an increased risk of MPNs in first-degree relatives of patients with MPNs, but that risk is still low (4-5 fold higher than the normal risk which is 1/100,000 according to some estimates).  We are all working to figure out why this is, but given the risk is still low it does not impact clinical care or how I would care for the family member of a MPN patient.

HH – Rare cases of MPNs cluster in families – this has been known for decades but most recently a large epidemiological Swedish study has shown that “It is in the Family “  in a subset of patients. Inheritance of  MPNs has recently been reviewed : Ranjan A, Penninga E, Jelsig AM, Hasselbalch HC, Bjerrum OW. Inheritance of the chronic myeloproliferative neoplasms. A systematic review. Clin Genet. 2013 Feb;83(2):99-107.

149

PV treatment for juveniles

RB- As the parent of a 15 year old boy recently diagnosed with PV in August 2013, how would treatment for him differ from treatment for an adult recently diagnosed with PV?

DS – Treatment of adolescents with PV follows the same principles as for adults: phlebotomy to maintain a hematocrit within the goal range is essential; aspirin may help prevent clots and relieve certain symptoms; and hydroxyurea or other cytoreductive therapy is considered for higher-risk patients who have had a clot already.  Because adolescents have many years to live, it is more likely for them than for older adults that treatment approaches will change and improve during their lifetime, and also there is more time for their disease to potentially evolve into fibrotic spent phase where stem cell transplantation or another approach may be a consideration.

SC- It would not differ in our practice.

CH – Sorry to hear about your son. He is young and therefore has a younger set of blood vessels his risk of developing blood clot is perhaps less. This means often we are less likely to use drugs to lower his blood counts unless these are very high or he has other worrying symptoms. Secondly if we use drugs our choice is likely slightly different for a younger patient. In my practice I would tend to use aspirin and venesection but if I need to use a drug I would consider IFN. Third having a 15 year old myself I am aware of the emotional side of his age which will need to be nurtured at this difficult time. You are clearly already doing this but there are specialist facilities likely available to him too.

HH- No difference – IFN is the drug of choice.

150

Can carbon monoxide cause PV?

RJ– Can PV be caused by carbon monoxide Poisoning? I had long term exposure and then the water heater busted and carbon on top of it and my RBC’S are still messed upband so are my WBC’s

 

DS-  Carbon monoxide exposure can cause erythrocytosis (red cell elevation) by interfering with oxygenation, but not polycythemia vera. If a JAK2 mutation is present, that is likely to be PV and not carbon monoxide related.

SV- I am not aware of the connection between the two

RS- Carbon monoxide can cause erythrocytosis, but it cannot cause polycythemia vera.

CH – Not as far as I am aware but carbon monoxide poisoning can mimic PV.

HH – To the best of my knowledge – no

CH=Claire Harrison;  HH= Hans Hasselbalch;   RL= Ross Levine;   RM= Reuben Mesa;   RS= Richard Silver;   DS=David Steensma;   MT= Moshe Talpaz;   SV= Srdan Verstovsek;

151

Is it cancer or not?

LH- As a PV patient and member of many MPN support groups, I’ve watched many of us struggle with the question:  “Is it cancer?”  Then the question:  “Why is it cancer?”   And if it’s cancer, can it metastasize?  I’ve found no writings that contain a layperson’s simple explanation or answer. The folk history goes something like: “In 2008, the WHO classified these diseases as neoplasms…” and the conflicting opinions go from there.

DS – This is somewhat of a semantic issue: there are ways in which PV is like “cancer” and ways in which it is not.  Cancer is surprisingly difficult to define, and this confusion arises for other disorders such as myelodysplastic syndromes, colon polyps, high-grade cervical dysplasia, and “monoclonal gammopathy of undetermined significance.” PV is classified as cancer by the WHO because it is a clonal disorder (i.e., the blood cells in patients with PV are mostly copies of each other, rather than the normal more diverse repertoire), acquired DNA mutations in genes such as JAK2 are present that drive the process, and there is a tendency for PV to be unstable and to evolve over time into myelofibrosis or AML as additional DNA mutations are acquired.  Clonality, DNA mutations, and instability are hallmarks of cancer.  However, unlike the solid tumors that people commonly think of as “cancer” (e.g. breast, lung, colorectal), PV does not metastasize, and, if treated properly, is associated with a very long survival – many years. 

RS – By definition, this is not a cancer such as cancer of the lung, breast, prostate or colon.  However, the myeloproliferative neoplasms by definition represent uncontrolled growth. On  the other hand, the connotation should not frighten patients since there are so many ways we can address the issues regarding treatment.

SV- If we define a cancer as uncontrolled growth of abnormal (neoplastic) cells (certainly open to a debate) then PV is a cancer. It is considered benign cancer, however.  I frequently make a parallel to skin cancer where basal cell cancer is benign and can easily be dealt with in great majority of patients, while melanoma is the deadly one. So PV might be considered like basal cell cancer.

CH – Biologically speaking it is a cancer yes. We do not use the term metastasize for MPN however.

RM- In the strictest sense of the word myeloproliferative neoplasms are a type of cancer.  However, even with the word cancer it depends on how one defines it.  Myeloproliferative neoplasms are not the equivalent of having breast cancer or brain cancer or pancreatic cancer.  However, we do know that individuals with advanced myeloproliferative neoplasms, advanced myelofibrosis or those who have changed to acute leukemia have diseases that are just as serious as any cancer which can arise from a solid organ.  The word cancer is incredibly emotionally charged and hence so much controversy over whether or not to use this label.  Without question the myeloproliferative neoplasms are clonal diseases and by that strictest definition of cancer or cancer of the blood, such as leukemia, they do fit in this category.  However, using that term in no way makes them any more serious or any less serious.  I advise my patients that if it is beneficial for them to use the word in terms of explaining the disease, then it is perfectly fine, but not to view the diagnosis of ET or PV in particular as being anywhere near synonymous with the serious implications of having a solid tumor malignancy, such as a prostate cancer or colorectal cancer.

HH- PV is classified as a cancer defined by uncontrolled “autonomous” growth of myeloid cells. After several years PV may transform into post – PV myelofibrosis which is characterized by enlargement of the spleen – often massive. Hopefully, the  progression of PV to myelofibrosis may be prohibited by early treatment with interferon – a concept , which has been described in several reviews in recent years.

RL – The current definition of neoplasm is a disease caused by acquired changes in DNA (mutations), which has a growth advantage over normal cells. By that definition MPNs are neoplasms.  That being said, they do not metastasize, or progress the same way some other cancers do.

152

Anagrelide and tingling in the extremities

GF- Three years ago I was diagnosed with ET and put on hydrea. After a year I began to experience tingling in the extremities. Eventually, I was switched to anagrelide, but though gabapentin has afforded some relief, the cause of the tingling has yet to be found. I’ve had two MRIs, three EMGs of my legs and two of my arms, the small fiber neuropathy test and blood work twice. All have come back negative. Aspirin doesn’t seem to help… and twenty treatments of the electric current/local anesthetic combination treatment ultimately did next to nothing. Since the switch to anagrelide a little over a year ago, my platelet numbers have stayed in the mid to high 300 range. Is there any other test or anything else I could try, to alleviate this symptom? Thank you.

RS – This situation should be evaluated by a neurologist, which I presume has since you have had MRIs etc.  It is unusual to have these symptoms associated with anagrelide or HU but it should be evaluated clinically.  These are difficult questions to answer and we can only give indirect opinions.

SV- Tough situation, best evaluated in clinical setting by expert neurologist.

CH – I am aware that HU can be associated with some of these symptoms but likely this is not related to drugs or your MPN.

HH – “Tingling “ of the extremities may have several explanations and require several different investigations which have also been performed in your situation. I assume that vitamin B12 deficiency, diabetes mellitus and disturbances in calcium and magnesium homeostasis have been excluded as well. Finally , left without any obvious reason I have experienced a patient  with “tingling,”  which actually had iron deficiency and the “tingling” disappeared after iron substitution. Accordingly, if you have not been screened for iron deficiency (low plasma ferritin ) this is recommended.

153

JAK-STAT pathway and combo therapy

RM– JAK2 continues to be an important therapeutic target.  However, since the mutated clone persists with a JAK inhibitor alone I am wondering what you think the future is for trials that also target proteins in that pathway such as PU-H71(HSP-90 inhibitor) + JAK inhibitor, or Panobinostat (HDAC inhibitor) + JAK inhibitor, and others?  Do you believe these combination therapies have potential efficacy in halting or reversing the disease without severe adverse events?  Are you interested in pursuing these therapies in your practices?

DS – Combination therapy is of great interest in MPN and many trials are going on right now with JAK2 inhibitors plus other agents.  It is too early to say what the effectiveness is going to be.

SV- Yes, this is where the MPN field is going, combination studies. There are a number of such studies underway.

HH –Several combination studies are ongoing , including those that you mention. In addition studies on combination therapy  interferon + JAK1-2 inhibitor  will  soon be launched.

CH – Yes I recruit patients into these trials since I believe that they offer a way forward to achieving better control of disease and hopefully a cure.

RM-  At the current time there are many different combination therapies which are being investigated.  Most accurately, as a medical community we do not know which combination will be the most helpful or truly we don’t know whether the addition of another drug to JAK2 inhibition will be superior to JAK2 inhibition alone.  With this there are many additional pathways that are trying to be inhibited in parallel with JAK2.  Panobinostat is one of those pathway inhibitor drugs and there are multiple others which are ongoing at the moment.  Most accurately, it is too early to know which of these combinations might be helpful but we await the results of these trials with great interest.  These clinical trials are for appropriate patients and are a reasonable consideration as long as they recognize that it is not yet proven that combination therapy with a JAK2 inhibitor will be superior to single agent therapy.

CH: Claire Harrison;  HH: Hans Hasselbalch;   RL: Ross Levine;   RM: Reuben Mesa;   RS: Richard Silver;   DS: David Steensma;   MT: Moshe Talpaz;   SV: Srdan Verstovsek

154

RA and PV – is interferon possible?

MS– Is Interferon a viable treatment option for a high risk PV patient who also has a 30 year history of Rheumatoid Arthritis (past 10 years on the TNF-a inhibitor, Enbrel)?   What, if any, is the consequence of having two diseases that each utilize JAK-STAT pathways? Thank you for your response.  

SV- Using JAK inhibitor in this setting may be clinically prudent. There is one approved for RA, I believe.

CH – I think it is viable. It would however required careful evaluation and monitoring.

HH – Interferon is an option – RA is not a contraindication for using IFN . However, a subset of patients experiences  joint pains during IFN and some also develop an RA-like clinical picture including swelling of finger  joints. In such cases IFN has to be withdrawn and glucocorticoid treatment given for a short period of time. It has been discussed whether  those patients developing joint pain etc during IFN therapy have a particular “tissue type” or propensity to develop “autoimmune disease” – this has to be investigated in  a larger series of patients. Studies of ruxolitinib in high risk PV patients are ongoing and very promising results have been published so far.

Most likely, inflammation-mediated diseases in MPN-patients may also improve during ruxolitinib treatment. Actually, you may be a candidate for ruxolitinib treatment, which may both improve your PV and RA as well. It is a clinical experience that e.g., psoriasis, arthritis and skin lesions dramatically improve after a few days treatment with ruxolitinib.This issue – and the rationale for combination therapy with IFN and a JAK-inhibitor  has most recently been described in greater detail  (Hasselbalch HC. Perspectives on the impact of JAK-inhibitor therapy upon inflammation-mediated comorbidities in myelofibrosis and related neoplasms.  Expert Rev Hematol. 2014 Feb 13. [Epub ahead of print])

RS – In general, we have not used interferon in patients with rheumatoid arthritis or any other autoimmune disease.  In fact, a side effect of interferon is an autoimmune disease including hemolytic anemia.  I would favor treatment with HU or a JAK inhibitor if this is clinically indicated in a high risk patient, particularly in the older age group.

155

How safe is hydroxyurea for a PV patient with co-morbidities?

ML– What is your opinion on safety of hydroxyurea for a PV patient with a previous history of long term treatment with low dose methotrexate and two incidents of tumor based cancers plus a familial history of various cancers?

RS –  Hydroxyurea is a potent medication as anyone can learn from reading the PDR or the black box warning associated with its use like any other potent medication.  This must be discussed in relation to the disease being treated and in consultation with your physician.

SV: Interferon might be a better choice in this setting.

CH – I would pursue other therapies probably before HU but it would depend a lot on individual circumstance.

HH –A difficult question – no definite answer can be given. However, concern exists in regard to the potential leukemogenicity of hydroxyurea  (HU) after several years of drug exposure ( above 10-15 years ). Indeed, this issue is  very controversial since  “high scientific evidence “ for the leukemogenic potential of HU and its potential role as a tumor promoter as well is lacking. This level of evidence is only achieved in a large randomized study with drug exposure above 10-15 years. Such a study will likely never be performed, unless the MPN-Consortium Study, randomizing high risk patients between Pegasys and HU, is following their patient cohort for such a long period.

However, concern exists about exposing patients long-term for HU, since studies by the French group (Kiladjian et al ) have shown that after 10 years on HU treatment about 10% may develop acute myeloid leukemia, after 15 years 15% and after 20 years of HU exposure approximately 20%.

157

Slight increase in spleen, stable on Pegasys. What to do?

KV – I have been on Pegasys for a total of 2.5 years, with a 6 mo. drug holiday, back on 5 mos. ago at 90mcg weekly. I have never experienced side effects with Peg, even at 180mcg.  BMB looked good when I came off Peg, CBC’s are all good. In 2010 my spleen measured 11 cm. Had an ultrasound in 11/14 and measurement was 14. Should I be concerned?

RS – The decision to discontinue Pegasys or other forms of interferon is a judgmental decision made based upon many other factors besides spleen size alone.  In general, I do not discontinue treatment before 5 years of therapy since as I have indicated previously, early discontinuation tends to be associated with early relapse.  However, many factors go into the decision and this must be discussed between the patient and his/her physician. 

SV: following a trend in change over time is prudent. spleen may decrease now that you are back on Pegasys. I am not concerned.

HH: As noted previously patients need IFN for an extended period of time – at least 5 years. If treated only 2-3 years some relapse already after a few months . Although we have no data from larger series of patients treated long term ( > 5 years ) and having discontinued IFN, it is a clinical experience that at least 5 years IFN exposure is needed. If your blood counts are all normal  – do not worry – continue IFN and your spleen will likely not further enlarge but diminish instead.

CH – I would monitor this. Naturally it is a worry but is something that could probably safely be monitored for now provided blood counts and everything else is OK.

RM-  It is difficult to advise in this format how to proceed with your disease.  I would say in general, in terms of monitoring the impact of pegylated interferon alpha, the main purposes are several:  to try to control the counts; to try to decrease the risk of a blood clotting or bleeding event; and to try to delay progression.  What is the appropriate time to change to another therapy would depend if the medicine had failed in any of these three regards or whether another therapy was more appropriate.

158

Rutin pill relevant to MPNs?

CW:  In late November of 2010, I heard about a rutin pill — being developed by a team of Harvard doctors —   to prevent and treat strokes, heart attacks, DVT’s and pulmonary embolism.  If any of you know more about this, and think it would have relevance to our world of MPN, please let us know.

DS –  Rutin, also known as quercetin, is a flavonoid found in black tea and various plant products such as buckwheat.  It has diverse biological effects including an effect on platelet aggregation, inhibition of inflammation, and inhibition of angiogenesis.  It has not been studied in MPN and thus far studies in other conditions have not shown clear benefit.  With natural products it is often challenging to obtain a preparation with consistent dose and biological effect.

159

PV with rising white counts.  Is this normal?

KB – I am concerned about my increasing WBC and neutrophil levels. In April they were 14 and 12, respectively. In December they were 22.5 and 20, respectively.

I underwent many tests attempting to resolve other symptoms that might be the cause ordered by an infectious disease doc. I was informed no infection was found although my hematologist said might need another BMB.  Are these high levels typical with PV or do they give rise to other concerns since the other counts seem stable?

RS – An increase in white blood cell count is characteristic with patients with PV reflecting hyperactivity of the bone marrow.  However, as all of us on the panel have indicated, we simply cannot look at one parameter and make a judgmental decision.  The rising white blood cell count must be considered together with other parameters of the disease, including hematocrit, spleen size, bone marrow, etc, etc, etc. 

SV: some patient experience an increase in WBC over time. Following a change over longer period of time is prudent, and seeing whether there will be any other change along the way. On its own, presented change is not alarming in my mind

CH –  The rising counts are likely to reflect the PV but it is wise to have had other tests to exclude other issues.

HH – Rising cell counts in PV are a reflection of PV disease activity provided that infectious, inflammatory ( eg connective tissue disease ) or another neoplasia can be ruled out. Most likely . the elevated leukocyte counts in your situation – with eg otherwise normal tests  I suppose – actually depict PV-activity and should be treated . Thus, an elevated white blood cell count per se is a risk for thrombosis in MPNs. I agree with your hematologist that a BMB is needed and  an abdominal UL may be relevant as well to assess spleen size before cytoreductive treatment is instituted

RM —  Trying to answer this in a more general way, all of the myeloproliferate neoplasms can be associated with an increase in the white count.  In general, white counts of over 15,000 with ET, PV or myelofibrosis have each been associated with perhaps a bit of greater concern; whether that be of greater concern for risk of blood clots or risk of progression.  It is not clear above that level whether changing between a certain level of the overall white blood cell count has implications in terms of the behavior of the disease; i.e. we don’t know whether there is any significance to increasing from 18,000 to 24,000 or from 30,000 to 35,000.  We know that people that have a dramatic increase, I’d say well over 40,000 or 50,000; that is clearly a concern; or individuals in which early cells from the bone marrow, blasts in particular, increase can be a sign of disease progression.  A change in the white count has to be taken in the context of any other evidence of changes in the disease.

CH: Claire Harrison;  HH: Hans Hasselbalch;   RL: Ross Levine;   RM: Reuben Mesa;   RS: Richard Silver;   DS: David Steensma;   MT: Moshe Talpaz;   SV: Srdan Verstovsek

160

MF with night sweats, shortness of breath. Go back on Hydrea?

EK- i was diag with ET three years ago ( was possible MF from the beginning) and myelofibrosis last year.  I took Hydrea for 2 years (stopped when my WBC suddenly increased from 14 to 24)  and stopped aspirin early this year because I got an ulcer .
Apart from shortness of breath, if I  walk a kilometer, I feel fine.The last 2 nights, i have also night sweats. I see the need to take something to try to influence the fibrosis.
As Jakafi doesnt influence the fibrosis and Pegasys seems to do that only in an early stage , i am considering to restart with hydrea 500mg/day. I have found a few studies that Hydrea might help.  I have no spleen pain and my appetite is normal.

What do you suggest?

RS –  This complicated case should be discussed with the patient’s physician

SV – I would suggest an evaluation by expert hematologist and discussion about possible therapies once the doctor has them for review. I don’t think one can suggest therapies over internet without seeing a patient and having full evaluation done

CH –   I think you need to have a discussion with a clinician who has all your details infront of them and the ability to ask further questions. If you had for example and enlarging spleen or other symptoms I would consider therapy yes.

HH – Shortness of breath in your situation may have several causes , which all should be ruled out by clinical examination and relevant additional studies . Thus, I advice you to contact your local hematologist as soon as possible

161

23andMe test, T Cell leukemia and neutropenic. 

TS – Basically I had my genome done (by “23and me”) and have predisposing JAK2 variants for the V617F positive mutation, according to their findings. I am 67yr old female and was dx 6/12 with T cell Large Granular Lymphocytic  leukemia. One month ago developed severe neutropenia, (ANC<500) so I just began methotextrate one day /week. My question is:   Are there newer “targeted” therapies I should be investigating….? I am being treated by experts with LGL and am in the process of getting a second opinion at MSKCC.  Lucky for me, I have the availability and means to seek other expert opinions nearby and since I am a retired internist myself, have some medical knowledge and understanding but mostly LOTS of curiosity.

RS – Patient should discuss this with the expert that performed the 23 epigenomic analysis.  This is the problem associated with such tests, in my opinion.

SV –  Presence of JAK2 mutation does not call for therapy. Even in patients with established MPN, we would treat patient when clinically relevant issues develop, like significant anemia, symptomatic splenomegaly, etc.

CH – I don’t think the genetic tests showing predisposition are relevant here.

RL – 23andme does assessment of inherited DNA changes, which can increase the risk for MPN but do not denote MPN itself.  Unless you are found on bone marrow exam to have an additional disease in addition to LGL, which the hematologists can assess, there is no clear data to suggest you have a MPN.  We would advise you have your full case carefully evaluated by experts as you are doing.

HH – Too complicated to address – contact your doctor who did all these tests . I assume that your doctor has a plan to follow based on the test results obtained. Otherwise such tests are meaningless.

162

Adult son with ET, JAK +…what’s the significance?                                                          

JH– My son presented with extensive clotting in his pelvis, abdomen and left leg in 2010 at the age of 29. The diagnosis of ET was made in 2011 which included the finding of JAK2.  His hematologist started him on a regimen of Hydrea and low dose ASA, and his platelet count was lowered and is well controlled. ..However, I do not exactly understand the significance of JAK2. From what I understand, one can have ET with or without JAK2. … With JAK2, is he at a higher risk of developing myelofibrosis or leukemia? Is this an inherited or familial disease? Should our younger son, grandson or other family members be concerned?

 

SV- JAK2 mutation is one of the genetic abnormalities present in ET and its presence helps in diagnosing ET. For practical purpose that is all; there is no conclusive evidence that it with any certainty affects overall outcome of the patients. Therapy is aimed to decrease further episodes of clotting and it seems that proper therapy is in place. This is not directly inherited so other family members do not need to be tested for JAK2.

CH – The JAK2 is a change which has occured in your sons blood making stem cells. You are correct not all patients have JAK2. The risk of complications is not affected by whether JAK is there or not.
There is weak inheritance of these conditions. We would not usually test family members unless they have worrying signs or symptoms. There risk is of the order of 1 in 20-000-30,000 ie less than being stuck by lightning.

HH – JAK2+ ET is  by some considered a precursor stage of PV in the “Biological Continuum“ from early cancer disease stage (ET/PV) to the advanced cancer stage, myelofibrosis; actually about 40-60 % of JAK2+ “ET”-patients do not have “ET” but PV if a red cell mass estimation is being performed. In addition – carrying the JAK2V617F mutation implies a higher risk of thrombosis in comparison to the JAK2-negative ET-patients.

The risk of myelofibrosis and leukemic transformation in MPNs is not related to the JAK2V617F-status – In regard to inheritance of the chronic myeloproliferative neoplasms, please address Question 148 and my answer.

163

 

MF – from Gilead to Jakafi, transfusion dependent.  What’s next?

W- I am a 47 year old female, JAK2+, intermediate-2/high risk, post-PV MF patient on 25 mg Jakafi 6/16/13,  > 95% fibrosis with < 5% blasts.   I was diagnosed with hypothyroidism on May ’12 and MF on Aug. ’12.  My current list of meds are: 25 mg Jakafi, 50 mcg levothyroxine, 81 mg aspirin,,,.  I participated in the Gilead gs-6624 clinical trial for over 1 year… and remained stable throughout.  I have had a blood transfusion about every 4 weeks.  I made it to 6 weeks at 20 mg b.i.d. Jakafi, and then dosage was increased because of constitutional symptoms. Trying to make the decision (between transplant and clinical trial)  and considering Imetelstat or whichever one is best for my particular situation.  Should I start a trial immediately regardless of mileage required or stay on only Jakafi?

SV:  Any therapy that provides benefit should not be stopped until all the benefit is gone. There are medications that can be added to it, if needed, both commercially available (off label use of medications known to potentially benefit patients with myelofibrosis) and investigational agents.

CH – You need a proper thorough clinical evaluation to assess your risks, this is not a straight forward decision. I am a bit confused as to why you stopped the Gilead drug.

HH – Too complicated to address in this Forum – follow the advice given by your hematologist.

RS – This is a complicated clinical question and requires a thorough hematologic evaluation.

164

Reducing fibrosis post-transplant, PRM-151?

KF- I understand that there is a Phase II study of PRM-151 in subjects with myelofibrosis, to determine whether this drug has any effect on the disease. I understand that one of the secondary outcome measures of this trial is to quanitfy whether this drug may also reduce bone marrow fibrosis.

I am eight months past my second allogeneic stem cell transplant for MF, and in remission (100% donor cells and now JAK2 negative.) However, my fibrosis is still very heavy and I have been told that it is likely it will take “longer than typical” to reverse.  Is there any possibility that PRM-151 might at some point be considered for use post-transplant in patients with heavily fibrosed / “stubborn” bone marrow? Or is this unlikely in a case where remission has been achieved?

SV – This medication is in phase 2 open label study for patients with myelofibrosis that need therapy. We don’t know the results yet and it is premature to speculate if and how it might be used in the future

CH – I would leave your marrow to recover on its own if all the other markers look great chimerism, JAK2 etc.

RS – We do not have sufficient information regarding PRM-151 and I would suggest allowing your bone marrow to recover on its own.

166

Warfarin, aspirin, blood thinners….

DH – When starting on Ruxolitnib 3 months ago,  my haematologist was assured by Novartis that the drug was compatible with Warfarin. My INR dropped steadily to non-existent. I’m now back on aspirin. Ruxo has stabilized my blood counts, (platelets, white cells fine, haemoglobin ok). And I feel terrific, sleep much better. My enlarged spleen doesn’t show as reduced yet in recent ultrasound, but I feel less puffed up! I take 40mg daily….was diagnosed with MF/ET 11years ago and took only aspirin until prescribed Warfarin following a PE, 4 years ago. Would you recommend other blood thinners/stroke preventatives in this case?

RS –  This depends upon your clinical situation and the opinion of your physician.

CH –  I have had experience of using warfarin and JAKAFI without problems. It would depend upon the circumstances but I would review you very carefully to make sure you didn’t need anything in addition to the aspirin.

HH –  Follow the advice given by your doctor.

167

CALR and JAK2 mutations, new options? 

AP – Why is it that the CALR and JAK2 mutations are mutually exclusive?  Will the finding that the CALR mutations follow a more indolent and less thrombotic course than the JAK2 mutations suggest different therapeutic options given similar clinical presentations?

RL-  The observation that CALR and JAK2 mutations are mutually exclusive suggests, but does not prove, that they function in a similar way and that CALR mutations lead to activation of the JAK2 pathway.  Many labs are now trying to figure out exactly how this works.  In terms of therapies, the differences between JAK2 and CALR mutations in terms of outcome and risk of thrombosis are not sufficient to justify any changes in treatment, though future studies might be able to investigate whether such an approach would be worthwhile.

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