Jason Gotlib =JG Claire Harrison= CH Hans Hasselbalch= HH Ross Levine=RL Attilio Orazi= AO Ruben Mesa=RM Richard Silver=RS Srdan Verstovsek= SV
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.
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?
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 treatment – likely your dosage may be decreased thereafter but I assume that you have no side effects from Pegasys. I 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 therapy 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.
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?
AO: The diagnosis of all myeloid neoplasms (ET and AML included) is based on a combination of clinical and laboratory findings and not only on bone marrow biopsy. The hallmark of acute myeloid leukemia is the presence of cytopenia(s), usually marrow replacement by blasts, and/or specific cytogenetic abnormalities (also detected in the bone marrow). In most cases these are above 19% of the marrow nucleated cells. They can also occur in the peripheral blood and be detected on a blood smear. ET is a myeloproliferative neoplasm in which the number of blasts are within normal limits. The distinction in most cases is therefore pretty straightforward. However, ET has a slight risk of transformation to AML after many years from the disease outset. In those rare cases, the transformation is usually clinically suspected and confirmed by peripheral blood and bone marrow examination.
Take me back to the Contents
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