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Jason Gotlib =JG Claire Harrison= CH Ross Levine=RL Attilio Orazi= AO Ruben Mesa=RM Richard Silver=RS Srdan Verstovsek= SV
(Links to earlier MPNclinic pages can be found here)
ET with high platelets , baby aspirin enough?
98. Dx ET 25 yo, platelets at 700-800, briefly one million. Went down after pregnancies. Baby aspirin only. Hem. Turned me down for second opinion on meds. Needed?
HARRISON: In general if you are otherwise well with no complications and based on this information I would manage you with baby aspirin only.
VERSTOVSEK: The number of platelets does not corresponds to the risk of thrombosis, therefore whether the number is 700 or a million it does really matter. The risk of thrombosis is related to other factors: age over 60 or history of thrombosis make a patient at a high risk for a thrombotic event and these patients require a medication (e.g. hydrea, anagrelide or interferon) to normalize the count. Conversely younger patients without thrombotic event are low risk and need nothing more than baby aspirin.
SILVER: It would seem that no additional treatment is necessary, Charyl.
JAK+ with PV but 23andMe doesn’t catch it.
99. DNA result confusing, have PV, positive for JAK, on hi dose HU but my 23andme DNA test doesn’t show high risk for MPN. Any idea why?
MESA: : The DNA testing by 23andMe is still exploratory. The reports that you received have issues of risks for common diseases and dosing for current medications. The report that one receives is not diagnostic testing for the presence or absence of an MPN. If your doctor has diagnosed you with polycythemia vera, this I am certain is the accurate diagnosis. What 23andMe is reporting on is that there are certain genes that are more commonly associated with a predisposition to MPNs, but one does not necessarily have to have one of those genes to actually have an MPN, so unfortunately, I fear the result you have received has caused inadvertent confusion, but the diagnosis from your doctor is correct.
CH: I think the issue is the differences between what these tests are looking at. The JAK 2 test is searching for the specific mutations found in PV, the most frequent being V617F. The 23 and me panel is essentially a fishing exercise done on saliva to look for genetic changes or even normal features that are seen more often in MPN. It isn’t a validated test essentially its a research exercise whose findings have to be examined and tested by the rest of the community. So in essence I would be confident you had PV and be interested in the 23 and me results.
SV: I am not familiar with 23andme DNA test, very sorry
LEVINE: The 23andMe test just notes the risk of MPN, but does not mean anything if you already have an MPN. In other words, even if the test comes back low-risk, the risk is not zero, and some MPN patients will come back low-risk on their genetic profile but still develop MPN. Inherited risk factors, are just that, factors.
RS: I have no experience with 23andme DNA test per se in PV but if your JAK2 is positive, it certainly suggests that you have PV so assuming all other criteria are met for the diagnosis of this disease.
Breast feeding and Pegasys?
100. Breast feeding and Pegasys or older INTs safe for infant? Any reference to studies for my hem to review?
SV: This is perfect question for Dick Silver
CH: there are several reviews on this subject which are visible in medical literature. Interferon and probably pegasys are found in small quantities in breast milk. However these drugs are not absorbed well in a fully mature digestive system and so we think the risk to a baby with an immature gut is less. We support our mums to breast feed as there is clear overwhelming evidence of the benefit of breast vs bottle.
RS: Your hem can look up the literature regarding Pegasys in chronic hepatitis regarding breast feeding or call Roche ( the pharmaceutical company). In general, it is not wise to take any potent medication, which includes interferon, while breast feeding.
Can testosterone injections cause MPN?
101. 56 yo woman, dx w/ET maybe PV now. Had depo-testosterone injections every 16 days for about the last 15 years – for low libido. Can this cause PV or marrow failure?
RM: At this point, we know testosterone can have an impact on the number of red blood cells and cause erythrocytosis. If an individual has a diagnosis of P-Vera or ET, we do not think that has been associated with a prior use of testosterone. It is important that the diagnosis be confirmed, both on the appearance of the bone marrow and ideally with the presence of a definitive marker such as JAK2 to be certain that the changes in the blood counts are from an MPN and not secondary to medication.
CH: I am not aware of a link between depo-testosterone and either PV or marrow failure.
SV: Testosterone can raise red blood cell count. What the role, if any, these injections had in the disease process is not possible to say; would not cause bone marrow failure, however.
RS: Insufficient evidence to comment.
High hematocrit. A result of dehydration?
102. 15 yo son being tested for PV based on his HCT and symptoms (fatigue, rosy cheeks, etc.). Now normal counts. JAK neg. Could high counts have resulted from dehydration?
RM: The diagnosis of polycythemia vera clearly requires more than just a high hematocrit in symptoms at this point in time, and with normal counts in JAK2 being negative, it is certainly possible that your son does not have polycythemia vera. That being said, it clearly needs to be a case evaluated by an MPN expert to be certain whether there is or is not an illness, but from what you describe it does seem possible that the increase in the hemocrit was a temporary finding and not a sign of an MPN.
CH: High counts could have resulted from dehydrated or the testosterone surge at this point in a young man’s growth.
SV: Unlikely. Happy he is doing well now and no disease is present.
RS: We have repeatedly pointed out that, for more than 50 years it has been known that a single hematocrit cannot determine whether or not blood volume (the number of red cells) is truly increased.
PV with bleeding. Stop aspirin?
103. I’m 64, PV diagnosed in 2006, JAK2 positive, on phlebotomies and 81 mg aspirin. Endoscopy showed small intestine bleeding due to aspirin. Stop aspirin? Alternative?
RM: Best not to answer in a forum such as this a very specific question as to whether or not you should stop or start a medicine such as aspirin given that there are a lot of complexities that a physician has to consider in this regard. I would answer that in generalities, if an individual has had bleeding from an ulcer or from the intestine, it does give us greater pause for the use of aspirin and certainly needs to be discussed with your doctor whether that is necessary.
CH: Usually under these circumstances I would switch to aspirin and a proton pump inhibitor once the bleeding has healed or depending on the severity of symptoms and need for aspirin to an alternative agent like Plavix.
SV: I would agree to stop aspirin and try alternative, not to risk significant bleeding through GI track.
RS: One might try Plavix.
GOTLIB: This is a discussion with your GI doctor and hematologist, particularly as it relates to the severity of the bleeding. One or both doctors may provide recommendations about temporarily holding the aspirin or reducing its frequency. Other anti-platelets may be considered but may not provide any more safety margin compared to aspirin.
My platelets up. Time to worry?
104. ET…My platelets were at 1050 every time my FBC (CBC) was taken. On 75mg of aspirin. In the last seven weeks platelets jumped to 1466.Should I worry?
RM: The platelet count at which we are concerned in ET depends on many things, including an individual’s age, other medical problems, symptoms and whether or not there is any predisposition to bleeding. A platelet count rise to 1466 could be a consideration for therapy to reduce the platelet count, but needs to be done so with careful consideration by your physician looking at all of these other issues.
CH: Platelet counts can vary due to underlying factors, for example cold, etc. I would see what the next reading is. Watch out for bleeding (usually minor bruising) as this is more frequent with higher counts. This may mean you are coming close to needing to make a decision about additional treatment.
SV: The number of platelets does not corresponds to the risk of thrombosis, therefore whether the number is 700 or a million it does really matter. The risk of thrombosis is related to other factors: age over 60 or history of thrombosis make a patient at a high risk for thrombotic event and these patients require a medication (e.g. hydrea, anagrelide or interferon) to normalize the count. Conversely younger patient without thrombotic event are low risk and need nothing more than baby aspirin. Very high platelets, 1.5 million, 2 million… may predispose a patient to bleeding (!) so close monitoring by hematologist is prudent; when platelets are that high they use up protein called Von Willebrand factor that is present in the blood and is important for coagulation; if it is low then that predisposes patients to bleeding. In that case one would stop aspirin.
RS: I would worry mostly about the laboratory doing the test. Once cannot make a blanket statement unless more information is provided regarding co-existent risk factors to determine whether your platelet count should be lowered.
When is Watch and Wait not enough?
105. Watch and Wait–Afraid of HU and not sick enough for ruxo and panobinostat. When can you tell it’s really time to treat an MPN?
CH: Watch and wait can be an entirely appropriate strategy for many patients. The decision or recommendation to treat will be based upon the specific features of your disease type.
SV: This is something that is usually decided between a patient and physician, based on the assessment of one’s situation, prognosis, etc. there is no one parameter or test that would determine the right time to start therapy. In general ruxolitinib is indicated for patients that have symptomatic spleen, or have general symptoms from myelofibrosis.
RM: It is indeed a very difficult and complex choice when an individual should receive therapy for an MPN and which therapy should be given. There are many factors that need to be considered and it is a complex discussion between you and an MPN expert whether or not therapy for your disease would be helpful in the setting where the disease has not been overly advanced. There has been some information suggesting interferon may be helpful in earlier forms and phases of myelofibrosis, but this is a complex discussion that needs to occur between you and your physician.
Bone marrow biopsy vs. blood smear
106. Can odd cells be detected in CBC or only blood smear. What does BMB uncover that blood smear can’t?
CH: Generally while odd cells can be detected in a CBC done by an analyser a blood smear evaluation will be required for their correct identification. Depending upon the type of odd cells a bone marrow biopsy is an excellent tool to evaluate bone marrow architecture and how orderly blood cell production is. All three — CBC, smear, BMB — plus others, for example, spleen exam are needed to fully evaluate MPN patients.
ORAZI: Circulating atypical cells (e.g., immature cells such as blasts) are usually detected by manually reviewing the blood smear at the microscope, although if numerous, they might also show up in the automated CBC result. In patients with fibrotic myeloproliferative disorders (e.g., PMF, post-PV myelofibrosis), the bone marrow aspirate smear which is used to detect the presence of atypical cells in the bone marrow is often hemodiluted because of the fibrosis and frequently spotty cellularity, and thus may be non- representative of the marrow cellularity. The bone marrow biopsy offers the advantage of being able to assess such fibrotic marrow. It allows confirmation of marrow cellularity, lineage composition, determination of the degree of fibrosis and identification of eventual atypical cells (including e.g., blasts). If needed, confirmation of morphological finding can be obtained by immunohistology. A complete hematopathologic evaluation, e.g., to exclude disease progression should always include review of peripheral blood and bone marrow aspirate smears (touch preparations if bone marrow aspirate fails), bone marrow biopsy sections stained also for reticulin, flow cytometry of both peripheral blood (if atypical cell are present in the blood smear) and bone marrow aspirate. Karyotype analysis of bone marrow aspirate. If aspirate is unobtainable and peripheral blood smear shows circulating atypical cells karyotype should be done on peripheral blood. Atypical cells should always be separated out and preserved for eventual molecular genetic studies.
RS: “Odd” cells can be detected both in blood smears and in the bone marrow. That is what makes hematology a specialty.
RM: A bone marrow biopsy gives three pieces of information that the blood smear does not – the degree of fibrosis, whether there is not an increase in the blasts and whether there are any chromosomal changes. The peripheral blood smear gives us a sense of the appearance of the blood cells and that can give insight into the illness. A complete blood count, which is an automated, machine-generated series of values will only give us certain information, but will not tell us information about the appearance of the blood cells or the white blood cells.
Does Red Cross use PV blood
107. At the clinic for my PV I was told I could go to the Red Cross for my phlebotomy. Does this mean they would later use PV blood for transfusions?
CH: No, PV blood sadly cannot be used for transfusions. You would be advised to make your diagnosis clear to the Red Cross.
RM: Can you donate blood with polycythemia vera? At this point there is nothing about polycythemia vera that we consider to be transmissible. It is not something that by giving blood someone is going to develop by receiving that blood. That being said, at least as of my last understanding, the American Association of Blood Banks will not accept blood from patients with polycythemia vera or having blood removed for therapeutic purposes. They do this with the greatest abundance of caution. Whether its necessary, I think is something that is debatable, but I think at the moment, they will not accept blood from patients with polycythemia vera.
RS: In general, PV blood is not used because of medical-legal reasons irrespective of whether the Red Cross or any other phlebotomy center performs the test.
JG: Blood banks will not use blood from PV patients since PV is considered a chronic blood disease and has some potential to evolve into acute leukemia.
Jakafi side effect
108. After 3 weeks on Jakafi, swelling of neck, breathing constriction. Had to get off drug despite its help with my itching. Any ideas?
CH: You may have had a bad reaction to JAKAFI there is a study with SAR302503 for patients who have run into these problems – its called JAKARTA-2. Discuss with your haematologist.
SV: Have not heard about this type of side effect although I have treated several hundred patients with Jakafi so far; very sorry you experienced it.
RS: This is a complicated question. It would depend on the rest of your clinical and laboratory status including bone marrow findings. One cannot give a meaningful answer to this.
RM: It seems that you are describing a possible allergy to ruxolitinib or Jakafi. If that is the case, it is probably best not to go back on the medicine if there was a true allergy. There are times if this was after the first dose of the medication, people may with their physician’s help and under guidance have a second try to make certain that there was a true allergy. If there is an allergy to the medication, that allergy is not likely to be present by using alternative JAK2 inhibitors. There are several ongoing clinical trials of other JAK2 inhibitors that could be considered in the setting. There is specifically a trial of SAR302503 in a variety of centers; a trial called JAKARTA 2 for individuals that might benefit from a JAK2 inhibitor but were not able to remain on ruxolitinib.
Stem cell transplant problems. Jakafi an option?
109. SCT age 60 for MF.Relapse at 2 & 12 yrs. Good control w/Pegasys but discontinued because GVHD. Now inflammation, erythema nodosum. Is Jakafi an option?
RM: The use of ruxolitinib after a stem cell transplant has not been extensively studied. There is in theory a possible activity of JAK2 and JAK1 inhibition for individuals who have graft vs. host disease. I would say that the use in your setting likely would be experimental and there is really no good information on its use in this setting yet at this time
CH: JAKAFI may be an option but your case is obviously complicated so many things also need to be considered. There is not much experience of using Jakafi in patients with GVHD. I have had one experience which was positive. So I would discuss with your transplant expert and haematologist.
SV: In general ruxolitinib is indicated for patients that have symptomatic spleen, or have general symptoms from myelofibrosis. I would discuss this issue with your doctor if you have either of the two.
RS: Jakafi has been used in patients post-transplant. It may be an option.
JG: Jakaki is useful for MF-related symptomatic splenomegaly and symptoms. The use of Jakafi in MF should be judged on a case by case basis, and more information would be needed. For example, if your major issue was just anemia, Jafaki may not prove particularly useful in your case since it is not expected to make a large impact in this regard and could make it worse.
Worried about high dose of hydroxyurea
110. PV, 2008, 59 yo Female., After cardiac event on 1500 mg of HU, put on Plavix, Lipitor, 81 mg. of aspirin. HU seems high and is interferon an option?
CH: HU doses vary greatly between patients and may go up to 2500mg or more. Interferon may be an option but some clinicians (including myself) prefer not to use this at or around the time of a cardiac event.
RM: Fifteen hundred mg of hydroxyurea or 21 pills a week is on the high end for the medication but not a concerning dose. I would say that the average patient with an MPN will require between 10 to 20 pills of Hydrea a week or somewhere under two pills a day to somewhere in the range of three pills a day. Four pills a day or 2000 mg would be an uncommon dose. Now, whether or not a change to interferon is appropriate or necessary would depend on whether the Hydrea is giving you any side effects and also how the disease is behaving.
SV: If HU is providing desired benefit without side effects, then one in general would not change it (regardless of the dose). Interferon of course is good alternative.
RS: Interferon can have adverse cardiac effects. It depends what the cardiac event was. This requires evaluation.
111. 67 yo PV…desperate to relieve itching. Can’t sleep. Take Piriton 5 mg 3x/day, HU 500mg/day. Can I increase either to relieve itching?
CH: I am sorry to hear this. You need to discuss these and other ways to relieve itching such as other medications, possibly light (PUVA) therapy, etc. with your clinician. I would not exceed the maximum recommended piriton and would not increase HU. You could also discuss another antihistamine with your pharmacist.
SV: HU can be increased, but that needs to be done under supervision of your doctor, and is based on your counts. Alternative strategy is to engage in a clinical study with JAK2 inhibitor for patients with PV, that are symptomatic despite the use of HU. Ruxolitinib (jakafi) is being evaluated in such a study, for example, throughout the USA.
RM: A JAK2 inhibitor may be helpful in this setting. There is a clinical trial ongoing called the RELIEF Study, which is a randomized study for patients who have persistent symptoms on Hydrea being randomized between remaining on the Hydrea and changing over to a JAK2 inhibitor. A JAK2 inhibitor may be helpful for the refractory itching. Other things that can help itching are therapeutic UV light as well as a variety of the antidepressive drugs such as Zoloft or Paxil that have some benefit.
RS: The best drug to relieve itching in PV is interferon. Paxil is also helpful and should be considered.
JG: The JAK inhibtors are very good in providing relief from itching so, if there is a center that is conducting a trial with Jakafi for PV, and you are eligible, this is an option. I have had success with a medicine aprepitant (brand name Emend) in controlling itching. It is an anti-nausea medicine for which a good literature also exists for its anti-itching (pruritis) benefits.
Familial blood cancer. I’m symptomatic.
112. 41 yo female, Mother has PV, father CML. My plts 500-700, HCT 47-51. Fatigue, joint pain rash. Hem says unrelated to MPN. Get a second opinion?
RM: With both parents having a hematologic disorder and your counts being abnormal, I certainly would be concerned that there could be an underlying blood disorder, although it is not definitive. One could have some erythrocytosis and thrombocytosis for alternative reasons, but I do think being 100% certain as to the cause, given your symptoms, would be wise. It is possible that if your symptoms are from a secondary cause, that secondary cause is also responsible for the increased counts.
CH: these symtpoms could well relate to your blood count. I would say you need a thorough evaluation.
ET….a myeloid malignancy?
113. BMB showed atypical megakaryocytes. High platelets. Dx ET. No AML. Can I be sure I have no myeloid malignancy?
CH: The term atypical megakaryocytes is tricky as it covers a variety of potential diagnoses. I would take this question back to your physician or the bone marrow specialist for a second opinion. Remember that the WHO classed ET and all MPN as -neoplasms and hence by definition myeloid malignancy. Please also remember that the term malignancy covers many non-aggressive conditions which ET usually is.
AO: The morphology of the megakaryocytes provides some indication of the type of myeloid disease. Careful review of the bone marrow finding may be needed to confirm a diagnosis of ET. In ET the “atypical” features are limited to a predominance of large megakaryocytes with deeply lobulated nuclei. The bone marrow cellularity is more often within normal (age-related) limits or only mildly increased. There should not be a significant granulocytic proliferation. Moreover, to confirm ET, the presence of significant fibrosis must be excluded by performing reticulin stain (Gomori stain). The presence of an increased number of blasts in bone marrow or peripheral blood and/or the presence of specific karyotypic findings identify AML. If the report does not describes blasts and the karyotype is normal you most likely do not have AML. Is JAK2 mutation or other marker of clonality (e.g., MPL) detected in your case?
RM: The spectrum of myeloid diseases do exist on a spectrum of which ET is a myeloid malignancy, although frequently the one that is the least likely to progress to acute leukemia. What the expectation over the prognosis is with your ET depends on many things and you should have a thoughtful discussion with your physician.
RS: If the bone marrow does not show an overt myeloid malignancy, the chances are you do not have one. However, far more sophisticated test are now being used such as flow cytometry, cytogenetics, special stains etc. to conclusively exclude myeloid malignancies.
Five year old is JAK+, likely to progress?
114. Five year old daughter JAK+ dx ET considering age what are chances of progressing to PV MF, AML?
CH: We know very little about these diseases in children however I have several patients diagnosed as teenagers who are now in their mid to late 40s and fine. You can hopefully take comfort in the huge advances in treatment which will benefit your daughter.
RL: This is a difficult question as ET is rare in children. Most studies suggest there is a lower, but not zero, risk of progression to PV/MF/AML. She should be followed, and treated carefully by an expert in pediatric MPNs.
Drug interactions with hydroxyurea.
115. What drugs are contraindicated while taking HU.
CH: Most drugs are fine. Be cautious with drugs which also lower the blood count such as methotrexate. If you have a specific question I would discuss with a pharmacist.
SV: None, but one would not like to use other chemotherapy drugs in the same patient to control the disease. It has been shown that patients who were treated with HU (which is a chemotherapy agent) and with any of the other chemotherapeutic agents (e.g. busulfan, melphalan,…) had much higher risk of transformation to acute leukemia.
RS: Your hem should consult the PDR or the drug insert which accompanies hydroxyurea when delivered from the pharmacy.
Stick with interferon…or Jakafi?
116. MF 2003, Intron A was effective in raising Hg and then not. Now back on interferon w/Darbopoetin. Counts low but stable. Is this regimen effective or would Jakafi be a better option?
CH: Jakafi may be an option to be considered particularly if you have troublesome symptoms or are bothered by a large spleen. It sounds as though low counts may also be a problem in which case you would need cautious dosing with Jakafi and to be aware it may worsen this issue.
SV: In general ruxolitinib is indicated for patients that have symptomatic spleen, or have general symptoms from myelofibrosis. I would discuss this issue with your doctor if you have either of the two. Jakafi does not improve red blood cell count, in general.
RS: How effective was interferon in raising your hemoglobin and then how high? What happened to spleen size? Interferon can cause marrow reversion of architecture abnormalities whereas Jakafi does not
Jakafi trial for PV?
117. Is there a trial for Jakafi and PV? And will Jakafi lower WBCs and eosinophils?
SV: Yes to both questions. There is a large multicenter study of Jakafi in PV, called RELIEF study, for patients on Hydrea that are still symptomatic from PV.
CH: There are 2 global trials for Jakafi and PV response and relief, and a separate study in the UK. These studies have very specific inclusion criteria but most relate to having tried and failed or been intolerant to HU or having persisting symptoms. We do know that Jakafi lowers WBC and in my experience eosinophils too although they may be lowered by relieving itch.
RS: There are a number of trials at major MPN centers around the country. At Cornell we have a number of studies besides Jakafi as do other centers. It depends upon your location.
RM: There are two ongoing studies for Jakafi in P-Vera – the response trial and the relief trial. These trials have very specific eligibility criteria, but would refer you to the web to look at those. There are many individuals who might benefit from JAK2 inhibition with P-Vera, but at the moment the clinical trials are relatively narrow in their eligibility. Ruxolitinib may lower an increase in the white count eosinophils. Eosinophilia has not been frequently treated with ruxolitinib to this point in time so I think whether it would reduce it, I am less certain.
Cause of PV weight loss.
118. How do you know if your weight and muscle loss is from PV or a statin?
SV: Tough question. One would need to be seen, examined, check blood tests, and similar, and then provide opinion.
CH: Very difficult to know. Timing could be a hint. An alternative is to discuss pausing the statin and see if the problem resolves.
RS: Please remember your hematologist should be an internist first and thus, careful evaluation is necessary before weight and muscle loss is ascribed to one disease or another.
RM: It is difficult to know for certain, but we do know that, particularly in the myelofibrosis end of the spectrum, muscle loss, wasting and weight loss is associated with myelofibrosis. If the disease is stable PV, I would take this as a possible sign of progression. Although I think these difficulties have occurred with statins, they are not common, so I would be a bit more suspicious of the P-Vera/myelofibrosis than all the statin use.
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