Here’s how readers responded to a You Make the Call question about cytoreductive therapy in a patient with low-risk polycythemia vera.
Disclaimer: ASH does not recommend or endorse any specific tests, physicians, products, procedures, or opinions, and disclaims any representation, warranty, or guaranty as to the same. Reliance on any information provided in this article is solely at your own risk.
I would treat with anagrelide.
Carlos Fondevilla, MD
Buenos Aires, Argentina
I would continue the current treatment with hydroxyurea and keep her on anticoagulants for at least the next 6 months (assuming her platelet count normalizes). I recently had a young patient with JAK2 positive ET who developed acute pancreatitis when I switched her treatment from hydroxyurea to interferon. I wonder if these young patients would be good candidates for allotransplantation, or if we should wait for the availability of the appropriate JAK2 inhibitors in the near future.
Sergio A. Sánchez-Guerrero, MD
Mexico City, Mexico
I am concerned that the presence of fibrosis in this situation may be an early feature of JAK2 positive post-ET myelofibrosis. The primary myelofibrosis (PMF) COMFORT studies using ruxolitinib recruited patients with higher risk scores than this patient, so the information regarding overall survival is difficult to extrapolate here. Interestingly, the RESPONSE studies for PV showed an apparent benefit in the risk of thrombosis in the ruxolitinib group, but this was not a primary end point and it remains an interesting hypothesis-generating finding.
I would feel comfortable treating this patient with interferon as a first-line treatment. We treat PVT for at least 3 months with a DOAC. Then we reassess with a venous doppler ultrasound to look for recanalization and flow pattern and, simultaneously, make an assessment of MPN response and tolerability of therapy, and make a decision on whether to continue with interferon or proceed to another line of treatment.
Julio Hajdenberg, MD
I have some doubt that she is taking hydroxyurea regularly, as I would expect a higher mean corpuscular volume if she were. I would first try to improve her treatment adherence, then consider putting her on pegylated interferon alfa (or, if available, ropeginterferon alfa-2b). Since she has suffered from severe splanchnic vein thrombosis (albeit posttraumatic/postoperative), I would continue her on infinite anticoagulation with a direct oral anticoagulant (DOAC).
Bernhard Lämmle, MD
I would recommend cytoreductive therapy, not only because she has a history of thrombosis (although that might be due to post-splenectomy complications), but also because of her history of splenectomy (which puts her at a higher risk of coagulopathy than the general population). I would give her hydroxyurea instead of interferon because it is equally effective, more tolerable, and will not affect her mental health. Some reports don’t prefer hydroxyurea in younger populations due to the risk of secondary leukemia, but it is not clear whether this secondary leukemia is due to the treatment or if it is a part of the disease course.
I would give her anticoagulation for only 6 months post thrombosis, as it might have been a post-surgery complication rather than a result of her ET. After 6 months, she could be on antiplatelet therapy along with therapy to control her ET. If she later develops unprovoked deep vein thrombosis, then long term therapy can be considered.
Shady Tantawy, BSc
She probably should be given cytoreduction therapy as one cannot be 100% sure of the primary cause of her PVT; if it recurred it would be a big problem for her. I would anticoagulate for 6 months, then assess other prothrombotic risk factors with a haemostasis expert (d-dimer, etc.), then decide. Likely we could stop anticoagulation, control her platelet count tightly, start aspirin, and watch closely. With regards to cytoreduction, I would consider a trial of pegylated interferon if she gets better control of her mental health issues. Otherwise, I would continue hydroxyurea.
Paolo Gallipoli, MD
This is a controversial topic and the decision to start cytoreductive therapy is highly individualized and should include shared decision-making between the patient and the physician. In this patient’s case, her platelet count is 1.2 million and she is at greater risk for hemorrhagic complications than thrombotic complications.
The hemostatic paradox of ET has been shown in the analysis of the prospective PT-1 cohort, which failed to demonstrate a relationship between elevated platelet count and thrombotic risk (p = 0.4), either at diagnosis or during follow-up.1 In the revised IPSET-thrombosis study that reanalyzed the retrospective data from 1,019 patients with World Health Organization [WHO]−defined ET that was subsequently validated by a Mayo Clinic study, again platelet count did not predict for recurrent thrombosis (hazard ratio [HR] = 1; p=0.233).2
In another study that investigated the relationship between prior thrombosis (at diagnosis or follow up) and characteristics at diagnosis in 977 patients with thrombocythemia and myeloproliferative neoplasms (MPNs) per WHO 2008 criteria, there was an inverse relationship between thrombosis and thrombocytosis.3 Akin to these studies, there are many other studies that could argue for and against the use of cytoreductive therapy in this scenario. This particular topic was recently reviewed in detail by Kuykendall, et al.4 Furthermore, cytoreductive therapy decreased the risk of recurrent arterial thrombosis, but not venous thrombosis.5
Generally speaking, the impact of platelet count in ET is difficult to evaluate specifically. Heterogeneous study design, population and the treatment of platelet count as either a dichotomous or continuous variable, and an increasing molecular understanding of ET have confounded the ability to precisely understand the relationship between platelet count and ET and thrombosis.
In this patient’s case, I would consider her to be intermediate risk and her thrombocytosis to be multifactorial due to both her post splenectomy state and the ET itself. I would evaluate her for acquired von Willebrand disease (aVWD) and, if she is positive (i.e., has evidence of aVWD), would start her on hydroxyurea with the goal of mitigating her bleeding risk.
If she is negative for aVWD, then I would not start her on cytoreductive therapy. I am not in favor of committing her to lifelong therapy at this point, as I think this thrombosis is likely to be related to her post-operative state and therefore provoked. But after a detailed risk-benefit discussion, if the patient says “Doc, I don’t want to take a chance with a recurrent thrombosis,” then I would start her on cytoreductive therapy (hydroxyurea, with appropriate contraceptive precautions given her ongoing mental health issues) regardless of the presence or absence of aVWD.
I would continue anticoagulation indefinitely, as there is a high rate of recurrent venous thromboembolism in patients with MPNs and the risk is significantly decreased with anticoagulation.6 In addition to anticoagulation, I would evaluate her for thrombolysis and/or thrombectomy because it has been shown that patients with MPNs who are JAK2 V617F positive have poor outcomes despite anticoagulation.7
- Campbell PJ, MacLean C, Beer PA, et al. Correlation of blood counts with vascular complications in essential thrombocythemia: analysis of the prospective PT1 cohort. Blood. 2012 Aug 16;120(7):1409-1411.
- Barbui T, Vannucchi AM, Buxhofer-Ausch V, et al. Practice-relevant revision of IPSET-thrombosis based on 1019 patients with WHO-defined essential thrombocythemia. Blood Cancer J. 2015 Nov 27;5(11):e369.
- Gugliotta L, Iurlo A, Gugliotta G, et al. Unbiased pro-thrombotic features at diagnosis in 977 thrombocythemic patients with Philadelphia-negative chronic myeloproliferative neoplasms. Leuk Res. 2016;46:18-25.
- Kuykendall AT and Komrokji R. What’s in a Number? Examining the Prognostic and Predictive Importance of Platelet Count in Patients With Essential Thrombocythemia. J Natl Compr Canc Netw 2020;18(9):1279-1284.
- De Stefano V, Za T, Rossi E, et al. Recurrent thrombosis in patients with polycythemia vera and essential thrombocythemia: incidence, risk factors, and effect of treatments. Haematologica. 2008 Mar;93(3):372-80.
- De Stefano V, Ruggeri M, Cervantes, F, et al. High rate of recurrent venous thromboembolism in patients with myeloproliferative neoplasms and effect of prophylaxis with vitamin K antagonists. Leukemia. 2016;30(10):2032-2038.
- Naymagon L, Tremblay D, Zubizarreta N, et al. Portal vein thrombosis patients harboring JAK2V617F have poor long-term outcomes despite anticoagulation. J Thromb Thrombolysis. 2020;50:652-660.
Sangeetha Venugopal, MD
This patient represents, in the proverbial nutshell, all the problems associated with the current diagnosis and management of ET.
First, it is unclear how the diagnosis of ET was made. The patient has JAK2 mutation so has clonal disorder, but thrombocytosis as an initial clinical manifestation is common to the three main MPNs because first, the thrombopoietin receptor, MPL, is the only hematopoietic growth receptor expressed in hematopoietic stem cells (HSCs) and megakaryocytes are necessary for maintaining HSC quiescence in their bone marrow niches. Therefore, with any significant benign or malignant perturbation of hematopoiesis, thrombopoiesis is the default HSC response.
Second, in polycythemia vera (PV), plasma volume expansion is common, particularly in women, who develop ET or PV earlier in life than men, masking the presence of erythrocytosis.
Third, the JAK2 V617F allele burden often dictates the extent of clinical manifestations. Thus, at allele burdens <50%, hematocrit elevation may not initially be present in PV until homozygosity occurs due to uniparental disomy, though admittedly, host genetic variation also plays a role (e.g., we have seen PV with JAK2 V617F allele burdens in the 5-10% range.)
When thrombocytosis is discovered and an MPN is a diagnostic consideration, the first question should be whether a JAK2 mutation is present and, if so, what is the allele burden? This is because first, JAK2 V617F is the most common cause of ET and PV and second, PV is the MPN diagnosis of exclusion since it is associated with the greatest risk of thrombosis. Unfortunately, the WHO does not provide this type of guidance despite the fact that it has been 15 years since the discovery of JAK2 V617F. Furthermore, it cannot be emphasized enough that one of the most catastrophic types of MPN-associated thrombosis is hepatic vein thrombosis, which is almost exclusively a complication in young women, usually with thrombocytosis alone, to which the thrombosis is erroneously attributed (Stein, et al. 2019). Of course, if you read any publication on ET, you find that at least 25% of these patients actually have PV. In this patient, what is needed is the JAK2 V617F allele burden; this is more important than a marrow examination, which in this situation provides no useful information despite unfounded claims to the contrary by pathologists who don’t see patients. If the allele burden is <50%, either ET or PV are possibilities; if it is >50%, PV is the diagnosis in this sex and age group.
We are also told that the patient was on aspirin. Why, if she was asymptomatic? Aspirin doesn’t prevent venous thrombosis in ET. She then has trauma requiring splenectomy; this alone would increase the platelet count in an otherwise healthy person. In an MPN, it increases even more but there is no correlation between the height of the platelet count and thrombosis; the correlation is with bleeding, which is virtually never spontaneous and cytoreduction is unnecessary in the absence of symptoms.
And why would anyone use hydroxyurea in a patient with ET for cytoreduction? It has been shown repeatedly that there is no correlation between the platelet or leukocyte count and thrombosis. So, one can conclude that evidence is still lacking in this patient as to what is going on, except of the need for anticoagulation for the PVT. This is unfortunate since it is 2020. PVT is unusual following splenectomy, but this may have been occasioned by the antecedent trauma. If it proves to be the case that the patient actually has ET, the need for long term anticoagulation becomes a matter of clinical judgement. If cytoreduction needs to be used here for any reason, pegylated interferon is the drug of choice since it can yield molecular remissions. Cytoreduction with hydroxyurea, except in an urgent situation, is never indicated in ET or PV because tying to suppress what is essentially normal hematopoiesis by chemotherapy is a fool’s errand.
Jerry L. Spivak, MD
I consider PVT a serious event in a patient with ET, and splenectomy is a formidable risk factor. It is known that PVT and Budd-Chiari syndrome are specific recurrent complications of chronic Ph-negative myeloproliferative diseases, and can happen even when the thrombocytosis is minimal.
Therefore, I suggest continuing hydroxyurea (as its oncogenicity is not convincingly proved) and anticoagulation for years.
Radu Gologan, MD, PhD
This patient’s PVT is provoked and she may need anticoagulation for at least 3 to 6 months. Regarding cytoreduction, I would continue with hydroxyurea at the optimal maximum dose while watching for any skin complications.
Aspirin 81 mg could be given twice a day after cessation of anticoagulation for PVT if her platelet count is still higher than 800×109/L. I believe she does not need cytoreduction now. If she develops a thrombosis, she has to be on cytoreduction. Otherwise, she has to be on low-dose aspirin and regular venesection to keep her hematocrit level below 45%.
Abdulrahman Saifudeen, MD, MBBS, MRCP
I would give anticoagulation for 6 months with aspirin and would not give cytoreductive therapy.
Khalid Sharif, MD