- Management of polycythemia vera (PV) should involve sex-specific hematocrit targets of less than 42% for women and less than 45% for men.
- All patients with PV should undergo regular abdominal imaging to monitor for spleen and liver changes, as well as molecular monitoring for JAK2 V617F mutation shifts. Increased monitoring allows providers to forecast disease progression and anticipate treatment needs.
- Janus kinase inhibitors, as well as novel interferon formulations, can improve treatment integration. PTG-300, a hepcidin mimetic, offers promise for treating symptomatic iron deficiency and might reduce the need for therapeutic phlebotomy.
- Careful symptom inventories — and symptom journals — can help determine how patients respond to a stepwise treatment approach for PV and reveal when patients who have seemingly good laboratory values are, in fact, in need of a newer or more aggressive approach.
- Ruxolitinib reduces intolerable symptoms and hydroxyurea-related adverse events associated with PV.
- Ropeginterferon alfa-2b could, if approved, help more patients with PV achieve meaningful remission.
Michael J. Mauro, MD, is a board-certified hematologist and head of the myeloproliferative neoplasms program and leukemia service at Memorial Sloan Kettering Cancer Center, in New York City. His area of clinical focus includes treatment of chronic myeloid leukemia and myeloproliferative disorders, including polycythemia vera and thrombocytosis.
What patient outcomes are not addressed by current cytoreductive therapy for PV?
There are a number of unmet needs or, rather, things we can do better for patients with PV. First and foremost, we need to optimally manage the condition with the following basic elements:
· Cardiovascular risk assessment and management of risk factors that can add to disease risk — specifically, thrombosis and vascular disease;
· Integration of the correct type and dosage of antiplatelet therapy; and
· Guideline- and research-driven control of erythrocytosis, the main disease manifestation.
Control of erythrocytosis, and how tightly you control it, is guided by sex-specific hematocrit targets (<42% for women and <45% for men, when possible, or, at the least, <45% for all patients1) and sorted by adequate peripheral blood count monitoring.
I believe there is merit to, first, continual monitoring of a potential shift toward fibrosis with regular abdominal imaging for spleen and liver changes and, second, monitoring for high-risk molecular mutations. The latter might detect a major shift in so-called driver mutations — JAK2 V617F in the overwhelming majority of cases. Evidence in myelofibrosis highlights the role of the mutational landscape2; the more we monitor, the more we learn about, and the better we forecast, treatment needs and risk of progression.
What new treatments are available for PV? How do they address current deficiencies in treatment, and what are the limitations of current therapy?
Probably the most anticipated treatments are inhibitors of the Janus kinase-signal transducer and activator of transcription pathway, which are not that new, insofar as their availability and licensing for clinical use, but “new” in the sense of how they can be integrated into treatment protocols. With longer follow-up of key trials in PV3 and continued research into myeloproliferative neoplasm (MPN) therapy, better integration and optimization of use is anticipated.
Research continues into the integration of interferons into PV therapeutic regimens.4 New interferon formulations are expected to be approved soon by the US Food and Drug Administration (FDA), with a focus on their efficacy for long-term PV disease control and molecular response. Both PV and essential thrombocytosis will benefit from greater understanding and development of therapy for myelofibrosis, given significant overlap in disease pathways, the landscape of molecular mutations, and, to a degree, a “final common pathway” paradigm.5 Specifically in PV patients, the agent PTG-300, a mimetic of the iron regulator hepcidin, has shown promise in, first, limiting or eliminating the need for therapeutic phlebotomy and, second, reversing iron deficiency.6 This represents a unique novel pathway for potential treatment.
What symptom management adjuncts to primary therapy can improve quality of life for individuals with PV?
A principle not unique to PV, but true given the symptoms generated by MPNs, would be avoiding additional stressors and drivers of inflammation. This advice isn’t easy to pin down but boils down to basics of nutrition, hydration, rest, and generalized stress and anxiety management. This advice can overlap with risk assessment and management of contributors to vascular disease, such as managing or avoiding weight gain, hypertension, diabetes, and a sedentary lifestyle. These interventions might seem obvious but likely can all be helpful in improving quality of life.
In addition, keeping a symptom diary to monitor or log symptoms and circumstances that are intrinsic and specific to PV can help identify response to treatment, aggravating factors, and successful avoidance strategies.
How might developing therapies, such as inhibitors of the murine double minute 2 (MDM2) ligase, histone deacetylase inhibitors, and long-acting pegylated interferon alfa-2b contribute to better PV clinical outcomes? Which patients would be eligible for their use?
A stepwise approach to treating PV remains the wisest approach.7 We need to deploy our best and proven therapies, which can be as simple as antiplatelet therapy and therapeutic phlebotomy, and then color that approach with a deeper dive into myelofibrosis risk early, often by way of imaging and molecular diagnostics, and by being held to a high standard — in the case of minimal or absent inflammatory symptoms, that means ideal hematocrit control and reduction or elimination of contributing risk factors.
To expect that patients with “perfect numbers” are going to have a perfect response and no symptoms or minimal risk is too often the assumption; in fact, a careful symptom inventory and follow-up can reveal that patients need a change in therapy or more therapy. More precise molecular risk stratification will help dictate who needs, and who responds to, more intensive therapies such as histone deacetylase inhibitors or reactivation of the tumor suppressor p53 through inhibition of MDM2. With more confidence in the interferons and their long-term benefit, acceptance of the broad but manageable (and avoidable) adverse effects associated with this class of drugs, and FDA approval, they might prove to be a valuable tool when indicated.
Has availability of newer therapies, such as ropeginterferon alfa-2b and ruxolitinib, changed standard PV treatment protocols?
Ruxolitinib offers respite for patients with hydroxyurea-related adverse events, patients with unbalanced or incomplete response with hydroxyurea, and patients with good blood count control but intolerable symptoms from persistent PV.
Ropeginterferon alfa-2b, if eventually approved, will help move the needle on interferons for more indolent MPNs (PV and, potentially, essential thrombocytosis as well) and allow us to aim for more comprehensive and potentially meaningful remission in our patients.
How can further research into clonal hematopoiesis change clinical care for patients with PV?
Genome sequencing and the discovery of more age-related pervasive clonal blood changes have already helped unravel the underpinnings of MPNs. Sequencing led to identification of driver mutations, has aided in molecular risk stratification (confirmed in myelofibrosis and confirmed or suspected in PV, with more data to come), and has begun to lead to better interventions. An example of such progress is the concept of adding isocitrate dehydrogenase (IDH)1 or IDH2 inhibitors to therapy for patients with an MPN in whom higher risk is expected because of added mutations in IDH1 and IDH2.8
I find myself advising patients that “information is power”: The more we seek, the more we find. Although it is advisable to not over-interpret or over-call observations, we have come a long way in PV. It is a highly treatable and chronic disease with varying threats over time, yet understanding it well, and staying a step ahead and beyond — rather than reacting to its complications or to its evolution into myelofibrosis — is an opportunity gained, rather than an opportunity lost.
Posted by Haymarket’s Clinical Content Hub. The editorial staff of Hematology Advisor had no role in this content’s preparation.
- Marchioli R, Finazzi G, Specchia G, et al; for the CYTO-PV Collaborative Group. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med. 2013;368(1):22-33. doi:10.1056/NEJMoa1208500
- Delhommeau F, Dupont S, Tonetti C, et al. Evidence that the JAK2 G1849T (V617f) mutation occurs in a lymphomyeloid progenitor in polycythemia vera and idiopathic myelofibrosis. Blood. 2007;109(1):71-77. doi:10.1182/blood-2006-03-007146
- Venugopal S, Mascarenhas J. Novel therapeutics in myeloproliferative neoplasms. J Hematol Oncol. 2020;13(1):162. doi:10.1186/s13045-020-00995-y
- Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2021 update on diagnosis, risk-stratification and management. Am J Hematol 2020;95(12):1599-1613. doi:10.1002/ajh.26008
- Spivak JL. Are polycythemia vera, essential thrombocytosis, and primary myelofibrosis 1, 2, or 3 diseases? Leukemia. 2021;35(7):1890-1893. doi:10.1038/s41375-021-01254-w
- Ginzburg Y, Kremyanskaya M, Kuykendall AT, et al. Hepcidin mimetic (ptg-300) reverses iron deficiency while controlling hematocrit in polycythemia vera patients. Presented at: the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition; December 5-8, 2020. Abstract 1689.
- Mesa RA, Jamieson C, Bhatia R, et al. NCCN guidelines insights: Myeloproliferative neoplasms, version 2. 2018. J Natl Compr Canc Netw. 2017;15(10):1193-1207. doi:10.6004/jnccn.2017.0157
- Tefferi A, Lasho TL, Abdel-Wahab O, et al. IDH1 and IDH2 mutation studies in 1473 patients with chronic-, fibrotic- or blast-phase essential thrombocythemia, polycythemia vera or myelofibrosis. Leukemia. 2010;24(7):1302-1309. doi:10.1038/leu.2010.113