Introduction to a How I Treat series on myeloproliferative neoplasms

Like other hematologic malignancies, the management of myeloproliferative neoplasms (MPNs) reflects a dynamic assessment of the grades of clinical evidence to guide the appropriateness of therapeutic interventions. The National Comprehensive Cancer Network and European LeukemiaNet have synthesized these data into risk-stratified guidelines to provide foundational approaches for diagnosing and treating MPNs.^1,2 However, the biologic, clinical, and molecular heterogeneity of MPNs, as well as the unique treatment goals of individuals often leads to a melding of data-driven algorithms with personalized care approaches informed by shared decision-making between patients and their physicians. Although this hybrid heuristic may introduce some imprecision in this era of precision medicine, it also recognizes that treatment decisions are not completely fated by the results of a multigene next-generation sequencing panel. This is a common theme running through the following 6 articles featured in this How I Treat series on MPNs:

• Mary Frances McMullin and Claire N. Harrison, “How I treat patients with low-risk polycythemia vera who require cytoreduction”

• Lucia Masarova and Helen T. Chifotides, “How I individualize selection of JAK inhibitors for patients with myelofibrosis”

• Akriti G. Jain and Aaron T. Gerds, “How I treat anemia in myelofibrosis”

• Deepti H. Radia, “How I diagnose and treat systemic mastocytosis with an associated hematologic neoplasm”

• Andreas Reiter, Georgia Metzgeroth, and Nicholas C. P. Cross, “How I diagnose and treat myeloid/lymphoid neoplasms with tyrosine kinase gene fusions”

• Alexandre Guy, Pierre-Emmanuel Morange, and Chloé James, “How I approach the treatment of thrombotic complications in patients with myeloproliferative neoplasms”

In the first How I Treat article, McMullin and Harrison discuss their approach to the use of cytoreduction in patients with low-risk polycythemia vera (PV).³ For high-risk patients (aged >60 years or history of thrombosis), standard care includes the addition of cytoreduction to the low-risk treatment backbone of low-dose aspirin and phlebotomy. In low-risk PV, progressive splenomegaly, leukocytosis, or thrombocytosis (eg, >1500 × 10⁹/L); high symptom burden (related to PV and/or severe iron deficiency); and persistence of frequent phlebotomy are examples of indications that may justify the use of cytoreduction.^1,2 In the last several years, molecular remission, eg, reduction of Janus kinase 2 (JAK2) V617F variant allele fraction, has increasingly animated the conversation between patients and physicians. This shift has likely been accelerated by the encouraging longer-term molecular results with ro-PEG-interferon-α-2b (BESREMi) in the CONTINUOUS-PV/PROUD-PV studies.^4,5 Although molecular remission is an intuitively attractive therapeutic goal, it remains to be established whether such deeper responses will ultimately translate into disease modification (eg, reduction in thrombosis, decreased evolution to myelofibrosis [MF] or acute myeloid leukemia, and improved overall survival). Individuals without a conventional indication for cytoreduction (especially younger patients who have a longer survival runway ahead of them), may still wish to seek an active treatment plan. The “if and when” to use cytoreduction in the patient with low-risk PV is a complicated calculus of potential side effects, impact on quality of life, financial toxicity, and a hedge that committing to a long-term treatment program will favorably bend the arc of the disease.

MF, particularly in its advanced phase, is the most challenging of the Philadelphia chromosome–negative MPNs to treat. In their How I Treat review, Masarova and Chifotides discuss how to individualize selection of JAK inhibitor therapy for patients with MF patients,⁶ and Jain and Gerds address how to think about and treat the causes of MF-associated anemia.⁷ The current 4 US Food and Drug Administration–approved JAK inhibitors (ruxolitinib, fedratinib, pacritinib, and momelotinib) all share the potential to mitigate splenomegaly and disease-related symptoms but also exhibit unique hematologic and nonhematologic side-effect profiles. Patient- and disease-specific variables such as age, performance status, degree of splenomegaly, the extent of marrow fibrosis, depth of cytopenias, molecular profile (including high-risk gene mutations), and comorbidities are some of the relevant factors used for individualizing therapy. At least some of these factors have been integrated into prognostic scoring systems such as DIPSS plus, GIPSS, MIPSS70+ version 2.0, and MYSEC.^8-11 The dosing of specific JAK inhibitors must also take into account the patient’s blood counts (eg, pacritinib is approved for a platelet count of <50 × 10⁹/L)¹² and disease phenotype (eg, the patient with MF who only has cytopenia(s) vs the individual with a high symptom burden and marked splenomegaly). Another consideration is whether JAK inhibition is being used on a time-limited basis to reduce splenomegaly and symptoms in anticipation of hematopoietic stem cell transplantation.

Anemia can be a presenting feature of MF, but may emerge over time for several reasons, including disease progression or the on-target effects of JAK inhibitors. Disentangling the relative contributions of each is not always easy or possible. As reviewed by Jain and Gerds,⁷ momelotinib and pacritinib may be preferred agents for their potential anemia remitting activity, which has been attributed to inhibition of ACVR1/ALK2.^13-15 In selected cases, an empiric trial of reducing the JAK inhibitor (eg, ruxolitinib) dose to ameliorate anemia may provide clinical benefit. The use of erythropoiesis stimulating agents (eg, erythropoietin and darbepoietin) and erythroid maturation agents (eg, luspatercept) either as monotherapy or in combination with JAK inhibitors is also discussed. MF-associated anemia remains a large unmet need and has been incorporated into several registrational trials as primary or secondary end points.

Included in this How I Treat series are topics related to the World Health Organization and International Consensus Classification major disease categories of “Mastocytosis” and “Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase (TK) gene fusions.”^16,17 At the American Society of Hematology (ASH) annual meeting, educational session titles for mast cell disease have sometimes been branded with the teaser “anxiety-provoking consultations.” This sentiment is understandable given the relative rarity of these diseases and their protean presentations. It can take time and some measure of “Sherlock Holmes”–level sleuthing to correctly diagnose systemic mastocytosis and its variants. This challenge is magnified in the subtype “SM with an associated hematologic neoplasm (SM-AHN),” the How I Treat feature authored by Radia.¹⁸ The AHN component, almost always of myeloid phenotype, can be masked by SM, and SM can lurk in the shadow of the AHN. Navigating this histopathologic fog can be helped by having an experienced hematopathologist as one’s copilot. The coexistence of these 2 diseases also makes it difficult to determine whether a patient’s active clinical issues relate to SM or the AHN (or both), and therefore how to prioritize treatment.

SM-AHN is also the subtype that most commonly exhibits a multimutated profile beyond the KIT D816V mutation, and it is the AHN that usually drives prognosis. Although KIT-targeting drugs have been highly effective in advanced SM, and reduce AHN-associated monocytosis and eosinophilia in the peripheral blood, ∼10% to 15% of patients with SM-AHN patients treated with KIT inhibitors have exhibited progression of their AHN, including transformation to acute myeloid leukemia during trial follow-up.^19,20 However, to date, there are no propensity-matched cohort studies comparing the natural histories of AHNs alone with the AHN component of SM-AHNs under the pressure of KIT inhibition. In her How I Treat piece,¹⁸ Radia discusses how to approach the challenges of SM-AHN in the modern KIT inhibitor era, including the roles of AHN-directed therapy and hematopoietic stem cell transplantation.

Myeloid/lymphoid neoplasms with eosinophilia and TK gene fusions relate to rearrangements involving PDGFRA, PDGFRB, FGFR1, JAK2, FLT3, and ETV6::ABL1.^16,17 Despite the term “eosinophilia” being part of the disease nomenclature, it is variably present and its absence cannot be reliably used as a prediagnostic checkpoint to rule out most subtypes comprising these ultrarare diseases. Their substantial phenotypic diversity also contributes to diagnostic delay and confusion. For example, the bone marrow/peripheral blood can be involved by a chronic or acute myeloid neoplasm, acute B- or T-cell acute lymphoblastic leukemia, or mixed phenotype acute leukemia. Extramedullary disease can present alone or together with bone marrow involvement, with the possibility for discordant immunophenotypes between the 2 tissue compartments.^16,17,21 In their How I Treat article, Reiter, Metzgeroth, and Cross discuss the variable prognoses of these diseases based on the involved TK and other disease factors such as whether the disease presents in chronic or blast phase.²² They also review the use of TK inhibitors (TKIs) such as imatinib for favorable disease subtypes (eg, PDGFRA and PDGFRB rearranged) and the use of TKIs as a cytoreductive bridge to hematopoietic stem cell transplantation for historically poor-risk subtypes (eg, FGFR1, JAK2, and FLT3 rearranged).

Thrombosis is an ever-present concern in MPNs. Prognostic scoring systems have been generated, primarily in PV and essential thrombocythemia, to stratify this risk and include variables such as age, prior history of thrombosis, JAK2 V617F status, presence of cardiovascular risk factors, and leukocytosis. In their How I Treat review, “How I approach the treatment of thrombotic complications in patients with myeloproliferative neoplasms,” Guy, Morange, and James discuss their cytoreductive, antiplatelet, and antithrombotic strategies for preventing arterial and venous thrombosis occurrence and recurrence.²³ Their cases touch on several management of deep and superficial (or distal) venous thrombosis, thrombosis in unusual sites (eg, splanchnic vein thrombosis), duration of anticoagulation, and the level of available evidence for use of direct oral anticoagulants (DOACs). Given the hemorrhagic diathesis of the MPN population, the authors also contextualize the bleeding risk for different approaches, especially DOACs, and for scenarios in which combination antiplatelet and antithrombotic agents may be warranted.

We hope you come away from this How I Treat series on MPNs with an increasing appreciation of their diagnostic and therapeutic challenges, while also feeling more informed (and less anxious) by the management pearls provided in these cases. I would also direct readers to the articles published in Hematology from the ASH 2024 annual meeting MPN education session, including How and Hobbs’ review on how to manage MPNs in the setting of pregnancy.²⁴ 

Conflict-of-interest disclosure: J.G. is a member of steering committees, chairman of central response review committees, serves on advisory boards, and receives honoraria from Blueprint Medicines, Cogent Biosciences, and Incyte, Inc; receives funding (institutional) for the conduct of clinical trials from Blueprint Medicines, Cogent Biosciences, Incyte, Protagonist Therapeutics, and Merck; and serves as vice chair of the National Comprehensive Cancer Network guidelines committee on myeloproliferative neoplasms.