Dr Harrison on Factors Influencing Patient Prognosis and Treatment Selection in Myelofibrosis

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April, 22, 2025

Author(s): Claire Harrison, MD, FRCP, FRCPath

Fact checked by: Ashling Wahner ,Courtney Flaherty

Claire Harrison, MD, FRCP, FRCPath, a professor of myeloproliferative neoplasms, a consultant, and a clinical director at Guy’s and St. Thomas’ Hospital, discussed the general treatment algorithm for myelofibrosis management, as well as how certain mutations affect patient prognosis and treatment decision-making.

Myelofibrosis is a heterogeneous myeloproliferative neoplasm with significant variability in clinical presentation and disease trajectory, Harrison began. Accurate diagnosis is the foundational step, necessitating careful review of histopathology, peripheral blood findings, bone marrow morphology, and molecular genetics—even in patients who have been referred from other institutions, she stated. Key diagnostic indicators include the presence of splenomegaly and constitutional symptoms, as well as driver mutations, such as JAK2, CALR, and MPL, which support a diagnosis of myeloproliferative neoplasm, Harrison detailed.

Furthermore, assessment of patient-specific factors is essential to inform therapeutic strategy, she continued. This includes evaluating comorbid conditions that may limit treatment options and determining the dominant clinical manifestations of each patient’s disease, Harrison noted. Patient education plays a critical role in this step, with efforts made by oncologists to ensure patient comprehension of the diagnosis—often explicitly referring to myelofibrosis as a “blood cancer”—and to connect patients with advocacy resources when appropriate, she explained.

Prognostication in myelofibrosis incorporates multiple validated models, with modern tools integrating both clinical and molecular data, Harrison said. Driver mutations aid diagnostic classification; however, the absence of these mutations in triple-negative cases warrants expanded next-generation sequencing to identify alternative pathogenic mutations, according to Harrison. The presence of high molecular risk mutations—including ASXL1, IDH1/2, SRSF2, U2AF1, TP53, RUNX1, and NRAS—portends a poorer prognosis and should influence risk stratification and treatment planning, Harrison concluded.

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Thrombosis May Increase Risk of Cardiovascular Disease, Secondary Cancers in Myeloproliferative Neoplasms

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April 21, 2025

Sarah Dingli, Saubia Fathima, Priyansh Faldu, Naseema Gangat, David Dingli & Ayalew Tefferi

Primary myelofibrosis (PMF) is a myeloid neoplasm that is currently classified in the category of JAK2 mutation-prevalent myeloproliferative neoplasms (JAK2-MPNs) [1]; other members of JAK2-MPNs include essential thrombocythemia (ET) and polycythemia vera (PV). JAK2-MPNs are characterized molecularly by JAK-STAT activating mutations, involving JAK2, CALR, and MPL genes, and morphologically by trilineage myeloid proliferation in the bone marrow (BM) that is accentuated by megakaryocyte proliferation and atypia [2]. Peripheral blood (PB) manifestations of JAK2-MPNs include leukocytosis, thrombocytosis, and/or erythrocytosis while other disease features include splenomegaly, thrombosis, bleeding, microvascular disturbances, pruritus, and constitutional symptoms. Patients with MPN are at risk for premature death and disease progression into a fibrotic or leukemic disease phase [3]. Disease complications in JAK2-MPNs are most severe in PMF where median survival is estimated at 4.4 years and leukemic progression at 9%, at a median follow-up of 3.2 years [4].

Leukocytosis, in general, has long been identified/suspected as a risk factor for a number of disease complications in JAK2-MPNs including overall and leukemia-free survival [5, 6], disease progression [7, 8], thrombosis risk [9,10,11], and extramedullary hematopoiesis [12]. Considering the multicomponent nature of leukocytes, more recent studies in JAK2-MPNs have appropriately looked into the differential prognostic impact of absolute neutrophil (ANC) [13,14,15], monocyte (AMC) [13, 16,17,18,19], and lymphocyte (ALC) counts [13,14,15]. By comparison, fewer studies have reported on the prognostic contribution of absolute basophil (ABC) or eosinophil (AEC) counts in JAK2-MPNs, in general, and in PMF, in particular, not associated with tyrosine kinase fusion genes [20,21,22,23,24]. On the other hand, the prognostic relevance of basophilia in chronic myeloid leukemia (CML) is well established and is taken under consideration in defining accelerated phase CML [25, 26]. In the current study, we utilized a large Mayo Clinic database of patients with PMF in order to describe the prevalence and the clinical, molecular, and prognostic correlates of ABC and AEC.

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Introduction to a How I Treat series on myeloproliferative neoplasms

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April 17, 2025

Jason Gotlib, MD

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.

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Real world outcomes of momelotinib in myelofibrosis patients with anemia: results from the MOMGEMFIN study

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Lucía Pérez-Lamas, Adrián Segura Diaz, Regina García Delgado, Alberto Álvarez-Larrán, María Alicia Senin, Elvira Mora, María Laura Fox, Irene Pastor Galan, Gemma Azaceta, et al.

Standard treatment for symptomatic myelofibrosis (MF) patients includes JAK inhibitors (JAKi) like ruxolitinib and fedratinib [1,2,3,4], but their effectiveness is often limited by transient responses and the development of cytopenias [5]. Recently, momelotinib received FDA and EMA approval for treating splenomegaly and disease-related symptoms in adult patients with MF and anemia. In addition to JAK1/JAK2 inhibition, momelotinib targets the activin A receptor type 1 (ACVR1), which regulates iron metabolism through hepcidin, contributing to its unique therapeutic profile [6]. The efficacy of momelotinib in improving symptoms, reducing spleen size, increasing hemoglobin (Hb) levels, and reducing transfusion dependency in both JAKi naïve and JAKi exposed MF patients has been demonstrated in several clinical trials [7,8,9,10,11].

Given its recent approval, real-world data on momelotinib use is still limited. To gather evidence on its efficacy and safety in routine practice, the Spanish Group of Philadelphia-negative Myeloproliferative Neoplasms (GEMFIN) initiated the MOMGEMFIN study, analyzing MF patients treated with momelotinib through a managed access program.

This study was a multicenter, retrospective analysis of adult patients treated with momelotinib (JAK-naïve or JAK-exposed) from March 2023 to July 2024. Eligible participants had primary or secondary MF with anemia and disease-related symptoms or symptomatic splenomegaly. Anemia was defined as Hb values less than 11 g/dL for men and less than 10 g/dL for women. Anemia response was based on the 2024 IWG-ELN criteria [12]. Transfusion dependency was classified as requiring at least one red blood cell (RBC) unit per month or three or more units over 12 weeks. Spleen evaluation followed the 2013 ELN (IWG-MRT) criteria [13]. Adverse events (AEs) were graded per CTCAE version 5.0.

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Advances in Blood Cancer Care for Veterans

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April 16, 2025| Federal Practitioner
Thomas Rodgers, MD

Hematologic malignancies encompass a broad range of distinct cancers, generally categorized as lymphoid (eg, lymphoma), myeloid (eg, leukemia, myelodysplastic syndromes, myeloproliferative neoplasms [MPNs]), and plasma cell neoplasms (eg, multiple myeloma).1 The veteran population is aging; this, in combination with other potential veteran-specific risk factors, is leading to an increased risk of hematologic malignancies.2 Of note, the risk for MPN diagnosis has recently been studied in veterans who served during the Korean, Vietnam, and Persian Gulf War eras.3 In addition, survival trends for different blood cancers, such as lymphoid malignancies, vary among veterans exposed to Agent Orange.4 Conflicting results have been found that point to the importance of future research.4 

Veterans in rural areas face barriers to treatment and clinical trial enrollment due to long travel distances and lack of trial availability, creating what are termed “clinical trial deserts.”5 Teleoncology has become crucial in bridging this gap by improving access to blood cancer treatments and clinical trials.5,6 Novel decentralized trial designs involving telehealth can further expand participation in remote areas.5

Over the past year, there have been advances in the treatment of blood cancers as well as the use of large data sets to better understand cancers trends and new technologies to reduce disparities in access to care.6,7 The availability of greater therapeutic options, new care modalities, and improved risk assessments herald an exciting time in the care of patients with hematologic malignancies, with the expectation that this care will continue to advance through 2025.

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Fedratinib Shows Promise in Long-Term MPN Success With Tolerable Toxicity

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By Hany Elmariah, MD

A phase 1 trial investigated the safety and tolerability of maintenance therapy with the JAK2 inhibitor fedratinib (Inrebic) following allogeneic hematopoietic cell transplant (HCT) for myeloproliferative neoplasms (MPNs) and myelodysplastic syndrome/MPN overlap syndromes.

While HCT offers potential cure for MPNs, posttransplant relapse remains a significant challenge. Fedratinib, effective in myelofibrosis, with a favorable safety profile and oral administration, presents a rational strategy to reduce relapse and potentially prevent graft-vs-host disease (GVHD) while preserving the graft-vs-tumor (GVT) effect.

“Usually with fedratinib, the main toxicities are cytopenia, so low blood counts. We also see a fair amount of [gastrointestinal (GI)] toxicity, nausea, vomiting, or diarrhea,” said Hany Elmariah, MD, associate member at the Moffitt Cancer Center in the Department of Bone Marrow Transplant and Cellular Immunotherapy, in an interview with Targeted OncologyTM.

The study enrolled patients post-HCT who received fedratinib between days +60 and +100 for up to 1 year. The trial utilized a 3+3 design to determine the maximum tolerated dose (MTD). Eleven patients were evaluable for dose-limiting toxicities (DLTs). The MTD was identified as 400 mg daily. While no DLTs occurred within the 30-day window, 4 patients withdrew due to non-DLT adverse events. Notably, only 1 patient developed severe chronic GVHD. The median progression-free survival was 12.4 months, and the 1-year overall survival was 100%.

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New Trial Will Assess Safety and Efficacy of MF Drug

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Leonardo Jaimes, MD

Publish Date

A clinical trial aiming to determine the efficacy, safety, and pharmacokinetics of the experimental drug WJ01024 combined with ruxolitinib in patients with myelofibrosis (MF) is set to begin soon.

“Although the clinical efficacy of ruxolitinib tablets has been confirmed, only about half of MF patients can achieve the ideal therapeutic effect (≥35% reduction in spleen volume and ≥50% improvement in disease symptoms at 24 weeks),” the authors wrote. “Therefore, there is an urgent need for innovative drugs that can be combined with ruxolitinib tablets to enhance therapeutic efficacy and meet clinical needs,” they added.

WJ01024 aims to enhance the therapeutic efficacy of ruxolitinib through  XPO-1 inhibition. Previous in vitro studies have confirmed that the drug enhances ruxolitinib anti-cell proliferation activity, the researchers noted. Furthermore, preliminary studies on humans suggest that WJ01024 is effective as monotherapy for relapsing patients and those intolerant to JAK inhibitors, they added.

The trial will consist of a dose escalation and a dose extension phase (phase 1a and phase 2). Phase 1b will divide patients into three groups receiving 40 mg, 60 mg, and 80 mg of WJ01024, respectively. Phase 2 will be an open-label evaluation of the efficacy and safety of the recommended dose in combination with ruxolitinib.

The study will only include patients diagnosed with MF and with the international prognostic scoring system risk category of intermediate-1, intermediate-2, or high-risk. Patients in the accelerated blast phase or previous treatment with either JAK or XPO-1 inhibitors are not eligible for participation.

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Rusfertide Cuts Phlebotomy Need in Polycythemia Vera: Andrew Kuykendall, MD

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April 10, 2025

Author(s): Maggie L. Shaw, Andrew Kuykendall, MD

With an expected completion date sometime in June, the phase 3 VERIFY trial (NCT05210790) will soon conclude its investigation of rusfertide (Takeda) as add-on therapy to a patient’s current course of treatment for their polycythemia vera. The investigative agent has already received breakthrough therapy, orphan drug, and fast track designations from the FDA.

In this fourth part of a discussion with The American Journal of Managed Care®, Andrew Kuykendall, MD, clinical researcher at Moffitt Cancer Center and VERIFY investigator, speaks to the impressive patient-reported outcomes seen thus far.

This transcript has been lightly edited for clarity; captions were auto-generated.

Transcript

Can you summarize the key findings seen so far in the phase 3 VERIFY study?

Super exciting results that we saw. The study design, a lot of this was really built on a phase 2 study that was published in The New England Journal of Medicine that took patients with polycythemia vera who were requiring phlebotomies on a regular basis. That study basically put everyone on rusfertide and assessed over time their need for phlebotomy. There are a couple of different nuances to that study, but I would say the take home point of what we saw is that rusfertide very effectively eliminated the need for these patients that were regularly needing phlebotomies to need any phlebotomies at all—really rapidly reduced that and so certainly paved the way for designing a phase 3 clinical trial that could show that in comparison to standard therapy.

This trial took patients that had polycythemia vera that were requiring regular phlebotomy—so at least 3 over the preceding 28 weeks or 5 over the course of the prior year—and it randomized them to either stay on their standard therapy and add rusfertide or stay on their standard therapy and add a placebo. Everyone was treated in kind of the standard way, even if you were randomized to the “placebo arm”; that was just the standard therapy. If you were on cytoreductive therapy like hydroxyurea or interferon or ruxolitinib—these are agents we use to treat the disease as well—you stayed on those agents and you continued to get phlebotomies, as you would if you if you were kind of in routine clinical care. Then the other group did the same thing, but they added on rusfertide as a weekly subcutaneous injection. For 20 weeks, there was a a dose-finding period where rusfertide, the doses were increased based on hematocrit level and various different control of the disease.

The primary end point, at least in the US, was looking at the number of patients that were “phlebotomy eligible,” meaning that they needed a phlebotomy to control their disease—and that was being looked at between weeks 20 and 32. What we found is significantly more patients in the placebo group, so in the patients that were not receiving rusfertide, were “phlebotomy eligible” during that period of time. Another way to say that is, more patients in the rusfertide group did not need a phlebotomy during that that critical time period. Just another way of showing the control that rusfertide has, and that was the primary end point. Based on the phase 2 data, we certainly were optimistic that this was going to be reached.

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Exploring the interplay between myeloproliferative disorders and atherosclerosis

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Published April 3, 2025

Maham Khan, Sandipta Banerjee, Rekha Kumari, Shubhayu Roy Chowdhury, Nada Madkour, Ikponmwosa Jude Ogieuhi, Chinonyelum Emmanuel Agbo, Victor Oluwatomiwa Ajekiigbe, Olanipekun Lanny Ntukidem, Folajimi Josiah Atunde & Chukwuemelie Darlington Okeke

Abstract

The relationship between hematologic malignancies and atherosclerosis is vital in clinical conditions due to common risk factors. These two diseases may negatively affect cardiovascular health, so understanding their complex dynamics is essential for detecting disease mechanisms and establishing effective patient care. This review aims to focus on the involvement of hematologic malignancies in the onset and progression of atherosclerosis at a biological level. Furthermore, it looks at the case for heightened cardiovascular risk in patients with hematological cancers and the chances of management and treatment against it. A comprehensive literature review was performed, and studies that revealed the link between hematologic malignancies and atherosclerosis were preferred. Inclusion and exclusion criteria guided the selection of studies for consideration. The biological pathways between hematologic malignancies and atherosclerosis have been elucidated, including the inflammatory pathways and the shared risk factors. Clinical evidence reveals that cardiovascular diseases are more likely to occur in patients with hematologic cancers, thus showing the necessity of targeted preemptive measures to lower this risk. The findings reveal that it is essential to consider cardiovascular health when handling hematologic malignancies. Future research should focus on creating holistic treatment procedures that jointly deal with both conditions, which will be necessary to enhance patients’ lives and well-being.

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Navigating the peginterferon Alfa-2a shortage: practical guidance on transitioning patients to ropeginterferon alfa-2b

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Published April 3, 2025

Ruben Mesa, Abdulraheem Yacoub, Tsewang Tashi, Wanxing Chai-Ho, Chang Ho Yoon & John Mascarenhas

Dear Editor,

We write to highlight the critical shortage of peginterferon alfa-2a (peg-IFN), as confirmed by the FDA [1], which has impacted many patients with myeloproliferative neoplasms (MPNs). Those relying on peg-IFN for long-term disease control in polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) face supply disruptions that can compromise disease stability and overall health.

Ropeginterferon alfa-2b (ropeg-IFN) is a viable alternative. It is the only FDA-approved interferon for PV and is considered first-line therapy as per the January 2025 NCCN Guidelines [2]. Though not yet approved for ET or MF, off-label use may be justified in situations where no other options exist. Our group has accumulated experience in transitioning patients from peg-IFN to ropeg-IFN due to historic insurance issues and clinical trial participation, allowing us to propose practical strategies for safe conversion.

A best-practice approach to dose equivalence, based on collective experience and real-world data, is pragmatic given that no formal head-to-head dosing trials exist.[3,4,5] For patients previously on peg-IFN 135–180 µg weekly, we typically initiate ropeg-IFN at 250–350 µg every two weeks, adjusting for hematologic response and tolerability. Those on lower peg-IFN doses (45–90 µg/week) may begin on 200–250 µg every two weeks. If disease control proves challenging, starting at, e.g., 350 µg with possible escalation to 500 µg every two weeks can be considered. Whichever starting dose is chosen, close monitoring and dose adjustments are essential to maintain efficacy while minimizing toxicity.

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