Category Archives: Treatment

Real-World Findings Confirm Clinical Data on Momelotinib in MF With Anemia

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May 1, 2025

Author(s): AJMC Contributor

Real-world insights on momelotinib (Ojjaara; GlaxoSmithKline) in patients with myelofibrosis (MF) and anemia have been published, showing consistent and, in some cases, better results than those shown previously in clinical studies of the drug.1

The results offer some of the first glimpses into real-world findings of the Janus kinase (JAK) inhibitor, which received approval toward the end of 2023, becoming the first and only treatment indicated for patients with MF and anemia.2

“This study presents the largest real-world cohort of MF patients treated with momelotinib and is the first to apply the recently proposed 2024 criteria for anemia response,” wrote the researchers, publishing the insights in Blood Cancer Journal.1

The retrospective study included 122 patients with MF and anemia across multiple treatment centers. Patients had disease-related symptoms or symptomatic splenomegaly and could be JAK-naive (23.4%) or previously received treatment with a JAK inhibitor (76.6%).

At treatment initiation, 73.8% of patients were dependent on transfusions. Among these patients, the median Hb level increased from 7.7 g/dL (range, 4.7-9.8) at treatment initiation to 8.7 g/dL at 3 months of follow-up. By 6 months, 30.6% of patients had major responses and 36.1% had minor responses. At the time follow-up point, median red blood cell transfusion frequency had dropped from 4 units per month to 1 unit per month.

The results offer some of the first glimpses into real-world findings of the JAK inhibitor momelotinib, which was approved in 2023.

Among the remaining patients who were not dependent on transfusions at treatment initiation, the median Hb level increased from 8.9 g/dL (range, 7.2-10.8) to 10.2 g/dL. At 6 months of follow-up, 36.4% of patients demonstrated a major response, and 27.3% demonstrated a minor response.

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Prediction of resistance to hydroxyurea therapy in patients with polycythemia vera: a machine learning study (PV-AIM) validated in a prospective interventional phase IV trial (HU-F-AIM)

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Published April 25, 2025

Florian H. Heidel, Valerio De Stefano, Matthias Zaiss, Jens Kisro, Eva Gückel, Susanne Großer, Mike W. Zuurman, Kirsi Manz, Kenneth Bryan, Armita Afsharinejad, Martin Griesshammer & Jean-Jacques Kiladjian

Abstract

Polycythemia vera (PV) is a myeloproliferative neoplasm associated with increased thromboembolic (TE) risk and hematologic complications. Hydroxyurea (HU) serves as the most frequently used first-line cytoreductive therapy worldwide; however, resistance to HU (HU-RES) develops in a significant subset of patients, leading to increased morbidity and necessitating alternative treatments. This study, part of the PV-AIM project, employed machine learning techniques on real-world evidence (RWE) from the Optum® EHR database containing 82.960 PV patients to identify baseline predictors of HU-RES within the first 6–9 months of therapy. Using a Random Forest model, the study analyzed data from 1850 patients, focusing on laboratory parameters and clinical characteristics. Key predictive markers included red cell distribution width (RDW) and hemoglobin (HGB), showing the strongest association with HU-RES. A synergistic interaction between RDW and HGB was identified, enabling TE risk stratification. This study provides a robust framework for early detection of HU-RES using readily available clinical data, facilitating timely intervention. These findings underscore the importance of personalized treatment approaches in managing PV and highlight the utility of machine learning in enhancing predictive accuracy and clinical outcomes. Based on the results of PV-AIM we initiated an open-label, prospective, single-arm, interventional, phase IV study (HU-F-AIM) evaluating HU-resistance/intolerance. Validation of predictive biomarkers may facilitate identification of patients at risk of HU resistance who may benefit from alternative treatment options, possibly preventing ongoing phlebotomy during HU treatment, a frequent therapeutic choice in high-risk PV associated with early disease progression and increased thromboembolic complications. We propose an updated terminology that differentiates between true molecular resistance and clinical resistance, that may indicate the requirement for alternative therapeutic strategies.

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Assessing Risk for JAK Inhibitor Selection in Myelofibrosis

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By Targeted Oncology Staff

In part 1, experts explores how assessing individual risk factors is crucial in selecting the appropriate JAK inhibitor for patients with myelofibrosis.

CASE

AARON T. GERDS, MD, MS: How do you use molecular testing, bone marrow results, and clinical features to stratify risk in patients with myelofibrosis?

PRITHVIRAJ BOSE, MD: At this point, I believe we are all receiving the myeloid mutation panels. We also order JAK2, MPL, and CALR: the 3 drivers. However, most clinicians would order a myeloid mutation panel because we know that many of the mutations are prognostic. This is the whole point of risk stratification, which is now increasingly sophisticated and integrates multiple clinical, molecular, [and] cytogenetic variables to determine who needs a transplant.

These are the first actions I take when speaking with a new patient. I get an idea of their risk in terms of survival and prognosis, and that informs my decision to refer them to transplant. I then counsel the patient appropriately.

I do not believe molecular testing informs treatment because our drugs are, for the most part, mutation agnostic. All we have are JAK inhibitors, which are not mutation specific. However, from a prognostic standpoint, the [role] of molecular testing is key.

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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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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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JAK Inhibitors Associated With Less Thromboembolic Events in MF

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Leonardo Jaimes, MD
Publish Date:

Janus kinase inhibitors (JAKi) therapy could prevent thromboembolic events in patients with myeloproliferative neoplasms (MPNs) such as myelofibrosis (MF), according to a recently published meta-analysis in the Journal of the British Society of Hematology.

Despite the well-documented clinical improvement associated with JAKi therapy in patients with MPNs, adverse effects such as weight gain and cholesterol increase have raised concerns about increased cardiovascular risk. Furthermore, the ORAL surveillance trial demonstrated that JAKi was associated with an increase in the rate of major adverse cardiovascular events (MACEs).

As the effects of JAKi therapy on thrombotic risk are still poorly understood, the authors aimed to compare the rates of MACEs, thrombosis, and hypertension in patients with MPN taking JAKis through a meta-analysis.

The meta-analysis included prospective and retrospective studies involving patients taking JAKi and a JAKi-naive control group. The initial search yielded over 1500 studies, of which 23 met the inclusion criteria.

Nine studies, including over 1800 patients, assessed thromboembolic risk. The pooled analysis with a confidence interval of 95% revealed that the rate of thromboembolic events was 48% lower in patients receiving JAKi therapy. The pooled analysis of the 16  studies analyzing MACE or hypertension, on the other hand, revealed no significant difference between groups.

The authors remarked that the findings correspond with evidence presented by Samuelson et al., which demonstrated that ruxolitinib was associated with lower rates of hemolysis. Furthermore, recent posthoc analysis of the ORAL surveillance trial found that the apparent increased frequency of MACE in patients receiving JAKi therapy was observed in patients with preexisting atherosclerotic disease.

“JAKi treatment was not associated with an increased risk of MACE or hypertension, adding to the existing body of evidence demonstrating the safety of JAKi in the treatment of MPNs,” the authors wrote.

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Real World Management of Cytopenias and Infections in Patients With Myelofibrosis Treated With Ruxolitinib

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Liesl A. Butler, Cecily Forsyth, Claire Harrison, Andrew C. Perkins

ABSTRACT
Introduction: Ruxolitinib was the first JAK2 inhibitor approved for the treatment of primary and secondary myelofibrosis. It is
currently used worldwide as first-line therapy for advanced disease (intermediate-2 and high-risk) and is effective in polycythaemia
vera (PV) and essential thrombocythaemia (ET), but not funded for this indication in many countries. Ruxolitinib has proven
benefits with respect to symptom control, reduction in spleen size and prolongation of survival; however, it rarely induces a
substantial reduction in allele burden and never provides a cure. Moreover, there are frequently encountered adverse effects and
dosing issues that require careful management to optimise its therapeutic benefit.

Methods and Results: In this case-based review, we use seven informative common clinical scenarios to discuss appropriate
investigation and management of cytopenias and infection issues.

Conclusions: We make recommendations based on 15 years of experience in using ruxolitinib and other JAK inhibitors for the
treatment of myelofibrosis. We discuss when allogeneic haematopoietic stem cell transplantation (AHSCT) should be considered
and some of the currently available alternative JAK inhibitors and trial options when AHSCT is not an option.

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Emerging Therapies in Myelofibrosis Could Extend Beyond JAK Inhibitors

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March 24, 2025

Author(s): Ashley Chan

Fact checked by: Ashling Wahner

The September 2023 FDA approval of momelotinib (Ojjaara) for the treatment of patients with primary and secondary myelofibrosis with anemia provided the treatment paradigm with its fourth FDA-approved JAK inhibitor, a class of drugs that has helped improve symptoms associated with myelofibrosis and decrease spleen size, according to Raajit Rampal, MD, PhD.

Additional classes of drugs, such as BET inhibitors and immunotherapy agents, are also currently under investigation in clinical trials and could become “game-changers” if effective, Rampal noted.

“The major [message is] that myelofibrosis is not a monolithic disease, and the selection of the treatment needs to be tailored to the underlying issues and challenges the patient is facing,” said Rampal in an interview with OncLive®.

In the interview, Rampal discussed currently available JAK inhibitors and their limitations, emerging treatments for myelofibrosis, tips for treatment selection, and his takeaways from the 6th Annual Miami Cancer Institute Global Summit on Immunotherapies for Hematologic Malignancies.

Rampal is a hematologist-oncologist, the director of the Center for Hematologic Malignancies, and the director of the Myeloproliferative Neoplasms Program at Memorial Sloan Kettering Cancer Center in New York, New York.

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Dr Bhat on the Influence of MPN Risk Stratification on Treatment Decision-Making

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March 20, 2025

Author(s): Seema A. Bhat, MD

Fact checked by: Ashling Wahner, Courtney Flaherty

Seema A. Bhat, MD, a hematologist at The Ohio State University Comprehensive Cancer Center—James; as well as an assistant professor in the Department of Internal Medicine in the Division of Hematology at The Ohio State University, discusses the importance of risk stratification for navigating treatment selection for patients with myeloproliferative neoplasms (MPNs).

Stratifying patients with MPNs into appropriate risk groups is crucial for treatment decision-making, as patients’ individual risk factors strongly factor into selection, Bhat says. Typically, patients with low-risk disease will receive treatments directed at symptom management, whereas cytoreductive agents like hydroxyurea, as well as targeted therapies like JAK inhibitors, are considered for patients with high-risk disease, she explains. Furthermore, allogeneic stem cell transplantation may be a curative treatment option for patients with very high–risk MPNs, she notes.

The revised IPSET Thrombosis Score is used for essential thrombocythemia (ET) risk stratification. Patients are considered to have low-risk polycythemia vera (PV) if they are younger than 60 years of age and have no history of thrombosis; patients are considered to have high-risk PV if they are older than 60 years of age and/or have a thrombosis history.

Four JAK inhibitors are FDA approved for the treatment of patients with MPNs. Ruxolitinib (Jakafi) is indicated for adult patients with intermediate- or high-risk myelofibrosis, including primary myelofibrosis and secondary (post-PV or post-ET) myelofibrosis; as well as adult patients with PV who have had an inadequate response or are intolerant to hydroxyurea. Fedratinib (Inrebic) is approved for adult patients with intermediate-2 or high-risk primary or secondary myelofibrosis. Pacritinib (Vonjo) is indicated for use in adult patients with intermediate- or high-risk primary or secondary myelofibrosis with a platelet count below 50 × 109 /L. Finally, momelotinib (Ojjaara) is approved for adult patients with intermediate- or high-risk primary or secondary myelofibrosis with anemia.

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Understanding Hematocrit Thresholds in Polycythemia Vera Treatment

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March 19, 2025

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

In early March, The American Journal of Managed Care® spoke with Andrew Kuykendall, MD, a clinical researcher at Moffitt Cancer Center who focuses on myeloproliferative neoplasms (MPNs), myelodysplastic syndrome/MPN overlap syndromes, and systemic mastocytosis. Kuykendall is an investigator on the phase 3 VERIFY trial (NCT05210790) of the injectable hepcidin mimetic rusfertide (Takeda) to treat polycythemia vera (PV) by enabling patients to achieve and sustain hematocrit control.1 Hematocrit is the measure of the percentage of red blood cells in the body.2

Treatment guidelines in PV currently recommend maintaining hematocrit below 45%, with a higher threshold for men vs women.2 For part 2 of this interview, Kuykendall explains the reasoning behind having different hematocrit thresholds.

In the first part of the interview, Kuykendall discussed how PV manifests and common ways to reduce its negative impact on patient quality of life.

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