Author Archives: MPN Advocacy & Education

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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Lactate is a Key Regulator of Immune Escape, Bone Marrow Fibrosis in Myelofibrosis

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February 11, 2025

Author(s):

Luke Halpern, Assistant Editor

New study results published in the Journal of Translational Medicine reveal that circulating lactate is a key regulator of immune escape and bone marrow (BM) fibrotic transformation in patients with myelofibrosis (MF), with a marked increase in lactate concentration and lactate import channel monocarboxylate transporter 1 (MCT1) expression in the site of blood cell production. The investigators suggest that MCT1 blocking could be used as a novel antifibrotic strategy in patients with MF.1

An enlarged image of fibrous scar tissue, dense collagen network
Myelofibrosis can cause fibrosis in bone marrow. | Image Credit: © Jasmine – stock.adobe.com

According to the study authors, the pathophysiology of MF is significantly influenced by alterations in the BM microenvironment, and these changes are often associated with the metabolic reprogramming of cancer cells in patients. Glycolysis is a hallmark aspect of the changes that occur in cancer cells; prior evidence from investigational models strongly suggests that lactate production is associated with tumor microenvironment (TME) progression in patients with certain types of cancer.1-3

Prior observations also indicate that increases in lactate dehydrogenase A (LDHA) have a central role in glycolysis, with high LDHA levels typically found in the sera of patients with MF, predicting shorter overall and leukemia-free survival. Within this context, excess lactate that is secreted by cancer cells can promote immune suppression and angiogenesis while also possibly playing a role in increasing the number of cancer-affiliated phenotypes (CAF), which promote fibrotic tumor formation, the investigators wrote.1,4

These authors sought to fill a gap in knowledge within the characterization of TME metabolic composition in patients with MF. Through their analysis, they demonstrated that the amount of circulating lactate increases in patients with MF, which eventually leads to the expansion of immunosuppressive subsets and the development of fibrosis. Furthermore, they observed that the expression of lactate export channel monocarboxylate transporter 4 (MCT4) in the TME becomes deeply remodeled during fibrotic transformation, “suggesting a link between lactate trafficking and pro-fibrotic establishment.”1

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Forget about ‘robot uprisings’, AI is a force for good

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7th Feb 2025 – Dr Sammy Eden

Professor Daniel Royston is a haematopathologist at Oxford University Hospitals NHS Trust who is using AI to help improve the diagnosis and treatment of blood cancer. Here he writes about the benefits of AI in his research.

An artificial intelligence imagines what a Blood Cancer UK researcher working with AI might look like

AI imagines what a Blood Cancer UK researcher using AI in their work might look like. This image was AI generated for illustrative purposes.

AI is ever present in our world today

The majority of us use AI regardless of whether we realise it, and whether we like it or not. From social media platforms such as Instagram and Facebook, to Google Maps, to computer tools such as Spell Check and virtual assistants like Siri and Alexa. AI has been around for decades, but the rate of development and growth of AI is now surprising us all.

There is a lot of speculation and uncertainty around the use and impact of artificial intelligence or AI. I want to illustrate that when used responsibly, AI is truly a force for good in the healthcare space. But of course, I would say that… because I’m currently harnessing AI to help beat blood cancer.

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Reevaluating Available Options for Anemia in Myelofibrosis

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February 6, 2025

By Targeted Oncology Staff
Fact checked by Jonah Feldman

DISCUSSION QUESTIONS

  • How do you monitor and manage anemia in patients with primary myelofibrosis prior to starting Janus kinase (JAK) inhibitor therapy?​
  • While receiving a JAK inhibitor therapy?

Andrew Kuykendall, MD: How do you monitor and manage anemia in patients with myelofibrosis even prior to starting a JAK inhibitor? If you’re initially evaluating someone, they come in with hemoglobin of 7 or 8 g/dL or something like that, how does that impact your thinking, and how do you work that up?

Lazaros Lekakis, MD: The first thing is to make sure that they don’t have something easily fixable [such as] iron, B12, or folate deficiency. Theoretically, if you don’t have any nutritional cause or any immune causes, you could use erythropoietin analogs, but they are very tricky because they don’t help with the spleen, at least in my experience, and they may increase the risk of clots. I try to avoid them if possible. If I have to start a JAK inhibitor, if they have symptoms, either I go away from ruxolitinib [Jakafi] or I start a low dose of ruxolitinib. Sometimes I use anabolic steroids and prednisone. We have the thalidomide/prednisone [regimen] that now is kind of forgotten about.

Kuykendall: Erythropoietin-stimulating agents [ESAs] are limited in what they do, and certainly not helping other aspects of the disease. You did mention one of my favorite regimens, thalidomide/prednisone, which is looked over a bit nowadays, but has quite a potential for efficacy in terms of improving hemoglobin. But it’s probably something that’s gone by the wayside in many practices.

Luis Sumoza, MD: As Dr Lekakis says, there are some other options that you can use. Danazol is sometimes something you can use perfectly in this patient population. From the JAK inhibitors, there is momelotinib [Ojjaara]. But a priority for me is to refer a patient for a stem cell transplant; when I was a fellow, we did the first allogeneic bone marrow transplant at the University of Illinois, Chicago, and it was a very nice experience.

Kuykendall: [Dr Lekakis] also mentioned steroids, [and we are] thinking about things like danazol, androgen derivatives. We saw from the MOMENTUM study [NCT04173494] looking at momelotinib that danazol is an active agent.1 It was a large, randomized trial, one of the first randomized trials with danazol. The focus there was on momelotinib, but there’s also a lot to learn about what danazol could do as well from that study.

Sumoza: You’re mainly talking about anemia here, and [if], the patient is not a candidate for a transplant or a clinical trial [there are] the data about navitoclax/ruxolitinib, which basically double the response and reduction of the spleen.2

Kuykendall: Yes, these emerging therapies to some degree may change how we approach this disease. But I think that with some of these older therapies, especially when you’re when you’re first talking about someone who’s coming in with anemia, you need to think about ESA, danazol, and thalidomide/prednisone.

I think that ESA is probably the most prominently used. How many of you are checking serum erythropoietin levels in these patients to assess their candidacy for ESAs, is that a common practice?

Mukesh Kumar, MD: Yes, I’m checking on all of my patients.

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