Tag Archives: mpn

Defective neutrophil clearance in JAK2V617F myeloproliferative neoplasms drives myelofibrosis via immune checkpoint CD24

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May 15, 2025

Eman Khatib-Massalha, Christian Andrea Di Buduo, Agathe L Chédeville, Ya-Hsuan Ho,…Simón Méndez-Ferrer Corresponding Author
Myeloproliferative neoplasms (MPNs) are hematopoietic stem cell-driven malignancies marked by excessive myelopoiesis and high risk of myelofibrosis, which remains therapeutically challenging. Senescent neutrophils home daily to the bone marrow (BM) to be cleared by macrophages. This avoids their accumulation, which can increase the risk of chronic inflammation or oncogenesis. Neutrophils carrying the most common oncogenic MPN driver (JAK2V617F) are protected from apoptosis, which may prolong their lifespan and enhance their pro-inflammatory activity. On the other hand, abnormal interactions of neutrophils with megakaryocytes (“emperipolesis”) have been associated with BM fibrosis in disparate hematological disorders, including MPN and grey platelet syndrome; however, the underlying pathophysiology remains unclear. We investigated neutrophil homeostasis and cellular interactions in MPN. We found that senescent neutrophils evade homeostatic clearance and accumulate in JAK2V617F MPN, but not in MPN caused by the second most prevalent mutations affecting Calreticulin (CALR) gene. This is explained by GM-CSF-JAK2-STAT5-dependent upregulation of the “don’t-eat-me” signal CD24 in neutrophils. Mechanistically, JAK2V617F CD24hi neutrophils evade efferocytosis, invade megakaryocytes and increase active TGF-b. Collectively, JAK2V617F neutrophil-megakaryocyte interactions promote platelet production in a humanized bioreactor and myelofibrosis in mouse models. Notably, chronic antibody blockade or genetic loss of CD24 restores clearance of senescent neutrophils, reduces emperipolesis and active TGF-b. Consequently, CD24 blockade improves thrombocytosis and prevents myelofibrosis in MPN mice. Taken together, these findings reveals defective neutrophil clearance as a cause of pathogenic microenvironmental interactions of inflammatory neutrophils with megakaryocytes, associated with myelofibrosis in MPN. Our study postulate CD24 as a candidate innate immune checkpoint in MPN.

Interferon Lowers Myelofibrosis Risk in Young Patients With Polycythemia Vera, Essential Thrombocytopenia

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May 15, 2025

Author(s): Alexandra Gerlach, Associate Editor

Early treatment with interferon reduced secondary myelofibrosis (sMF) risk in adolescent and young adult (AYA) patients with polycythemia vera (PV) or essential thrombocytopenia (ET), according to study data published in Leukemia.1

Red blood cells | Image Credit: © fotogurmespb - stock.adobe.com

MF is an incurable, rare hematologic malignancy characterized by the overproduction of red blood cells. This causes bone marrow scarring, which leads to severe anemia—a key factor impacting overall survival (OS) for patients with MF. It can develop as a primary disease or secondary to ET and PV, as well as progress to acute myeloid leukemia in some cases. Although MF is primarily diagnosed in older adults, 20% of cases are in individuals under the age of 40.1,2

AYA patients with ET or PV face unique clinical challenges due to their longer life expectancy because of a lack of data on long-term outcomes and treatment strategies. Existing guidelines are specific to older populations, despite the unique clinical considerations in younger patients.1

“These patients are expected to live for several decades, and the accumulation of additional thrombotic risk factors (age, cardiovascular conditions, additional mutations) may progressively heighten this risk,” the authors wrote. “This highlights a substantial and emerging concern regarding thrombotic events in this younger demographic.”1

The study evaluates complication rates, including thrombosis and progression to sMF, and the impact of interferon (IFN) on outcomes in patients diagnosed before the age of 25. The primary outcomes of the study were thrombosis-free survival (TFS), myelofibrosis-free survival (MFS), and OS in the entire cohort and for ET and PV patients separately, and the impact of treatment on these outcomes. Secondary outcomes were identification of risk factors associated with thrombotic events and sMF.1

The study included a total of 348 patients, of whom 278 were diagnosed with ET and 70 with PV, with a median age at diagnosis of 20 years. The incidence of thrombotic events was about 1.9 per 100 patient-years, with elevated white blood cell count (≥ 11 × 109/L) and absence of splenomegaly at diagnosis identified as significant risk factors. However, cytoreductive therapy did not reduce thrombotic risk. The incidence of sMF was 0.7 per 100 patient-years, with CALR mutations and a history of thrombosis associated with higher risk.1

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The evolving landscape of epigenetic target molecules and therapies in myeloid cancers: focus on acute myeloid leukemia and myeloproliferative neoplasms

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Published May 15, 2025

Michael W. M. Kühn, Naveen Pemmaraju & Florian H. Heidel

Abstract

Research on myeloid neoplasms, a field that has been driving scientific advances in cancer for over 50 years, has yielded many discoveries that have fundamentally reshaped our understanding of cancer biology. These insights, often the product of leukemia research, have been instrumental in developing more mechanism-based treatments in the early 2000s [1]. Recognizing epigenetic dysregulation as a common disease mechanism in myeloid cancers has been groundbreaking regarding recent treatment developments that exploit chromatin-based oncogenic mechanisms. In the case of acute myeloid leukemia (AML), sequencing studies aimed at assessing the complement of genetic alterations demonstrated that more than 60% of AML cases harbored disease-driving mutations in epigenetic regulators. This high prevalence underscores the importance of epigenetic dysregulation in AML pathogenesis [2, 3]. Chromatin regulators commonly control disease-specific transcriptional programs, making them attractive therapeutic targets to manipulate neoplastic gene expression programs, particularly in myeloid neoplasms. Several drugs targeting epigenetic mechanisms and exploiting myeloid disease-specific dependencies have recently been approved for treating myeloid neoplasms. Many additional drugs are currently being investigated in clinical trials, and numerous new compound developments are being studied in preclinical studies. This manuscript will review (1) chromatin-based disease mechanisms, such as DNA methylation, chromatin regulatory complexes, and histone modifications, currently investigated for therapeutic exploitation in myeloid malignancies, and (2) therapeutic developments already approved or investigated for treating these diseases.

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Seiter Explores Time of Initiation and Alternate Dosing of Ruxolitinib in Myelofibrosis

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By Targeted Oncology Staff
Fact checked by Jonah Feldman

During a live event, Karen Seiter, MD, discussed the role of the JAK/STAT pathway in myeloproliferative neoplasms and the use of ruxolitinib to treat myelofibrosis.

Karen Seiter, MD

Karen Seiter, MD

Professor of Medicine
New York Medical College
Director of  the Adult Leukemia Service
Westchester Medical Center
Valhalla, NY

CASE SUMMARY

  • A 68-year-old woman presented to her physician with symptoms of mild fatigue.
  • Spleen was palpable 6 to 7 cm below the left costal margin
  • Past medical history: no known comorbidities
  • Next-generation sequencing testing: JAK2 V617F mutation
  • Karyotype: 46,XX
  • Bone marrow biopsy: megakaryocyte proliferation and atypia with evidence of reticulin fibrosis
  • Blood smear: leukoerythroblastosis
  • Diagnosis: primary myelofibrosis

Risk

  • Dynamic International Prognostic Scoring System: intermediate-1
  • Mutation-Enhanced International Prognostic Scoring System for Transplantation-Age Patients: intermediate risk

Laboratory Values

  • Red blood cell count: 3.40 ×106/μL
  • Hemoglobin level: 9.7 g/dL
  • Hematocrit: 32.3%
  • Mean corpuscular volume: 94 μm3
  • White blood cell count: 23,000/μL
  • Platelet count: 450,000/μL
  • Peripheral blood blasts: <1%

Peers & Perspectives in Oncology: What disease states are currently classified as myeloproliferative neoplasms (MPNs)?

Seiter: The latest classification is the 2022 World Health Organization [WHO] classification.1,2 As a clinician, when we have myeloproliferative diseases, we think of MPNs [as meaning the patient] has too much of something: The WBC count is too high but with maturing myeloid and not with a lot of blasts, or the hemoglobin [level] is too high, or the [platelet count is] too high. That would be potentially chronic myelocytic leukemia [CML], polycythemia vera [PV], essential thrombocytopenia [ET], and for primary myelofibrosis, the most common presentation would be somebody with either anemia, with abdominal distension or early satiety from splenomegaly. The WBC count could be high; it could be low; platelets could be high, or they could be low.

When we’re working up patients with MPN, the first step is always to make sure that they don’t have CML, because CML can look like myelofibrosis because CML can present with a high platelet count. The first step is always to [test for] the Philadelphia chromosome and perform BCR::ABL1 testing to make sure it’s not CML.

Most of these patients are going to have a bone marrow [biopsy] done. There’s always the debate about, if you have somebody with a hemoglobin level of 20 g/dL, where it looks pretty clear that they have PV, do you need a bone marrow [biopsy] in order to formally diagnose the patient? You do because that’s part of the diagnostic criteria. But sometimes, if you have a much older patient with frailty, you have to consider the goals of care. Sometimes, there may be cases of patients who don’t get the bone marrow biopsy done. The only time it would be reasonable is if the hemoglobin level is high; for anything else, there are so many other things that [it] could be that it’s important to do the bone marrow biopsy for a diagnosis.

Mastocytosis used to be [listed among the] MPNs, but [the WHO] made it its own classification. MPNs with eosinophilia are a separate category. Now we have the myelodysplastic syndrome [MDS]/MPN overlap; that’s a separate category. Then, we have MDS, secondary myeloid neoplasms, and acute myeloid leukemia.

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Fedratinib Shows Promise in Rare Myeloproliferative Neoplasms

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By Andrew Kuykendall, MD

Andrew Kuykendall, MD, an assistant member at the H. Lee Moffitt Cancer Center of University of South Florida in Tampa, FL, discusses data from a phase 2 trial (NCT05177211) which evaluated fedratinib (Inrebic), a JAK2-selective kinase inhibitor, in patients with atypical chronic myeloid leukemia (aCML), chronic neutrophilic leukemia (CNL), myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN)-unclassifiable, and MDS/MPN-ring sideroblasts and thrombocytosis per the 2016 WHO classification.

According to findings from this multi-institutional, investigator-initiated study presented at the 2024 American Society of Hematology (ASH) Annual Meeting, fedratinib demonstrated promising efficacy and a manageable safety profile in this patient population.

At the time of data cutoff, 24 patients were enrolled and 19 patients were evaluable. A total of 53% of patients achieved a response at 24 weeks, including 50% symptom responses and 37.5% spleen responses. Of those treated for ≥24 weeks, spleen volume decreased by an average of 32%, and 85% showed symptomatic improvement. Responses were enriched in patients with CSF3R mutations (83%) and JAK-STAT pathway mutations (70%). Further, the median overall survival (OS) was estimated at 19.7 months.

“This was a very high-risk population, as these diagnoses are associated with poor prognosis. Despite that, we observed spleen responses in approximately 35% of patients, symptom responses in 50%, and some durable responses, with the median time on treatment nearing a year. These outcomes were particularly exciting given the molecular features of this patient population, which typically predict lower response rates,” Kuykendall shares.

Safety findings showed that fedratinib was well tolerated, The majority of adverse events (AEs) were grades 1 or 2, and the most commonly seen AEs were diarrhea (37.5%), constipation (37.5%), and anemia (29%). A single grade 4 neutropenia event resolved with dose adjustments.

“Regarding the safety profile, it was consistent with prior studies of fedratinib. There were some manageable low-grade gastrointestinal [adverse events]. We implemented a more proactive approach to mitigate these, including the use of antiemetics during the first 8 weeks. Overall, the [adverse event] profile remained manageable, and the efficacy outcomes likely exceeded our initial expectations,” adds Kuykendall.

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Management of common autoimmune diseases in patients with myeloproliferative neoplasms treated with pegylated interferon alfa—case report, review of the literature and multidisciplinary clinical practice recommendations

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May 8, 2025

Axel Rüfer, Christoph Brand, […], and Sacha S. Zeerleder

Abstract

Pegylated interferons alfa are increasingly used in patients with myeloproliferative neoplasms (MPN) due to their potential disease-modifying effect. Ropeginterferon alfa-2b has been approved for patients with polycythemia vera (PV) with no symptomatic splenomegaly as first-line cytoreductive therapy, based on the results of the PROUD-PV/CONTINUATION-PV studies, documenting significantly higher rates of complete hematologic response (CHR) compared with hydroxyurea from 2-year timepoint onward. Although safety profile of pegylated interferons is overall good, interferon-related toxicities can occur. Focus of this article is on interferon-mediated autoimmune diseases. We describe two patients with PV treated with pegylated interferons alfa, one patient developed a cutaneous, paranasal sarcoidosis without any systemic symptoms and was successfully treated with topical steroids. The other patient developed widespread psoriatric skin lesions, which were treated with moderate effect with topical therapy with calcipotriene and betamethasone dipropionate foam, antidry calm lotion and in the course of the disease with ultraviolet light therapy (UVB). Only with methotrexate she achieved a nearly complete remission of the psoriasis. In both patients pegylated interferon was continued in view of the CHR and therefore the beneficial effect on MPN. We review the pertinent literature on the management of interferon-mediated autoimmune diseases in patients with MPN. As there is little published evidence on that topic, we propose multidisciplinary clinical practice recommendations based on available evidence and clinical experience in the management of patients with MPN treated with pegylated interferon alfa.

Multihit TP53 Gene Mutations May Be Detrimental in MF

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Özge Özkaya, MSc, PhD
Publish Date

Multihit mutations in the TP53 gene (mTP53MUT) have an equally detrimental effect on long-term survival in patients with both myeloproliferative neoplasms (MPN) like myelofibrosis (MF) and those with acute myeloid leukemia (AML), according to a new study published in the American Journal of Hematology. mTP53MUT could, therefore, be used as a predictor of short-term survival in both diseases.

These findings are based on the analysis of data from 142 patients from the Mayo Clinic database with mTP53MUT-associated MPN or AML. Of these patients, 14 had accelerated phase MPN, 19 had chronic phase MPN, 28 had blast phase MPN, and 81 had AML.

Mutations in the ASXL1, EZH2, IDH1, and IDH2 genes were more common in patients with blast-phase MPN and mTP53MUT compared to those with AML and mTP53MUT.

At a median follow-up of 11.6  months, 124 patients died, and 19 patients had an allogeneic stem cell transplantation.

Overall survival, which was calculated from the time of the detection of a mTP53MUT, was similar between patients with blast-phase and accelerated-phase MPN at 4.6 and 5.6  months, respectively.

However, overall survival was longer in patients with chronic phase MPN and mTP53MUT at 11.6 months, which was similar to overall survival in patients with AML and mTP53MUT, which was 7.4 months.

Multivariable analysis showed that disease stage, allogeneic stem cell transplantation, and response to pre-transplant chemotherapy positively affected overall survival while the presence of concurrent TET2 or DNMT3A mutations affected it negatively.

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Ruxolitinib Discontinuation at Conditioning Does Not Increase GVHD Risk in Myelofibrosis

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May 7, 2025

Author(s): Alexandra Gerlach, Associate Editor

Stopping ruxolitinib (Jakafi; Incyte Corp) prior to the conditioning regimen may not influence graft-versus-host disease (GVHD) risk more than in patients with myelofibrosis (MF), according to data published in Cancer Immunology, Immunotherapy.1

MF is an incurable, rare hematologic malignancy that is part of a group of diseases called myeloproliferative neoplasms, which are characterized by the overproduction of red blood cells. This causes bone marrow scarring, leading to severe anemia—a key factor impacting overall survival for patients with MF. Other symptoms include fatigue, enlarged spleen, night sweats, bone pain, and weight loss. MF can develop as a primary disease or secondary to essential thrombocythemia and polycythemia vera. In some cases, it can progress to acute myeloid leukemia.2

Ruxolitinib is the standard of care for first-line treatment of patients with MF that was originally approved by the FDA in 2011 for the treatment of intermediate- and high-risk MF. It was also the first approved treatment for patients 12 years of age and older with steroid-refractory acute GVHD in 2019. Ruxolitinib is a Janus kinase (JAK) 1/2 inhibitor that targets the JAK/STAT pathway, a critical cellular signaling pathway that helps cells respond to cytokines. Identification of mutations within the JAK/STAT pathway paved the way for the development of agents such as ruxolitinib, fedratinib (Inrebic; Bristol Myers Squibb), momelotinib (Ojjaara; GSK), and pacritinib (Vonjo; CTI BioPharma).2,3

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MOMENTUM Trial Outcomes: Guiding Therapy for Myelofibrosis With Anemia and Splenomegaly

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By Pankit Vachhani, MD
Edward Pearson, MD
elists discuss how the MOMENTUM trial demonstrated momelotinib’s superiority over danazol in symptomatic anemic myelofibrosis patients, showing significant improvements in symptoms (the primary end point), meaningful spleen volume reduction (SVR25/SVR35), and anemia benefits, with experts noting that the inclusion of a washout period provided clearer evidence of momelotinib’s efficacy profile compared to the SIMPLIFY-2 trial.

Summary of MOMENTUM Trial: Momelotinib in Anemic, Symptomatic Myelofibrosis

Study Design and Population

  • Patient characteristics:
    • Required hemoglobin <10 g/dL
    • Symptomatic disease
    • Previously treated with Janus kinase (JAK) inhibitor therapy
  • Design elements:
    • Primary end point was symptom-driven
    • Active comparator arm (danazol) rather than placebo
    • Included a washout period (unlike SIMPLIFY-2)

Key Findings

  • Primary end point:
    • Momelotinib demonstrated superior symptom benefits compared to danazol
  • Secondary end points:
    • Multiple secondary end points met with superiority
    • Stronger spleen volume reduction data (SVR25, SVR35) than in SIMPLIFY-2
    • Confirmed anemia benefits

Clinical Implications

  • Comprehensive benefit profile:
    • Triple benefit: spleen reduction, symptom improvement, and anemia benefits
    • Washout period may have contributed to clearer demonstration of spleen benefits compared to SIMPLIFY-2
  • Clinician perspective:
    • Some practitioners noted less direct relevance of danazol comparison in their practice
    • Nevertheless, provided further evidence of momelotinib’s anemia benefit
    • Results support momelotinib use in patients with anemic, symptomatic myelofibrosis who have received prior JAK inhibitor therapy

The MOMENTUM trial reinforces momelotinib’s position in the treatment algorithm, particularly for patients with anemia who have been previously treated with other JAK inhibitors.

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Strategic JAK Inhibitor Sequencing: Translating SIMPLIFY I/II Outcomes to Optimize Myelofibrosis Management

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By Pankit Vachhani, MD
Edward Pearson, MD

Summary of Momelotinib Clinical Trials and Second-Line Applications

SIMPLIFY-1 (First-Line Setting)

  • Efficacy comparison with ruxolitinib in newly diagnosed myelofibrosis:
    • Spleen response: Momelotinib demonstrated spleen volume reduction
    • Symptom improvement: Not as robust as ruxolitinib
    • Anemia benefit: Preserved transfusion independence at week 24 vs baseline, while ruxolitinib showed slight decline
  • Clinical considerations for newly diagnosed myelofibrosis with moderate anemia:
    • Potential benefit of single-agent therapy (avoiding combination with erythropoiesis-stimulating agents)
    • When anemia contributes significantly to symptom burden, momelotinib may be preferable

SIMPLIFY-2 (Second-Line Setting)

  • Study design: Effectively a comparison of momelotinib vs ruxolitinib in previously treated patients
    • No washout period between treatments
  • Key outcomes:
    • Spleen response: Comparable between momelotinib and control (“a wash”)
    • Anemia: Clear advantage for momelotinib
    • Symptom control: Superior with momelotinib in the second-line setting
  • Expert opinion on optimal positioning:
    • Panel indicated greater preference for momelotinib in the second-line setting
    • Particularly valuable in patients with worsening anemia or diminishing spleen response on ruxolitinib
    • Setting appropriate expectations is crucial; emphasize anemia and symptom benefits rather than additional spleen reduction

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