Tag Archives: myelofibrosis

Interferon Improves Myelofibrosis-Free Survival in AYA Patients with ET and PV

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By Melissa Badamo – Last Updated: May 27, 2025

While cytoreductive drugs did not reduce thrombosis risk in adolescent and young adult (AYA) patients with essential thrombocythemia (ET) and polycythemia vera (PV), interferon “significantly improved” myelofibrosis-free survival (MFS) compared with other treatments, according to a study published in Leukemia.

The retrospective study explored the long-term complications and impact of cytoreductive drugs on patient outcomes, thrombotic risk, and progression to secondary myelofibrosis (sMF) in 348 patients diagnosed with ET (n=278) or PV (n=70) before the age of 25 years. The primary end points were MFS, thrombosis-free survival (TFS), and overall survival. Secondary end points included identification of risk factors associated with thrombotic events and progression to sMF.

In the ET cohort, 147 (53%) patients had JAK2 mutations, 43 (16%) had CALR mutations, 3 (1%) had MPL mutations, and 85 (30%) were triple negative (TN). All patients with PV had JAK2 mutations.

A total of 237 (68%) patients were treated with a cytoreductive drug, including 185 patients with ET (66.5%) and 52 patients with PV (74.3%). Patients received one line of therapy (n=97; 41%), two lines of therapy (n=82; 35%), or three or more lines of therapy (n=58; 24%). The most prescribed first-line treatments were hydroxycarbamide (n=126; 53%), interferon (n=55; 23%), anagrelide (n=52; 22%), and alternative drugs (n=4; 2%). The median follow-up was 8.5 years.

Thrombotic Risk

Forty-four patients presented 57 thrombotic events, with a risk of 1.9 per 100 patient-years. The 10- and 20-year probability of TFS was 86.8% and 78.8% for the entire cohort, 86.9% and 80.0% for patients with ET, and 84.4% and 76.3% for patients with PV.

In a multivariate analysis, elevated white blood cell count (>11 × 109/L; hazard ratio [HR], 2.7; P=0.012) and the absence of splenomegaly at diagnosis (HR, 5.7; P=0.026) were associated with increased risk for thrombosis.

Choice of first treatment did not correlate with differences in TFS. The 10- and 20-year TFS were 83.9% and 79.9% for interferon, 81.4% and 70.2% for hydroxycarbamide, and 91.6% and 76.3% for anagrelide (P=0.281)

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SVR With Pacritinib Is Linked With OS Benefit in Myelofibrosis With Thrombocytopenia

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May 26, 2025

Author(s): Ashling Wahner

Fact checked by: Gina Mauro

The achievement of spleen volume response (SVR) of at least 10% (SVR10) at week 12 with pacritinib (Vonjo) was positively associated with overall survival (OS) in patients with myelofibrosis and thrombocytopenia, although more stringent SVR thresholds were not significantly associated with OS, according to findings from a post hoc landmark analysis of the phase 3 PERSIST-2 trial (NCT02055781).1

The investigators assessed OS among SVR responders vs nonresponders using 4 different SVR thresholds: at least 35% (SVR35), at least 20% (SVR20), SVR10, and greater than 0% (SVR0). The data, which were published in the European Journal of Haematology, showed that the greatest separation of OS curves between responders and nonresponders was observed among patients who received pacritinib (n = 89) at 200 mg twice daily and achieved SVR10 vs those who did not respond at that threshold (HR, 0.00; 95% CI, 0.00-0.14; P < .01). No deaths were observed among the responders, whereas 5 nonresponders died.

“We found that a significant association was not observed with more stringent SVR or total symptom score [TSS] thresholds, likely because the number of responders was lower, and thus a larger number of observations would be needed to detect statistical significance at such thresholds,” lead study author Helen Ajufo, MD, MS, of the Department of Medicine, Leukemia Service, at Memorial Sloan Kettering Cancer Center, in New York, New York, and coinvestigators explained in the paper.

SVR0 and SVR20 also conferred improved OS, although these more stringent response thresholds were less prognostic of the pacritinib survival benefit.

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Efficacy of JAK1/2 inhibition in murine myeloproliferative neoplasms is not mediated by targeting oncogenic signaling

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May 24, 2025

Sivahari Prasad Gorantla, Michael Rassner, Kirstyn Anne Crossley,…Robert Zeiser & Justus Duyster

Abstract

Ruxolitinib is a potent JAK1/JAK2 inhibitor, approved for the treatment of primary myelofibrosis (PMF) patients based on the concept of inhibition of oncogenic signaling. However, the effect of ruxolitinib on JAK2-V617F allelic burden is modest, suggesting that inhibition of JAK2-V617F signaling-driven clone expansion is not the main mechanism of action. We evaluate whether ruxolitinib mainly blocks the proliferation of the malignant clone or exerts its effects also by targeting non-malignant cells. Therefore, we develop two JAK2-V617F-driven myeloproliferative neoplasm (MPN) mouse models harboring ruxolitinib resistance mutations. Mice carrying ruxolitinib-resistant JAK2-V617F-driven MPN respond to ruxolitinib treatment similar to mice with ruxolitinib-sensitive JAK2-V617F MPN with respect to reduction of spleen size, leukocyte count and pro-inflammatory cytokines in the serum. Ruxolitinib reduces pro-inflammatory cytokines in both stromal cells and non-malignant hematopoietic cells. Using a rigorous ruxolitinib resistance mutation approach, we can prove that ruxolitinib acts independent of oncogenic JAK2-V617F signaling and reduces the main features of MPN disease such as spleen size and leukocyte counts. Our findings characterize the mechanism of action for ruxolitinib in MPN.

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Post Hoc Data Show Anemia Benefits, Reduced Transfusion Burden With Momelotinib in Myelofibrosis

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Author(s): Chris Ryan

Fact checked by: Ashling Wahner

A post hoc analysis of a single-arm, phase 2 study (NCT02515630) and the phase 3 SIMPLIFY-1 (NCT01969838), SIMPLIFY-2 (NCT02101268), and MOMENTUM (NCT04173494) studies showed that momelotinib (Ojjaara) was associated with anemia-related benefits in most patients and a reduction in transfusion burden vs comparator treatments in patients with JAK inhibitor–naive and –experienced myelofibrosis.1

Findings published in Clinical Lymphoma, Myeloma & Leukemia showed that more than 77% of patients treated with momelotinib across the 4 trials experienced a numerical reduction in red blood cell (RBC) transfusion requirements during treatment compared with baseline.

“This [post hoc analysis] demonstrates that across all 3 phase 3 trials of momelotinib in myelofibrosis to date, at least 75% of patients treated with momelotinib either maintained or experienced improved transfusion intensities vs baseline,” lead study author Claire Harrison, MD, FRCP, FRCPath, a professor of myeloproliferative neoplasm and clinical director of Guy’s and St Thomas’ NHS Foundation Trust in London, United Kingdom, and colleagues wrote in the publication. “These results provide evidence that underscores the consistent anemia benefits provided by momelotinib for the majority of patients.”

In September 2023, the FDA approved momelotinib for the treatment of adult patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis, and anemia.2 This regulatory decision was supported by data from MOMENTUM and a subgroup of patients with anemia treated during SIMPLIFY-1.

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Evolving Myelofibrosis Treatments Aims to Fill Unmet Needs

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May 21, 2025

Author(s): Ryan Scott

Fact checked by: Spencer Feldman

Myelofibrosis is a Philadelphia-negative myeloproliferative neoplasms (MPN) and can occur as de novo disease. Myelofibrosis creates varying degrees of fibrosis and can cause driver mutations such as JAK2, CALR or MPL in approximately 90% of patients. These mutations cause constant activation of the JAK-STAT pathway, which can lead to uncontrolled cell growth.

Other mutations that can occur, such as ASXL1, SRSF2, EZH2, IDH1/2 and U2AF1, may also affect how the disease develops and prognosis. Moreover, common symptoms of the disease include fatigue, night sweats, fever, bone pain, cachexia, pruritus, thrombosis, and bleeding. Although disease progression is the most common reason for death and occurs in approximately 20% of patients, many patients also face serious risks from other complications. These include heart problems, infections, or bleeding due to low blood counts.

To combat the unmet needs within the myelofibrosis treatment landscape, there have been a number of studies investigating novel treatments for JAK inhibitor-ineligible or relapsed/refractory patients. To further explore these investigations, and the current and future states of the treatment landscapes, investigators broke everything down in research published in the American Journal of Hematology.

Understanding the Present Landscape and Ongoing Studies

The discovery of genetic mutations, as well as the role of the JAK-STAT pathway in the treatment of MPNs has led to the development of oral KAK inhibitors. These drugs work by blocking overactive JAK signaling involved in disease progression and symptom burden.

One such drug being used is Rituxan (ruxolitinib), which is the first ever U.S. Food and Drug Administration (FDA)-approved JAK inhibitor for myelofibrosis, approved by the regulatory agency in 2011. The agent elicits effective for symptom relief and spleen size reduction in approximately 50% of patients who are treated with it.

Common side effects of Rituxan include anemia and low platelets; other non-blood-related side effects include fatigue, diarrhea and infections. Long-term use of the agent may also increase the risk of secondary cancers (like non-melanoma skin cancer) and round 40% to 50% of individuals discontinue the drug within three years due to side effects or lack of efficacy. However, stopping Rituxan is linked to new mutations and poorer outcomes.

Another agent used in the treatment of myelofibrosis is Inrebic (fedratinib), which was approved in 2019 by the FDA for both patients with newly diagnosed disease and those who are refractory and/or intolerant to Rituxan. This agent provides similar benefits to those seen with Rituxan, including reduction of spleen size and symptoms, but with frequent gastrointestinal side effects, like nausea, diarrhea and vomiting.

Notably, Inrebic carries a black box warning for risk of Wernicke’s encephalopathy, making monitoring essential. Additionally, treatment with the agent is less effective in patients who were on high-dose Rituxan prior to switching.

Vonjo (pacritinib) is another treatment which was approved in 2022 for patients with severe low platelet counts in the myelofibrosis treatment space. Unlike Rituxan and Inrebic, it can be used in high-risk patients with more advanced disease and cytopenias. In trials such as the PERSIST-1 and PERSIST-2 studies, Vonjo showed modest spleen and symptom response but improved transfusion independence.

Vonjo is currently being tested in the PACIFICA trial for patients with platelets less than 50 × 10⁹/L.

Finally, Ojjaara (momelotinib) is also being used in the treatment space for patients with this disease and was approved by the FDA in 2023. Ojjaara targets JAK1/2 and ALK2, with a unique effect on anemia. Trials, including the SIMPLIFY-1 and SIMPLIFY-2 studies, showed similar spleen responses to Rituxan but greater improvements in anemia and transfusion independence.

The MOMENTUM study confirmed Ojjaara’s improved both symptoms and anemia in symptomatic, anemic patients previously treated with a JAK inhibitor.

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Ruxolitinib Plus Siremadlin Yielded Superior Spleen Volume Reduction in Patients With Myelofibrosis

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May 20, 2025

Author(s): Alexandra Gerlach, Associate Editor

Data from the ADORE trial (NCT04097821) suggest combining ruxolitinib (Jakafi; Incyte Corp) with novel agents such as siremadlin (HDM201, Novartis), rineterkib (LTT462; Novartis), sabatolimab (MBG453; Novartis), crizanlizumab (Adakveo; Novartis), or NIS793 (Novartis) was superior to ruxolitinib monotherapy in patients with myelofibrosis (MF). The investigators reported improved spleen volume reductions (SVR), which were greatest in patients treated with ruxolitinib in combination with siremadlin.1

3D visualization of red blood cells | Image Credit: © Thipphaphone – stock.adobe.com

MF is a disease that falls under the umbrella of myeloproliferative neoplasms, which is a group of diseases characterized by the overproduction of red blood cells, white blood cells, or platelets in the bone marrow. In MF, there is an ongoing reduced production of red blood cells that leads to bone marrow fibrosis, extramedullary hematopoiesis, recurrent splenomegaly, and anemia. Other symptoms can include fatigue, nocturnal sweats, bone pain, enlarged spleen, and weight loss. can arise as a main disease (primary MF) or as a subsequent condition to essential thrombocythemia (post-ET MF) and polycythemia vera (post-PV MF). In some cases, MF can progress to acute myeloid leukemia.2

Janus kinase (JAK) inhibitors, such as ruxolitinib, are the standard of care for treatment and management of MF-related complications and have yielded significantly favorable outcomes; however, they are associated with various adverse effects (AEs). Ruxolitinib was initially approved in 2011 for first-line treatment of patients with intermediate- and high-risk MF, but the agent is known to be highly associated with increased risk of persistent or worsening anemia. Despite its widespread use, approximately 70% of patients discontinue treatment after about 5 years, with a third citing an inadequate reduction in spleen volume as a key reason.3,4

ADORE is a randomized, open-label, phase 1/2 open platform study evaluating the safety and efficacy of 5 novel agents with ruxolitinib in patients with MF. The trial utilized an innovative open platform design and enrolled 44 patients in part 1 of the trial who were treated with ruxolitinib in combination with 1 of 5 investigational agents: siremadlin, rineterkib, sabatolimab, crizanlizumab, or NIS793. The largest cohort (n = 23) received the combination of ruxolitinib (orally at a dosage of 5 mg) and siremadlin (orally at a dosage of 10, 20, or 40 mg).1,4

Among those patients, the most common AEs were gastrointestinal issues, such as nausea and diarrhea, and hematologic toxicities, including thrombocytopenia, anemia, and neutropenia. Based on safety and efficacy findings, once-daily 30 mg siremadlin taken orally on days 1 through 5 of a 28-day cycle was chosen as the recommended phase 2 dose.4

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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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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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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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