Tag Archives: blood cancer

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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Molecular Response to Therapy Linked With Event-Free Survival in PV

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May 23, 2025

Author(s): Jared Kaltwasser

Fact checked by: Rose McNulty

Molecular response to therapy appears to correlate with event-free survival in patients with early polycythemia vera (PV), according to a new analysis. The findings were published in a research letter in the journal HemaSphere.1

While clonal expansion of JAK2V617F-mutated hematopoietic stem cells is implicated in almost all cases of PV, the potential implications of molecular response to therapy (MR) as demonstrated by reduced frequency of the variant allele have been disputed, the authors explained.

The findings also show that ropeginterferon alfa-2b is an effective therapy for molecular response in early polycythemia vera. | Image credit: fotogurmespb.- stock.adobe.com

The question is difficult to study, they noted, since the early onset of PV is associated with nonspecific symptoms. However, the authors cited a 2023 study assessing ruxolitinib (Jakafi; Incyte) in patients with high-risk PV found molecular response was correlated with superior outcomes, including event-free survival (EFS).2

In the new report, researchers examined data from the phase 3 PROUD-PV study and its extension trial, CONTINUATION-PV, to see whether there was a meaningful relationship between MR and EFS in patients with early-stage PV.1

The PROUD-PV trial involved participants with low- or high-risk PV requiring cytoreduction who were treatment naive or who had been pretreated with hydroxyurea for less than 3 years without resistance or intolerance. Participants were randomized on a 1:1 basis to receive either ropeginterferon alfa-2b (Besremi; PharmaEssentia) or hydroxyurea for 12 months. In CONTINUATION-PV, participants remained in their same treatment arm, though control-arm patients were allowed to switch from hydroxyurea to any standard treatment.

The final analysis of CONTINUATION-PV included 95 participants in the ropeginterferon alfa-2b cohort and 74 in the hydroxyurea/best available therapy control group. The median treatment duration for the two study arms was 6.3 years and 6.0 years, respectively.

The authors found that patients in the ropeginterferon alfa-2b arm had a reduction of median JAK2V617F variant allele frequency from 37.3% at baseline to 8.5% at year 6, with 66.0% of patients achieving MR. Patients in that cohort spent a median cumulative proportion of time in MR of 66.7%.

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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Real-World Data Shows Favorable Efficacy and Safety With Busulfan for MPNs

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Andrea S. Blevins Primeau, PhD, MBA
Publish Date

Busulfan treatment of myeloproliferative neoplasms (MPNs) demonstrated high response rates and infrequent adverse events (AEs), according to a study of real-world data from hospitals in the United Kingdom.

“Given the lack of prospective studies on the use of busulphan, our study contributes valuable real-world data on the safety and efficacy of busulphan which clinicians should find useful in managing this challenging cohort,” the researchers wrote in their report.

In the retrospective study, researchers analyzed data from 115 patients with MPNs from 13 hospitals. The median age of the cohort was 78 years and 44% of patients were male. The majority of patients had a diagnosis of essential thrombocythemia (ET) at 67%, followed by 24% with polycythemia vera (PV), 5% with MPN not otherwise specified, and 4% with myelofibrosis. JAK2 and CALR mutations were present among 62% and 13% of patients, respectively.

There were 16% of patients with a history of malignancy, including 8% of nonmelanoma skin cancers, and 8% with cancers that included those of the breast, prostate, lung, low-grade lymphoma, and melanoma.

One previous line of therapy (LOT) had been received by 13% of patients, 63% had 2 LOTs, 19% had 3 LOTs, and 5% had 4 LOTs. The most common previous cytoreductive therapy was hydroxycarbamide (78%), followed by anagrelide (16%), pegylated interferon (8%), P32 (3%), and ruxolitinib (2%).

The dosing regimens of busulfan included repeated single doses (31%) with a median dose of 38 mg, 1- to 4-week courses (30%) with a median dose 3.5 mg, and continuous therapy lasting more than 4 weeks (35%) with a median dose of 2 mg.

Our study contributes valuable real-world data on the safety and efficacy of busulphan which clinicians should find useful in managing this challenging cohort.

The median time from busulfan initiation to last follow-up or death was 23 months. There were 14% of patients who were alive with acceptable blood count control without any other cytoreductive therapy.

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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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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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