Tag Archives: blood cancer

FDA Grants Fast Track Designation to Givinostat for Polycythemia Vera

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May 6, 2025

Author(s): Jax DiEugenio

Fact checked by: Chris Ryan

The FDA has granted fast track designation to givinostat (Duvyzat), an orally administered histone deacetylase (HDAC) inhibitor, for the treatment of patients with polycythemia vera (PV).1

The agent is being evaluated in the ongoing phase 3 GIV-IN PV trial (NCT06093672), which aims to compare the efficacy and safety of givinostat to hydroxyurea in patients with JAK2 V617F–positive, high-risk PV, which is characterized by the clonal overproduction of erythroid, myeloid, and megakaryocytic lineages within the bone marrow. By targeting aberrant gene expression, givinostat may suppress pathologic cell proliferation associated with driver mutations such as JAK2 V617F, which are common in patients with PV.

“The FDA decision to grant givinostat fast track designation underscores the urgent need for innovative treatments for PV and highlights the potential of givinostat to make a meaningful difference,” Paolo Bettica, MD, PhD, chief medical officer at Italfarmaco Group, stated in a news release. “We look forward to working closely with the FDA as we plan for completion of our phase 3 clinical trial.”

The FDA and European Medicines Agency both previously granted orphan drug designation to givinostat for PV. In the United States, the FDA previously approved givinostat for the treatment of patients 6 years of age or older with Duchenne muscular dystrophy.2

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Disc Medicine to Host Webinar with Key Opinion Leaders on Anemia of Myelofibrosis (MF)

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Disc Medicine Inc – (GLOBE NEWSWIRE)

April 29, 2025

WATERTOWN, Mass., April 29, 2025 (GLOBE NEWSWIRE) — Disc Medicine, Inc. (NASDAQ:IRON), a clinical-stage biopharmaceutical company focused on the discovery, development, and commercialization of novel treatments for patients suffering from serious hematologic diseases, today announced it will host a virtual KOL investor event on Friday, May 9 at 1:00 PM ET / 10:00 AM PT to provide an overview of anemia of myelofibrosis (MF) and discuss the evolving treatment landscape for this disease. The event will also include an overview of Disc’s clinical data and development plans for DISC-0974 in MF anemia.

Intended for investors and other interested audiences, the virtual event will feature presentations from leading experts on myeloproliferative neoplasms (MPNs), including MF. The KOL speakers will provide an overview of MF anemia, its epidemiology, pathogenesis, and impact on patients, then discuss the current and emerging therapeutic landscape for MF and highlight the clear unmet need for anemia-focused treatments. Invited speakers include:

  • Dr. Aaron Gerds, M.D., M.S., a hematologist-oncologist at Cleveland Clinic and associate professor at Case Western University School of Medicine, where he runs the cancer center’s Clinical Research Office. Dr. Gerds has been a principal investigator in various clinical trials for MPNs.
  • Dr. Prithviraj Bose, M.D., a professor at MD Anderson Cancer Center with a focus on MPNs. Dr. Bose has been a leader in multiple clinical trials in myelofibrosis.

Members of Disc’s leadership team will review the therapeutic rationale for DISC-0974, summarize clinical data from the Phase 1b trial of DISC-0974 in MF anemia originally presented at the 2024 American Society of Hematology (ASH) annual meeting, discuss the design for its ongoing Phase 2 trial, and reiterate expected timing for an interim Phase 2 data readout in 2025. Management will also provide a view of the expected market opportunity and positioning for DISC-0974 in MF anemia.

A live webcast of the event will be available in the Events and Presentations section of the Investor Relations page of Disc’s website (https://ir.discmedicine.com/). A webcast replay will be available after the live presentation and will be accessible for 90 days. Please register for the event on the Events and Presentations page of Disc’s website ( https://edge.media-server.com/mmc/p/5c72d8fu ).

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Molecular predictors of venous and arterial thrombotic events in patients with myelofibrosis

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Olga Morath, Jenny Rinke, Annabell Walter, Carl Crodel, Manja Meggendorfer, Constance Baer, Andreas Hochhaus & Thomas Ernst

Abstract

While patients with myelofibrosis (MF) face an elevated risk of thrombosis, no validated scoring system currently exists to effectively assess this specific risk. This study aimed to explore distinct molecular risk factors for arterial (ATE) and venous (VTE) thrombosis in a cohort of 141 MF patients. Mutation analysis was performed by next-generation sequencing for a panel of 30 target myeloid genes as previously described: 137 driver and 164 non-driver mutations were detected. JAK2-V617F was identified in 77 (55%) patients, CALR in 45 (32%) patients, and seven (5%) patients carried an MPL variant. Patients #58 and #60 harbored JAK2-V617F and MPL; and patient #67 was positive for all three driver genes. The JAK2–V617F variant allele frequency (VAF) was assessed in 66/80 patients, revealing a median of 34.0% (range, 5.0–96.0). ASXL1 (n = 34 patients) were the most common non-driver mutations, followed by TET2 (n = 26), U2AF1 (n = 12), and DNMT3A (n = 11). During a median follow up of 4.8 years, 24 (17%) patients experienced VTE, 15 (11%) ATE, and two patients experienced both. Among the 24 patients with VTE, 12 (50%) experienced splanchnic vein thrombosis. The JAK2-V617F mutation was associated with VTE (OR 2.6, 95% CI 1.01–7.16), while the DNMT3A mutation was an independent predictor of ATE (OR 5.40, 95% CI 1.30-22.42). High JAK2-V617F VAF (> 50%) was not related with an increased thrombotic risk. Results of this study demonstrate the significance of DNMT3A mutations as an independent molecular risk factor for ATE, highlighting the potential to include these somatic non-driver mutations in future thrombosis risk scores.

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Working to Address Unmet Medical Needs in MPNs

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April 24, 2025

Author(s): John Crispino

Fact checked by: Alex Biese, Spencer Feldman

In his research into myeloproliferative neoplasms, or MPNs, John Crispino is focused on a couple of key areas when it comes to understanding the underlying biology of the disease, as he explained in an interview with CURE.

Crispino is the director of the division of experimental hematology at St. Jude Children’s Research Hospital in Memphis, Tennessee, where he is also the Wall Street Committee Endowed Chair and principal investigator of the Crispino Lab. The Crispino Lab, according to its website, is focused primarily on myeloid cells, centered on the mechanisms of normal and abnormal cell development.

“There are two major areas that we study,” Crispino told CURE. “The first is the biology of megakaryocytes. Those are the cells that make platelets. … The second major area of research is on leukemic progression. So I would say that that progression to acute leukemia is really terrible outcome for patients, and we have very few therapies for patients that do advance at that stage. So our research in the past few years has focused on understanding the mechanism.”

Crispino sat down recently with CURE to discuss his research.

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Protein Disulfide Isomerase Could Be Therapeutic Target for MF

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Özge Özkaya, MSc, PhD
Publish Date

Protein disulfide isomerase may be involved in the underlying pathogenesis of thrombotic events in Philadelphia-negative myeloproliferative neoplasms such as myelofibrosis (MF), according to a new study published in the Egyptian Journal of Internal Medicine.

It could also be valuable in predicting the risk of developing thromboembolic events, the researchers noted.

These findings suggest that protein disulfide isomerase could be used as a therapeutic target to prevent thrombotic events in patients with MF and other myeloproliferative neoplasms.

For the study, a team of researchers, led by Mai Galal Elshenoufy, MD, PhD, from Cairo University in Egypt, measured the levels of protein disulfide isomerase in the serum of patients with myeloproliferative neoplasms and assessed its role as a possible marker of increased risk of thromboembolic events.

They found that the levels of the enzyme were pathologically high in the serum of patients with myeloproliferative neoplasms compared to controls. The levels were also higher in patients with arterial thrombosis, but this finding had no statistical significance.

Future work should evaluate the levels of protein disulfide isomerase in a larger group of patients with myeloproliferative neoplasm with and without thrombotic events, and in patients with arterial versus venous thrombosis, they said.

Finally, measuring the levels of protein disulfide isomerase before and after aspirin therapy could give clues about the effect of this treatment, they added.

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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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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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