Tag Archives: mpn

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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Pegylated Interferons: Still a Major Player for the Treatment of Myeloproliferative Neoplasms

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Michael Daunov, DO1 and Rebecca B. Klisovic, MD1

Overview

Over the past 35 years, interferons have been explored in various formulations for the management of Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs), such as essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis, and remain a key tool in caring for patients with these diseases. These agents are excellent cytoreductive agents with high rates of hematologic response, are helpful in symptom management, and have a long track record of safety and manageable toxicities. More recently, they have shown promise in sustaining responses over many years, with associated reductions in driver mutations (JAK2, MPL, CALR) of these diseases, particularly in PV and ET. Since reductions in molecular mutant allele burden have been correlated with several response outcomes such as reductions in both thrombotic risk and disease progression, there is emerging proof that interferons may offer disease-modifying activity. These long-term benefits and their use as the preferred agent in young pregnant women who need cytoreduction make interferons often the first choice in young adult population who harbor a lifetime risk of progression. Looking forward, the prospect of sustained treatment-free responses, like chronic myeloid leukemia after deep molecular response, and normal life expectancy may also be on the frontier. Despite relative rookies such as JAK inhibitors in the MPN landscape, the veteran in the game, interferon, remains a key player.

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Clinical Trial Aims to Test Tagraxofusp and Pacritinib Combination Therapy in Patients With MF

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Özge Özkaya, MSc, PhD
Publish Date

A new study testing the combination of tagraxofusp and pacritinib in patients with myelofibrosis (MF) is now open.

The single-center, open-label, early phase 1, pilot trial aims to recruit 20 patients with MF who are at least 18 years of age and who have previously been treated with a Janus kinase (JAK) 1/2 inhibitor or in whom JAK1/2 inhibitor therapy is not appropriate, is contraindicated, or was declined.

Participants will be given 12 µg/kg of intravenous tagraxofusp once a day for 3 consecutive days and 200 mg of oral pacritinib twice a day starting at the 4th day of the second cycle and administered continuously with subsequent cycles starting on day 1 of each cycle.

The primary outcome measures will be a spleen volume reduction of 35% of more and the change in the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score Version 2.0 (MPN-SAF TSS 2.0) from baseline to week 24.

Secondary outcome measures will include the number of participants with treatment-related adverse events, the change from baseline in anemia and platelet count, and any improvement in patients’ quality of life based on the global impression of change.

Tagraxofusp is a cytotoxin directed at CD123, and pacritinib is a small-molecule kinase inhibitor. The rationale of using these 2 drugs in combination is their compatible mechanisms of action targeting MF stem cells and the bone marrow. It is thought that the combination may lead to improvements in symptoms associated with myeloproliferative neoplasms and reduce splenomegaly.

Both agents have previously been studied in cases of mildly depleted bone marrow and were shown to be safe and led to hematological improvements.

The trial is not yet recruiting participants but aims to recruit 20 participants. It is estimated to be completed in December 2026.

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Real-World Findings Confirm Clinical Data on Momelotinib in MF With Anemia

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May 1, 2025

Author(s): AJMC Contributor

Real-world insights on momelotinib (Ojjaara; GlaxoSmithKline) in patients with myelofibrosis (MF) and anemia have been published, showing consistent and, in some cases, better results than those shown previously in clinical studies of the drug.1

The results offer some of the first glimpses into real-world findings of the Janus kinase (JAK) inhibitor, which received approval toward the end of 2023, becoming the first and only treatment indicated for patients with MF and anemia.2

“This study presents the largest real-world cohort of MF patients treated with momelotinib and is the first to apply the recently proposed 2024 criteria for anemia response,” wrote the researchers, publishing the insights in Blood Cancer Journal.1

The retrospective study included 122 patients with MF and anemia across multiple treatment centers. Patients had disease-related symptoms or symptomatic splenomegaly and could be JAK-naive (23.4%) or previously received treatment with a JAK inhibitor (76.6%).

At treatment initiation, 73.8% of patients were dependent on transfusions. Among these patients, the median Hb level increased from 7.7 g/dL (range, 4.7-9.8) at treatment initiation to 8.7 g/dL at 3 months of follow-up. By 6 months, 30.6% of patients had major responses and 36.1% had minor responses. At the time follow-up point, median red blood cell transfusion frequency had dropped from 4 units per month to 1 unit per month.

The results offer some of the first glimpses into real-world findings of the JAK inhibitor momelotinib, which was approved in 2023.

Among the remaining patients who were not dependent on transfusions at treatment initiation, the median Hb level increased from 8.9 g/dL (range, 7.2-10.8) to 10.2 g/dL. At 6 months of follow-up, 36.4% of patients demonstrated a major response, and 27.3% demonstrated a minor response.

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National Health Expenditure Associated With Myeloid Neoplasms Survival in Europe

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Andrea S. Blevins Primeau, PhD, MBA
Publish Date

An analysis of the EUROCARE found that lower total national health expenditure (TNHE) was associated with shorter survival among patients with some types of myeloid neoplasms (MNs), according to a report published in the European Journal of Oncology.

The researchers also reported that 10-year relative excess risk of death (RER) was generally higher for patients in regions with lower TNHE.

EUROCARE-6 is a dataset in the EUROCARE study that is derived from 27 European countries of patients aged 15 or older diagnosed with an MN between 2001 and 2013. MNs included acute myeloid leukemia (AML), myeloproliferative neoplasms (MPNs), chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and myelodysplastic syndrome (MDS).

There were a total of 267,968 MN cases in the dataset, of which, 41.1% were AML, 32.2% were MPNs, 11.7% were CML, 6.8% were PV, 7.4% were ET, and 19.6% were MDS, and 4.4% were MDS/MPN.

Countries in the lowest TNHE quartile included Bulgaria, Croatia, Estonia, Latvia, Lithuania, Poland, and Slovakia. Countries in the highest TNHE quartile included Austria, Denmark, Germany, Norway, and Switzerland. The median follow-up was 13 years.

At 10 years, the age-standardized relative survival (ASRS) ranged from 61.2% for MPNs to 15.6% for AML. Within MPNs, the 10-year ASRS was 75.2% for ET, 70.9% for PV, and 52.5% for CML.

Countries in the lowest TNHE quartile demonstrated lower 10-year ASRS rates compared with countries in the highest quartile for AML, MPN, and MDS.

A similar trend was observed for 10-year RERs for most MNs, with higher RERs associated with lower TNHE quartile. For example, the lowest TNHE quartile was significantly associated with a greater 10-year RER for MPN (RER, 1.32; 95% CI, 1.30-1.35), AML (RER, 1.28; 95% CI, 1.25-1.31), and acute promyelocytic leukemia (RER, 1.42; 95% CI, 1.12-1.80).

The highest quartile was significantly associated with lower 10-year RER for MPN (RER, 0.80; 95% CI, 0.78-0.81) and AML (0.86; 95% CI, 0.84-0.88), but not some subtypes of AML and APL.

“TNHE is associated with geographical inequalities in MN prognosis,” the researchers concluded in their report. “Policy decisions on allocating economic resources are needed to reduce these differences.”

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Biomed Valley Discoveries Announces First Patient Dosed in Phase 1/2 Combination Study of Ulixertinib with Ruxolitinib (Jakafi®) in Patients with Myelofibrosis

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Provided by GlobeNewswire  

— Dual targeting of JAK 1/2 (ruxolitinib) and ERK 1/2 (ulixertinib) may represent a novel treatment approach for myelofibrosis and possibly other myeloproliferative neoplasms

KANSAS CITY, Mo., April 28, 2025 (GLOBE NEWSWIRE) — Biomed Valley Discoveries (BVD), a clinical-stage biotechnology company guided by its founders’ intent of bringing hope for life to patients, today announced that the first patient has been dosed in a Phase 1/2 combination study of ulixertinib, BVD’s highly selective, first-in-class ERK 1/2 inhibitor with ruxolitinib, a JAK1/JAK2 inhibitor for the treatment of myelofibrosis, a rare type of bone marrow cancer that disrupts the body’s normal production of blood cells.

Raajit Rampal, M.D., Ph.D., a hematologist-oncologist with Memorial Sloan Kettering Cancer Center who specializes in the treatment of myeloproliferative neoplasms and leukemia, is the lead principal investigator for this investigator-initiated trial.

“We’re thrilled to announce the milestone of first patient dosed in this trial, and grateful for the opportunity to collaborate with Dr. Rampal and Incyte to explore the potential of ERK inhibition as a complement to JAK inhibition for the treatment of patients with myelofibrosis,” said Brent Kreider, Ph.D., President of BVD. “This trial helps further our commitment to fully interrogate the potential of direct ERK inhibition to address unmet patient needs in various cancer settings where MAPK signaling is implicated.”

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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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Fatigue, Quality of Life Improve With Rusfertide: Andrew Kuykendall, MD

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April 27, 2025

Author(s): Maggie L. Shaw, Andrew Kuykendall, MD

Bringing this interview with Andrew Kuykendall, MD, clinical researcher at Moffitt Cancer Center, to a close, he addresses safety concerns that have been linked to the injectable hepcidin mimetic rusfertide (Takeda) and its overall impact on patient quality of life. Rusfertide is under investigation for treatment of polycythemia vera, a myeloproliferative neoplasm, in the ongoing phase 3 VERIFY trial (NCT05210790), on which Kuykendall is an investigator.

Previous segments of this interview focused on managing polycythemia vera, understanding hematocrit thresholds, reducing thrombotic risk, and reducing patient dependence on phlebotomy.

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Prediction of resistance to hydroxyurea therapy in patients with polycythemia vera: a machine learning study (PV-AIM) validated in a prospective interventional phase IV trial (HU-F-AIM)

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Published April 25, 2025

Florian H. Heidel, Valerio De Stefano, Matthias Zaiss, Jens Kisro, Eva Gückel, Susanne Großer, Mike W. Zuurman, Kirsi Manz, Kenneth Bryan, Armita Afsharinejad, Martin Griesshammer & Jean-Jacques Kiladjian

Abstract

Polycythemia vera (PV) is a myeloproliferative neoplasm associated with increased thromboembolic (TE) risk and hematologic complications. Hydroxyurea (HU) serves as the most frequently used first-line cytoreductive therapy worldwide; however, resistance to HU (HU-RES) develops in a significant subset of patients, leading to increased morbidity and necessitating alternative treatments. This study, part of the PV-AIM project, employed machine learning techniques on real-world evidence (RWE) from the Optum® EHR database containing 82.960 PV patients to identify baseline predictors of HU-RES within the first 6–9 months of therapy. Using a Random Forest model, the study analyzed data from 1850 patients, focusing on laboratory parameters and clinical characteristics. Key predictive markers included red cell distribution width (RDW) and hemoglobin (HGB), showing the strongest association with HU-RES. A synergistic interaction between RDW and HGB was identified, enabling TE risk stratification. This study provides a robust framework for early detection of HU-RES using readily available clinical data, facilitating timely intervention. These findings underscore the importance of personalized treatment approaches in managing PV and highlight the utility of machine learning in enhancing predictive accuracy and clinical outcomes. Based on the results of PV-AIM we initiated an open-label, prospective, single-arm, interventional, phase IV study (HU-F-AIM) evaluating HU-resistance/intolerance. Validation of predictive biomarkers may facilitate identification of patients at risk of HU resistance who may benefit from alternative treatment options, possibly preventing ongoing phlebotomy during HU treatment, a frequent therapeutic choice in high-risk PV associated with early disease progression and increased thromboembolic complications. We propose an updated terminology that differentiates between true molecular resistance and clinical resistance, that may indicate the requirement for alternative therapeutic strategies.

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