Category Archives: Polycythemia Vera

Rusfertide, a Hepcidin Mimetic, for Control of Erythrocytosis in Polycythemia Vera

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Marina Kremyanskaya, M.D., Ph.D., Andrew T. Kuykendall, M.D., Naveen Pemmaraju, M.D., Ellen K. Ritchie, M.D., Jason Gotlib, M.D., Aaron Gerds, M.D., Jeanne Palmer, M.D., Kristen Pettit, M.D., Uttam K. Nath, M.D., Abdulraheem Yacoub, M.D., Arturo Molina, M.D., Samuel R. Saks, M.D., et al., for the REVIVE Trial Investigators*

Abstract

BACKGROUND

Polycythemia vera is a chronic myeloproliferative neoplasm characterized by erythrocytosis. Rusfertide, an injectable peptide mimetic of the master iron regulatory hormone hepcidin, restricts the availability of iron for erythropoiesis. The safety and efficacy of rusfertide in patients with phlebotomy-dependent polycythemia vera are unknown.

METHODS

 

In part 1 of the international, phase 2 REVIVE trial, we enrolled patients in a 28-week dose-finding assessment of rusfertide. Part 2 was a double-blind, randomized withdrawal period in which we assigned patients, in a 1:1 ratio, to receive rusfertide or placebo for 12 weeks. The primary efficacy end point was a response, defined by hematocrit control, absence of phlebotomy, and completion of the trial regimen during part 2. Patient-reported outcomes were assessed by means of the modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) patient diary (scores range from 0 to 10, with higher scores indicating greater severity of symptoms).

RESULTS

Seventy patients were enrolled in part 1 of the trial, and 59 were assigned to receive rusfertide (30 patients) or placebo (29 patients) in part 2. The estimated mean (±SD) number of phlebotomies per year was 8.7±2.9 during the 28 weeks before the first dose of rusfertide and 0.6±1.0 during part 1 (estimated difference, 8.1 phlebotomies per year). The mean maximum hematocrit was 44.5±2.2% during part 1 as compared with 50.0±5.8% during the 28 weeks before the first dose of rusfertide. During part 2, a response was observed in 60% of the patients who received rusfertide as compared with 17% of those who received placebo (P=0.002). Between baseline and the end of part 1, rusfertide treatment was associated with a decrease in individual symptom scores on the MPN-SAF in patients with moderate or severe symptoms at baseline. During parts 1 and 2, grade 3 adverse events occurred in 13% of the patients, and none of the patients had a grade 4 or 5 event. Injection-site reactions of grade 1 or 2 in severity were common.

CONCLUSIONS

In patients with polycythemia vera, rusfertide treatment was associated with a mean hematocrit of less than 45% during the 28-week dose-finding period, and the percentage of patients with a response during the 12-week randomized withdrawal period was greater with rusfertide than with placebo. (Funded by Protagonist Therapeutics; REVIVE ClinicalTrials.gov number, NCT04057040. opens in new tab.)

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Rusfertide Improves Responses in Phlebotomy-Dependent Polycythemia Vera

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Caroline Seymour

Patients with phlebotomy-dependent polycythemia vera, a type of myeloproliferative neoplasm, treated with rusfertide experienced a response rate of 60% (n = 18/30) compared with 17% (n = 5/29) in those who received placebo (P = .002), according to updated findings from part 2 of the phase 2 REVIVE trial (NCT04057040) published in the New England Journal of Medicine.1

The international trial was designed with 3 parts: a 28-week, open-label, dose-finding portion in which rusfertide was added to a patient’s ongoing therapy of phlebotomy alone or cytoreductive therapy with optional phlebotomy; a double-blind, randomized withdrawal portion wherein patients were randomly assigned to receive rusfertide or placebo for 12 weeks (weeks 29 to 41); and an open-label extension period following patients on rusfertide therapy for up to 3 years.

Findings from part 1 showed that the estimated mean number of annual phlebotomies was 8.7±2.9 during the 28 weeks before the first dose of rusfertide and 0.6±1.0 during part 1 (estimated difference, 8.1 phlebotomies per year). Moreover, the mean maximum hematocrit level was 44.5±2.2% during part 1 vs 50.0±5.8% during the 28 weeks before the first dose of rusfertide. Patient quality of life was also improved on rusfertide, with a lower severity of disease-related symptoms.

“Rusfertide appears to represent a significant step forward in treating [patients with] polycythemia vera through its unique approach of limiting the amount of iron available for blood cell production,” Marina Kremyanskaya, MD, PhD, an associate professor of medicine (hematology and medical oncology) at Icahn School of Medicine at Mount Sinai in New York, New York, and lead author of the study, stated in a news release.2 “Pending further clinical studies, this injectable agent could become a valuable therapeutic tool for a disease which many patients and their physicians struggle to bring under control.”

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Rusfertide More Than Triples Responses Vs Placebo in Phlebotomy-Dependent Polycythemia Vera

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Caroline Seymour

Treatment with rusfertide led to a 60% response rate (n = 18/30) vs 17% (n = 5/29) with placebo in patients with phlebotomy-dependent polycythemia vera (P = .002), according to updated findings from part 2 of the phase 2 REVIVE trial (NCT04057040) which were published in the New England Journal of Medicine.1

The international trial was designed with 3 parts: a 28-week, open-label, dose-finding portion in which rusfertide was added to a patient’s ongoing therapy of phlebotomy alone or cytoreductive therapy with optional phlebotomy; a double-blind, randomized withdrawal portion wherein patients were randomly assigned to receive rusfertide or placebo for 12 weeks (weeks 29 to 41); and an open-label extension period following patients on rusfertide therapy for up to 3 years.

Findings from part 1 showed that the estimated mean number of annual phlebotomies was 8.7±2.9 during the 28 weeks before the first dose of rusfertide and 0.6±1.0 during part 1 (estimated difference, 8.1 phlebotomies per year). Moreover, the mean maximum hematocrit level was 44.5±2.2% during part 1 vs 50.0±5.8% during the 28 weeks before the first dose of rusfertide. Patient quality of life was also improved on rusfertide, with a lower severity of disease-related symptoms.

“Rusfertide appears to represent a significant step forward in treating [patients with] polycythemia vera through its unique approach of limiting the amount of iron available for blood cell production,” Marina Kremyanskaya, MD, PhD, an associate professor of medicine (hematology and medical oncology) at Icahn School of Medicine at Mount Sinai in New York, New York, and lead author of the study, stated in a news release.2 “Pending further clinical studies, this injectable agent could become a valuable therapeutic tool for a disease which many patients and their physicians struggle to bring under control.”

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PharmaEssentia’s BESREMi (ropeginterferon alfa-2b-njft) Now Recommended as a Preferred First-line Cytoreductive Therapy for Polycythemia Vera in Updated NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines)

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Update based on NCCN’s determination of superior efficacy, safety and evidence for BESREMi in high and low-risk patients, reflecting an ongoing shift in PV care toward earlier intervention

BURLINGTON, Mass.–(BUSINESS WIRE)–PharmaEssentia USA Corporation, a subsidiary of PharmaEssentia Corporation (TWSE: 6446), a global biopharmaceutical innovator based in Taiwan leveraging deep expertise and proven scientific principles to deliver new biologics in hematology and oncology, today announced that the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines®) have recently been updated to include ropeginterferon alfa-2b-njft, marketed as BESREMi®, as a preferred first-line cytoreductive therapy option for the treatment of adults with symptomatic, low-risk polycythemia vera (PV). Ropeginterferon alfa-2b-njft is the only preferred therapeutic option for both high-risk and low-risk (symptomatic) PV regardless of treatment history.1

“The recent update to the NCCN Guidelines® reflects the ongoing shift in PV care towards earlier intervention, focusing on long-term patient health,” said Rami Komrokji, M.D., Vice Chair of the Malignant Hematology Department and Head of the Leukemia and MDS Section at Moffitt Cancer Center.

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Study shows early success of a novel drug in treating a rare and chronic blood cancer

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February 21, 2024

by The Mount Sinai Hospital

A novel treatment for polycythemia vera, a potentially fatal blood cancer, demonstrated the ability to control overproduction of red blood cells, the hallmark of this malignancy and many of its debilitating symptoms in a multi-center clinical trial led by the Icahn School of Medicine at Mount Sinai.

In the phase 2 study, the drug rusfertide limited excess production of red blood cells, the main manifestation of polycythemia vera, over the 28-week course of treatment. The results suggest it could replace therapeutic phlebotomy, a common form of treatment which has proven to be a burden for many patients. The results of the study were published today (Feb. 21) in The New England Journal of Medicine.

“Rusfertide appears to represent a significant step forward in treating polycythemia vera through its unique approach of limiting the amount of iron available for blood cell production,” says Marina Kremyanskaya, MD, Ph.D., Associate Professor of Medicine (Hematology and Medical Oncology) at Icahn Mount Sinai and lead author of the study.

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Disc wins orphan drug tag for rare blood cancer

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February 12, 2024

By Jeanne Philpott

The US Food and Drug Administration (FDA) has granted an orphan drug designation (ODD) to US-based biotech Disc Medicine’s DISC-3405 to treat rare blood cancer polycythemia vera (PV).

Disc gained exclusive rights to develop and market the anti-TMPRSS6 (Transmembrane Serine Protease 6) humanized antibody in the US and other territories when it teamed up with Mabwell Therapeutics in a $412.5m licensing agreement in January 2023.

In October 2023, DISC initiated an ongoing Phase I clinical trial (NCT06050915) for DISC-3405, previously named MWTX-003 with data from the study now expected in H1 2024. The orphan drug designation comes after the drug had previously received fast-track designation from the FDA.

The 64-patient Phase I study is divided into groups receiving either a single or multiple doses of DISC-3405, or a placebo. In the single ascending dose (SAD) phase, two subjects serve as sentinels: one receives DISC-3405, and the other placebo. Additional subjects in the cohort are dosed at least 24 hours after the last sentinel dosing, following approval from the principal investigator. Subsequent multiple ascending dose (MAD) cohorts are enrolled only after a sufficient safety observation period for the SAD cohort, removing the need for sentinels in MAD cohorts.

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Tremblay’s Approach to Cytoreduction Across MPNs

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Douglas Tremblay, MD

Douglas Tremblay, MD, assistant professor of medicine at the Icahn School of Medicine at Mount Sinai, discusses the factors which influence the decision to recommend cytoreduction for patients with essential thrombocytopenia (ET) and polycythemia vera (PV).

According to Tremblay, deciding when to start cytoreductive therapy in patients with chronic myeloproliferative neoplasms (MPN) patients like those with PV and ET hinges on accurate risk assessment. While risk stratification tools like the European LeukemiaNet (ELN) classification or the IPSET-Thrombosis score are valuable, Tremblay cautions against oversimplifying things.

He also emphasizes that different factors can indicate which patients are high-risk, including biological age and individual cardiovascular risk factors. Overall, utilizing a personalized approach to risk assessment is key when deciding on cytoreductive therapy for patients with MPN patients. Age should be considered within the context of their overall health and potential for vascular complications. With a personalized approach, experts can ensure that cytoreductive therapy is reserved for those who truly stand to benefit and avoids unnecessary treatment for others.

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Red Blood Cell Contribution to Thrombosis in Polycythemia Vera and Essential Thrombocythemia

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Julien Grenier, Wassim El Nemer, and Maria De Grandis

Abstract

Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms (MPN) characterized by clonal erythrocytosis and thrombocytosis, respectively. The main goal of therapy in PV and ET is to prevent thrombohemorrhagic complications. Despite a debated notion that red blood cells (RBCs) play a passive and minor role in thrombosis, there has been increasing evidence over the past decades that RBCs may play a biological and clinical role in PV and ET pathophysiology. This review summarizes the main mechanisms that suggest the involvement of PV and ET RBCs in thrombosis, including quantitative and qualitative RBC abnormalities reported in these pathologies. Among these abnormalities, we discuss increased RBC counts and hematocrit, that modulate blood rheology by increasing viscosity, as well as qualitative changes, such as deformability, aggregation, expression of adhesion proteins and phosphatidylserine and release of extracellular microvesicles. While the direct relationship between a high red cell count and thrombosis is well-known, the intrinsic defects of RBCs from PV and ET patients are new contributors that need to be investigated in depth in order to elucidate their role and pave the way for new therapeutical strategies.

SRSF2 Mutation in JAK2V617F-Associated MPNs Reduces Polycythemia, Impairs Hematopoietic Progenitor Activity

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Ryner Lai

SFSR2 mutation reduces polycythemia and impairs the activity of hematopoietic stem/progenitor cells in JAK2V617F-associated myeloproliferative neoplasms (MPNs), according to a study published in Blood Cancer Journal. 

Prior research has shown that JAK2V617F is one of the most common somatic mutations associated with MPNs; in turn, SFSR2 mutations are commonly associated with JAK2V617F, especially in myelofibrosis. Nevertheless, the consequences of SRSF2 mutation in JAK2V617F-associated MPNs have yet to be clearly elucidated in existing medical literature.

Researchers conducted a study on Cre-induced SRSF2P95H/+JAK2V617F/+ knock-in mice. The research team induced Mx1Cre expression by injecting mice models with 3 doses of polyinosine-polycytosine (pl-pC) at a dose of 300 μg at 4 weeks after birth. This allowed the researchers to identify the impact of SRSF2 mutation on blood parameters and the bone marrow 24 weeks after pl-pC administration (or 28 weeks after birth).

Additional mutations or genetic abnormalities are required in association with SRSF2P95H and JAK2V617F mutations in the development of full-blown myelofibrosis.

The research team discovered that concurrent SRSF2P95H and JAK2V617F mutations resulted in a reduction in the polycythemia phenotype; mice with concurrent mutations demonstrated a significant reduction in erythrocytes, leukocytes, platelets, neutrophils, and hematocrit parameters compared to mice that only had the JAK2V617F mutation. In addition, mice with concurrent SRSF2P95H and JAK2V617F mutations had higher mean corpuscular volume (MCV) volumes compared to JAK2V617F/+ mice.

Although Jak2V617F/+ mice demonstrated significant splenomegaly, the investigators found that SRSF2P95H/+JAK2V617F/+ mice exhibited reduced spleen size. In addition, whereas JAK2V617F/+ mice exhibited bone marrow hypercellularity alongside significant increases in erythroid precursors and megakaryocyte clusters, SRSF2P95H/+JAK2V617F/+ mice exhibited normal bone marrow cellularity.

The research team found absent/mild bone marrow fibrosis at 24 weeks in both mice groups. They also reported that SRSF2P95H mutation reduced the competitiveness of hematopoietic stem/progenitor cells; in addition, mice with this mutation had reduced transforming growth factor (TGF)-β levels and increased expressions of S100A8 and S100A9 compared to mice without this mutation; overexpression of S100A8 and S100A9 in turn led to erythroid differentiation defects and myelodysplastic syndrome pathogenesis.

“In conclusion, we demonstrate that SRSF2P95H mutant reduces development of bone marrow fibrosis in JAK2V617F-induced MPNs,” the authors of the study wrote in their report. “Additional mutations or genetic abnormalities are required in association with SRSF2P95H and JAK2V617F mutations in the development of full-blown myelofibrosis.”

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Ruxolitinib has positive effect on polycythemia vera symptoms

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December 24, 2023

SAN DIEGO — First-line treatment with ruxolitinib led to “clinically meaningful” positive results versus best available therapy in patients with high-risk polycythemia vera, according to data presented at ASH Annual Meeting.

The therapy had a notable improved impact on symptoms, according to a German team headed by Steffen Koschmieder, MD, head of the clinical hematology laboratory at University of Aachen, Germany.

Ruxolitinib (Jakafi, Incyte) is currently approved in the European Union for patients with hydroxyurea-resistant or intolerant polycythemia vera, but hydroxyurea or ropeginterferon-alpha (Besremi, PharmaEssentia) is currently in practice as the first option.

As ruxolitinib had not been examined against best available therapy in patients with previously untreated polycythemia vera, Koschmieder’s team probed the difference, hypothesizing that ruxolitinib may have higher efficacy.

The randomized phase 2B RuxoBEAT trial — a multicenter, two-arm, open-label trial — had a target population of 190 patients in each arm and a primary endpoint of clinicohematologic complete response rate at 6 months.

By the 6-month mark, the RuxoBEAT data showed that patients in the ruxolitinib arm showed lower hematocrit, pruritus and fatigue, as well as fewer headaches, weight loss and abdominal discomfort.

While the best available therapy and ruxolitinib both displayed reduced platelet counts, white blood cell counts, hematocrit and phlebotomy rates, the best available therapy did not have the same effect on symptoms, and it did not show the impact on spleen size, hemoglobin levels or splenomegaly levels that ruxolitinib had.

Koschmieder noted that the trial is continuing and more patients are being enrolled.

Reference:

Koschmieder S, et al. Firstline treatment with ruxolitinib versus best available therapy in patients with polycythemia vera: Pre-specified interim analysis of the randomized phase 2b Ruxobeat clinical trial of the German study group for myeloproliferative neoplasms. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2023; San Diego.

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