Tag: Polycythemia Vera

SUMMARY: Polycythemia vera (PV) is a clonal myeloproliferative neoplasm characterized by excessive Red Blood Cell (RBC) production, most often driven by JAK2 mutations. A hallmark of PV is sustained erythrocytosis, which contributes to increased blood viscosity and significantly elevates the risk of thrombotic events. Standard management strategies include phlebotomy, low-dose Aspirin, and cytoreductive agents such as Hydroxyurea, Interferons, and Ruxolitinib. While phlebotomy remains a key tool for hematocrit (Hct) control, frequent procedures are burdensome for many patients, can worsen iron deficiency, and often fail to alleviate constitutional symptoms like fatigue. In this context, Rusfertide, a novel, self-injectable hepcidin mimetic, has emerged as a promising therapeutic strategy targeting iron metabolism to modulate erythropoiesis more precisely.

A Hepcidin-Based Therapeutic Approach
Hepcidin is a hormone produced by the liver that regulates iron absorption in the intestine and iron release from storage sites like macrophages and the liver. It does this by binding to ferroportin, an iron transport protein responsible for transporting iron out of intestinal cells and from storage sites (like macrophages) into the bloodstream. Following its binding to ferroportin, hepcidin causes its degradation, which in turn reduces iron export from cells and lowers iron levels in the blood. Hepcidin levels are generally low in iron deficiency anemia facilitating increased intestinal iron absorption and release of iron from storage sites and promoting iron availability for erythropoiesis. Hepcidin therefore is the master regulator that controls iron homeostasis in the bone marrow for RBC production.

Rusfertide is a first-in-class synthetic peptide the mimics hepcidin and reduces iron availability for erythropoiesis in the bone marrow, thereby mitigating RBC overproduction, characteristic of PV, potentially reducing or eliminating the need for phlebotomies. The unique, subcutaneously administered formulation of Rusfertide allows for convenient weekly self-injection, potentially decreasing reliance on phlebotomy and improving patient quality of life.

VERIFY Trial Design and Objectives
The VERIFY study (NCT05210790) is an ongoing, multinational, randomized, double-blind, placebo-controlled Phase 3 trial, designed to assess the safety and efficacy of Rusfertide in patients with phlebotomy-dependent PV receiving standard-of-care therapy. Enrolled patients were required to have frequent phlebotomies to maintain hematocrit control, with or without concurrent cytoreductive therapy. In Part 1a of the study (Weeks 0–32), patients (N=293) were randomized 1:1 to receive once-weekly Rusfertide (N=147) or placebo (N=146) and patients were stratified by concurrent cytoreductive therapy. The median patient age was 57 years. The Primary endpoint was the proportion of patients achieving clinical response, defined as the absence of phlebotomy eligibility, and no phlebotomies between weeks 20–32. Key Secondary endpoints included number of phlebotomies, proportion of patients with Hct <45%, and changes in patient-reported outcomes (PROMIS Fatigue Short Form-8a and MFSAF Total Symptom Score). Following the 32-week blinded phase (Part 1a), patients could enter an open-label extension (Part 1b, weeks 32–52), with a planned long-term follow-up (Part 2) for up to 3 years.

Clinical Outcomes: Efficacy Highlights
The trial met its Primary endpoint, demonstrating that 76.9% of patients treated with Rusfertide achieved a clinical response compared with 32.9% in the placebo group (P< 0.0001).

Key efficacy findings included:

• Phlebotomy reduction: Mean number of phlebotomies from weeks 0–32 was o.5 with Rusfertide versus 1.8 with placebo (P< 0.0001).
• Hematocrit control: 62.6% of Rusfertide-treated patients maintained Hct <45%, compared with 14.4% in the placebo group (P< 0.0001).
• Symptom improvement: Statistically significant improvements were seen in fatigue (PROMIS Fatigue SF-8a) and PV-related symptom burden (MFSAF TSS), highlighting a benefit on patient quality of life (P<0.03).

Patients at baseline averaged over four phlebotomies in the preceding 28 weeks, yet the majority receiving Rusfertide required none during the first 32 weeks of the study. Notably, 72.8% of patients on Rusfertide required no phlebotomy at all during this period, compared to 21.9% on placebo.

Safety Profile and Tolerability
Rusfertide was generally well tolerated and injection site reactions were the most common adverse event (55.9% in Rusfertide vs. 32.9% in placebo). Anemia was more frequent with Rusfertide (15.9% vs. 4.1%), reflecting its mechanism of reducing iron availability. Interestingly, fewer new malignancies were reported in the Rusfertide arm (N=1) versus placebo (N=7), though the significance of this observation requires longer follow-up.

Implications for Practice
The VERIFY trial supports Rusfertide as a potential paradigm shift in the management of PV, particularly for patients who are phlebotomy-dependent. By addressing erythrocytosis through iron restriction rather than marrow suppression, Rusfertide introduces a novel mechanism that complements existing therapies.

If approved, rusfertide would:

• Offer an effective alternative to repeated phlebotomies.
• Provide symptom relief, particularly in domains like fatigue and cognitive impairment, which are often unaddressed by standard treatments.
• Be suitable as an adjunct to cytoreductive therapy or as a standalone intervention for those who decline or are ineligible for such agents.
• Improve patient autonomy and quality of life through self-administration and reduced healthcare interactions.

Ongoing Evaluation and Regulatory Outlook
VERIFY continues in its open-label and long-term follow-up phases to evaluate the durability of response, long-term safety, and thrombotic outcomes over 3 years. Regulatory submissions are in preparation across the U.S., Europe, and Japan. Should Rusfertide gain regulatory approval, it is anticipated to become a valuable component of the standard treatment landscape for PV—potentially freeing patients from the physical, logistical, and emotional burdens of recurrent phlebotomy.

Results from VERIFY, a phase 3, double-blind, placebo (PBO)-controlled study of rusfertide for treatment of polycythemia vera (PV). Kuykendall A, Pemmaraju N, Pettit K, et al. J Clin Oncol 43, 2025 (suppl 17; abstr LBA3)

SUMMARY: Polycythemia Vera (P. Vera) is a clonal myeloproliferative neoplasm characterized by isolated erythrocytosis in a majority of the patients, with the remaining demonstrating leukocytosis and/or thrombocytosis along with erythrocytosis. Patients usually present with this disorder in their sixth decade and are often asymptomatic, with the diagnosis made incidentally on routine laboratory evaluation. About 30% of the patients however, may initially present with a thrombotic episode, whereas a small percentage of patients may present with disease related symptoms such as pruritus and fatigue. The conventional risk factors for thrombotic events in MyeloProliferative Neoplasms (MPN) are age more than 60 years and prior thrombosis, and the presence of both these risk factors is associated with a 7-fold increased risk of thrombosis.

Overactivation of the JAK-STAT signal transduction pathway caused by V617F mutation has been implicated in majority of the patients with P. Vera. This pathway normally is responsible for passing information from outside the cell through the cell membrane to the DNA in the nucleus for gene transcription. Janus Kinase (JAK) family of tyrosine kinases are cytoplasmic proteins and include JAK1, JAK2, JAK3 and TYK2. JAK1 helps propagate the signaling of inflammatory cytokines whereas JAK2 is essential for growth and differentiation of hematopoietic stem cells. These tyrosine kinases mediate cell signaling by recruiting STATs (Signal Transducer and Activator of Transcription), with resulting modulation of gene expression. In patients with P. Vera, the aberrant myeloproliferation is the result of dysregulated JAK2-STAT signaling as well as excess production of inflammatory cytokines, associated with this abnormal signaling. JAK2 mutations such as JAK2 V617F are seen in approximately 95% of patients with P. Vera.

Studies have shown that JAK2 mutations that result in the overproduction of erythrocytes, leukocytes, and platelets in P. Vera also promote direct activation of leukocytes and platelets. Activated platelets and leukocytes bind to each other and activate endothelial cells, which may in turn contribute to the prothrombotic state. The prospective CYTO-PV trial published in 2011, established that maintaining hematocrit less than 45% through phlebotomies and/or cytoreductive drugs significantly decreased the risk of thrombotic events in P. Vera patients. Even though several retrospective analyses strongly suggest an association between leukocytosis and thrombosis and leukocytosis particularly at the time of the thrombotic event in P. Vera patients, no prospective trial has been conducted to assess the impact of WBC counts on thrombotic risk in P. Vera.

The REVEAL study is a large, real-world, multicenter, prospective, noninterventional, observational study, in which patients with P. Vera from US community practice and academic centers were enrolled, to evaluate the association between elevated blood counts and occurrence of thrombotic events in patients with P. Vera, using data from the REVEAL study.

This study analyzed the data of 2271 eligible patients for this analysis (78% high risk and 22% low risk). The median patient age was 66 years and 54% were male. The median disease duration was 4.1 years, 20% had a history of thrombotic events and majority of patients (53%) were receiving Hydroxyurea. Patient data was collected at diagnosis, at a 6-month period, and during follow up, 3 years from last patient enrollment, between July 2014 and August 2019 and the researchers analyzed the association between blood counts and thrombotic events. Out of 106 patients who had thrombotic events, 30 had arterial thrombotic events, most commonly, Transient Ischemic Attack and 76 had venous thrombotic events, most commonly, Deep Vein Thrombosis.

It was noted that hematocrit greater than 45% versus 45% or less (P=0.0028), WBC more than 11×10⁹/L versus 11×10⁹/L or less (P<0.0001), and Platelet counts more than 400×10⁹/L versus 400×10⁹/L or less (P=0.0170) were each associated with increased risk of thrombotic events. A WBC count of 11×10⁹/L or more was associated with the highest thrombotic event risk compared with WBC count less than 7×10⁹/L (P<0.0001).  When the HCT was controlled at 45% or less, an elevated WBC count (more than 12 × 10⁹/L) was significantly associated with increased risk of thromboembolism (HR=1.95; P=0.03). In all models analyzed, advanced age and history of thrombotic events, were associated with increased thrombotic event risk.

The authors concluded that in this analysis of the largest real-world cohort of P. Vera patients to date, hematocrit more than 45%, as well as WBC more than 11×10⁹/L and Platelet counts more than 400×10⁹/L, were each associated with increased risk of thrombotic events. WBC more than 12×10⁹/L was significantly associated with increased thrombotic risk, even when the HCT was controlled, suggesting that thrombotic risk may be reduced by controlling both the WBC count and HCT level. The authors added that these data support the incorporation of blood count values into risk stratification and treatment strategies for patients with P. Vera in clinical practice, and to move beyond the conventional risk model.

A Real-World Evaluation of the Association between Elevated Blood Counts and Thrombotic Events in Polycythemia Vera: An Analysis of Data from the REVEAL Study). Gerds AT, Mesa RA, Burke JM, et al. Presented at: 2022 European Hematology Association Congress; June 10, 2022; Vienna, AT. Poster # P1062.

SUMMARY: Polycythemia Vera (P. Vera) is a clonal myeloproliferative neoplasm characterized by isolated erythrocytosis in a majority of the patients, with the remaining demonstrating leukocytosis and/or thrombocytosis along with erythrocytosis. Patients usually present with this disorder in their sixth decade and are often asymptomatic, with the diagnosis made incidentally on routine laboratory evaluation. About 30% of the patients however, may initially present with a thrombotic episode, whereas a small percentage of patients may present with disease related symptoms such as pruritus and fatigue. The conventional risk factors for thrombotic events in MyeloProliferative Neoplasms (MPN) are age more than 60 years and prior thrombosis, and the presence of both these risk factors is associated with a 7-fold increased risk of thrombosis.

Overactivation of the JAK-STAT signal transduction pathway caused by V617F mutation has been implicated in majority of the patients with P. Vera. This pathway normally is responsible for passing information from outside the cell through the cell membrane to the DNA in the nucleus for gene transcription. Janus Kinase (JAK) family of tyrosine kinases are cytoplasmic proteins and include JAK1, JAK2, JAK3 and TYK2. JAK1 helps propagate the signaling of inflammatory cytokines whereas JAK2 is essential for growth and differentiation of hematopoietic stem cells. These tyrosine kinases mediate cell signaling by recruiting STAT’s (Signal Transducer and Activator of Transcription), with resulting modulation of gene expression. In patients with P. Vera, the aberrant myeloproliferation is the result of dysregulated JAK2-STAT signaling as well as excess production of inflammatory cytokines, associated with this abnormal signaling. JAK2 mutations such as JAK2 V617F are seen in approximately 95% of patients with P. Vera.

Studies have shown that JAK2 mutations that result in the overproduction of erythrocytes, leukocytes, and platelets in P. Vera also promote direct activation of leukocytes and platelets. Activated platelets and leukocytes bind to each other and activate endothelial cells, which may in turn contribute to the prothrombotic state. The prospective CYTO-PV trial published in 2011, established that maintaining hematocrit less than 45% through phlebotomies and/or cytoreductive drugs significantly decreased the risk of thrombotic events in P. Vera patients. Even though several retrospective analyses strongly suggest an association between leukocytosis and thrombosis, leukocytosis particularly at the time of the thrombotic event in P. Vera patients, no prospective trial has been conducted to assess the impact of WBC counts on thrombotic risk in P. Vera.

The REVEAL study is a large, real-world, multicenter, prospective, noninterventional, observational study, in which patients with P. Vera from US community practice and academic centers were enrolled , to evaluate the association between elevated blood counts and occurrence of thrombotic events in patients with P. Vera, using data from the REVEAL study.

This study analyzed the data of 2271 eligible patients for this analysis (78% high risk and 22% low risk). The median patient age was 66 years and 54% were male. The median disease duration was 4.1 years, 20% had a history of thrombotic events and majority of patients (53%) were receiving Hydroxyurea. Patient data was collected at diagnosis, at a 6-month period, and during follow up, 3 years from last patient enrollment, between July 2014 and August 2019 and the researchers analyzed the association between blood counts and thrombotic events. Out of 106 patients who had thrombotic events, 30 had arterial thrombotic events, most commonly, Transient Ischemic Attack and 76 had venous thrombotic events, most commonly, Deep Vein Thrombosis.

It was noted that hematocrit greater than 45% versus 45% or less (P=0.0028), WBC more than 11×10⁹/L versus 11×10⁹/L or less (P<0.0001), and Platelet counts more than 400×10⁹/L versus 400×10⁹/L or less (P=0.0170) were each associated with increased risk of thrombotic events. A WBC count of 11×10⁹/L or more was associated with the highest thrombotic event risk compared with WBC count less than 7×10⁹/L (P<0.0001). In all models analyzed, advanced age and history of thrombotic events, were associated with increased thrombotic event risk.

The authors concluded that in this analysis of the largest real-world cohort of P. Vera patients to date, hematocrit more than 45%, as well as WBC more than 11×10⁹/L and Platelet counts more than 400×10⁹/L, were each associated with increased risk of thrombotic events. The authors added that these data support the incorporation of blood count values into risk stratification and treatment strategies for patients with P. Vera in clinical practice, and to move beyond the conventional risk model.

A Real-World Evaluation of the Association between Elevated Blood Counts and Thrombotic Events in Polycythemia Vera (Analysis of Data from the REVEAL Study). Gerds AT, Mesa RA, Burke JM, et al. Presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 239.