Tag Archives: pv

Ropeginterferon Alfa-2b Demonstrates Similar Pharmacokinetics Across Ethnic Groups With PV

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Andrea S. Blevins Primeau, PhD, MBA

The pharmacokinetic (PK) profile of ropeginterferon alfa-2b (Ropeg) was consistent between Chinese and Caucasian populations with polycythemia vera (PV), according to a modeling study published in Frontiers in Pharmacology.

These results confirm “its efficacy and safety in the global treatment of PV” and “support the broader application of Ropeg in diverse patient populations,” the researchers wrote in their report.

The researchers used data from studies of Ropeg in subjects without myeloproliferative neoplasms (MPN) and among patients with PV to perform modeling analyses for PK parameters, efficacy, and safety in Chinese and Caucasian populations.

PK was assessed using a population PK model using data from phase 1 studies of Chinese and Caucasian volunteers without MPN. There was no significant difference in Ropeg clearance, volume of distribution, or absorption rate between the groups.

In an exposure-response analysis, data from phase 2 clinical trials were used to inform the model. A higher complete hematologic response (CHR) rate was observed in the study of Chinese patients due to a higher starting dose. The CHR was 63% among Chinse patients and 35% among Caucasian patients at 24 weeks. The CHR rates reported from the trials were similar at 61.2% and 27%, respectively.

Our results support the use of Ropeg as an effective and tolerable first-line treatment for PV regardless of ethnic variations.

This “indicates that there is a similar exposure-response relationship between Chinese and Caucasian populations,” the researchers explained.

Phase 2 data were also used to inform the exposure-safety analysis. In the Chinese group, the high dose level of Ropeg was associated with asymptomatic higher liver transaminase levels. There was no association between exposure and gamma-glutamyl transferase, white blood cell count, or neutrophil count.

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Ruxolitinib Provides Better Efficacy Than Best Available Therapy in Polycythemia Vera

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Andrea S. Blevins Primeau, PhD, MBA
According to the results of a systematic review and meta-analysis published in the journal APMIS, patients with polycythemia vera (PV) achieved greater hematocrit control and improved symptoms with ruxolitinib compared with best available therapy (BAT). Ruxolitinib was also associated with higher rates of nonmelanoma skin cancer, anemia, and certain infections.

Researchers identified 6 studies, including 4 randomized controlled trials and 2 observational studies, comprising 1061 patients with PV during the systematic review of reports published through 2023. The meta-analyses used a risk ratio (RR) to estimate effect size.

All patients received treatment with ruxolitinib or BAT, which included hydroxyurea, interferon, pegylated interferon, pipobroman, or anagrelide. The primary outcomes were hematocrit control and complete hematologic response (CHR).

In the cohort, the median age was 66.4 years and 72.8% of patients were male. There were 41.6% of patients were treated with ruxolitinib, 34% were hydroxyurea resistant, and 60% were hydroxyurea intolerant.

Higher rates of hematocrit control were observed in the ruxolitinib group compared with the BAT group (RR, 1.907; 95% CI, 1.135-3.205; P =.015). Ruxolitinib was also associated CHR compared with BAT (RR, 1.965; 95% CI, 1.025-3.768; P =.042).

Among patients with hydroxyurea-resistant or intolerant PV, higher rates of CHR (RR, 2.28; 95% CI, 1.36-3.84; P <.01), at least a 50% reduction in the MPN-SAF score (RR, 3.19; 95% CI, 1.21-8.46; P =.02), and PGIC score (RR, 6.86; 95% CI, 3.45-13.63; P <.01).

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Neutrophil-to-lymphocyte ratio as a prognostic indicator of mortality in Polycythemia Vera: insights from a prospective cohort analysis

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Tiziano Barbui, Alessandra Carobbio, Arianna Ghirardi, Francesca Fenili, Maria Chiara Finazzi, Marta Castelli, Alessandro M. Vannucchi, Paola Guglielmelli, Alessandro Rambaldi, Naseema Gangat & Ayalew Tefferi

Abstract

We analyzed the neutrophil-to-lymphocyte ratio (NLR) in 1508 patients with PV and found that those with an NLR ≥ 5 were generally older, had a longer disease history, and had higher cardiovascular risk factors, more arterial thrombosis, and more aggressive blood counts, indicating a more proliferative disease. NLR was an accurate predictor of mortality, with patients with NLR ≥ 5 having significantly worse overall survival and more than twice the mortality rate compared to those with NLR < 5. Multivariable models confirmed that increasing age, previous venous thrombosis and NLR ≥ 5 were strong predictors of death, further influenced by cardiovascular risk factors. We examined the interaction between NLR and the number of cardiovascular risk factors and found a progressive trend of increased mortality risk for NLR values ≥ 5 in addition to the presence of more than one risk factor. In conclusion, patients with NLR ≥ 5 require careful monitoring and management of cardiovascular risk factors because they increase mortality when associated with progressive levels of NLR.

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Jakafi, Pegasys Combination Beneficial in Newly Diagnosed Polycythemia Vera

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November 4, 2024

Author(s): Alex Biese

Fact checked by: Spencer Feldman

Among patients with who were newly diagnosed polycythemia vera (PV), treatment with Jakafi (ruxolitinib) and low-dose Pegasys (pegylated interferon alfa-2a) was found to be beneficial, resulting in high rates of hematologic and molecular response, research has shown.

Findings from the two-year end-of-study results of the phase 2 COMBI II clinical trial, published in Blood Advances, showed that the combination treatment was associated with improvements to patients’ cell counts with what researchers described as acceptable toxicity.

Researchers utilized the participation of 25 patients with PV, with a median age of 70 years. According to the study, 14 patients (56% of participants) achieved remission at 24 months, with three (12%) attaining complete remission and 11 (44%) reaching partial remission. Researchers reported what they observed as significant reductions to abdominal discomfort, night sweats, itching and bone pain, while the median JAK2V617F VAF was decreased from 47% to 7% and 60% of patients achieved molecular remission.

One of the 25 patients dropped out of the study within two years, while one patient discontinued both drugs while two patients each discontinued Jakafi and Pegasys and continued stand-alone therapy with the other drug.

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Ruxolitinib Plus Pegylated Interferon Alfa-2a Show Promise in Newly Diagnosed Polycythemia Vera

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November 1, 2024

Author(s): Alexandra Gerlach, Associate Editor

Ruxolitinib (Jakafi; Incyte Corp) in combination with pegylated interferon alfa-2a demonstrated efficacy and tolerability in patients with newly diagnosed polycythemia vera (PV). According to the 2-year end-of-study results from the phase 2 COMBI 2 clinical trial (EudraCT2018-004150-13), the treatment improved cell counts, bone marrow cellularity, and fibrosis in patients with PV.1

In the phase 2 COMBI 2 trial, researchers evaluated the safety and efficacy of ruxolitinib and low-dose peg-IFN-α2a in patients with newly diagnosed PV.

Image Credit: © MdBabul – stock.adobe.com

PV is a chronic, progressive myeloproliferative neoplasm characterized by the overproduction of red blood cells. The excess cells thicken the blood, slowing its flow and contributing to serious complications, such as blood clots. Almost all patients with PV have the JAK2V617F mutations, and the JAK2V617F variant allele frequency (VAF) is key for determining outcomes, including thrombosis and progression to myelofibrosis.2-4

Ruxolitinib is a Janus kinase inhibitor approved by the FDA in 2011 and is indicated for the treatment of patients with high-risk MF with reduced abnormal expression of PF4, which can lead to decreased fibrosis. It is additionally indicated as a second-line treatment of PV for patients who have an inadequate response to or cannot tolerate hydroxyurea. In the COMBI 2 trial, researchers assessed the efficacy of ruxolitinib in combination with pegylated interferon alfa-2a (peg-IFN-α2a) (Pegasys ProClick; Genentech), an injection commonly used to treat hepatitis B and C infections. According to data from prior studies, peg-IFN-α2a has been shown to induce durable hematologic and molecular remissions in patients with PV. However, approximately 20% to 40% of patients are intolerant or show limited response to peg-IFN-α2a.5-8

In the phase 2 COMBI 2 trial, researchers evaluated the safety and efficacy of ruxolitinib and low-dose peg-IFN-α2a in patients with newly diagnosed PV in an effort to counterbalance intolerance to peg-IFN-α2a. The primary end point was safety, with secondary end points including efficacy, based on hematologic parameters, quality-of-life measurements, and JAK2V617F variant allele frequency (VAF).8

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FORUS Therapeutics Inc. and PharmaEssentia Corporation Have Entered Into an Exclusive Licensing Agreement for The Registration and Distribution of BESREMi(R) (ropeginterferon alfa-2b) for The Treatment of polycythemia vera (PV), in Canada

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October 31, 2024 8:30 AM EDT | Source: FORUS Therapeutics Inc.

  • Under the terms of the agreement, FORUS is licensing BESREMi from PharmaEssentia for PV in Canada, with potential expansion to other investigational myeloproliferative neoplasms (MPN) indications.
  • FORUS will oversee the drug registration and commercialization of BESREMi in Canada, including securing approval of BESREMi in PV and meeting certain milestones.

Oakville, Ontario–(Newsfile Corp. – October 31, 2024) – FORUS Therapeutics Inc (“FORUS”) and PharmaEssentia Corporation (“PharmaEssentia”) have entered into an exclusive licensing agreement for the registration and distribution of BESREMi® (ropeginterferon alfa-2b) for the treatment of polycythemia vera (PV), in Canada.

“On behalf of the FORUS Therapeutics team, I am truly excited to announce this licensing agreement with PharmaEssentia and to commence the process of commercializing BESREMi in Canada. BESREMi represents the second novel therapeutic in the FORUS hematology-oncology pipeline and is another important step in fulfilling the organization’s mission and vision. We are committed to rapidly advancing BESREMi through the regulatory and reimbursement pathways to ensure that PV patients in Canada have broad access to this novel medication,” said Kevin Leshuk, President and CEO of FORUS. “We are making this announcement today to support the momentum created by the September 12th, Annual MPN Awareness Day and the International Congress on Myeloproliferative Neoplasms, recently held in Brooklyn, New York. We believe that continuing to elevate awareness with the goal of meeting the unmet needs of the MPN community is critical to making a difference in the lives of patients.”

“BESREMi is an important and significant development for clinicians who treat patients with PV. BESREMi as a potential future treatment option is particularly critical for Canada, where treatment options are notably limited for these patients,” says Dr. Shireen Sirhan, a founding member and the current President of the Canadian MPN group, and Vice-President for research in MPNs of the Groupe Québécois de recherche en LMC-NMP. “Canadian physicians have played a significant role in the clinical development program for BESREMi and we look forward to having this important treatment available in the clinic for our patients in need.”

“This is very exciting news for the PV community across Canada,” says Doug Chisholm and Patricia Saluk, the former and current Chair, Board of Directors of the Canadian MPN Network Patient Advocacy group. “Polycythemia vera is a rare blood cancer and the future commercialization of BESREMi in Canada offers highly anticipated new hope for patients, families, and their support networks. We hope the Canadian regulatory and payor systems will work as quickly as possible to ensure our patient community has access to this much needed new treatment regimen.”

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Update: Ruxolitinib Beats Best Available Therapy in Treating Polycythemia Vera

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October 14, 2024

Author(s): Mary Caffrey

An updated meta-analysis confirms that ruxolitinib, the Janus kinase (JAK) 1/JAK2 inhibitor sold as Jakafi, offers improvements in key measures of efficacy compared with best available therapy (BAT) for patients with polycythemia vera (PV),1 a rare, slow-progressing disorder that causes the blood to make too many red blood cells.

Caused by a genetic mutation, PV is not typically fatal on its own, but it can cause dangerous blood clots and damage to the spleen. In a small number of cases, it progresses to more aggressive forms of blood cancer.

The latest results were reported in the journal APMIS,1 formerly known as Acta Pathologica, Microbiologica, et Immunologica Scandinavica.

The analysis followed a 2020 meta-analysis involving 16 studies that appeared in Blood Advances.2 That analysis included evidence from 4 randomized controlled trials and included 663 patients; the authors estimated a thrombosis incidence of 3.09% per year for ruxolitinib vs 5.51% for BAT, but noted that globally, this did not reach significance (P = .098). “A clinical trial on selected patients at high risk of thrombosis would be warranted, but its feasibility is questionable,” the authors wrote.2

The current analysis examines ruxolitinib’s efficacy and safety compared BAT in 1061 patients with PV and in hydroxyurea-resistant and intolerant patients with PV across 6 studies, with a cutoff of November 2023. The patients included 620 on BAT and 441 on ruxolitinib. According to the investigators:

  • Those taking ruxolitinib showed higher hematocrit control (P = .015) and treatment response (P = .04) compared to BAT.
  • Patients taking ruxolitinib had significantly improved Myeloproliferative Neoplasms-Symptom Assessment Form scores (MPN-SAF), P < .01.

However, on the safety front, patients with PV treated with ruxolitinib had higher rates of nonmelanoma skin cancer (P < .01), as has been previously documented.

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High Rates of Polycythemia Vera Remission Seen With Ruxolitinib Plus Peg-IFN

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Andrea S. Blevins Primeau, PhD, MBA

Final results from the phase 2 COMBI II trial demonstrated high rates of remission of newly-diagnosed polycythemia vera (PV) after treatment with ruxolitinib plus pegylated-interferon-α2a (peg-IFN), according to a report published in Blood Advances.

The COMBI I trial previously demonstrated efficacy and safety of the combination of ruxolitinib with peg-IFN among patients who were refractory or intolerant to peg-IFN monotherapy and/or hydroxyurea.

“This study supports the previously described theory that combination therapy with ruxolitinib and peg-IFN may be one of the most promising treatment options in patients with myeloproliferative neoplasms,” the researchers wrote in their report.

In the investigator-initiated, single-center, phase 2 study, researchers treated 25 adult patients with newly-diagnosed PV with ruxolitinib and peg-IFN. All patients underwent pretreatment phlebotomies and patients who were high-risk, aged 60 or older, or who had a prior thrombosis also received hydroxyurea.

The primary endpoint was safety and secondary endpoints included complete remission (CR), peripheral blood count remission (PBCR), and bone marrow histologic remission (BMHR).

The median age of the patients was 70 years and 56% were male. The median number of phlebotomies from diagnosis to study entry was 3. There were 76% of patients who were considered high-risk, 20% had a prior thrombosis, and 12% had splenomegaly. The median hemoglobin was 13.8 g/dL and the median hematocrit was 0.44 IQR. The median variant allele fraction (VAF) of JAK2 V617F at baseline was 54 IQR.

Remission was achieved by 52% of patients by 12 months, with 12% of patients having achieved a CR. At 24 months, the overall remission rate was 56% and the CR rate remained at 12%.

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Dr Grunwald on the Patient Population and Limitations of the REVEAL Study in PV

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September 4, 2024

Author(s): Michael R. Grunwald, MD, FACP

Michael R. Grunwald, MD, FACP, hematologist/oncologist, chief, Leukemia Division; director, Transplantation and Cellular Therapy Program, Levine Cancer Institute, Atrium Health, discusses the key characteristics of patients with polycythemia vera (PV) enrolled onto the real-world, observational REVEAL study (NCT02252159), as well as thelimitations of the investigation.

This observational study represents the largest prospective cohort study of patients with PV conducted to date, Grunwald begins. Patients were not uniformly enrolled at the time of diagnosis; rather, they could be enrolled at any stage of their disease progression. A total of 2510 patients were included in the study, with 2023 having a confirmed diagnosis of PV, ensuring the accuracy of their inclusion in the study, he explains. The remaining patients may or may not have had PV, which introduces a level of uncertainty regarding their inclusion, Grunwald adds.

The analysis focused those who exhibited signs of progression to myelofibrosis, he continues. By comparing the characteristics of patients in the transformed group with those in the non-transformed group, it was observed that patients in the transformed group had a longer duration between their initial diagnosis and enrollment in the study, Grunwald elucidates.

Although the study offers valuable insights, it has limitations, according to Grunwald. Although its findings are effective in generating hypotheses, they do not provide definitive guidance on therapeutic interventions, he explains. Real-world data can offer insights into the outcomes of patients with low-risk disease treated with various therapies, Grunwald says. However, the true validation of a therapy’s effectiveness, particularly for low-risk disease, lies in clinical trials, Grunwald reports.

Looking ahead, there is a need for clinical trials that focus on early intervention in patients classified as low risk, who may harbor features indicating a higher risk of disease progression, he continues. Early intervention may alter the disease course, though this must be balanced against the risk of introducing toxicity prematurely or exhausting treatment options too early, Grunwald says. Fortunately, the treatment paradigm for myeloproliferative neoplasms is evolving, with a significant increase in drug development and approvals over the past decade, he notes. It is anticipated that concerns about exhausting treatment options prematurely will diminish as more therapies become available for patients, he concludes.

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What are the future prospects for polycythemia vera pharmacotherapies for patients with hydroxyurea resistance?

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August 26, 2024

Megan Metzger & John Mascarenhas

Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by erythrocytosis in the context of a somatic JAK2 mutation and a hypercellular marrow with an atypical megakaryocyte morphology. Virtually, all patients with PV harbor a point activating JAK2 mutation, including >95% with JAKV617F and the remainder with other activating JAK2 mutations, including exon 12 [Citation1]. Beyond the JAK2 driver mutation, acquired subclonal mutations have been described in PV involving epigenetic regulation (i.e. TET2 and ASXL1), splicing (i.e. SRSF2), and cellular metabolism (i.e. IDH2) [Citation2]. While clinically derived risk factors including advanced age, thrombosis history, and leukocyte count influence survival outcomes, clonal genomics have recently been integrated into prognostication with the mutation-enhanced international prognostic systems for PV (MIPSS-PV), which highlights the adverse prognostic role of non-driver mutations [Citation3].

Current management of PV is based on risk stratification, favoring cytoreductive treatment in patients with higher risk of thrombosis. The principal goal of PV management is to optimize patients in a way that improves the quality of life and decreases PV-related events, namely, thrombotic events, progression to myelofibrosis, and transformation to blast phase, which are ultimately associated with poor prognosis. While low-dose aspirin and therapeutic phlebotomy are standard management for all risk groups, patients with high-risk PV are recommended to be treated with the addition of a cytoreductive agent. Furthermore, cytoreductive therapy should be considered in certain subgroups of low-risk PV, including patients intolerant of venesection, those with progressive splenomegaly, individuals with persistent leukocytosis or thrombocytosis, or cases of high symptom burden such as intractable pruritus [Citation4]. Regardless of the risk group or treatment strategy, a target hematocrit (Hct) of <45% is required, as control of this hematologic parameter is associated with a lower rate of cardiovascular death and major thrombosis [Citation5].

First-line drugs of choice for PV currently include hydroxyurea (HU) and pegylated interferon alfa-2a (peg-IFN). HU was first introduced as cytoreductive therapy for PV in 1970 and has, therefore, accumulated a significant amount of data endorsing efficacy and tolerability. Despite a lack of randomized control trials and continued debate over potential leukemogenicity, there is general agreement on the net benefit of HU. Early non-randomized trials demonstrated a lower incidence of early thrombosis in HU-treated patients compared to phlebotomy-only historical controls [Citation6]. A recent reappraisal of over 1000 patients enrolled in the ECLAP study confirmed less frequent fatal and non-fatal cardiovascular events with HU treatment compared to phlebotomy alone [Citation7]. However, approximately 25% of PV patients are considered intolerant to HU because of emergent toxicities or are resistant to HU due to lack of effective cytoreduction.

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