Tag Archives: mpn

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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Talazoparib Plus Pacritinib Aims to Improve the Limitations of Second-Line Therapy in MPNs

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September 5, 2024

Author(s): Caroline Seymour

Fact checked by:Kristi Rosa

The combination of talazoparib (Talzenna) and pacritinib (Vonjo) could provide more than symptom burden relief for patients with myeloproliferative neoplasms (MPNs) who have become unresponsive to frontline JAK2 inhibition with ruxolitinib (Jakafi), according to Peter Abdelmessieh, DO, MSC.

The regimen is under study in a phase 1 trial (NCT06218628) at Fox Chase Cancer Center and is supported by earlier work published in Blood showing the synergistic disease-modifying activity of the regimen.1

To be eligible for enrollment, patients must have received a diagnosis of histologically or cytologically confirmed primary myelofibrosis, post-polycythemia vera-myelofibrosis, post-essential thrombocythemia-myelofibrosis, chronic myelomonocytic leukemia, polycythemia vera, or essential thrombocytosis according to the 2008 World Health Organization criteria. Patients must also have at least 2 symptoms with a score of 3 or greater or a total score of 12 or greater, according to the Myelofibrosis Symptom Assessment Form v4.0; intermediate-2 or high-risk myelofibrosis according to the Dynamic International Prognostic Scoring System Plus; and a baseline QTc less than 0.47 seconds per Bazett formula.

Additionally, patients must have prior exposure to a JAK2 inhibitor for at least 12 weeks with documented disease progression or have new, palpable splenomegaly measuring at least 5 cm below the left costal margin in patients who had no evidence of splenomegaly before the start of any frontline JAK2 inhibitor.2

“Second-line treatment for patients with this disease is an unmet need along with the need to investigate other possible pathways that might be effective in this disease. The tool shed is essentially barren for clinicians outside of JAK2 inhibitors,” Abdelmessieh said in an interview with OncLive®.

In the interview, Abdelmessieh, an assistant professor in the Department of Bone Marrow Transplant and Cellular Therapies at Fox Chase Cancer Center, in Philadelphia, Pennsylvania, discussed the basis for the phase 1 trial in patients with MPNs.

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Essential Thrombocythemia Trial Launched Evaluating Bomedemstat

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By Alex Biese
Fact checked by Ashley Chan

A second phase 3 clinical trial has been launched for the investigational oral drug bomedemstat as a potential new treatment for patients with essential thrombocythemia.

The Shorespan-007 clinical trial, according to a news release from bomedemstat manufacturer Merck, will investigate the use of the drug among patients with essential thrombocythemia who have not previously received cytoreductive therapy.

The global trial, which is currently recruiting, will compare bomedemstat to the current standard of care chemotherapy, hydroxyurea. The trial, with 300 participants, is expected to be concluded in May 2029, according to its listing on clinicaltrials.gov.

Essential thrombocythemia, part of a group of blood cancers known as myeloproliferative neoplasms (MPNs), is a rare disease in which the bone marrow produces too many platelets, according to The Leukemia & Lymphoma Society. This disease, The Leukemia & Lymphoma Society explained, can cause blood clots to form in a patient’s blood vessels, in turn resulting in serious health issues such as stroke, heart attack or pulmonary embolism.

“The standard of care in essential thrombocythemia has remained unchanged for decades, and patients are in need of new options that have the potential to not only improve disease control but also improve their quality of life,” said Dr. Gregory Lubiniecki, vice president of global clinical development for Merck Research Laboratories, in the company’s news release. “We are rapidly advancing our clinical development programs with the goal of helping to address these unmet needs and bring more options to patients living with myeloproliferative neoplasms.”

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Momelotinib May Improve Survival and Quality of Life in MF

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August 30, 2024

Leonardo Jaimes

Momelotinib appears to positively impact quality of life and overall survival in patients with myelofibrosis (MF), according to a recently published study in Frontiers in Oncology.

Most MF cases are associated with JAK or CALR mutations, which lead to an uncontrolled proliferation of stem cells and a decrease in the production of red blood cells (RBCs) and thrombocytes, the researchers noted.

Stem cell transplantation is currently the only curative alternative available for patients with MF. The advent of JAK inhibitors represented a significant advancement in symptom management, but patients often observed decreased efficacy after 3 years.

Anemia is largely responsible for the decrease in quality of life seen in patients with MF and represents an important cause of treatment discontinuation, as some of the treatments used in MF can contribute to the development of anemia.

“Anemia in MF is a complex condition resulting from factors such as displacement of erythropoietic tissue by fibrotic stroma, suboptimal environments in extramedullary sites, and splenomegaly-induced RBC sequestration,” the authors wrote.

Momelotinib is an effective JAK1/2 inhibitor that can successfully treat anemia in patients with MF, decreasing the need for transfusions. It can also prevent hepcidin synthesis, which in turn leads to increased iron circulation and increased erythropoiesis.

The effectiveness of momelotinib is supported by the results of the MOMENTUM trial; the double-blind included almost 200 patients who received either momelotinib or danazol to treat MF-associated anemia.  Results showed that patients who received were significantly less likely to require blood transfusions and have better Total Symptom Score than their counterparts.

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Metformin for MPN: teaching an old drug new tricks

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August 27, 2024

Michelle H. Lee, Gabriela S. Hobbs

In this issue of Blood Advances, Kristensen et al1 identified an association between metformin use and decreased risk of myeloproliferative neoplasms (MPNs). In this Danish population–based case-control study, 7% of patients with MPN (268 out 3816) had taken metformin compared with 8.2% of the matched general population (1573 out 19 080) without MPNs. Metformin use was associated with lower odds of developing MPNs, with a marked dose-response relationship by cumulative duration in years. Among individuals with long-term metformin use between 5 and 10 years, the adjusted odds ratio was 0.42 (95% confidence interval [CI], 0.29-0.61). This protective effect was observed across all age groups, sex, driver mutations (JAK2-V617F and CALR), and subtypes of classical Philadelphia-chromosome negative MPNs, though most pronounced with polycythemia vera (PV) and essential thrombocythemia (ET). To our knowledge, this study is among the first to examine and report the potential leukemia preventive-impact of metformin.

Philadelphia-negative MPNs comprise a group of chronic leukemias that stem from aberrant clonal expansion of mature myeloid cells. Clinical presentation varies widely across the spectrum of these diseases, but major causes of morbidity and mortality include arterial and venous thromboses, along with transformation to myelofibrosis and acute myeloid leukemia. The majority of MPNs harbor recurrent somatic mutations in JAK2, CALR, or MPL genes, all of which result in the dysregulated activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway. The subsequent derangement in immune homeostasis plays a key role in MPN pathogenesis. The mutant hematopoietic clones of MPNs not only thrive in, but also propagate a hyperinflammatory environment through the production of proinflammatory cytokines such as interleukin 6 and tumor necrosis factor alpha among others.2

Metformin is a synthetic derivative of galegine, a natural product of the plant Galega officinalis (goat’s rue or French lilac), with blood glucose-lowering activity that was first reported in 1957 by the French physician Jean Sterne.3 It is now the most commonly prescribed medication for type 2 diabetes mellitus (T2DM) worldwide. Several epidemiologic studies have revealed decreased solid cancer risk and related mortality among patients taking metformin, but this study augments the findings of a previous retrospective investigation, which reported significantly lower risk for developing hematologic malignancies among veterans taking metformin vs those taking sulfonylureas.4 Although the means by which metformin prevents MPNs require further examination to complement the data presented by Kristensen et al, metformin may attenuate leukemogenesis through downregulation of JAK/STAT signaling and subsequent reduction of the inflammatory cytokines that drive MPN. Notable anti-inflammatory mechanisms of metformin on JAK2 V617F-positive MPN cell lines include intracellular reactive oxygen species production and inhibition of downstream mTOR signaling via adenosine monophosphate-activated kinase (AMPK)-dependent pathways, and inhibition of mitochondrial activity and activation of a subfamily of protein tyrosine phosphatase PP2A via AMPK-independent pathways.5

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Merck Announces Phase 3 Trial Initiation for Bomedemstat, an Investigational Candidate for the Treatment of Certain Patients With Essential Thrombocythemia

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August 27, 2024 6:45 am ET

The initiation of a second Phase 3 clinical trial for bomedemstat demonstrates company’s commitment to advancing research in myeloproliferative neoplasms (MPNs)

RAHWAY, N.J.–(BUSINESS WIRE)– Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced the initiation of Shorespan-007, a pivotal Phase 3 clinical trial evaluating bomedemstat, an investigational orally available lysine-specific demethylase 1 (LSD1) inhibitor, for the treatment of patients with essential thrombocythemia (ET) who have previously not received cytoreductive therapy. Essential thrombocythemia is a chronic, rare blood disorder and is the most common type of myeloproliferative neoplasm. Global recruitment of the Shorespan-007 trial has begun, with patients now enrolling.

“The standard of care in essential thrombocythemia has remained unchanged for decades, and patients are in need of new options that have the potential to not only improve disease control, but also improve their quality of life,” said Dr. Gregory Lubiniecki, vice president, global clinical development, Merck Research Laboratories. “We are rapidly advancing our clinical development programs with the goal of helping to address these unmet needs and bring more options to patients living with myeloproliferative neoplasms.”

Shorespan-007 is a Phase 3, randomized, double-blind, active comparator-controlled clinical trial ( NCT06456346 ) evaluating bomedemstat compared to the current standard of care chemotherapy, hydroxyurea, for treatment of patients with ET who have previously not received cytoreductive therapy. The trial will enroll approximately 300 patients globally. The primary endpoint of the study is durable clinicohematologic response rate (CHR). Key secondary endpoints include Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0) individual fatigue symptom item score, Patient-reported Outcomes Measurement Information System (PROMIS) Fatigue SF-7a total fatigue score and MFSAF v4.0 total symptom score. Additional secondary endpoints include duration of hematologic remission, event-free survival and disease progression rate.

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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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Assessing and Managing Bleeding Risk Pre-Surgery in Patients With MPNs

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August 20 , 2024

Risk factors for bleeding and thrombosis among patients with myeloproliferative neoplasms (MPNs) who are scheduled for surgery are multifaceted and require consideration of individual patient characteristics, risk assessment, and perioperative management, according to results published in Cureus.

“Thrombosis, venous or arterial, is a major cause of mortality and morbidity in [essential thrombocythemia (ET)] and [polycythemia vera], while bleeding is more concerning in [myelofibrosis] and ET,” Mihaela Andreescu, MD, PhD, and colleagues wrote. “Surgical procedures also pose a significant risk for bleeding in MPNs, with a probability of 7.2% during surgery. Assessing bleeding and thrombosis risk in patients scheduled for surgery is crucial to optimize patient outcomes.”

Specific Risks for Bleeding and Thrombosis

Risk assessment tools included rational elastrometry (ROTEM), International Predictive Score for Thrombosis in ET (IPSET), and the dynamic international prognostic scoring system (DIPSS).

The researchers identified age (>60), history of thrombosis, and genetic mutations, particularly variants of JAK2V617F, as risk factors for thrombosis in patients with MPN. Risk factors for bleeding included leukocytosis, thrombocytosis, acquired von Willebrand syndrome, and history of bleeding.

“Individual patient factors must be considered to minimize severe bleeding and thrombotic complications in surgeries,” Dr. Andreescu and colleagues wrote. “Risk assessment and perioperative management are important aspects of improving the QOL and preventing complications in surgeries.”

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A randomized, double-blind, placebo-controlled phase 3 study to assess efficacy and safety of ropeginterferon alfa-2b in patients with early/lower-risk primary myelofibrosis

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Ghaith Abu-Zeinah, Albert Qin, Harinder Gill, Norio Komatsu, John Mascarenhas, Weichung Joe Shih, Oleh Zagrijtschuk, Toshiaki Sato, Kazuya Shimoda, Richard T. Silver & Ruben Mesa

Abstract

Primary myelofibrosis (PMF) is the most aggressive of the myeloproliferative neoplasms and patients require greater attention and likely require earlier therapeutic intervention. Currently approved treatment options are limited in their selective suppression of clonal proliferation resulting from driver- and coexisting gene mutations. Janus kinase inhibitors are approved for symptomatic patients with higher-risk PMF. Additionally, most ongoing clinical studies focus on patients with higher-risk disease and/or high rates of transfusion dependency. Optimal treatment of early/lower-risk PMF remains to be identified and needs randomized clinical trial evaluations. Pegylated interferon alfa is recommended for symptomatic lower-risk PMF patients based on phase 2 non-randomized studies and expert opinion. Ropeginterferon alfa-2b (ropeg) is a new-generation pegylated interferon-based therapy with favorable pharmacokinetics and safety profiles, requiring less frequent injections than prior formulations. This randomized, double-blind, placebo-controlled phase 3 trial will assess its efficacy and safety in patients with “early/lower-risk PMF”, defined as pre-fibrotic PMF or PMF at low or intermediate-1 risk according to Dynamic International Prognostic Scoring System-plus. Co-primary endpoints include clinically relevant complete hematologic response and symptom endpoint. Secondary endpoints include progression- or event-free survival, molecular response in driver or relevant coexisting gene mutations, bone marrow response, and safety. Disease progression and events are defined based on the International Working Group criteria and well-published reports. 150 eligible patients will be randomized in a 2:1 ratio to receive either ropeg or placebo. Blinded sample size re-estimation is designed. Ropeg will be administered subcutaneously with a tolerable, higher starting-dose regimen. The study will provide important data for the treatment of early/lower-risk PMF for which an anti-clonal, disease-modifying agent is highly needed.

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Platelet proteomic profiling reveals potential mediators of immunothrombosis and proteostasis in myeloproliferative neoplasms

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August 14, 2024

Sarah Kelliher, Sara Gamba, Luisa Weiss, Zhu Shen, Marina Marchetti, Francesca Schieppati, Caitriona Scaife, Stephen Madden, Kathleen Bennett, Anne Fortune, Su Maung, Michael Fay, Fionnuala Ní Áinle, 
Patricia Maguire, Anna Falanga, Barry Kevane, Anandi Krishnan

Myeloproliferative neoplasms (MPNs) are chronic bone marrow malignancies characterized by clonal proliferation of hematopoietic precursors and elevated cell counts in peripheral blood.1 Patients with MPN are at risk of progression to myelofibrosis or acute leukemia and experience a substantial burden of microvascular symptoms.2,3 However, thrombosis (both arterial and venous) represents the leading cause of morbidity and mortality for patients with polycythemia vera (PV) and essential thrombocythemia (ET).4-6

Translational studies have indicated that the platelet proteome influences pathways relating to immune response, inflammation, and malignancy.7,8 Thrombocytosis and platelet hyperactivity are hallmarks of MPN;9 however, platelet count in isolation is not predictive of clinical outcome, and conventional antiplatelet therapy does not fully mitigate thrombotic risk.10 A comprehensive picture of the MPN platelet molecular profile is lacking, and to date, no studies have evaluated the unbiased platelet proteome in a sizable clinical cohort of affected patients. Here, we performed untargeted quantitative profiling of the platelet proteome in a large (n = 140) cohort of patients with PV and ET.

Using standardized platelet isolation protocols (supplemental Methods), we prepared purified platelets from peripheral blood samples of patients with an established diagnosis of MPN (World Health Organization defined, n = 59 ET, n = 41 PV) and a cohort of healthy controls (n = 40) recruited across 2 sites: Hospital Papa Giovanni XXIII, Bergamo, Italy and Mater Misericordiae University Hospital, Dublin, Ireland. Pertinent clinical features are shown in Figure 1 (and listed in supplemental Table 1). Interpatient variability, including age, sex, and treatment, as well as experimental batch effects, were adjusted as confounding factors in downstream expression analyses (supplemental Methods). Focusing on the most prothrombotic subtypes of MPNs, we hypothesized that the platelet proteome differs in MPN, and its characterization would offer insights into the underlying pathobiology and possible mechanisms underlying the associated clinical complications.

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