Author Archives: MPN Advocacy & Education

Exploring Possibilities in Disease Modification in MPNs

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October 25, 2024

Author(s): Mary Caffrey

Treatment of myeloproliferative neoplasms (MPNs) has historically focused on delaying or avoiding transformation to acute myeloid leukemia (AML) as well as symptom relief and improving quality of life; strategies addressed thrombosis or enlarged spleen both with therapy and with nonpharmacological strategies such as smoking cessation or encouraging patients to lose weight.

Although these strategies were associated with improving life expectancy, they did not measure disease modification through molecular responses that signal survival benefits, in the way that trials do with AML and chronic myeloid leukemia (CML).

Claire N. Harrison, MD, FRCP, FRCPath | Image credit: Guy’s and St Thomas

Now, in an essay appearing in HemaSphere, a publication of the European Hematology Association (EHA), investigator Claire N. Harrison, MD, FRCP, FRCPath, of the Department of Haematology, Guy’s and St Thomas NHS Foundation Trust, asks whether the study and treatment of MPNs is ready for a new era with new end points, with data that show how survival benefits are biologically linked to changes in the spleen, reduction in fibrosis, or other responses.

The challenge, Harrison writes, is that the requirements will be different from today’s standards. “These data should hopefully influence a paradigm shift for the regulatory agencies and the field toward a focus instead of disease modification, but this will certainly require data extending beyond the recent standard of 24 weeks,” she writes.

In the perspective piece, “Are we ready for disease modification in myeloproliferative neoplasms?” Harrison notes that a dramatic shift that came with arrival of Janus kinase (JAK) inhibitor–based therapy for patients with myelofibrosis (MF) who could not receive a stem cell transplant. Therapy shows the capacity to reduce spleen size and symptoms. “Both of these facets of MF do probably reflect underlying pathophysiology and, furthermore, spleen size reduction has been shown to correlate with overall survival advantage.”

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INCA033989 May Address Need for Disease-Modifying Therapies in Myelofibrosis

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October 25, 2024

Author(s): Courtney Flaherty

Fact checked by: Megan Hollasch

Unlike the array of JAK inhibitors available for the treatment of patients with myelofibrosis, the novel monoclonal antibody INCA033989 may have disease-modifying potential among those expressing CALR type 1 mutations, potentially addressing an area of need in myeloproliferative neoplasm (MPN) management, according to Daniel J. DeAngelo MD, PhD.

“With the 4 [FDA-approved] JAK inhibitors, we see clear improvements in symptoms, reduction in spleen [volume], and decreased counts for patients with polycythemia or essential thrombocytopenia, but we’re not seeing eradication and normalization of the bone marrow,” DeAngelo said in an interview with OncLive®. “We don’t know if this agent is going to change that, but the hypothesis is that [INCA033989] may be getting at the heart of the disease, although only for patients with CALR type 1 mutations.”

In engineered cell lines and primary CD34-positive cells from patients with MPN, INCA033989 was shown to antagonize mutant CALR–driven signaling and cellular proliferation. Moreover, in a mouse model of MPN with mutant CALR, administration of an INCA033989 mouse surrogate antibody prevented the development of thrombocytosis and accumulation of platelet-producing megakaryocytes in the bone marrow. The agent’s disease-modifying potential is supported by its reduction of pathogenic self-renewal among MPN cells expressing CALR mutations in both primary and secondary transplantations.1

These preclinical data support the agent’s ongoing investigation in a phase 1 study (NCT06034002) for patients with MPN.2

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Recognizing Symptoms of Myeloproliferative Neoplasms and Clinical Trial Challenges

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October 24, 2024

Author(s): Mary Caffrey, Laura Joszt, MA

The symptoms of myeloproliferative neoplasms can be variable and common, which can make it difficult to diagnose if you aren’t looking for the right thing, said Ruben Mesa, MD, FACP, executive director of Atrium Health Wake Forest Baptist Comprehensive Cancer Center and president of Atrium Health Levine Cancer.

He also discusses the challenges with getting patients enrolled in clinical trials, such as the limited availability of them and patient factors that make it difficult to participate.

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Thrombosis in myeloproliferative neoplasms: a viewpoint on its impact on myelofibrosis, mortality, and solid tumors

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October 25, 2024

Tiziano Barbui, Arianna Ghirardi, Alessandra Carobbio, Valerio De Stefano, Alessandro Rambaldi, Ayalew Tefferi & Alessandro M. Vannucchi

Abstract

This viewpoint summarizes findings from analyses of large personal patient databases of myeloproliferative neoplasms (MPNs) to assess the impact of thrombosis on mortality, disease progression, and second cancers (SC). Despite advances, the current incidence of arterial and venous thrombosis remains a challenge. These events appear to signal a more aggressive disease course, as evidenced by their association with myelofibrosis progression and mortality using multistate models and time-dependent multivariable analysis. Inflammatory biomarkers, such as the neutrophil-to-lymphocyte ratio (NLR), are associated with the aggressiveness of polycythemia vera (PV) and essential thrombocythemia (ET), linking thrombosis to SC risk. This suggests a common inflammatory pathway likely influencing cardiovascular disease and cancer incidence. Notably, this is observed more frequently in younger patients, likely due to prolonged exposure to MPN and environmental inflammatory triggers. These data underscore the need for new studies to validate these associations, delineate the sequence of events, and identify therapeutic targets to mitigate thrombotic events and potentially improve overall patient outcomes in MPN.

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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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Role of Long Noncoding RNA Defined in Pathogenesis of MPNs

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August 22, 2024

Vicki Moore, PhD

A role for lnc-AC004893, a long noncoding RNA (lncRNA), in the pathogenesis of myeloproliferative neoplasms (MPNs) was revealed in a study reported in the journal Hematology.

“Treatment with JAK2 inhibitors combined with the inhibition of lnc-AC004893 might improve the clinical treatment efficiency in MPN patients,” the study investigators wrote in their report.

A lncRNA is a nonprotein coding transcript with a length of more than 200 nucleotides, which may potentially have a biological function and could be dysregulated in the setting of disease. The investigators set out to explore whether lncRNA may have a role in MPN pathogenesis.

To evaluate this, the investigators conducted lncRNA sequencing from bone marrow mononuclear cells in 3 patients with MPN and 3 control individuals. They identified approximately 500 different lncRNAs that appeared expressed at a level of greater than or less than 2.0-fold in patients with MPN, in comparison with the expression level in control individuals.

From among these lncRNAs, the investigators performed further analyses related to expression and other characteristics. These analyses identified lnc-AC004893 as being of potential interest.

The investigators further evaluated lnc-AC004893 in samples from 150 patients with MPN, compared with 20 control individuals, and identified an approximately 5-fold increase in lncRNA transcript in patients with MPN, compared with the control population.

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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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