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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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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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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Which Factors Predict Thrombotic Events in Essential Thrombocythemia?

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August 13, 2024

The risk for essential thrombocythemia-related events in patients with the disease can be predicted using currently available clinical data, researchers wrote in a letter to the editor appearing in Blood Cancer Journal.

“Although considered the most indolent myeloproliferative neoplasm (MPN), essential thrombocythemia (ET) is linked to burdensome vasomotor symptoms and potentially fatal complications that include thrombosis, hemorrhage, and disease progression to myelofibrosis and aggressive myeloid neoplasms,” Ghaith Abu-Zeinah, MD, a hematologist and oncologist at the Richard T. Silver Myeloproliferative Neoplasms Center at Weill Cornell Medicine, New York, and colleagues wrote. “Prognostic measures to identify those at greatest risk for thrombosis, progression, and death in ET [events] are important for timely risk-adapted intervention with available treatments, and for development of interventional trials to improve event-free survival [EFS]. But predicting risks of events in ET has been difficult because ET is an uncommon and clinically heterogeneous chronic disease.”

Predicting excess mortality and disease progression related to ET presents challenges because such events often occur decades after a patient is diagnosed, the researchers continued.

“Thus, retrospective analysis of large cohorts with sufficiently long follow-up is required to identify prognostic measures to stratify risk in patients with ET,” they wrote.

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Triple-Negative Myelofibrosis Associated With Decreased Survival, Aggressive Clinical Behavior and Shorter Duration of Response to Ruxolitinib

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August 14, 2024

Amber Denham

According to recently published research in Clinical Lymphoma, Myeloma & Leukemia, triple-negative myelofibrosis (TN-MF) was found to be continually associated with decreased survival, enhanced aggressive clinical behavior with higher rates of leukemic transformation, and a shorter duration of response to ruxolitinib.

“Myelofibrosis is the most aggressive subtype among classical BCR::ABL1 negative myeloproliferative neoplasms…Triple-negative myelofibrosis accounts for only 5% [to] 10% of cases and carries the worst outcomes,” explained lead study author Luis Aguirre, MD, Dana-Farber Cancer Institute, Harvard Medical School, Cambridge, Massachusetts, and colleagues. They added, “Little has been described about this subset of disease…identification of features of interest and assessment of treatment response are areas in need of further investigation.”

Researchers evaluated baseline clinical and molecular parameters from 626 patients with myelofibrosis who presented to the H. Lee Moffitt Cancer Center in Tampa, Florida, between 2003 and 2021. These data were compared based on the presence or absence of the 3 classical phenotypic driver mutations.

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