Author Archives: MPN Advocacy & Education

Polycythemia vera and essential thrombocythemia in children, still a challenge for pediatricians

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February 4, 2025

Agathe Picard, Sophie Bayart, Marianna Deparis, Cécile Dumesnil De Maricourt, Sophie Haro, Anne Jourdain, Coralie Mallebranche, Fanny Rialland, Damien Luque Paz, Cedric Pastoret, Virginie Gandemer & Elie Cousin

Abstract

Polycythemia vera (PV) and essential thrombocythemia (ET) are rare myeloproliferative neoplasms (MPN) in children, adolescents and young adults. No recommendations are available concerning these patients’ management. Transposing to children the knowledge established in adult patients is not acceptable. For a better understanding of difficulties encountered by pediatricians and adult hematologists, we conducted a national practice analysis concerning follow-up of patients under 18 diagnosed with ET or PV, in France. Then, we present data from a multicentric, descriptive, retrospective study, including 17 patients with ET or PV, diagnosed under 18, coming from 7 hematopediatric departments in France. Interviewed physicians reported a lack of expertise and theoretical training in the hematological field to diagnose and follow children with MPNs. Data from 17 patients (15 ET, 2 PV) confirmed a high proportion of asymptomatic patients at the time of diagnosis (41%). Proportion of “triple-negative” patients (59%) was higher than in adult cohorts. 60% of patients underwent a bone marrow biopsy and 31% of cases were discussed during a multi-disciplinary staff meeting. 76.5% patients were treated, with a high frequency of antithrombotic and cytoreductive drugs. No complications were observed during the 45 months of median follow-up.
Conclusion: Physicians insisted on the need for training. Only the accumulation of descriptions of MPNs in children will lead to a better management of these diseases. Considering the small proportion of pediatric patients with complications after diagnosis, rapid therapeutic de-escalation seems essential to consider during the follow-up in a close collaboration with adult hematologists.

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Second-Line Fedratinib Produces Early Platelet Count Improvements in Myelofibrosis

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February 5, 2025

Author(s): Jax DiEugenio

Fact checked by: Chris Ryan

Patients with myelofibrosis who received second-line fedratinib (Inrebic) experienced early increases in platelet count compared with those given best available therapy (BAT), and a higher magnitude of benefit was observed in patients with a low platelet count at baseline, according to findings from the phase 3 FREEDOM2 trial (NCT03952039) presented at the 2024 ASH Annual Meeting.

Findings showed that in the overall safety population, fedratinib generated improvements in mean platelet count and mean change from baseline platelet count, most noticeably in early treatment cycles.

In patients with a low platelet count at baseline, defined as at least 50 to less than 100 x 109/L, patients treated with fedratinib (n = 34) experienced a mean increase in platelet count of 45% on day 15 of cycle 1 compared with 11% for those given BAT (n = 21). Among patients with a high platelet count at baseline of at least 100 x 109/L, these rates were 27% for fedratinib (n = 85) and –6% for BAT (n = 39).

During a presentation of the data, lead study author Haifa Kathrin Al-Ali, MD, explained that increased platelet count was not correlated with changes in spleen size, pointing to a potential benefit for fedratinib on thrombopoiesis.

“These data suggest a platelet-sparing effect of second-line fedratinib vs BAT, and support fedratinib as a promising second-line treatment option for patient with myelofibrosis with low or high baseline platelet count,” said Al-Ali, who is a professor of translational oncology and head of the Krukenberg Cancer Center at the University Hospital of Halle (Saale) in Germany.

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Spleen volume assessment in Ph-negative chronic myeloproliferative neoplasms: a real-life study comparing ultrasonography vs. magnetic resonance imaging scans

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January 21, 2025

Novella Pugliese, Carlo Cavaliere, Luca Basso, Laura De Fazio, Rosalia Malafronte, Claudia Giordano, Annamaria Vincenzi, Silvia Varricchio, Massimo Mascolo, Vincenzo Martinelli, Marco Picardi, Marco Salvatore & Fabrizio Pane

Abstract

Splenomegaly is a quite common clinical feature of Philadelphia (Ph) negative chronic myeloproliferative neoplasms (MPNs) and its presence may, in some cases, drives treatment decision. Most importantly, palpable splenomegaly is a minor criterion for both pre-fibrotic/early primary myelofibrosis and primary myelofibrosis (PMF) diagnosis, even if clinical assessment by physical examination is poorly reliable and accurate. On the other hand, despite the International Working Group-Myeloproliferative Neoplasms Research and Treatment and European LeukemiaNet guidelines defined spleen response criteria by palpation, they also recognized the highly subjective nature of spleen size assessment by physical examination, and recommended objective confirmation of volume reduction via computed tomography or magnetic resonance imaging (MRI). In particular, spleen volume (SV) reduction of at least 35% via MRI is typically the primary endpoint in PMF and in some polycythemia vera clinical trials. Nevertheless, this technique seems inconvenient in routine clinical practice. To simplify serial monitoring of spleen size by using ultrasonography (US), we retrospectively analyzed medical records of 39 newly diagnosed MPN patients who underwent spleen ultrasonography as well as MRI. The median SV assessed by US was 600 ml (range 200–5000 ml) while median SV evaluated by MRI was 553.1 ml (range 172–5140 ml), revealing a strong linear relationship between methods, with a correlation coefficient of r = 0.96 (95% CI 0.92–0.98, P < 0.0001). Our findings support the role of US into pre-screening assessments for clinical trials and practice, offering a pragmatic solution for evaluating SV in MPN patients and ultimately improving patient care and clinical decision-making in this complex disease landscape.

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Mutated Calreticulin Could Lead to MF Onset

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Brian Murphy, PhD

Mutations in the CALR gene, including a 52 base pair (bp; CALR Del52) deletion and 5 bp insertion (CALR Ins5), affect several signaling pathways in cells leading to the pathogenesis of myelofibrosis (MF) and other myeloproliferative neoplasms (MPNs), according to a study published in the International Journal of Molecular Sciences.

Cells carrying CALR Del52 and CALR Ins5 mutations had increased activation of the Janus kinase/signal transducer and activator of the transcription (JAK/STAT) and the phosphatidylinositol 3-kinase/Protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathways which have been previously implicated in the pathogenesis of MPNs. These effects were still present in a cell culture model lacking MPL gene (thrombopoietin receptor) expression.

The CALR mutations resulted in reduced functionality of calreticulin proteins. Calreticulin generally functions as a major chaperone in the endoplasmic reticulum and is involved in several processes, including control of protein folding, calcium homeostasis, and responses to cellular stress.

The study found cells with CALR Del52 mutations had statistically significant higher levels of DNA damage compared to controls when exposed to hydrogen peroxide. Cells with CALR Ins5 had significantly higher levels of phosphorylated ATM and H2AX than controls. Both cell types were not able to repair DNA damage after 24 hours following oxidative stress.

Apoptosis levels were also significantly higher in cells with the CALR Ins5 mutation compared to controls. Those with CALR Del52 also had higher rates of apoptosis, but it did not reach significance. Further analysis found that the CALR mutations not only led to increased apoptosis after hydrogen peroxide exposure-induced oxidative stress but also tended to arrest the cells in the G2/M phase.

“Functional analysis revealed that the accumulation of G2/M-CALR-mutated cells indicates that oxidative stress-induced DNA damage is difficult to repair. The mentioned cell cycle delay has not been shown in other studies analyzing mutated calreticulin,” the authors said.

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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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