Tag Archives: myeloproliferative neoplasms

Malignant JAK-signaling: at the interface of inflammation and malignant transformation

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March 26, 2025

Florian Perner, Heike L. Pahl, Robert Zeiser & Florian H. Heidel

Abstract

The JAK pathway is central to mammalian cell communication, characterized by rapid responses, receptor versatility, and fine-tuned regulation. It involves Janus kinases (JAK1, JAK2, JAK3, TYK2), which are activated when natural ligands bind to receptors, leading to autophosphorylation and activation of STAT transcription factors [1, 2]. JAK-dependent signaling plays a pivotal role in coordinating cell communication networks across a broad spectrum of biological systems including development, immune responses, cell growth, and differentiation. JAKs are frequently mutated in the aging hematopoietic system [3, 4] and in hematopoietic cancers [5]. Thus, dysregulation of the pathway results in various diseases, including cancers and immune disorders. The binding of extracellular ligands to class I and II cytokine receptors initiates a critical signaling cascade through the activation of Janus kinases (JAKs). Upon ligand engagement, JAKs become activated and phosphorylate specific tyrosine residues on the receptor, creating docking sites for signal transducer and activator of transcription (STAT) proteins. Subsequent JAK-mediated phosphorylation of STATs enables their dimerization and nuclear translocation, where they function as transcription factors to modulate gene expression. Under physiological conditions, JAK-signaling is a tightly regulated mechanism that governs cellular responses to external cues, such as cytokines and growth factors, ensuring homeostasis and maintaining the functional integrity of tissues and organs. Highly defined regulation of JAK-signaling is essential for balancing cellular responses to inflammatory stimuli and growth signals, thus safeguarding tissue health. In contrast, dysregulated JAK-signaling results in chronic inflammation and unrestrained cellular proliferation associated with various diseases. Understanding the qualitative and quantitative differences at the interface of physiologic JAK-signaling and its aberrant activation in disease is crucial for the development of targeted therapies that precisely tune this pathway to target pathologic activation patterns while leaving homeostatic processes largely unaffected. Consequently, pharmaceutical research has targeted this pathway for drug development leading to the approval of several substances with different selectivity profiles towards individual JAKs. Yet, the precise impact of inhibitor selectivity and the complex interplay of different functional modules within normal and malignant cells remains incompletely understood. In this review, we summarize the current knowledge on JAK-signaling in health and disease and highlight recent advances and future directions in the field.

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Association of Pruritus With Comorbidities and Survival in Myeloproliferative Neoplasms: A Systematic Review of the Literature

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March 5, 2025

J. Saucereau1 | E. Brenaut1,2 | A. S. Ficheux1,2 | L. Misery1,2 | C. Le Gall‐Ianotto

ABSTRACT

Background: Pruritus is a symptom frequently associated with systemic diseases, particularly hematological disorders.
Objectives: The aim of this study was to evaluate the association of pruritus with morbidity in myeloproliferative
neoplasms (MPN).

Methods: A systematic review of the literature was performed using two databases (Pubmed and Embase). Studies were
included if they were published between January 2000 and August 2022 and addressed an association between pruritus and
morbidity or survival in MPN patients.

Results: Ten articles were selected for the systematic review, 6 including patients with polycythemia vera (PV), 1 with essential
thrombocythemia (ET), 2 with primary myelofibrosis (PMF) and 1 including both ET and PV. While 2 studies found no
significant association between pruritus and mortality, 2 studies found a significant association between pruritus and improved
survival. Three studies reported a statistically significant association between pruritus and an increase in thromboembolic
events, while one study did not. One study showed an association between the presence of pruritus and sleep disturbance in PV.
One study demonstrated an association between pruritus and the presence of depressive symptoms in PV. Two studies found a
significant association between disease progression and the presence of pruritus, while three studies did not.

Conclusions: While pruritus appears to influence sleep quality and the onset of depressive symptoms, the effect of pruritus on
mortality is more controversial, but the presence of pruritus might be associated with better survival.

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Association of Pruritus With Comorbidities and Survival in Myeloproliferative Neoplasms: A Systematic Review of the Literature

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March 2025

J. Saucereau, Emilie Brenaut, Anne-Sophie Ficheux, L. Misery

Abstract

Background
Pruritus is a symptom frequently associated with systemic diseases, particularly hematological disorders.
Objectives
The aim of this study was to evaluate the association of pruritus with morbidity in myeloproliferative neoplasms (MPN).
Methods
A systematic review of the literature was performed using two databases (Pubmed and Embase). Studies were included if they were published between January 2000 and August 2022 and addressed an association between pruritus and morbidity or survival in MPN patients.
Results
Ten articles were selected for the systematic review, 6 including patients with polycythemia vera (PV), 1 with essential thrombocythemia (ET), 2 with primary myelofibrosis (PMF) and 1 including both ET and PV. While 2 studies found no significant association between pruritus and mortality, 2 studies found a significant association between pruritus and improved survival. Three studies reported a statistically significant association between pruritus and an increase in thromboembolic events, while one study did not. One study showed an association between the presence of pruritus and sleep disturbance in PV. One study demonstrated an association between pruritus and the presence of depressive symptoms in PV. Two studies found a significant association between disease progression and the presence of pruritus, while three studies did not.
Conclusions
While pruritus appears to influence sleep quality and the onset of depressive symptoms, the effect of pruritus on mortality is more controversial, but the presence of pruritus might be associated with better survival.
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Dr Bhat on the Influence of MPN Risk Stratification on Treatment Decision-Making

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March 20, 2025

Author(s): Seema A. Bhat, MD

Fact checked by: Ashling Wahner, Courtney Flaherty

Seema A. Bhat, MD, a hematologist at The Ohio State University Comprehensive Cancer Center—James; as well as an assistant professor in the Department of Internal Medicine in the Division of Hematology at The Ohio State University, discusses the importance of risk stratification for navigating treatment selection for patients with myeloproliferative neoplasms (MPNs).

Stratifying patients with MPNs into appropriate risk groups is crucial for treatment decision-making, as patients’ individual risk factors strongly factor into selection, Bhat says. Typically, patients with low-risk disease will receive treatments directed at symptom management, whereas cytoreductive agents like hydroxyurea, as well as targeted therapies like JAK inhibitors, are considered for patients with high-risk disease, she explains. Furthermore, allogeneic stem cell transplantation may be a curative treatment option for patients with very high–risk MPNs, she notes.

The revised IPSET Thrombosis Score is used for essential thrombocythemia (ET) risk stratification. Patients are considered to have low-risk polycythemia vera (PV) if they are younger than 60 years of age and have no history of thrombosis; patients are considered to have high-risk PV if they are older than 60 years of age and/or have a thrombosis history.

Four JAK inhibitors are FDA approved for the treatment of patients with MPNs. Ruxolitinib (Jakafi) is indicated for adult patients with intermediate- or high-risk myelofibrosis, including primary myelofibrosis and secondary (post-PV or post-ET) myelofibrosis; as well as adult patients with PV who have had an inadequate response or are intolerant to hydroxyurea. Fedratinib (Inrebic) is approved for adult patients with intermediate-2 or high-risk primary or secondary myelofibrosis. Pacritinib (Vonjo) is indicated for use in adult patients with intermediate- or high-risk primary or secondary myelofibrosis with a platelet count below 50 × 109 /L. Finally, momelotinib (Ojjaara) is approved for adult patients with intermediate- or high-risk primary or secondary myelofibrosis with anemia.

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Safety and Efficacy of Busulphan Based on Dosing Patterns in the Real‐World Management of Myeloproliferative Neoplasms

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March 2025

Ali Mahdi, Alexandros Rampotas, Patrick Roberts, Joanna Stokes

Abstract

Introduction
Myeloproliferative neoplasms (MPNs), such as polycythaemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF), are primarily treated by managing blood counts to reduce the thrombotic risk using cytoreductive agents. Busulphan, an oral alkylating agent, has been historically used for MPN management due to its myelosuppressive effects, but concerns about its risk of leukaemic transformation have limited its use.
Methods
This real‐world retrospective study evaluated the safety and efficacy of busulphan in 115 MPN patients across 13 UK hospitals. Responses in patients with ET and PV only were assessed using European LeukemiaNet (ELN) criteria.
Results
With a median age of 78 years, the overall response rate was 78.1%, with 29% of PV and 18% of ET patients achieving complete responses. Dosing regimens were similarly distributed between repeated single doses of busulphan (31%), courses of treatment lasting 1–4 weeks (30%) and continuous therapy for more than 4 weeks (35%). No cases of disease progression to acute leukaemia or myelofibrosis were recorded during the median follow‐up of 23 months. Adverse events were infrequent, with fatigue and cytopaenia being the most common (4% each).
Conclusion
Busulphan demonstrated a favourable safety profile and is a viable cytoreductive option, particularly for elderly patients who are intolerant to hydroxycarbamide.

Topics of Interest in Women With Myeloproliferative Neoplasms

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March 2025

Natasha Szuber, Paola Guglielmelli, Naseema Gangat

Abstract

Overview
Sex and gender have emerged as central modifiers of disease biology, phenotype, and clinical outcomes in myeloproliferative neoplasms (MPNs). This review will uniquely highlight issues affecting women with MPN and articulate their relevant determinants.
Epidemiology and Diagnosis
A higher overall prevalence of MPN has been established in women. The incidence of essential thrombocythemia (ET) predominates, while, conversely, polycythemia vera (PV) and myelofibrosis (MF) are seen in lower frequencies as compared to men. Diagnostic criteria are dictated by sex‐driven physiological variances in hemoglobin and hematocrit levels in PV, mandating separate diagnostic thresholds, respectively: > 16.0 g/dL and > 48% in women vs. > 16.5 and > 49% in men. Genetic Framework and Phenotype Women with MPN harbor fewer acquired somatic mutations and a lower frequency of high‐risk mutations than their male counterparts; lower JAK2V617F driver variant allele frequency and attenuated allele burden kinetics have also been reported. Women with MPN are younger at diagnosis than men and, contingent on subtype, display more indolent disease features. Importantly, validated symptom burden assessments consistently disclose higher scores in women vs. men.
Thrombosis and Outcomes
Women with MPN have a unique thrombotic diathesis with respect to men, more frequently involving the splanchnic venous system in those ultimately diagnosed with PV. Outcomes data depict female sex as a variable associated with more favorable clinical trajectories, including lower rates of MF/leukemic transformation and secondary cancers, as well as improved overall survival rates vis‐à‐vis men. Life‐Cycle Windows, Pregnancy, and Postpartum Potential challenges at each significant life stage will be addressed: puberty, preconception and fertility, and perimenopause; these include issues surrounding oral contraceptives and hormone use. Prospective studies suggest overall favorable maternal and fetal outcomes with pregnancy in women with MPN. Full details on risks and reported outcomes will be discussed, as well as a risk‐adapted approach to management informed by obstetric and thrombosis history. Recommendations include aspirin 81 mg daily in all patients and cytoreduction with interferon‐α in those with antecedent thrombosis, as well as in low‐risk cases with higher‐risk features (e.g., poorly controlled hematocrit and recurrent fetal loss). Antepartum anticoagulation with low molecular weight heparin (LMWH) is recommended in cases with previous venous thromboembolism.
Conclusions and Future Directions
This review highlights female sex and gender as critical drivers of MPN incidence, presentation, and natural history. It further outlines the impact and management of MPN as related to unique female reproductive phases. A sex‐informed lens will be required in order to recalibrate current prognostic tools, a requisite to refining patient counselling and clinical decision‐making in line with precision medicine. Moreover, while several mechanisms underpinning sex‐defined discrepancies have been defined, these mandate further prospective study. Finally, sex and gender‐based differences must be weighted in clinical trials with systematized procedures to correct participation imbalances in favor of sex and gender equity.

 

Risk for Specific Hematologic Cancers Down With GLP-1 Receptor Agonist Use in T2DM

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Publish Date

HealthDay News — For patients with type 2 diabetes (T2D), glucagon-like peptide-1 receptor agonist (GLP-1 RA) use is associated with a reduced risk for developing hematologic cancers compared with insulin and metformin use, according to a research letter published online March 6 in JAMA Network Open.

Omer S. Ashruf, from Northeast Ohio Medical University in Rootstown, and colleagues conducted a retrospective cohort study to compare the risks for hematologic cancers in patients with T2D treated with a GLP-1 RA versus metformin and insulin. The study included patients with T2D prescribed a GLP-1 RA, insulin, or metformin between April 30, 2005, and Oct. 31, 2023 (51,617; 611,115; and 938,602 patients, respectively). Groups were independently matched using a nearest neighbor greedy matching algorithm; 47,716 patients were included in the GLP-1 RA-insulin analysis and 50,590 were included in the GLP-1 RA-metformin analysis.

The researchers found that GLP-1 RA use was associated with significantly lower risks for of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) compared with metformin (hazard ratios, 0.61 and 0.67, respectively). No significant difference was seen in the risk for any other hematologic cancer. GLP-1 RA use was associated with significantly lower risks for myeloid leukemia, lymphoid leukemia, non-Hodgkin lymphoma, MDS, MPN, monoclonal gammopathy, multiple myeloma, and amyloidosis compared with insulin (hazard ratios, 0.39, 0.45, 0.42, 0.19, 0.50, 0.68, 0.49, and 0.52, respectively). GLP-1 RA use was associated with a 54 percent lower risk than that seen with insulin across all hematologic cancers.

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JAK Inhibitors Reduce Thromboembolic Risk in Myeloproliferative Neoplasm Therapy

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March 11, 2025

Author(s): Alex Biese

Fact checked by: Ryan Scott

Treatment with Janus kinase inhibitors (JAKis) has been found to be associated with a reduction in risk of thromboembolic events among patients with myeloproliferative neoplasms (MPNs), according to research findings.

These findings were published in eJHaem, and are driven by observations of treatment with Jakafi (ruxolitinib) for patients with polycythemia vera and myelofibrosis, researchers noted.

“In this meta-analysis, JAKi [used for] MPN [treatment] was associated with a reduced risk of thromboembolic events compared [with] control, primarily driven by studies of [Jakafi] in polycythemia vera and myelofibrosis,” first study author Roberta Dunn and colleagues wrote in the study. “JAKi treatment was not associated with an increased risk of [major adverse cardiovascular events] or hypertension, adding to the existing body of evidence demonstrating the safety of JAKi in the treatment of MPNs. Further prospective clinical trials are warranted to confirm these findings and characterize the cardiovascular profile of other JAKis in all types of MPNs.”

Dunn is a medical student at the School of Medical Education, King’s College London, as well as a student researcher at Guy’s and St Thomas’ NHS Foundation Trust, in the United Kingdom.

MPNs, according to the Cleveland Clinic, are rare blood cancers that involve the patient’s body making too many red blood cells, white blood cells or platelets. JAKis, as explained by the National Cancer Institute, block the actions of enzymes which control cell signaling and growth, the number of blood cells and platelets made in the bone marrow, inflammation, and immune cell activity. Blocking these enzymes may help prevent abnormal blood cells or cancer cells from growing.

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A Toolkit for Healthcare Transition for Adolescents With Classical Myeloproliferative Neoplasms

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March 2025

Nicole Kucine1, Holger Cario2, Ghaith Abu-Zeinah1, Maria Caterina Putti3, Nicolas Boissel4, Maria Luigi Randi3, Linda Resar5, Martin Griesshammer6, Jean-Jacques Kiladjian4

Abstract

Classical myeloproliferative neoplasms (MPNs) are being identified more frequently in adolescents. There is no guidance on the healthcare transition of young MPN patients from pediatric to adult medicine. Therefore, we convened an international panel of experts in both pediatric and adult MPN care to develop three tools to facilitate high-quality healthcare transition: a physician education tool, a transition readiness assessment tool, and a consensus statement of practice recommendations to ensure a more seamless transition in the care adolescents receive. These tools can help ensure a better healthcare transition for young patients. The next steps include evaluating the readiness assessment tool with adolescent patients.

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The role of psychosocial adjustment in the quality of life of patients with myeloproliferative neoplasms

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March 7, 2025

A.A.M. Eppingbroek, L. Lechner, E.C. Bakker, M.D. Niijkamp, M.A. de Witte, C.A.W. Bolman

Abstract

Purpose

Myeloproliferative neoplasms (MPNs) can cause a high symptom burden that negatively affects quality of life (QoL). The way patients deal with their disease and how this impacts their QoL is important to understand, yet virtually unknown. The aim of this study is to investigate whether and how psychosocial adjustment affects QoL in MPN patients.

Methods

A longitudinal study was conducted in 338 MPN patients to investigate whether and how baseline measurements of psychosocial adjustment could predict QoL outcomes six months later. Psychosocial adjustment to illness was operationalized by: coping, self-management, resilience and illness identity (II). We tested the hypotheses that high scores on respectively problem-solving coping, self-management, resilience, II-subscales acceptance and enrichment, and low scores on II-subscales rejection and engulfment are associated with high scores on QoL. We performed a multiple hierarchical regression analysis including sociodemographic and disease-related variables and baseline QoL as control variables.

Results

II-subscale engulfment had the most pronounced negative impact on QoL (β.47, p<.001). After the introduction of the control variables, the effect of engulfment remained statistically significant (β.16, p<.01). Additionally, baseline QoL (β.32, p<.001), treatment option wait-and-see (β.11, p<.05), and MPN symptom burden at T2 (β.36, p<.001) demonstrated significance. The other variables measuring psychosocial adjustment did not relate significantly to QoL.

Conclusion

The findings of this study illustrate the significant adverse effect of engulfment on patients’ QoL, underscoring the importance of providing psychosocial guidance to mitigate the patients’ feelings of being overwhelmed by the disease.