Category Archives: Research

Mutations With Diagnostic Potential for MF Identified

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Leonardo Jaimes, MD
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Next-generation sequencing (NGS) identified 14 gene mutations with diagnostic and prognostic potential in patients with myelofibrosis (MF), according to a recently published study in the Journal of Applied Genetics.

“The incredible progress that has been made over the last 10 years in the field of genetic diagnostics has prompted the identification of additional genetic abnormalities linked to MPN,” the authors wrote.

Driver mutations in the CALR, JAK2, and MPL genes have a high diagnostic and prognostic value in patients with myeloproliferative neoplasms, like MF. the researchers noted. However, other mutations are also involved in the pathophysiology of these conditions, and many of them are associated with treatment resistance and poorer prognosis, they added.

Therefore, the authors aimed to use an NGS of 40 genes to retrospectively study a cohort of 42 CALR-positive patients with either essential thrombocytosis (ET) or MF and determine the impact of gene mutations in disease progression.

Patients with ET (n=28) and MF (MF) were further divided according to the type of CARL mutation. Among patients with MF, the type 1 CARL mutation represented 92% of the population.

NGS revealed 44 potentially pathogenic variants. The most frequently mutated genes were associated with epigenetic regulatory mechanisms, namely ASXL1, TET2, and DNMT3A. Approximately 48% of patients had additional mutations, 33% had more than one additional mutation, and 23% had high molecular risk mutations.

The presence of additional mutations correlated with disease transformation, as five out of seven patients who progressed from ET to MF had additional mutations. Furthermore, the two patients that progressed to acute myeloid leukemia had additional mutations.

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Symptom burden in myeloproliferative neoplasms: clinical correlates, dynamics, and survival impact—a study of 784 patients from the Quebec MPN research group

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April 1, 2025

Alisa Poullet, Lambert Busque, Shireen Sirhan, Robert Delage, Ghislain Cournoyer, Ines Chamakhi, Danielle Talbot, Luigina Mollica, Daniele Marceau, Vincent Ethier, Pierre Desjardins, Harold J. Olney, Michaël Harnois & Natasha Szuber

Classic BCR::ABL1-negative myeloproliferative neoplasms (MPN) include polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). While patients may benefit from extended survival, they also endure lifelong symptoms, ranging from mild to incapacitating [1]. These include physical manifestations related to hyperviscosity, bone pain, pruritus, constitutional symptoms, and consequences of splenomegaly, among others, as well as psychological symptoms (e.g., depression, anxiety) [2, 3]. Ultimately, symptom burden impairs quality of life (QoL) [4], an independent predictor of mortality [5]. Addressing symptom burden in MPN patients is crucial in guiding and individualizing therapy; however, several important challenges remain, including obscure mechanistic underpinnings and scarcity of robust data to inform practice. While the current patient-reported symptom assessment tool was conceived as a universal instrument for the collective MPN population—facilitating its clinical application, distinct profiles across subtypes may not be captured. Cut-off values determining ‘significant’ scores may also warrant further evaluation. Furthermore, kinetics of symptom profiles over time and correlations with biological variables have not fully been explored. The objectives of the current study were to comprehensively characterize symptom burden in a large MPN cohort, determining: i) age/sex-associated differences; ii) longitudinal dynamics and treatment effects; iii) biologic correlatives; and iv) impact on overall survival (OS) in a real-world population-based setting.

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Optimal Ruxolitinib Dosing in Myelofibrosis Critical for Improved Effectiveness, Survival in Real-World Setting

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March 27, 2025

Author(s): Luke Halpern, Assistant Editor

Patients with myelofibrosis (MF) started on appropriate and highest tolerated doses of ruxolitinib (Jakafii; Incyte Corporation) experienced better trends in response and improved health-related quality of life (HRQoL), highlighting the importance of proper ruxolitinib dosing, timing, and administration to ensure the most effective patient responses in terms of symptom relief, spleen size reduction, and improved overall survival (OS).1

Diagnosis of Myelofibrosis. Laboratory blood bottle (tube), glass slide with blood smear, hematology test, stethoscope lying on notebook with printed text hematological diagnosis

Ruxolitinib is effective at reducing symptoms in myelofibrosis. | Image Credit: © shidlovski – stock.adobe.com

It’s critical for treatment providers administering ruxolitinib for MF to know the expected real-world presentation of treatment complications. Patients being administered ruxolitinib face higher health care resource utilization and clinical burdens, including an increased risk of anemia development and adverse treatment events. Still, the treatment is highly effective when dosed and administered appropriately and when proper consideration of adverse events, such as anemia or graft-versus-host disease, is included in counseling.1,2

According to the investigators, the expected optimal starting dose for initiating ruxolitinib is based on a patient’s baseline platelet count. Further dose titration—up to 25 mg twice daily—can be utilized to maximize efficacy, which has been demonstrated to be dose-dependent. However, suboptimal adherence is consistently reported among patients treated with ruxolitinib, which could contribute to poor survival outcomes and undermine disease control.1,3

Poor adherence rates have been observed in the ongoing Ruxolitinib Observational Study in Myelofibrosis Treated Patients in Italy (ROMEI), an observational study of ruxolitinib-treated patients with MF in Italy. Twenty-four-week findings confirmed ruxolitinib’s therapeutic effects and a favorable safety profile but also indicated that up to one third (25% to 40%) of patients receiving ruxolitinib could have been undertreated despite their clinical presentation necessitating higher doses. An interim analysis, conducted by the current authors, was commissioned to investigate ruxolitinib dosing patterns and correlations with clinical outcomes in patients who completed the first 12 months of follow-up or prematurely discontinued the ROMEI trial.1

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

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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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Comparison of recognition of symptom burden in MPN between patient- and physician-reported assessment – an intraindividual analysis by the German Study Group for MPN (GSG-MPN)

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Kirsi Manz, Florian H. Heidel, Steffen Koschmieder, Rudolf Schlag, Jörg Lipke, Frank Stegelmann, Martin Griesshammer, Martine Klausmann, Carl Crodel, Andreas Hochhaus, Holger Schulz, Joachim R. Göthert, Haifa Al-Ali, Heiko Becker, Andreas Reiter, Gernot Beutel, Kim Kricheldorf, Tim H. Brümmendorf, Wolfgang Hoffmann, Konstanze Döhner & Susanne Isfort On behalf of the German Study Group for Myeloproliferative Neoplasms (GSG-MPN)

Abstract

Myeloproliferative neoplasms (MPN) are associated with a variety of symptoms that severely impact patients’ quality of life and ability to perform daily activities. Recent studies showed differences in the perception of physician- versus patient-reported symptom burden. However, studies directly comparing patient- and physician-reported ratings are lacking. Here, a retrospective analysis on symptom burden of 3979 MPN patients of the Bioregistry of the German Study Group for MPN was conducted to intra-individually compare physician and patient reports collected at the same time. Cohen’s kappa was calculated to assess the degree of agreement between patient and physician reports. Factors influencing baseline symptom severity were identified using linear regression and adjusted Cox models were calculated to investigate the effect of symptom burden on survival. MPN patients had a high symptom burden, which neither decreased over time nor upon cytoreductive therapy. All symptoms were more frequently reported by patients compared to physicians. Agreement remained low and only slightly improved when considering a higher threshold for patient symptom severity. Patients with severe symptom burden had inferior survival compared to patients with less severe symptoms. Assessment of symptom burden in MPN is therefore insufficient and patient-reported outcome tools need to be implemented into clinical routine.

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Spotlight on amino acid changing mutations in the JAK-STAT pathway: from disease-specific mutation to general mutation databases

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February 20, 2025

Markus Hoffmann & Lothar Hennighausen

Abstract

The JAK-STAT pathway is central to cytokine signaling and controls normal physiology and disease. Aberrant activation via mutations that change amino acids in proteins of the pathway can result in diseases. While disease-centric databases like COSMIC catalog mutations in cancer, their prevalence in healthy populations remains underexplored. We systematically studied such mutations in the JAK-STAT genes by comparing COSMIC and the population-focused All of Us database. Our analysis revealed frequent mutations in all JAK and STAT domains, particularly among white females. We further identified three categories: Mutations uniquely found in All of Us that were associated with cancer in the literature but could not be found in COSMIC, underscoring COSMIC’s limitations. Mutations unique to COSMIC underline their potential as drivers of cancer due to their absence in the general population. Mutations present in both databases, e.g., JAK2Val617Phe/V617F – widely recognized as a cancer driver in hematopoietic cells, but without disease associations in All of Us, raising the possibility that combinatorial SNPs might be responsible for disease development. These findings illustrate the complementarity of both databases for understanding mutation impacts and underscore the need for multi-mutation analyses to uncover genetic factors underlying complex diseases and advance personalized medicine.

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High Levels of C5a Are Associated With Reduced Macular Sensitivity in Patients With Myeloproliferative Neoplasms

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February 2025

Kathrine Gotfredsen; Andreas Abou-Taha; Charlotte Liisborg; Marie Krogh Nielsen; Morten Kranker Larsen; Vibe Skov; Lasse Kjær; Hans Karl Hasselbalch; Torben Lykke Sørensen

Abstract

Purpose: Previous findings indicate that patients with myeloproliferative neoplasms (MPN) exhibit elevated levels of inflammatory biomarkers and have a high prevalence of AMD. In this study, we aim to determine whether drusen and systemic inflammation in patients with MPN affect macular sensitivity in the same manner as in patients with AMD.

Methods: The study was conducted as a prospective cross-sectional study. A total of 139 study eyes of 71 patients were included in this study. We measured macular sensitivity using microperimetry and extracted blood samples to evaluate systemic inflammation markers.

Results: Multilevel linear mixed-effect analysis did not show any difference in macular sensitivity when comparing eyes of MPN patients with AMD to those without drusen (β = −0.254, P = 0.657). However, higher levels of the complement system fragment C5a were significantly correlated with decreased total macular sensitivity (β = −0.561, P = 0.027), irrespective of the presence of drusen.

Conclusions: We found that high levels of the systemic inflammation marker C5a are associated with reduced macular sensitivity, regardless of the presence of visible degenerative changes in the macular area. These findings suggest an early contribution of the complement system to macular sensitivity.

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