Category Archives: Research

National Health Expenditure Associated With Myeloid Neoplasms Survival in Europe

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Andrea S. Blevins Primeau, PhD, MBA
Publish Date

An analysis of the EUROCARE found that lower total national health expenditure (TNHE) was associated with shorter survival among patients with some types of myeloid neoplasms (MNs), according to a report published in the European Journal of Oncology.

The researchers also reported that 10-year relative excess risk of death (RER) was generally higher for patients in regions with lower TNHE.

EUROCARE-6 is a dataset in the EUROCARE study that is derived from 27 European countries of patients aged 15 or older diagnosed with an MN between 2001 and 2013. MNs included acute myeloid leukemia (AML), myeloproliferative neoplasms (MPNs), chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and myelodysplastic syndrome (MDS).

There were a total of 267,968 MN cases in the dataset, of which, 41.1% were AML, 32.2% were MPNs, 11.7% were CML, 6.8% were PV, 7.4% were ET, and 19.6% were MDS, and 4.4% were MDS/MPN.

Countries in the lowest TNHE quartile included Bulgaria, Croatia, Estonia, Latvia, Lithuania, Poland, and Slovakia. Countries in the highest TNHE quartile included Austria, Denmark, Germany, Norway, and Switzerland. The median follow-up was 13 years.

At 10 years, the age-standardized relative survival (ASRS) ranged from 61.2% for MPNs to 15.6% for AML. Within MPNs, the 10-year ASRS was 75.2% for ET, 70.9% for PV, and 52.5% for CML.

Countries in the lowest TNHE quartile demonstrated lower 10-year ASRS rates compared with countries in the highest quartile for AML, MPN, and MDS.

A similar trend was observed for 10-year RERs for most MNs, with higher RERs associated with lower TNHE quartile. For example, the lowest TNHE quartile was significantly associated with a greater 10-year RER for MPN (RER, 1.32; 95% CI, 1.30-1.35), AML (RER, 1.28; 95% CI, 1.25-1.31), and acute promyelocytic leukemia (RER, 1.42; 95% CI, 1.12-1.80).

The highest quartile was significantly associated with lower 10-year RER for MPN (RER, 0.80; 95% CI, 0.78-0.81) and AML (0.86; 95% CI, 0.84-0.88), but not some subtypes of AML and APL.

“TNHE is associated with geographical inequalities in MN prognosis,” the researchers concluded in their report. “Policy decisions on allocating economic resources are needed to reduce these differences.”

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Prediction of resistance to hydroxyurea therapy in patients with polycythemia vera: a machine learning study (PV-AIM) validated in a prospective interventional phase IV trial (HU-F-AIM)

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Published April 25, 2025

Florian H. Heidel, Valerio De Stefano, Matthias Zaiss, Jens Kisro, Eva Gückel, Susanne Großer, Mike W. Zuurman, Kirsi Manz, Kenneth Bryan, Armita Afsharinejad, Martin Griesshammer & Jean-Jacques Kiladjian

Abstract

Polycythemia vera (PV) is a myeloproliferative neoplasm associated with increased thromboembolic (TE) risk and hematologic complications. Hydroxyurea (HU) serves as the most frequently used first-line cytoreductive therapy worldwide; however, resistance to HU (HU-RES) develops in a significant subset of patients, leading to increased morbidity and necessitating alternative treatments. This study, part of the PV-AIM project, employed machine learning techniques on real-world evidence (RWE) from the Optum® EHR database containing 82.960 PV patients to identify baseline predictors of HU-RES within the first 6–9 months of therapy. Using a Random Forest model, the study analyzed data from 1850 patients, focusing on laboratory parameters and clinical characteristics. Key predictive markers included red cell distribution width (RDW) and hemoglobin (HGB), showing the strongest association with HU-RES. A synergistic interaction between RDW and HGB was identified, enabling TE risk stratification. This study provides a robust framework for early detection of HU-RES using readily available clinical data, facilitating timely intervention. These findings underscore the importance of personalized treatment approaches in managing PV and highlight the utility of machine learning in enhancing predictive accuracy and clinical outcomes. Based on the results of PV-AIM we initiated an open-label, prospective, single-arm, interventional, phase IV study (HU-F-AIM) evaluating HU-resistance/intolerance. Validation of predictive biomarkers may facilitate identification of patients at risk of HU resistance who may benefit from alternative treatment options, possibly preventing ongoing phlebotomy during HU treatment, a frequent therapeutic choice in high-risk PV associated with early disease progression and increased thromboembolic complications. We propose an updated terminology that differentiates between true molecular resistance and clinical resistance, that may indicate the requirement for alternative therapeutic strategies.

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Diagnosis and Management of PV and ET in Pediatric Populations Needs Improvement

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Caleb Rans, PharmD
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Polycythemia vera (PV) and essential thrombocythemia (ET) are rarely diagnosed in children, adolescents, and young adults. As the median age at diagnosis for these conditions is usually over 60 years, few pediatricians are familiar with their clinical, biological, and genetic features.1-3 Early diagnosis is essential to assess the need for specialized treatments and to prevent long-term complications, such as hemorrhage, thrombosis, or progression to secondary malignancies.1

In a 2-part study published in the European Journal of Pediatrics, Agathe Picard, MD, of the department of pediatric oncohematology at the Rennes University Hospital in France, and colleagues, analyzed practices around the diagnosis and management of pediatric patients with PV and ET in France.

Methodology and Study Design

In the first part of the study, a national practice survey about pediatric patients diagnosed with PV or ET was performed. The 8-question survey was sent to all pediatrician members of the leukemia committee of Société Française de lutte contre les Cancers et leucémies de l’Enfant et de l’adolescent (SFCE), and all hematologist members of France Intergroupe des Syndromes Myéloprolifératifs (FIM).

AYA [patients] should be referred to specialized units that consider the social, psychological, and educational needs of these patients.

In the second part, a retrospective cohort study was conducted at 7 pediatric oncohematology departments in western France. The researchers analyzed clinical, biological, and genetic data, as well as treatment and complication patterns from 17 pediatric patients with PV or ET, all of whom were diagnosed before the age of 18.

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Protein Disulfide Isomerase Could Be Therapeutic Target for MF

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Özge Özkaya, MSc, PhD
Publish Date

Protein disulfide isomerase may be involved in the underlying pathogenesis of thrombotic events in Philadelphia-negative myeloproliferative neoplasms such as myelofibrosis (MF), according to a new study published in the Egyptian Journal of Internal Medicine.

It could also be valuable in predicting the risk of developing thromboembolic events, the researchers noted.

These findings suggest that protein disulfide isomerase could be used as a therapeutic target to prevent thrombotic events in patients with MF and other myeloproliferative neoplasms.

For the study, a team of researchers, led by Mai Galal Elshenoufy, MD, PhD, from Cairo University in Egypt, measured the levels of protein disulfide isomerase in the serum of patients with myeloproliferative neoplasms and assessed its role as a possible marker of increased risk of thromboembolic events.

They found that the levels of the enzyme were pathologically high in the serum of patients with myeloproliferative neoplasms compared to controls. The levels were also higher in patients with arterial thrombosis, but this finding had no statistical significance.

Future work should evaluate the levels of protein disulfide isomerase in a larger group of patients with myeloproliferative neoplasm with and without thrombotic events, and in patients with arterial versus venous thrombosis, they said.

Finally, measuring the levels of protein disulfide isomerase before and after aspirin therapy could give clues about the effect of this treatment, they added.

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Thrombosis May Increase Risk of Cardiovascular Disease, Secondary Cancers in Myeloproliferative Neoplasms

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April 21, 2025

Sarah Dingli, Saubia Fathima, Priyansh Faldu, Naseema Gangat, David Dingli & Ayalew Tefferi

Primary myelofibrosis (PMF) is a myeloid neoplasm that is currently classified in the category of JAK2 mutation-prevalent myeloproliferative neoplasms (JAK2-MPNs) [1]; other members of JAK2-MPNs include essential thrombocythemia (ET) and polycythemia vera (PV). JAK2-MPNs are characterized molecularly by JAK-STAT activating mutations, involving JAK2, CALR, and MPL genes, and morphologically by trilineage myeloid proliferation in the bone marrow (BM) that is accentuated by megakaryocyte proliferation and atypia [2]. Peripheral blood (PB) manifestations of JAK2-MPNs include leukocytosis, thrombocytosis, and/or erythrocytosis while other disease features include splenomegaly, thrombosis, bleeding, microvascular disturbances, pruritus, and constitutional symptoms. Patients with MPN are at risk for premature death and disease progression into a fibrotic or leukemic disease phase [3]. Disease complications in JAK2-MPNs are most severe in PMF where median survival is estimated at 4.4 years and leukemic progression at 9%, at a median follow-up of 3.2 years [4].

Leukocytosis, in general, has long been identified/suspected as a risk factor for a number of disease complications in JAK2-MPNs including overall and leukemia-free survival [5, 6], disease progression [7, 8], thrombosis risk [9,10,11], and extramedullary hematopoiesis [12]. Considering the multicomponent nature of leukocytes, more recent studies in JAK2-MPNs have appropriately looked into the differential prognostic impact of absolute neutrophil (ANC) [13,14,15], monocyte (AMC) [13, 16,17,18,19], and lymphocyte (ALC) counts [13,14,15]. By comparison, fewer studies have reported on the prognostic contribution of absolute basophil (ABC) or eosinophil (AEC) counts in JAK2-MPNs, in general, and in PMF, in particular, not associated with tyrosine kinase fusion genes [20,21,22,23,24]. On the other hand, the prognostic relevance of basophilia in chronic myeloid leukemia (CML) is well established and is taken under consideration in defining accelerated phase CML [25, 26]. In the current study, we utilized a large Mayo Clinic database of patients with PMF in order to describe the prevalence and the clinical, molecular, and prognostic correlates of ABC and AEC.

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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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