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

Posted on March 31, 2025March 31, 2025 by mpn_admin

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

Distress May Be Under-Recognized in Patients With MPN

Posted on March 31, 2025March 31, 2025 by mpn_admin

March 28, 2025

John Schieszer

Distress is a critical yet underrecognized factor affecting quality of life, treatment adherence, and healthcare utilization in classical Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs): polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis (MF), according to results of a retrospective study. The study revealed that despite consensus recommendations, most patients with distress ≥4 were not evaluated by supportive services (SS).

“Our findings underscore the importance of integrating distress screening with actionable follow-ups to ensure that patients receive timely supportive care,” said first study author Rushil V. Patel, MD, an assistant professor of Hematology/Oncology at The University of Alabama at Birmingham. “For hematologists, the key takeaway is that screening alone is insufficient and systematic referral pathways and proactive engagement with supportive services are essential. An interdisciplinary approach could significantly enhance patient-centered care.”

There is an urgent need to address the unmet needs of this population. The National Comprehensive Cancer Network (NCCN) recommends screening patients for distress by a self-reported scale (0-10) and to refer those with scores ≥4 to SS.

Researchers looked at 141 patients (44 PV, 49 ET, and 48 MF). The median age was 63 years (range, 25-89). The researchers retrospectively identified MPN patients at a single center to measure the proportions of patients with distress ≥4 evaluated by an SS (chaplaincy, integrative oncology, palliative medicine, psychiatry, psychology, and social work).

The team also investigated acute care utilization (ACU; ≥1 ED visit or hospitalization) within 6 months of electronic distress screening (EDS). In order to stratify variables associated with distress, the investigators obtained sociodemographic, disease characteristics, and symptom score data. The cohort was predominantly female (62%) and White (77%).

As part of routine care, the NCCN recommends using the MPN-Symptom Assessment Form Total Symptom Score (SAF TSS), which is a validated measure of 10 symptoms clinically relevant to MPNs. Data captured from the EDS included location, time of screening and patient-reported information (gender, race, ethnicity, psychosocial variables). These were linked to the electronic medical record (EMR). Distress was based on a single self-reported question: “How much distress have you been feeling in the past week?”

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

Posted on March 31, 2025March 31, 2025 by mpn_admin

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.

Thrombosis, Major Bleeding Events More Frequent in Myelofibrosis Compared With Other Myeloproliferative Neoplasms

Posted on March 31, 2025March 31, 2025 by mpn_admin

March 26, 2025

Author(s): Luke Halpern, Assistant Editor

Results of a nationwide Swedish population-based study indicate that patients with myelofibrosis (MF) have increased rates of thromboembolic events and major bleeding compared with presentations in other myeloproliferative neoplasms (MPN), with thromboembolic complications and major bleeding events diverging based on varying treatment groups. These results, published by study authors in Blood Advances, can help health care providers more effectively care for patients with MF, allowing them to counsel patients on associated bleeding risks.¹

Thrombosis can be a deadly complication in patients with myelofibrosis. | Image Credit: © Matthieu – stock.adobe.com

The clinical presentation of MF evolves throughout the development of the disease, eventually presenting as bone marrow fibrosis, hepatosplenomegaly, fatigue, and progressive pancytopenia, ultimately leading to reduced patient quality of life and heightened morbidity. Bleeding and thromboembolic events have been known to be possible complications of MF, but literature on this association is lacking. According to the present investigators, studies analyzing this association are plagued by small cohorts, seldom-included control patients, and populations containing varying MPNs, rather than MF specifically.^2,3

To fill the present gaps in literature regarding thromboembolic and bleeding event prevalence in patients with MF, the current study authors conducted a nationwide analysis to assess the frequency of arterial and venous events, major bleeding, all-cause stroke, and all-cause mortality in Swedish patients with primary MF (PMF) and secondary MF (SMF) compared with matched controls. They also aimed to investigate if outcomes varied based on the therapy used in MF while attempting to describe relevant risk factors for major bleeding and thromboembolic events among patients with MF.¹

Multiple Swedish registries of patients diagnosed with hematologic malignancies were consulted, with all adult patients registered with a diagnosis of MF from 2008 to 2021 included. In total, 1079 patients with MF and 395 controls were included, with a median age of 72 years at diagnosis. Notably, over a third of the patients (40.7%) had an International Prognostic Scoring System (IPSS) score of intermediate-2 or high risk. Furthermore, mutations were present in many patients enrolled in the study and diagnosed after June 1, 2016, with 53.6% having a JAK2 V617F mutation.¹

Across the follow-up period, 125 arterial and 51 venous events occurred in the MF cohort, with event rates of 2.59 and 1.06 events per 100 patient years, compared with 337 (rate 1.51, HR: 1.73; 95% CI, 1.40-2.12; P < .001) and 86 (rate 0.38, HR: 2.75; 95% CI, 1.95-3.90; P < .001) among the control patients. When patients were divided based on diagnoses of PMF or SMF, rates of arterial and venous events were noticeably higher among patients with SMF compared with PMF. In addition, 80 cases of acute myocardial infarction (rate: 1.66), 40 ischemic strokes (rate: 0.83), and 38 pulmonary emboli (rate: 0.79) were documented in the MF cohort.¹

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

Posted on March 31, 2025March 31, 2025 by mpn_admin

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.

Real World Management of Cytopenias and Infections in Patients With Myelofibrosis Treated With Ruxolitinib

Posted on March 25, 2025March 25, 2025 by mpn_admin

Liesl A. Butler, Cecily Forsyth, Claire Harrison, Andrew C. Perkins

ABSTRACT
Introduction: Ruxolitinib was the first JAK2 inhibitor approved for the treatment of primary and secondary myelofibrosis. It is
currently used worldwide as first-line therapy for advanced disease (intermediate-2 and high-risk) and is effective in polycythaemia
vera (PV) and essential thrombocythaemia (ET), but not funded for this indication in many countries. Ruxolitinib has proven
benefits with respect to symptom control, reduction in spleen size and prolongation of survival; however, it rarely induces a
substantial reduction in allele burden and never provides a cure. Moreover, there are frequently encountered adverse effects and
dosing issues that require careful management to optimise its therapeutic benefit.

Methods and Results: In this case-based review, we use seven informative common clinical scenarios to discuss appropriate
investigation and management of cytopenias and infection issues.

Conclusions: We make recommendations based on 15 years of experience in using ruxolitinib and other JAK inhibitors for the
treatment of myelofibrosis. We discuss when allogeneic haematopoietic stem cell transplantation (AHSCT) should be considered
and some of the currently available alternative JAK inhibitors and trial options when AHSCT is not an option.

Emerging Therapies in Myelofibrosis Could Extend Beyond JAK Inhibitors

Posted on March 25, 2025March 25, 2025 by mpn_admin

March 24, 2025

Author(s): Ashley Chan

Fact checked by: Ashling Wahner

The September 2023 FDA approval of momelotinib (Ojjaara) for the treatment of patients with primary and secondary myelofibrosis with anemia provided the treatment paradigm with its fourth FDA-approved JAK inhibitor, a class of drugs that has helped improve symptoms associated with myelofibrosis and decrease spleen size, according to Raajit Rampal, MD, PhD.

Additional classes of drugs, such as BET inhibitors and immunotherapy agents, are also currently under investigation in clinical trials and could become “game-changers” if effective, Rampal noted.

“The major [message is] that myelofibrosis is not a monolithic disease, and the selection of the treatment needs to be tailored to the underlying issues and challenges the patient is facing,” said Rampal in an interview with OncLive^®.

In the interview, Rampal discussed currently available JAK inhibitors and their limitations, emerging treatments for myelofibrosis, tips for treatment selection, and his takeaways from the 6th Annual Miami Cancer Institute Global Summit on Immunotherapies for Hematologic Malignancies.

Rampal is a hematologist-oncologist, the director of the Center for Hematologic Malignancies, and the director of the Myeloproliferative Neoplasms Program at Memorial Sloan Kettering Cancer Center in New York, New York.

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

Posted on March 25, 2025March 25, 2025 by mpn_admin

March 2025

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.

Dr Bhat on the Influence of MPN Risk Stratification on Treatment Decision-Making

Posted on March 25, 2025March 25, 2025 by mpn_admin

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.

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

Posted on March 25, 2025March 25, 2025 by mpn_admin

March 2025

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.