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

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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

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

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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.

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Emerging Therapies in Myelofibrosis Could Extend Beyond JAK Inhibitors

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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.

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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.

Understanding Hematocrit Thresholds in Polycythemia Vera Treatment

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March 19, 2025

Author(s): Maggie L. Shaw, Andrew Kuykendall, MD

In early March, The American Journal of Managed Care® spoke with Andrew Kuykendall, MD, a clinical researcher at Moffitt Cancer Center who focuses on myeloproliferative neoplasms (MPNs), myelodysplastic syndrome/MPN overlap syndromes, and systemic mastocytosis. Kuykendall is an investigator on the phase 3 VERIFY trial (NCT05210790) of the injectable hepcidin mimetic rusfertide (Takeda) to treat polycythemia vera (PV) by enabling patients to achieve and sustain hematocrit control.1 Hematocrit is the measure of the percentage of red blood cells in the body.2

Treatment guidelines in PV currently recommend maintaining hematocrit below 45%, with a higher threshold for men vs women.2 For part 2 of this interview, Kuykendall explains the reasoning behind having different hematocrit thresholds.

In the first part of the interview, Kuykendall discussed how PV manifests and common ways to reduce its negative impact on patient quality of life.

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Optimizing Myelofibrosis Care in the Age of JAK Inhibitors

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Author: Douglas Tremblay, MD

How do you assess a patient’s prognosis at the time that they are diagnosed with myelofibrosis?
In the clinic, we use several scoring systems that have been developed based on the outcomes of hundreds of patients with myeloproliferative neoplasms (MPNs) to try to predict survival from time of diagnosis. Disease features associated with a poor prognosis include anemia, elevated white blood cell count, advanced age, constitutional symptoms, and increased peripheral blasts. Some of these scoring systems also incorporate chromosomal abnormalities as well as gene mutations to further refine prognostication.1

Determining prognosis can be important to creating a treatment plan, particularly to decide if curative allogeneic stem cell transplantation is necessary. However, I always caution patients that these prognostic scoring systems cannot tell the future and that each patient may respond differently to treatment.

How do you monitor for disease progression?
I will discuss with patients how they are feeling in order to determine if there are any new or developing symptoms that could be a sign that their disease is progressing. I will also review their laboratory work looking for changes in blood counts that could be a signal of disease evolution.

For instance, development of anemia or thrombocytopenia may signal worsening bone marrow function or progression to secondary acute leukemia. If there are concerning signs or symptoms, I will then perform a bone marrow biopsy with aspirate that will include assessment of mutations and chromosomal abnormalities to determine if their disease is progressing.

What are the first-line treatment options for a patient newly diagnosed with myelofibrosis, and how do you determine the best course of action?
For patients with myelofibrosis, the first-line treatment options include Janus kinase (JAK) inhibitors, which are effective at improving spleen size and reducing symptom burden. The US Food and Drug Administration (FDA) has approved 4 JAK inhibitors for the treatment of myelofibrosis: ruxolitinib, fedratinib, pacritinib, and momelotinib (Table).2-13 In general, ruxolitinib is the first-line treatment option unless there is thrombocytopenia, in which case pacritinib is more appropriate. In patients with baseline anemia, momelotinib may be the best choice.

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