Tag Archives: JAK inhibitor

Efficacy of JAK1/2 inhibition in murine myeloproliferative neoplasms is not mediated by targeting oncogenic signaling

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May 24, 2025

Sivahari Prasad Gorantla, Michael Rassner, Kirstyn Anne Crossley,…Robert Zeiser & Justus Duyster

Abstract

Ruxolitinib is a potent JAK1/JAK2 inhibitor, approved for the treatment of primary myelofibrosis (PMF) patients based on the concept of inhibition of oncogenic signaling. However, the effect of ruxolitinib on JAK2-V617F allelic burden is modest, suggesting that inhibition of JAK2-V617F signaling-driven clone expansion is not the main mechanism of action. We evaluate whether ruxolitinib mainly blocks the proliferation of the malignant clone or exerts its effects also by targeting non-malignant cells. Therefore, we develop two JAK2-V617F-driven myeloproliferative neoplasm (MPN) mouse models harboring ruxolitinib resistance mutations. Mice carrying ruxolitinib-resistant JAK2-V617F-driven MPN respond to ruxolitinib treatment similar to mice with ruxolitinib-sensitive JAK2-V617F MPN with respect to reduction of spleen size, leukocyte count and pro-inflammatory cytokines in the serum. Ruxolitinib reduces pro-inflammatory cytokines in both stromal cells and non-malignant hematopoietic cells. Using a rigorous ruxolitinib resistance mutation approach, we can prove that ruxolitinib acts independent of oncogenic JAK2-V617F signaling and reduces the main features of MPN disease such as spleen size and leukocyte counts. Our findings characterize the mechanism of action for ruxolitinib in MPN.

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Strategic JAK Inhibitor Sequencing: Translating SIMPLIFY I/II Outcomes to Optimize Myelofibrosis Management

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By Pankit Vachhani, MD
Edward Pearson, MD

Summary of Momelotinib Clinical Trials and Second-Line Applications

SIMPLIFY-1 (First-Line Setting)

  • Efficacy comparison with ruxolitinib in newly diagnosed myelofibrosis:
    • Spleen response: Momelotinib demonstrated spleen volume reduction
    • Symptom improvement: Not as robust as ruxolitinib
    • Anemia benefit: Preserved transfusion independence at week 24 vs baseline, while ruxolitinib showed slight decline
  • Clinical considerations for newly diagnosed myelofibrosis with moderate anemia:
    • Potential benefit of single-agent therapy (avoiding combination with erythropoiesis-stimulating agents)
    • When anemia contributes significantly to symptom burden, momelotinib may be preferable

SIMPLIFY-2 (Second-Line Setting)

  • Study design: Effectively a comparison of momelotinib vs ruxolitinib in previously treated patients
    • No washout period between treatments
  • Key outcomes:
    • Spleen response: Comparable between momelotinib and control (“a wash”)
    • Anemia: Clear advantage for momelotinib
    • Symptom control: Superior with momelotinib in the second-line setting
  • Expert opinion on optimal positioning:
    • Panel indicated greater preference for momelotinib in the second-line setting
    • Particularly valuable in patients with worsening anemia or diminishing spleen response on ruxolitinib
    • Setting appropriate expectations is crucial; emphasize anemia and symptom benefits rather than additional spleen reduction

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Assessing Risk for JAK Inhibitor Selection in Myelofibrosis

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By Targeted Oncology Staff

In part 1, experts explores how assessing individual risk factors is crucial in selecting the appropriate JAK inhibitor for patients with myelofibrosis.

CASE

AARON T. GERDS, MD, MS: How do you use molecular testing, bone marrow results, and clinical features to stratify risk in patients with myelofibrosis?

PRITHVIRAJ BOSE, MD: At this point, I believe we are all receiving the myeloid mutation panels. We also order JAK2, MPL, and CALR: the 3 drivers. However, most clinicians would order a myeloid mutation panel because we know that many of the mutations are prognostic. This is the whole point of risk stratification, which is now increasingly sophisticated and integrates multiple clinical, molecular, [and] cytogenetic variables to determine who needs a transplant.

These are the first actions I take when speaking with a new patient. I get an idea of their risk in terms of survival and prognosis, and that informs my decision to refer them to transplant. I then counsel the patient appropriately.

I do not believe molecular testing informs treatment because our drugs are, for the most part, mutation agnostic. All we have are JAK inhibitors, which are not mutation specific. However, from a prognostic standpoint, the [role] of molecular testing is key.

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JAK Inhibitors Associated With Less Thromboembolic Events in MF

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Leonardo Jaimes, MD
Publish Date:

Janus kinase inhibitors (JAKi) therapy could prevent thromboembolic events in patients with myeloproliferative neoplasms (MPNs) such as myelofibrosis (MF), according to a recently published meta-analysis in the Journal of the British Society of Hematology.

Despite the well-documented clinical improvement associated with JAKi therapy in patients with MPNs, adverse effects such as weight gain and cholesterol increase have raised concerns about increased cardiovascular risk. Furthermore, the ORAL surveillance trial demonstrated that JAKi was associated with an increase in the rate of major adverse cardiovascular events (MACEs).

As the effects of JAKi therapy on thrombotic risk are still poorly understood, the authors aimed to compare the rates of MACEs, thrombosis, and hypertension in patients with MPN taking JAKis through a meta-analysis.

The meta-analysis included prospective and retrospective studies involving patients taking JAKi and a JAKi-naive control group. The initial search yielded over 1500 studies, of which 23 met the inclusion criteria.

Nine studies, including over 1800 patients, assessed thromboembolic risk. The pooled analysis with a confidence interval of 95% revealed that the rate of thromboembolic events was 48% lower in patients receiving JAKi therapy. The pooled analysis of the 16  studies analyzing MACE or hypertension, on the other hand, revealed no significant difference between groups.

The authors remarked that the findings correspond with evidence presented by Samuelson et al., which demonstrated that ruxolitinib was associated with lower rates of hemolysis. Furthermore, recent posthoc analysis of the ORAL surveillance trial found that the apparent increased frequency of MACE in patients receiving JAKi therapy was observed in patients with preexisting atherosclerotic disease.

“JAKi treatment was not associated with an increased risk of MACE or hypertension, adding to the existing body of evidence demonstrating the safety of JAKi in the treatment of MPNs,” the authors wrote.

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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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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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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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Optimizing Myelofibrosis Care in the Age of JAK Inhibitors

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December 12, 2024|Hematology and Oncology
Douglas Tremblay, MD

Myelofibrosis is a rare but serious bone marrow disorder that disrupts blood cell production and often leads to debilitating symptoms. In this interview, Douglas Tremblay, MD, Assistant Professor at the Tisch Cancer Institute, discusses the process for selecting the best treatment pathway for patients – from evaluating disease prognosis to navigating treatment resistance and intolerance.

Dr. Douglas Tremblay

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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Dr DeAngelo on the Integration of JAK Inhibitors in Myelofibrosis Management

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November 11, 2024

Author(s): Daniel J. DeAngelo, MD, PhD

Daniel DeAngelo, MD, PhD, professor, medicine, Harvard Medical School, chief, Division of Leukemia, institute physician, Dana-Farber Cancer Institute, discusses the integration of JAK inhibitors into clinical practice for patients with myelofibrosis. Lower third needs to be updated

When incorporating JAK inhibitors, such as ruxolitinib (Rituxan), into clinical practice, it is essential to understand both their benefits and the challenges they present, particularly regarding anemia, DeAngelo begins. The phase 3 COMFORT-I (NCT00952289) and COMFORT-II (NCT00934544) trials, which initially sought to address symptom control and spleen reduction, demonstrated a notable survival advantage with ruxolitinib over placebo in patients with intermediate-2 or high-risk myelofibrosis, or intermediate-1 disease with symptomatic splenomegaly, he reports. These results led to ruxolitinib becoming the standard of care for high-risk or symptomatic patients, especially as allogeneic transplantation remains limited to select candidates, DeAngelo shares.

A primary consideration with ruxolitinib is its tendency to induce a hemoglobin level drop of approximately 2 points during the first 2 months of treatment due to on-target JAK2 inhibition, which affects erythropoiesis, he continues. Although newer agents are now approved by the FDA specifically for patients with baseline anemia, clinicians using ruxolitinib should anticipate this hemoglobin level decline, he states. Importantly, the initial drop in hemoglobin level does not indicate treatment failure but is a manageable effect that is often misunderstood, leading some oncologists to discontinue or reduce dosing with the drug prematurely, DeAngelo notes.

He goes on to state that his advice for integrating JAK inhibitors into myelofibrosis management plans is to proactively address these expected effects with patients. Patients can be supported through transfusions, growth factors, or alternative JAK inhibitors if needed, according to DeAngelo. In most cases, hemoglobin levels tend to stabilize and improve after the first few months, typically between months 3 and 4, he notes. Setting clear treatment expectations helps ensure patient adherence to therapy and optimizes outcomes when using JAK inhibitors in clinical practice, DeAngelo concludes.

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Dr Scandura on the SENTRY-2 Trial of Single-Agent Selinexor in JAK Inhibitor–Naive Myelofibrosis

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October 16, 2024

Author(s): Joe Scandura, MD, PhD

Fact checked by: Ryan Scott, Courtney Flaherty

Joseph M. Scandura, MD, PhD, associate attending physician, NewYork-Presbyterian Hospital; associate professor, medicine, Weill Cornell Medical College, Cornell University, discusses the phase 2 SENTRY-2 study (XPORT-MF-044; NCT05980806) evaluating single-agent selinexor (Xpovio) in JAK inhibitor–naive myelofibrosis.

The FDA granted fast track designation to single-agent selinexor for the treatment of patients with primary myelofibrosis, post-essential thrombocythemia myelofibrosis, and post-polycythemia vera myelofibrosis in July 2023. Notably, selinexor will be assessed in combination with ruxolitinib (Jakafi) in the phase 3 portion of the SENTRY trial (NCT04562389) and as a monotherapy in the phase 2 SENTRY-2 study for JAK inhibitor–naive patients.

The primary aim of the SENTRY-2 study is to evaluate the efficacy of selinexor as a standalone treatment for patients with myelofibrosis who have not previously been treated with a JAK inhibitor, Scandura begins. Currently, JAK inhibitors are the only FDA-approved class of drugs for this condition, complicating the ability to test alternative treatments like selinexor independently, he states. However, evidence suggests that selinexor demonstrates activity, prompting the FDA to permit the study’s initiation, Scandura says. In SENTRY-2, patients will start treatment with selinexor, and responses will be measured based on spleen volume reduction and symptom improvement, particularly anemia, he details.

An innovative aspect of the study is its flexibility, Scandura notes. If a patient shows some degree of response but it is not deemed significant, they may have a JAK inhibitor added to their treatment regimen, he explains. This could include ruxolitinib or newer agents such as pacritinib (Vonjoy), which does not suppress platelet counts, making it suitable for patients with low platelets. Momelotinib (Ojjaara), known for its efficacy in improving anemia, will be added if patients are anemic and maintain adequate platelet counts.

The importance of safety and rigorous science is emphasized in clinical trials, especially when evaluating new treatments, Scandura continues. With selinexor already recognized as safe, the focus shifts to optimizing its use in the treatment landscape of myelofibrosis, he says. If selinexor gains FDA approval for myelofibrosis, it could play a significant role in a more nuanced treatment approach, reflecting the complexities of managing this condition amidst financial considerations and the availability of multiple JAK inhibitors, Scandura concludes.

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