Tag Archives: myelofibrosis

New Trial Will Assess Safety and Efficacy of MF Drug

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Leonardo Jaimes, MD

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A clinical trial aiming to determine the efficacy, safety, and pharmacokinetics of the experimental drug WJ01024 combined with ruxolitinib in patients with myelofibrosis (MF) is set to begin soon.

“Although the clinical efficacy of ruxolitinib tablets has been confirmed, only about half of MF patients can achieve the ideal therapeutic effect (≥35% reduction in spleen volume and ≥50% improvement in disease symptoms at 24 weeks),” the authors wrote. “Therefore, there is an urgent need for innovative drugs that can be combined with ruxolitinib tablets to enhance therapeutic efficacy and meet clinical needs,” they added.

WJ01024 aims to enhance the therapeutic efficacy of ruxolitinib through  XPO-1 inhibition. Previous in vitro studies have confirmed that the drug enhances ruxolitinib anti-cell proliferation activity, the researchers noted. Furthermore, preliminary studies on humans suggest that WJ01024 is effective as monotherapy for relapsing patients and those intolerant to JAK inhibitors, they added.

The trial will consist of a dose escalation and a dose extension phase (phase 1a and phase 2). Phase 1b will divide patients into three groups receiving 40 mg, 60 mg, and 80 mg of WJ01024, respectively. Phase 2 will be an open-label evaluation of the efficacy and safety of the recommended dose in combination with ruxolitinib.

The study will only include patients diagnosed with MF and with the international prognostic scoring system risk category of intermediate-1, intermediate-2, or high-risk. Patients in the accelerated blast phase or previous treatment with either JAK or XPO-1 inhibitors are not eligible for participation.

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JAK Inhibitors Associated With Less Thromboembolic Events in MF

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Leonardo Jaimes, MD
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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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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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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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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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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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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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Pelabresib Plus Ruxolitinib Improves Spleen Responses in Myelofibrosis

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By Roman Fabbricatore
Fact checked by Russ Conroy

Pelabresib (CPI 0610) in combination with ruxolitinib (Jakafi) significantly improved spleen responses and elicited robust clinical activity compared with placebo/ruxolitinib in patients with JAK inhibitor-naïve myelofibrosis, according to results from the phase 3 MANIFEST-2 trial (NCT04603495) published in Nature Medicine.1

Efficacy data from the trial revealed that the primary end point of spleen volume reduction of at least 35% at week 24 favored the investigational combination vs the placebo arm: 65.9% vs 35.2%, respectively (difference, 30.4%; 95% CI, 21.6%-39.3%; P <.001). Additionally, the mean percent change at week 24 in the respective arms was –50.6% (95% CI, –53.2% to –48.0%) vs –30.6% (95% CI, –33.7% to –27.5%). Spleen volume response was consistently higher with pelabresib vs placebo across predefined subgroups.

Furthermore, the hemoglobin response rate, defined as a 1.5 g/dl or greater mean increase, occurred in in 10.7% of the pelabresib arm (95% CI, 6.60%-14.90%) vs 6.0% of the placebo arm (95% CI, 2.85%-9.19%). Transfusions were received in the first 24 weeks of treatment in 27.6% and 37.5% of respective arms.

Greater reductions in NF-κB-regulated cytokines (–32.1% [95% CI, –34.9% to –29.2%] vs –19.4% [95% CI, –22.5% to –16.2%]), tumor necrosis factor (TNF; –43.5% [95% CI, –47.0% to –39.8%] vs –26.4% [95% CI, –30.5% to –22.1%]), and interleukin-6 (IL-6; –35.4% [95% CI, –44.2% to –25.2%] vs –14.5% [95% CI, –25.2% to –2.3%]) were seen in the investigational arm vs the placebo arm. Of note, a reduction in IL-8 levels was observed with pelabresib (–14.3% [95% CI, –22.3% to –5.5%]), but an increase was observed in the placebo arm (31.2% [95% CI, 17.5%-46.5%).

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Dr Rampal on ​Emerging Therapies Under Investigation in Myelofibrosis

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March 17, 2025

Author(s): Raajit K. Rampal, MD, PhD

Fact checked by: Ashling Wahner ,Chris Ryan

Raajit Rampal, MD, director of the Center for Hematologic Malignancies and director of the Myeloproliferative Neoplasms Program at Memorial Sloan Kettering Cancer Center, discusses emerging treatments for patients with myelofibrosis.

The therapeutic paradigm for myelofibrosis continues to expand with emerging treatment options, particularly with combination therapies, novel JAK inhibitors, and immunotherapeutic agents, Rampal begins. Among these, pelabresib (CPI-0610), a BET inhibitor, has completed phase 3 trials. Preliminary data from the phase 3 MANIFEST-2 trial (NCT04603495), which were presented in December 2023, demonstrated improved spleen responses and a trend toward better symptom management with the combination of pelabresib and ruxolitinib (Jakafi) vs placebo plus ruxolitinib in patients with JAK inhibitor–naive myelofibrosis. Updated findings from MANIFEST-2 were published in Nature Medicine in March 2025.

Beyond pelabresib, several other agents are currently in phase 3 trials for patients with myelofibrosis, Rampal says. Selinexor (Xpovio), which is currently FDA approved for the treatment of patients with relapsed/refractory multiple myeloma, is being studied in combination with ruxolitinib in patients with myelofibrosis in the phase 3 XPORT-MF-034 trial (NCT04562389). Additionally, navtemadlin (KRT-232), an MDM2 inhibitor, is undergoing clinical evaluation in patients with myelofibrosis. Notably, these trials are ongoing, and no conclusive data are available at this time, Rampal emphasizes.

The development of next-generation JAK inhibitors also represents a promising area of investigation, according to Rampal. These newer inhibitors are anticipated to demonstrate greater potency and selectivity compared with existing agents, though they remain in early-phase clinical trials, he notes.

Rampal states that one of the most exciting advancements in this setting is the emergence of immunotherapies. Calreticulin-targeted antibodies are currently being evaluated in clinical trials, and 2 candidates are in development, he reports. If these agents prove effective, they could significantly alter the treatment paradigm, he concludes.

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