Category Archives: Treatment

Fedratinib in 2025 and Beyond: Indications and Future Applications

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Alexander Coltoff (Medical University of South Carolina, United States) John Mascarenhas (Icahn School of Medicine at Mount Sinai, United States)

Abstract

Dysregulated JAK/STAT signaling underlies the pathogenesis of myelofibrosis, a myeloproliferative neoplasm characterized by cytopenias, splenomegaly and constitutional symptoms. JAK inhibitors, such as fedratinib, are the primary therapeutic option for patients with high-risk or symptomatic myelofibrosis. Fedratinib has characteristics that distinguish it from the other commercially available JAK inhibitors, such as its preferential inhibition of JAK2 and its inhibitory effects on kinases such as FLT3 and BRD4. Fedratinib is most often used in the second-line setting after intolerance or resistance to other JAK inhibitors, but there is substantial evidence that it is an effective first-line option in the appropriate patient population. Prevention and early treatment of fedratinib-related gastrointestinal toxicity is key to maintaining adequate drug exposure, and clinicians must remain vigilant for Wernicke encephalopathy during treatment. Fedratinib’s JAK2 selectivity and kinome profile make it an appealing agent for alternative indications, such as myelodysplastic/myeloproliferative neoplasms and maintenance after bone marrow transplantation, which are under active investigation.

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Second-Line Fedratinib Produces Early Platelet Count Improvements in Myelofibrosis

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February 5, 2025

Author(s): Jax DiEugenio

Fact checked by: Chris Ryan

Patients with myelofibrosis who received second-line fedratinib (Inrebic) experienced early increases in platelet count compared with those given best available therapy (BAT), and a higher magnitude of benefit was observed in patients with a low platelet count at baseline, according to findings from the phase 3 FREEDOM2 trial (NCT03952039) presented at the 2024 ASH Annual Meeting.

Findings showed that in the overall safety population, fedratinib generated improvements in mean platelet count and mean change from baseline platelet count, most noticeably in early treatment cycles.

In patients with a low platelet count at baseline, defined as at least 50 to less than 100 x 109/L, patients treated with fedratinib (n = 34) experienced a mean increase in platelet count of 45% on day 15 of cycle 1 compared with 11% for those given BAT (n = 21). Among patients with a high platelet count at baseline of at least 100 x 109/L, these rates were 27% for fedratinib (n = 85) and –6% for BAT (n = 39).

During a presentation of the data, lead study author Haifa Kathrin Al-Ali, MD, explained that increased platelet count was not correlated with changes in spleen size, pointing to a potential benefit for fedratinib on thrombopoiesis.

“These data suggest a platelet-sparing effect of second-line fedratinib vs BAT, and support fedratinib as a promising second-line treatment option for patient with myelofibrosis with low or high baseline platelet count,” said Al-Ali, who is a professor of translational oncology and head of the Krukenberg Cancer Center at the University Hospital of Halle (Saale) in Germany.

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Real-world treatment patterns and health outcomes for patients with myelofibrosis treated with fedratinib

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January 14, 2025

Francesco Passamonti Shalon Jones e , a,b , Siddhi Korgaonkar c Dorothy Zissler e , , Keith L Davis Rohan C Parikh c c , Manoj Chevli d , and Samantha Slaff

ABSTRACT

Aim: Assess real-world fedratinib (FEDR) treatment patterns and clinical outcomes in patients with primary or secondary myelofibrosis following discontinuation of ruxolitinib (RUX). Patients & Methods: This study was a retrospective, noninterventional medical record review of patients in Canada, Germany, and the United Kingdom (UK). A total of 70 physicians (primarily hematologist-oncologists [78.6%]) provided data for 196 eligible patients.

Results: Patients were mostly male (62.8%) with primary myelofibrosis (76.5%) and initiated FEDR at a mean age of 67.7 years. Median treatment duration was 11.5 months (median follow-up, 13.8 months), and nearly half (49.5%) of patients initiated FEDR at the label-indicated dose of 400 mg daily. Six months post-initiation, 77.7% and 66.8% of patients experienced symptom and spleen response, respectively. Kaplan-Meier estimates of median progression-free and overall survival from initiation were 23.8 months (95% CI, 21.1–27.6) and 29.8 months (95% CI, 23.9-NE), respectively.

Conclusion: These findings demonstrate real-world FEDR effectiveness among patients with myelofibrosis who discontinued RUX.

PLAIN LANGUAGE SUMMARY

What is this summary about?

Myelofibrosis (MF) is a rare blood cancer that can cause unhealthy spleen growth and symptoms, such as feeling tired, loss of appetite, bone pain, and fever. This is a summary of an article that reviewed medical records of patients with MF from treatment centers in Canada, Germany, and the United Kingdom (UK). The study looked at people who had been taking a medication called fedratinib (FEDR) for their MF after they had stopped taking a different medication called ruxolitinib (RUX). Many of the people stopped taking RUX because their MF got worse within a few years. The study wanted to see if taking FEDR reduced symptoms and spleen size for people with MF after they stopped taking RUX.

What were the results?

After at least 6 months of taking FEDR, 77.7% of the people in the study had fewer symptoms, and 66.8% of people in the study had a decrease in spleen size or no spleen growth. Additionally, most people taking FEDR after discontinuing RUX went nearly 2 years without their MF symptoms or illness getting worse.

What do the results mean?

These results suggest that FEDR is an effective treatment for people with MF who have stopped taking RUX.

In Charleston, West Virginia, Tracking MPN Symptoms Becomes a Priority

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January 17, 2025

Author(s): Mary Caffrey

When patients with myeloproliferative neoplasms (MPNs) must travel 2 hours for appointments with a cancer care team, capturing all their symptoms to ensure proper treatment is vital.

So, when Charleston Area Medical Center (AMC) Vandalia Health, located in Charleston, West Virginia, signed on to be part of the Association of Cancer Care Centers (ACCC) MPN Quality Improvement Program, systematic and accurate recording of patients’ symptoms was a priority. In a 12-month period, the cancer program serves 78 patients with polycythemia vera, 111 patients with essential thrombocythemia, and 48 patients with primary myelofibrosis.

Charleston AMC serves a large area in southern West Virginia, including some heavily rural areas. Its team includes general medical oncologists and hematologists who treat all types of cancers, 5 patient navigators, and 2 financial navigators who deal with insurance coverage, transportation issues, and other barriers to access. There is 1 social worker as well as nurses and other team members. Complementing the team are outside partners who help Charleston AMC meet multiple social needs.

As with ACCC Quality Improvement Program participants from Perlmutter Cancer Center at NYU Langone Health and Kent Hospital in Rhode Island, the multidisciplinary team in Charleston West Virginia, first took part in a webinar on MPN patient management.1

The ACCC Quality Improvement program was supported by Incyte.

The Charleston AMC team learned about the MPN Symptom Assessment Form Total Symptom Score (MPN-SAF TSS),2 a validated MPN patient-reported outcome tool that is recommended in the National Comprehensive Cancer Network Guidelines. Patients complete the assessment when they arrive at their appointments, giving providers an overview of symptoms that can be tracked over time.

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Fedratinib for the treatment of myelofibrosis: a critical appraisal of clinical trial and “real-world” data

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January 14, 2025

Adrian Duek, Ilona Leviatan, Osnat Jarchowsky Dolberg & Martin H. Ellis

Abstract

Fedratinib is a predominantly JAK2 inhibitor that has shown efficacy in untreated and ruxolitinib-exposed patients with myelofibrosis (MF). Based on randomized clinical trial data, it is approved for use in patients with International Prognostic Scoring System (IPSS) or Dynamic International Prognostic Scoring System (DIPSS) intermediate-2 or high-risk disease and is distinguished from ruxolitinib in that it can be administered without dose reduction in patients with thrombocytopenia, to a platelet count above 50,000/µL. In these trials, fedratinib achieved significant spleen volume reduction in ~30–45% of patients and improvement in total symptom scores in 35–40% with good tolerability. In contrast, recently published real-world data suggest that these responses may not be as robust outside clinical trials. In the context of routine clinical practice spleen responses are documented in only 13–68%, with varying degrees of symptom improvement. This may be due to the lack of a uniform definition of ruxolitinib failure, which may influence the timing of initiating fedratinib as a second-line treatment and result in a more prolonged exposure to ruxolitinib prior to intitaing fedratinib treatment. We suggest that given the growing number of drugs available for use in MF, recognizing the failure of first-line (and potentially subsequent) treatments is critical to allow timely transition to potentially more active agents, as highlighted by the data pertaining to fedratinib.

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Ruxolitinib Combinations in MPNs: Updates From ASH

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January 8, 2025

Author(s): Mary Caffrey

Following its approval in 2011 for myelofibrosis (MF), ruxolitinib (Jakafi, Incyte) became the backbone of treatment for MF and later for polycythemia vera (PV), 2 of the 3 common myeloproliferative neoplasms (MPNs).

But although ruxolitinib improves survival outcomes and quality of life, some patients may not respond to therapy, while others may stop due to genetic mutations, disease progression, or other factors. For years now, investigators have been studying the Janus kinase (JAK) inhibitor in combination with other drugs, both in first-line treatment and refractory disease. Abstracts and oral presentations at the recent 66th American Society of Hematology (ASH) Annual Meeting and Exposition, held December 7-10, 2024, in San Diego, California, offered updates on several combinations in the pipeline:

MANIFEST-2. Previous results from this phase 3 study (NCT04603495) of pelabresib, a selective bromodoman and extraterminal domain (BET) inhibitor, with ruxolitinib show it met its primary end point; in patients with MF not treated with a JAK inhibitor, a statistically significant higher proportion showed at least 35% reduction in spleen volume from baseline at week 24 with the combination vs ruxolitinib and placebo. Results presented at ASH showed those results were maintained after a median follow-up of 72 weeks, with a 48-week response rate of 57.0% for the combination vs 37.5% for ruxolitinib and placebo. An improvement in the Myelofibrosis Symptom Assessment Form total symptom score (TSS) by at least 50% was seen in 45.3% of patients receiving the combination vs 39.4% in the placebo group.1

Bomedemstat. An abstract at ASH reported on an ongoing phase 2 study (NCT05569538) involving bomedemstat combined with ruxolitinib in patients with advanced MF.2 Bomedemstat is an irreversible inhibitor of lysine-specific demethylase 1 (LSD1), which plays a role in gene regulation; blocking this enzyme alters cell differentiation and growth. In August 2024, Merck announced the second phase 3 trial of bomedemastat in another MPN, essential thrombocythemia (ET).

The abstract authors noted that about 50% of patients with MF stop ruxolitinib after 3 years, mostly due to disease progression or cytopenia; median OS after discontinuation is 14 months.2 LSD1, they write, is “critical for self-renewal” of cancerous stem cells, and has shown promise as a single agent. This study reported on 2 cohorts: Cohort A had a suboptimal response to ruxolitinib, and cohort B patients had MF and were treatment naive. Patients in cohort A remained on the entry dose of ruxolitinib while cohort B started 10 mg twice per day; all patients received a starting dose of 0.4 mg/kg/day of bomedemstat. Dose adjustments were permitted every 4 weeks to achieve an optimal platelet count; downward titrations were done at any time for safety reasons. After a median of 61.7 weeks, in 40 evaluable patients, at week 24, 11 patients had at least a 50% improvement in TSS, with 25.9% in cohort A and 30.7% in cohort B; 17.5% had at least 35% spleen volume reduction, with 7.4% in cohort A and 38.5% in cohort B; and 50% of patients had stable or improved hemoglobin (51.9% in cohort A and 46.3% in cohort B). There were no safety signals or deaths related to the drug, the authors said.2

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Options for MPN Treatment Are Expanding Rapidly With More on the Horizon

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December 24, 2024

Author(s): Laura Joszt, MA, Luke Halpern

The past few years have been an exciting time in myeloproliferative neoplasms (MPNs) with new treatments providing new options for patients and additional products in the pipeline that explore new mechanisms of action, explained Firas El Chaer, MD, associate professor of medicine, University of Virginia School of Medicine. At the American Society of Hematology annual meeting, El Chaer had presented research and been a coauthor on abstracts related to treatment for myeloproliferative neoplasms.

He discussed how MPNs are diagnosed, the current treatment landscape, and promising new therapies in the pipeline. When diagnosing for MPNs, particularly for myelofibrosis, a bone marrow biopsy is needed, but the challenge is that this can be “patchy,” he explained, and the amount of fibrosis present in the particular part of the bone marrow that is biopsied is what is relied upon to make the diagnosis.

The good news is that the approval of many new Janus kinase inhibitors has changed the treatment landscape of myelofibrosis dramatically in the last few years, El Chaer said, which has provided patients with additional options for treatment. In addition, there are new mechanisms of action that can improve anemia in this patient population.

“I’m very excited that currently we’re thinking about combination therapies,” he said, to improve anemia or that potentially have a disease-modifying capability. “Our field is expanding very quickly.”

He highlighted some of the new mechanisms of action being studied in myeloproliferative neoplasms, such as bromodomain molecules and TGF-β agonists, which can potentially be helpful for anemia and this patient population. He had presented phase 1/2 data on nuvisertib, or TP-3654, which is a highly selective PIM1 kinase inhibitor that has reduced spleen size and bone marrow fibrosis either alone or in combination with ruxolitinib. Nuvisertib has minimal cytopenia side effect and can be combined with other molecules for treatment. Currently, enrollment is ongoing in 3 arms of the study (NCT04176198) to continue to evaluate nuvisertib as a monotherapy and in combination with ruxolitinib and momelotinib.

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Patient-Reported Outcomes Drive Effective MPN Treatment

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December 16, 2o24

Author(s): Laura Joszt, MA

With patients with myeloproliferative neoplasms (MPNs) having long life expectancies, it’s important that treatments optimize quality of life and patient-reported outcomes, said Jennifer Vaughn, MD, hematologist-oncologist and assistant professor in the Division of Hematology at The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute.

This transcript has been lightly edited for clarity.

Transcript

How are patient-reported outcomes currently being used and incorporated into clinical practice to inform treatment for rare hematological conditions?

I think myeloproliferative neoplasms are an important area where patient-reported outcomes are so important. The drug ruxolitinib or Jakafi, which is a JAK [Janus kinase] inhibitor used in both polycythemia vera and myelofibrosis, was actually originally approved in myelofibrosis because of the improvement it led to in patient quality of life.

First of all, it was able to objectively reduce spleen volume, which led to improvement in patient symptoms, and it led to reductions in symptom scores on the MPN symptom assessment form, which is sort of the standard form we use now to assess how a patient is feeling over time. While there have been some data later on that suggests there may be an overall survival benefit in certain subsets of myelofibrosis, we really do decide to put patients on that treatment because of what they’re telling us about, how they feel. This was really one of the first models of using patient-reported outcomes in looking at whether or not a drug is valuable to society and to patients themselves.

Patients with MPNs become very symptomatic, and many of them will live [long] or have very excellent prognosis in terms of expected lifespan, but their quality of life is quite impeded by the symptoms of the disease. So, it’s really important for clinicians to be kind of reevaluating that on a regular, routine basis.

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Pacritinib and Momelotinib Display Positive Real-World Impact on Anemia and Transfusion Needs in Myelofibrosis

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December 12, 2024

Author(s): Kyle Doherty

Fact checked by: Caroline Seymour

Although long-term follow-up was limited, treatment with the JAK2 inhibitors pacritinib (Vonjo) and/or momelotinib (Ojjaara) led to favorable effects on anemia and transfusion requirements among patients with myelofibrosis, according to findings from a real-world study presented in a poster during the 2024 ASH Annual Meeting.1

Patients who received momelotinib (n = 32) had a median hemoglobin count of 8.7 g/dL (range, 6.5-1.2) at the start of therapy which increased to 9.0 g/dL after 3 months of treatment (P = .021). The median platelet count at the start of therapy was 141 x 109/L (range 15 x 109-504 x 109) and increased to 116 x 109/L after 3 months (P = .317). Patients required a mean of 1.9 red blood cell (RBC) units/month at the start of therapy and 0.47 units/month after 3 months of treatment (P = .015).

Patients treated with pacritinib (n = 27) had a median hemoglobin count of 8.5 g/dL (range, 6.9-12.9) at the start of treatment and a median count of 9.1 g/dL following 3 months of therapy (P = .402). The median platelet count at the start of therapy was 65 x 109/L(range, 18 x 109-441 x 109) compared with 31 x 109/L after 3 months of treatment (P = .303). Patients required a mean of 2.4 RBC units/month at the start of therapy vs 0.75 RBC units/month after 3 months of therapy (P = .099).

“The goal of this project was to [examine] the patients who have been treated so far at Moffitt Cancer Center with either pacritinib and/or momelotinib to gain a better understanding of the hematologic responses of these therapies, the duration of treatment, and other real-world data regarding these agents after they got their approvals,” Jeremy DiGennaro, MD, said during the presentation. “Patients receiving momelotinib and pacritinib are typically older with extended disease duration, multiple prior lines of therapy, high-risk mutations, and cytopenia. Pacritinib-treated patients have more prominent baseline thrombocytopenia. [However], there were favorable impacts on anemia and transfusion requirements [with both agents], although we still do need more long-term follow-up.”

DiGennaro is an internal medicine resident physician at the University of South Florida Morsani College of Medicine in Tampa.

In February 2022, the FDA granted accelerated approval to pacritinib for the treatment of adult patients with intermediate or high-risk primary or secondary myelofibrosis with a platelet count below 50,000/µL.2 Momelotinib was approved by the FDA in September 2023 for the treatment of adult patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis, and anemia.3

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Ten years of experience with ruxolitinib since approval for polycythemia vera: A review of clinical efficacy and safety

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Lucia Masarova MD1 | John Mascarenhas MD, MS2 | Raajit Rampal MD, PhD3 | Wilson Hu MD4 | Robert A. Livingston MD, MPH4 | Naveen Pemmaraju MD1

Abstract
The oral Janus kinase (JAK) 1/JAK2 inhibitor ruxolitinib was approved by the US Food and Drug Administration in 2014 for the treatment of patients with polycythemia vera (PV) who have an inadequate response to or intolerance of hydroxyurea (HU). PV is a chronic myeloproliferative neoplasm defined by primary absolute erythrocytosis, bone marrow hypercellularity, and JAK mutations such as JAK2V617F. Patients with PV experience burdensome symptoms and are at risk of thromboembolic events, in particular those with resistance to or intolerance of initial treatments such as HU. Other risks for patients with PV include progression of disease to more aggressive forms with worse prognoses, such as myelofibrosis or blast‐phase myeloproliferative neoplasms. This review summarizes the efficacy and safety of ruxolitinib from key phase 2 and 3 trials (MAJIC‐PV, RESPONSE, RESPONSE‐2, RELIEF, and Ruxo‐BEAT), large real‐world studies, and a decade of postmarketing surveillance safety data. The authors focus on improved blood count control, rates of thromboembolic events, symptom improvement, and markers of disease modification such as reduction of JAK2V617F allele burden in patients treated with ruxolitinib. They also discuss the well‐characterized safety profile of ruxolitinib regarding hematologic and other adverse events of interest. In the 10 years since its approval, ruxolitinib remains a safe and effective standard‐of‐care treatment for PV. As the treatment landscape for PV continues to evolve in the coming years, the efficacy and safety profiles of ruxolitinib suggest it will remain a
preferred treatment as monotherapy and as a potential backbone of future combination regimens.

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