Tag Archives: mf

Momelotinib May Improve Survival and Quality of Life in MF

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August 30, 2024

Leonardo Jaimes

Momelotinib appears to positively impact quality of life and overall survival in patients with myelofibrosis (MF), according to a recently published study in Frontiers in Oncology.

Most MF cases are associated with JAK or CALR mutations, which lead to an uncontrolled proliferation of stem cells and a decrease in the production of red blood cells (RBCs) and thrombocytes, the researchers noted.

Stem cell transplantation is currently the only curative alternative available for patients with MF. The advent of JAK inhibitors represented a significant advancement in symptom management, but patients often observed decreased efficacy after 3 years.

Anemia is largely responsible for the decrease in quality of life seen in patients with MF and represents an important cause of treatment discontinuation, as some of the treatments used in MF can contribute to the development of anemia.

“Anemia in MF is a complex condition resulting from factors such as displacement of erythropoietic tissue by fibrotic stroma, suboptimal environments in extramedullary sites, and splenomegaly-induced RBC sequestration,” the authors wrote.

Momelotinib is an effective JAK1/2 inhibitor that can successfully treat anemia in patients with MF, decreasing the need for transfusions. It can also prevent hepcidin synthesis, which in turn leads to increased iron circulation and increased erythropoiesis.

The effectiveness of momelotinib is supported by the results of the MOMENTUM trial; the double-blind included almost 200 patients who received either momelotinib or danazol to treat MF-associated anemia.  Results showed that patients who received were significantly less likely to require blood transfusions and have better Total Symptom Score than their counterparts.

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A randomized, double-blind, placebo-controlled phase 3 study to assess efficacy and safety of ropeginterferon alfa-2b in patients with early/lower-risk primary myelofibrosis

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Ghaith Abu-Zeinah, Albert Qin, Harinder Gill, Norio Komatsu, John Mascarenhas, Weichung Joe Shih, Oleh Zagrijtschuk, Toshiaki Sato, Kazuya Shimoda, Richard T. Silver & Ruben Mesa

Abstract

Primary myelofibrosis (PMF) is the most aggressive of the myeloproliferative neoplasms and patients require greater attention and likely require earlier therapeutic intervention. Currently approved treatment options are limited in their selective suppression of clonal proliferation resulting from driver- and coexisting gene mutations. Janus kinase inhibitors are approved for symptomatic patients with higher-risk PMF. Additionally, most ongoing clinical studies focus on patients with higher-risk disease and/or high rates of transfusion dependency. Optimal treatment of early/lower-risk PMF remains to be identified and needs randomized clinical trial evaluations. Pegylated interferon alfa is recommended for symptomatic lower-risk PMF patients based on phase 2 non-randomized studies and expert opinion. Ropeginterferon alfa-2b (ropeg) is a new-generation pegylated interferon-based therapy with favorable pharmacokinetics and safety profiles, requiring less frequent injections than prior formulations. This randomized, double-blind, placebo-controlled phase 3 trial will assess its efficacy and safety in patients with “early/lower-risk PMF”, defined as pre-fibrotic PMF or PMF at low or intermediate-1 risk according to Dynamic International Prognostic Scoring System-plus. Co-primary endpoints include clinically relevant complete hematologic response and symptom endpoint. Secondary endpoints include progression- or event-free survival, molecular response in driver or relevant coexisting gene mutations, bone marrow response, and safety. Disease progression and events are defined based on the International Working Group criteria and well-published reports. 150 eligible patients will be randomized in a 2:1 ratio to receive either ropeg or placebo. Blinded sample size re-estimation is designed. Ropeg will be administered subcutaneously with a tolerable, higher starting-dose regimen. The study will provide important data for the treatment of early/lower-risk PMF for which an anti-clonal, disease-modifying agent is highly needed.

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Triple-Negative Myelofibrosis Associated With Decreased Survival, Aggressive Clinical Behavior and Shorter Duration of Response to Ruxolitinib

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August 14, 2024

Amber Denham

According to recently published research in Clinical Lymphoma, Myeloma & Leukemia, triple-negative myelofibrosis (TN-MF) was found to be continually associated with decreased survival, enhanced aggressive clinical behavior with higher rates of leukemic transformation, and a shorter duration of response to ruxolitinib.

“Myelofibrosis is the most aggressive subtype among classical BCR::ABL1 negative myeloproliferative neoplasms…Triple-negative myelofibrosis accounts for only 5% [to] 10% of cases and carries the worst outcomes,” explained lead study author Luis Aguirre, MD, Dana-Farber Cancer Institute, Harvard Medical School, Cambridge, Massachusetts, and colleagues. They added, “Little has been described about this subset of disease…identification of features of interest and assessment of treatment response are areas in need of further investigation.”

Researchers evaluated baseline clinical and molecular parameters from 626 patients with myelofibrosis who presented to the H. Lee Moffitt Cancer Center in Tampa, Florida, between 2003 and 2021. These data were compared based on the presence or absence of the 3 classical phenotypic driver mutations.

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Cardiovascular Risk in Philadelphia-Negative Myeloproliferative Neoplasms: Mechanisms and Implications—A Narrative Review

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by Samuel Bogdan Todor, Cristian Ichim, Adrian Boicean, and Romeo Gabriel Mihaila

Abstract

Myeloproliferative neoplasms (MPNs), encompassing disorders like polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are characterized by clonal hematopoiesis without the Philadelphia chromosome. The JAK2 V617F mutation is prevalent in PV, ET, and PMF, while mutations in MPL and CALR also play significant roles. These conditions predispose patients to thrombotic events, with PMF exhibiting the lowest survival among MPNs. Chronic inflammation, driven by cytokine release from aberrant leukocytes and platelets, amplifies cardiovascular risk through various mechanisms, including atherosclerosis and vascular remodeling. Additionally, MPN-related complications like pulmonary hypertension and cardiac fibrosis contribute to cardiovascular morbidity and mortality. This review consolidates recent research on MPNs’ cardiovascular implications, emphasizing thrombotic risk, chronic inflammation, and vascular stiffness. Understanding these associations is crucial for developing targeted therapies and improving outcomes in MPN patients.

Donor Type Impacts Survival in MF Cell Transplantation

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Leonardo Jaimes

Patients with myelofibrosis (MF) who receive hematopoietic cell transplantation (HCT) from a matched sibling donor appear to have better overall survival (OS) than those who receive transplants from other donor types, according to a recently published study in Blood Advances.

“Understanding the impact of donor type is crucial not only to improve the clinical outcomes with HCT but also to establish the donor pool with viable options and eventually improve access to HCT,” the authors wrote.

HCT is currently the only disease-modifying therapy available for MF, the study team noted. The outcome after transplantation is diverse and dependent on several disease- and patient-associated factors, they added. According to recent research, donor type could also influence the prognosis of patients with MF after HCT. One study showed that patients with matched sibling donors had a better OS than the rest.

However, previous research has not taken the impact of posttransplantation cyclophosphamide for graft versus host disease prophylaxis into consideration, the researchers noted. Furthermore, no patients in previous studies had received vHLA-haploidentical donor grafts, they continued.

Therefore, the authors aimed to assess the impact of donor type in OS, considering the factors above and using the Center for International Blood and Bone Marrow Transplant Research registry data for HCTs done between 2013 and 2019. The study included over 1000 patients who received HCTs for MF.

Results showed that similarly to previous findings, matched sibling transplants were associated with better overall survival and lower graft failure than the rest. However, OS was only superior to the rest in the first 90 days after transplant. There was no significant difference in OS among patients who received mismatched unrelated, matched unrelated, and haploidentical donor transplants.

Despite the findings, the authors remarked that HCTs should not be delayed in the search for fully matched donors and highlighted the need for solutions regarding graft failure.

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Prospective Study to Evaluate Fedratinib Plus Nivolumab in Myelofibrosis

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Andrea S. Blevins Primeau, PhD, MBA

A single-arm, phase 2 study of fedratinib, a selective JAK2 inhibitor, plus nivolumab is planned for patients with myelofibrosis (MF) who had a suboptimal or no response to a JAK inhibitor was initiated, according to a report published in the Annals of Hematology.

“This study will provide new findings that may contribute to advancing the treatment landscape for MF patients with suboptimal responses and limited alternatives,” the researchers wrote in their report. Currently, 23 of 30 planned patients are enrolled in the study and recruitment is expected to be completed by December 2024.

The open-label FRACTION trial will treat patients with MF from 9 academic centers in Germany, who will receive 400 mg of fedratinib daily in 28-day cycles, followed by 240 mg of nivolumab every 2 weeks beginning in cycle 2. Treatment will be given until progressive disease, relapse, death, or study discontinuation.

This study will provide new findings that may contribute to advancing the treatment landscape for MF patients with suboptimal responses and limited alternatives.

The primary efficacy endpoints will be response rate within 12 treatment cycles and RCT independency. Secondary endpoints will include safety, incidence of leukemic transformation, clinical benefit, duration of response, progression-free survival, overall survival, and disease burden. Molecular analyses will also serve as exploratory endpoints for the study.

Patients with MF primary or secondary MF are eligible if they had a suboptimal or no response to a JAK inhibitor, which is defined by persistent symptoms, splenomegaly, cytopenia, or hyperproliferation. Patients who have received a prior immune checkpoint inhibitor or history of uncontrolled autoimmune disease are not eligible for the study.

Disclosures: This research was supported in part by Celgene/Bristol Myers Squibb. Please see the original reference for a full list of disclosures.

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Dr Watts on the Investigation of INCB057643 in Advanced Myelofibrosis and MPN

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July 24, 2024

Author(s): Justin M. Watts, MD

Justin M. Watts, MD, associate professor of medicine, Division of Hematology, chief, Leukemia Section, University of Miami Sylvester Comprehensive Cancer Center, discusses the design of a phase 1 trial (NCT04279847) investigating INCB057643 in patients with advanced myelofibrosis and other myeloid neoplasms, and highlights how this agent could address unmet needs in patients with relapsed/refractory myeloproliferative neoplasms (MPNs).

INCB057643 is an oral small molecule BET inhibitor that most selectively targets BRD-4, he begins. The agent is being evaluated in a phase 1 dose-escalation and -expansion study of patients with advanced myelofibrosis, including those with relapsed/refractory myelofibrosis and patients who are suboptimal responders to ruxolitinib (Jakafi), Watts details. Patients in the former group received the BET inhibitor as a monotherapy; those in the latter cohort received the agent as an add-on therapy, he explains.

Findings from the study were reported at the 2024 ASCO Annual Meeting, and demonstrated that INCB057643 when used as a monotherapy (n = 28) or in combination with ruxolitinib (n = 16), was generally well tolerated at doses ranging from 4 mg to 10 mg.

The maximum tolerated dose of the agent was established at 10 mg per day, Watts continues. INCB057643 monotherapy is currently being evaluated in a dose-expansion phase, with the combination regimen being assessed in the dose escalation phase at 8 mg, he reports. Watts notes that 8 mg is likely to be the optimal dose of INCB057643 when administered alongside ruxolitinib. During the dose expansion phases, different dosing of the BET inhibitor is permitted based on a patient’s platelet count, Watts says. This cohort includes both patients with myelofibrosis and those with essential thrombocythemia who have progressed on standard therapy, he states.

Initially, the dose escalation phase of the trial included a cohort of patients with myelodysplastic syndromes (MDS) and MDS/MPN overlap syndrome, Watts expands. However, the study’s focus has since shifted exclusively to patients with advanced myelofibrosis due to the significant unmet needs present in this patient population, Watts says. Many patients with advanced myelofibrosis have progressed on multiple lines of therapy or are completely intolerant or refractory to JAK inhibition, he explains. Accordingly, enhancing their response to therapy, reducing toxicities, decreasing spleen size beyond what can be achieved with ruxolitinib alone, and concurrently addressing anemia could benefit these patients, Watts concludes.

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Pelabresib/Ruxolitinib Data Underscore Need for Novel End Points in Myelofibrosis Trials

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July 15, 2024

Author(s): Jax DiEugenio

Although a 35% reduction in spleen volume (SVR35) and a 50% reduction in total symptom score (TSS50) have been established as key end points in clinical trials evaluating therapies for the treatment of patients with myelofibrosis, integrating end points such as overall survival (OS) and progression-free survival (PFS) as key objectives in future studies could help guide drug development and measure any disease-modifying properties of treatments, according to Aaron Gerds, MD.

“[Findings] from [the phase 3] MANIFEST-2 [NCT04603495] and TRANSFORM-1 [NCT04472598] trials are a wakeup call for the field that we need to move beyond SVR35 and TSS50 [as clinical trial end points in myelofibrosis]. We have drugs that are good at making patients’ symptoms better; however, we need are drugs that truly modify the disease course in a meaningful way,” Gerds explained.

Updated data from the MANIFEST-2 presented at the 2024 ASCO Annual Meeting showed that patients with myelofibrosis who received frontline pelabresib (CPI-0610) plus ruxolitinib (Jakafi; n = 214) experienced an SVR35 rate of 65.9% at week 24 compared with 35.2% for those given ruxolitinib plus placebo (n = 216). Notably, updated data showed that in patients who experienced an SVR35 at any time, 13.4% of patients in the experimental arm lost that response vs 27.8% of patients in the placebo arm.1

Additionally, the TSS50 rates at week 24 were 52.3% for pelabresib plus ruxolitinib vs 46.3% for placebo plus ruxolitinib, translating to a numerical improvement that was not statistically significant (difference, 6.0%; 95% CI, –3.5% to 15.5%; nominal P = .216).

Notably, 40.2% of patients in the pelabresib arm experienced both SVR35 and TSS50 at week 24 compared with 18.5% of patients in the placebo arm.

In an interview with OncLive®, Gerds an assistant professor of medicine, Hematology, and Medical Oncology at Cleveland Clinic Taussig Cancer Institute in Ohio, detailed prior data from MANIFEST-2 presented at the 2023 ASH Annual Meeting;2 expanded on updated data presented at the 2024 ASCO Annual Meeting; and emphasized the need to look beyond current end points in clinical trials evaluating treatments for patients with myelofibrosis.

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Dr Klisovic on the Early Use of JAK Inhibitors in Younger Patients With Low-Risk Myelofibrosis

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July 15, 2024

Author(s): Rebecca Klisovic, MD

Rebecca Klisovic, MD, chief medical information officer, University Hospitals Seidman Cancer Center, discusses a case study featuring a patient with newly diagnosed myelofibrosis and reviews the optimal JAK inhibitor–based treatment regimen for this patient, as determined by a panel of oncologists at an OncLive® State of the Science Summit™ on hematologic malignancies.

This case study featured a 40-year-old male patient with newly diagnosed myelofibrosis, Klisovic begins. She notes that the discussion about this patient was interesting discussion because the patient was young with low-risk disease. The panel’s conversation centered around the early use of the JAK inhibitor ruxolitinib (Jakafi) to potentially improve this patient’s overall survival outcome, Klisovic details.

Ruxolitinib has demonstrated superiority over placebo and best available therapy in the phase 3 COMFORT-I (NCT00952289) and COMFORT-II studies (NCT00934544). However, it was noted in the conversation that this patient would not have qualified for enrollment in the COMFORT studies due to his low-risk disease status, Klisovic explains. This led to a debate about the appropriateness of initiating treatment earlier rather than later, even in patients who may not otherwise require immediate therapy, according to Klisovic.

Another key question raised was whether ruxolitinib is truly disease-modifying, particularly in a younger patient, Klisovic says. This is a crucial consideration because the long-term benefits of a therapy and its potential for altering the disease course are significant factors in deciding early intervention, she expands.

Additionally, there was a strong recommendation to monitor this patient closely for transplant potential given his age, Klisovic continues. Although this patient’s molecular profile was not presented, discussants highlighted molecular stratification as an important factor for guiding treatment decision-making in similar cases, she states. Klisovic adds that the identification of higher-risk mutations could alter the treatment trajectory and influence whether early intervention or watchful waiting is more appropriate.

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Mascarenhas on the SENTRY Trial Design and Goals

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J

By John Mascarenhas, MD

John Mascarenhas, MD, professor, medicine, Icahn School of Medicine, Mount Sinai, director, Center of Excellence for Blood Cancers and Myeloid Disorders, member, The Tisch Cancer Institute, Mount Sinai, discusses the methods, design, and inclusion criteria of the phase 3 SENTRY trial (NCT04562389) for patients with JAK inhibitor treatment-naive myelofibrosis.

SENTRY is a global, multicenter, phase 1/3 study where investigators are assessing the efficacy and safety of selinexor (Xpovio) combined with ruxolitinib (Jakafi) in this patient population.

According to Mascarenhas, the primary end points of phase 3 of the trial include the proportion of patients with spleen volume reduction of greater than or equal to 35% at week 24 (SVR35), and the proportion of patients with a total symptom score reduction of greater than or equal to 50% at week 24 (TSS50), as measured by the myelofibrosis symptom assessment form V4.0.

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