Anna B. Halpern, MD, physician, assistant professor, Clinical Research Division, Fred Hutch, assistant professor, hematology, University of Washington School of Medicine, discusses ongoing efforts to address unmet needs in patients with primary myelofibrosis.

One prominent unmet medical need frequently observed in clinical practice is anemia, Halpern begins. Anemia, which is a condition characterized by a deficiency of red blood cells, can emerge as a result of specific diseases or as an adverse effect associated with treatments like JAK inhibitors, Halpern explains. For example, the kinase inhibitor ruxolitinib (Jakafi) disrupts erythropoietin signaling in the JAK-STAT pathway, which is crucial in the production of red blood cells, she adds.

The management of anemia stemming from both the disease itself and ruxolitinib treatment poses a substantial challenge, as effective treatment options in this space are difficult to develop, Halpern continues. This challenge is amplified by the fact that anemia is associated with a decline in the quality of life (QOL), Halpern says. Patients with myelofibrosis also contend with other factors that impact their QOL, such as inflammation and cytokine imbalances, Halpern adds. However, many of these features can be managed using JAK inhibitors, she notes.

Another significant unmet need in primary myelofibrosis is the management of high-risk disease, including the prevention of disease progression, Halpern states. Disease progression and worsening prognosis is typically signaled by an increase in anemia, circulating blasts, thrombo-hemorrhagic complications, and the presence of cytogenetic and molecular abnormalities outside of classical driver mutations. Notably, between 15-20% of patients will progress towards a leukemic transformation

This is a complex concern, Halpern says, as there is still uncertainty regarding the ability of current therapeutic strategies to alter disease trajectory. Accordingly, addressing these unmet needs is crucial for improving patient outcomes and enhancing their well-being in clinical practice, Halpern concludes.

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Anna B. Halpern, MD, discusses ongoing efforts to address unmet needs in patients with primary myelofibrosis.

Dr Halpern on Addressing Unmet Needs in Myelofibrosis

Anna B. Halpern, MD, physician, assistant professor, Clinical Research Division, Fred Hutch; assistant professor, hematology, University of Washington School of Medicine, discusses investigational efforts being developed to expand on the use of ruxolitinib and navitoclax in earlier treatment lines for patients with myelofibrosis.

In cohort 3 of the phase 2 REFINE trial (NCT03222609), the combination of ruxolitinib and navitoclax was evaluated in the upfront setting for patients (n=32) who had not been previously exposed to a JAK inhibitor. The study's primary end point was spleen volume reduction of 35% or greater from baseline at week 24.

An exploratory analysis of this cohort was presented at the 2022 ASH Annual Meeting and Exposition, Halpern begins. Findings showed that navitoclax plus ruxolitinib produced a spleen volume reduction of at least 35% at week 24 across specific patient subsets, she details. These subsets consisted of patients 75 years of age or older, those with a high Dynamic International Prognostic Scoring System score, and those with 

 mutations. The percentage of patients who experienced optimal spleen volume reduction in these subgroups are 50%, 33%, and 47%, respectively.

Notably, changes in bone marrow fibrosis and reductions in the variant allele frequency (VAF) of the driver gene mutation were seen with the combination regimen in many patients, Halpern continues. Half of patients achieved a greater than 20% reduction in VAF from baseline at week 12 or 24, while a greater than 50% VAF reduction from baseline occurred in 18% of patients. When comparing those with or without 

 mutations, no differences in greater than 20% VAF reduction from baseline to week 12 or 24 were observed between populations.

These results indicate the potential disease-modifying ability of ruxolitinib and navitoclax, suggesting that reductions in bone marrow fibrosis and VAF may serve as biomarkers for disease modification, Halpern states. Notably, long-term outcomes cannot be definitively assessed as correlates for leukemia, progression, and survival, she adds. The viability of these 2 biomarker candidates should be assessed more short term, and in larger study populations, Halpern concludes.

Anna B. Halpern, MD, discusses investigational efforts to utilize ruxolitinib and navitoclax in earlier treatment lines for patients with myelofibrosis.

Dr Halpern on the Investigation of Upfront Ruxolitinib and Navitoclax in Myelofibrosis

Anna B. Halpern, MD, physician, assistant professor, Clinical Research Division, Fred Hutch, assistant professor, hematology, University of Washington School of Medicine, discusses key efficacy data from the phase 1/2 MANIFEST trial (NCT02158858) investigating the BET inhibitor pelabresib (CPI-0610) plus ruxolitinib (Jakafi), and highlights the agents clinical significance in patients with myelofibrosis.

The global, open-label, nonrandomized, multicohort study evaluated the efficacy of the JAK inhibitor combination therapy vs pelabresib alone for treatment-naive or pretreated patient populations, Halpern begins. The trial involved 4 separate cohorts. These cohorts included the use of pelabresib in patients with JAK inhibitorpretreated myelofibrosis, pelabresib plus ruxolitinib in patients with ruxolitinib-pretreated myelofibrosis, pelabresib plus ruxolitinib in patients with JAK inhibitor–naïve myelofibrosis, and pelabresib alone in patients with essential thrombocythemia.

Halpern reports that results from the JAK inhibitor–naïve cohort showed that pelebresib plus ruxolitinib reduced spleen volume by at least 35% in 68% of patients, emphasizeing that total symptom score 

decreased by at least 50% in 56% of patients at 24 weeks. The data cutoff date for these findings was July 29, 2022.

Moreover, exploratory analysis revealed that 28% of patients had a grade 1 or greater improvement in fibrosis, while 29.5% experienced a greater than 25% reduction in 

 V617F VAF by week 24, Halpern details. These outcomes are of particular interest because they may indicate the disease-modifying ability of this combination, Halpern explains.

Based on these findings, the ongoing randomized, double-blind, phase 3 MANIFEST-2 trial (NCT04603495) is evaluating upfront pelabresib plus ruxolitinib vs ruxolitinib alone in a larger cohort of patients with JAK inhibitor–naïve myelofibrosis, Halpern concludes. Enrollment to this study was completed in May 2023, and topline findings are anticipated to report out in late 2023.

Anna B. Halpern, MD, discusses key efficacy data from the phase 1/2 MANIFEST trial (NCT02158858) investigating the BET inhibitor pelabresib plus ruxolitinib, and highlights the agents clinical significance in patients with myelofibrosis.

Dr Halpern on the MANIFEST Trial of Pelabresib and Ruxolitinib in Myelofibrosis

Anna B. Halpern, MD, physician, assistant professor, Clinical Research Division, Fred Hutch; assistant professor, hematology, University of Washington School of Medicine, discusses symptom control, transfusion independence, and spleen volume findings with the JAK and ACVR1 inhibitor momelotinib vs the JAK inhibitor ruxolitinib (Jakafi) and danazol in patients with myelofibrosis with anemia. 

The phase 3 SIMPLIFY-1 trial (NCT01969838) investigated the efficacy and safety of 24 weeks of treatment with momelotinib vs ruxolitinib in JAK inhibitor–naïve patients with myelofibrosis with anemia. In this trial, momelotinib improved anemia-related outcomes, including transfusion independence, Halpern says. Although symptom control was more effective with ruxolitinib than with momelotinib, the 2 agents generated similar spleen size control, Halpern explains. In total, 28.4% of patients in the momelotinib arm and 42.2% of those in the ruxolitinib arm achieved a 50% or greater total symptom score (TSS) reduction. At week 24, 26.5% and 29% of patients in the momelotinib and ruxolitinib arms, respectively, achieved at least a 35% reduction in spleen volume, showing that momelotinib was noninferior to ruxolitinib for spleen response (

The phase 3 MOMENTUM trial (NCT04173494) evaluated the efficacy and safety of momelotinib vs danazol in patients with symptomatic anemia and myelofibrosis who had previous JAK inhibitor exposure. At week 24, 24.6% of patients in the momelotinib arm achieved a 50% or greater TSS reduction compared with 9.2% of patients in the danazol arm (

 = .0095). Additionally, 23.1% of patients in the momelotinib arm achieved a 35% or greater reduction in spleen volume vs 3.1% of those in the danazol arm (

 = .0006). Furthermore, the transfusion independence rates were 30.8% and 20.0% with momelotinib and danazol, respectively (1-sided 

 = .0064). When compared with danazol in patients who have previously received JAK inhibitors, momelotinib has several efficacy and safety benefits, Halpern concludes. 

Anna B. Halpern, MD, discusses symptom control, transfusion independence, and spleen volume findings with the JAK and ACVR1 inhibitor momelotinib vs the JAK inhibitor ruxolitinib and danazol in patients with myelofibrosis with anemia. 

Anna B. Halpern, MD

Articles

Dr Halpern on Addressing Unmet Needs in Myelofibrosis

Dr Halpern on the Investigation of Upfront Ruxolitinib and Navitoclax in Myelofibrosis

Dr Halpern on the MANIFEST Trial of Pelabresib and Ruxolitinib in Myelofibrosis

Dr Halpern on Momelotinib in Myelofibrosis With Anemia