December 10, 2023
By Richard Simoneaux
Myelofibrosis is a somewhat rare hematologic malignancy that can lead to scarring of the patient’s bone marrow. It impacts patients with low blood counts, enlarged spleen, and symptoms. This scarring can hinder hematopoiesis, resulting in anemia. Prior to 2011, there were no approved therapies for this condition.
On November 16, 2011, the FDA approved ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor for the treatment of intermediate to high-risk myelofibrosis. Since then, there have been three additional JAK inhibitors approved for myelofibrosis. The most recent approval came on September 15, 2023, for momelotinib, which was approved by the FDA for the treatment of “intermediate or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis, and anemia.” This approval was based on the findings of two Phase III clinical trials: SIMPLIFY-1 (NCT01969838) and MOMENTUM (NCT04173494).
At the 2023 American Society of Hematology (ASH) Annual Meeting, Ruben Mesa, MD, President and Executive Director of the Atrium Health Levine Cancer Institute and Atrium Health Wake Forest Baptist Comprehensive Cancer Center, presented a research revealing longitudinal transfusion intensity data for these two trials (Abstract 3182).
“This post-hoc analysis of the SIMPLIFY-1 and MOMENTUM trials evaluated two different aspects of anemia: 1) treatment-emergent anemia, if the anemia worsened during the trial [and] a safety issue [developed], and 2) reduction of transfusion burden, which could be considered a measure of efficacy.”
In the Phase III SIMPLIFY-1 trial, patients with myelofibrosis who were JAK-inhibitor naïve were randomized in a 1:1 ratio to either momelotinib (200 mg QD orally) or ruxolitinib (20 mg BID orally). After the randomized phase, patients could receive open-label momelotinib. The results obtained showed that it was non-inferior to ruxolitinib during the 24-week randomized phase of the study. “Additionally, there was an association of momelotinib with reduced need for transfusion relative to the use of ruxolitinib,” Mesa observed.
The Phase III MOMENTUM trial compared the use of momelotinib and the androgen anti-anemia therapy danazol in patients with myelofibrosis who had previously received JAK inhibitor therapy and experienced relapse or disease that was resistant, recurrent, or recalcitrant to that therapy.
“The MOMENTUM trial examined the splenomegaly and anemia response of myelofibrosis to momelotinib in the second-line or greater setting,” Mesa noted.
In that study, patients were randomized in a 2:1 ratio to either momelotinib (200 mg QD orally) or danazol (300 mg BID orally). As in SIMPLIFY-1, there was a randomization phase followed by an open-label phase where patients could receive momelotinib. Trial results showed superiority for momelotinib over danazol for splenic (splenomegaly) and symptomatic responses, as well as the necessity for transfusions. The poster presented at the 2023 ASH Annual Meeting by Mesa provided additional analysis of the transfusion data for the Phase III trials evaluating momelotinib in JAK inhibitor-naïve and treated patients with myelofibrosis.
“It was important to track the anemia longitudinally to determine the effect that momelotinib had…to see if the patients experienced treatment-emergent worsening of their anemia from baseline or if there was a decrease in the transfusion burden,” Mesa explained.
Analysis of the data from the SIMPLIFY-1 revealed that treatment with momelotinib had an association with improved maintenance of both red blood cell transfusion status and red blood cell transfusion intensity relative to ruxolitinib. While momelotinib therapy was associated with reduced mean red blood cell transfusion burden, in contrast, treatment with ruxolitinib had an association with increased mean red blood cell transfusion burden. Interestingly, maintained or improved transfusion burden relative to baseline was observed in a majority of patients crossing over to momelotinib from ruxolitinib in the open-label portion of SIMPLIFY-1. Consequently, this led the investigators to conclude that transfusion burden increases were either prevented or delayed in momelotinib-treated patients relative to those receiving ruxolitinib.
Results in the MOMENTUM trial showed that red blood cell transfusion burden was diminished from baseline to a greater extent than treatment with danazol, a standard treatment for anemia. “This study showed that momelotinib was associated with both decreased splenomegaly and transfusion burden relative to the standard anemia therapy danazol,” Mesa stated.
When asked about the current status for these trials, Mesa replied, “Both trials have concluded and constitute mature datasets. Going forward, patients will continue to be tracked for any potential safety issues, as well as survival data.”
In terms of efficacy, approximately 85 percent of the momelotinib-treated patients in these two trials had either maintained or improved transfusion burden intensity relative to their baseline levels, providing evidence for anemia benefit.
“The main point to take away from this presentation is that this analysis quantified the anemia benefit associated with the use of momelotinib in these patients with anemia and myelofibrosis,” Mesa concluded.
Richard Simoneaux is a contributing writer.