JAK Inhibitor Improves Symptoms, Anemia in Myelofibrosis

Myelofibrosis treatment with the Janus kinase (JAK) inhibitor momelotinib resulted in clinically significant improvements in symptoms and spleen response compared with danazol for symptomatic, JAK inhibitor-exposed patients with anemia and intermediate- or high-risk disease, the phase III MOMENTUM trial showed.

A significantly greater proportion of patients in the momelotinib group reported a ≥50% reduction in the Myelofibrosis Symptom Assessment Form total symptom score — the trial’s primary endpoint — versus those in the danazol group (25% vs 9%, P=0.0095), reported Srdan Verstovsek, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, and colleagues.

In addition, more patients treated with momelotinib compared with danazol experienced a significant reduction in their spleen size at 24 weeks, on the basis of both a ≥25% reduction (40% vs 6%, respectively, P<0.0001) and a ≥35% reduction (23% vs 3%, P=0.0006). Furthermore, 35% of momelotinib patients versus 17% of danazol patients had a rate of zero transfusions to week 24 (P=0.0012), they noted in The Lancet.

Transfusion independence at week 24 was met by 31% of patients in the momelotinib group compared with 20% in the danazol group, for a non-inferiority difference of 15% (95% CI 3-26, P=0.0064).

“The clinical benefit seen with momelotinib in patients with myelofibrosis and anemia, including the reduction of transfusion burden for patients, underscores the potential for momelotinib as a treatment option for this population with high medical need,” Verstovsek and colleagues wrote.

The most frequent ≥grade 3 treatment-emergent adverse event observed in the momelotinib and danazol groups was anemia, which was more frequent in the danazol group, with 75% of patients experiencing this event versus 61% in the momelotinib group. Rates of ≥grade 3 thrombocytopenia were similar between groups.

The most frequent non-hematological ≥grade 3 treatment-emergent adverse events with momelotinib and danazol were acute kidney injury (3% vs 9%, respectively) and pneumonia (2% vs 9%).

“There are several insights into mechanisms of myelofibrosis-related anemia besides disrupted iron metabolism with ACVR1 or hepcidin, including bone marrow failure, splenomegaly, and disrupted erythroid differentiation,” noted Kazuhiko Ikeda, MD, PhD, and Koki Ueda, MD, PhD, both of the Fukushima Medical University School of Medicine in Japan, in a commentary accompanying the study. “However, MOMENTUM showed significant efficacy against anemia as well as constitutional symptoms and splenomegaly by targeting both JAK and ACVR1, rather than other causes.”

In explaining the rationale behind the study, Verstovsek and team noted that while JAK inhibitors approved for myelofibrosis can improve symptoms and reduce spleen size, they have not been shown to meaningfully improve anemia and may even worsen it. Here, they wanted to assess momelotinib, a first-in-class inhibitor of activin A receptor type 1, as well as JAK1 and JAK2, against the standard therapy danazol.

The study enrolled 195 adults (median age 71-72, 63% men, 81% white) from 107 research sites across 21 countries. Participants were randomly assigned 2:1 to momelotinib plus placebo or danazol plus placebo; 72% of those given momelotinib and 58% given danazol completed 24 weeks of treatment, which was followed by an open-label phase that allowed crossover.

Verstovsek and colleagues conducted a secondary endpoint analysis of overall survival (OS) over the entire study period, observing a hazard ratio of 0.73 (95% CI 0.38-1.41, P=0.35) favoring momelotinib versus danazol. They also saw a non-significant survival advantage for momelotinib relative to danazol during the randomized treatment period only, which included data up to week 24 (HR 0.51, 95% CI 0.24-1.08, P=0.072).

Ikeda and Ueda suggested that the trial’s crossover design “limits comparison of long-term survival,” and a long-term analysis is needed.

They also noted that the study contains a risk of potential bias. For example, more danazol patients than momelotinib patients discontinued the study early and were considered to be non-responders. “Therefore, a greater proportion of patients with [spleen volume reduction] were presumably available for analysis at week 24 in the momelotinib group than in the danazol group.”