Momelotinib May Be ‘No. 1 Choice’ for Second-Line Myelofibrosis, Anemia

Momelotinib, an inhibitor of ACVR1 and JAK1/JAK2, resulted in better total symptom scores (TSS), improved anemia measures, and better spleen responses than danazol (Danocrine) in patients with myelofibrosis and intermediate- or high-risk anemia previously treated with JAK inhibitors, according to data from the phase 3 MOMENTUM study (NCT04173494) published in Lancet.

"A combination of quality-of-life improvement, anemia response, and transfusion independence is the key to my excitement about momelotinib [for myelofibrosis.] [It] will probably become a number-one choice in the second-line setting," according to an expert from the University of Texas MD Anderson Cancer Center.

Roughly one quarter (n = 32/130) of patients treated with momelotinib reported a 50% or greater reduction in TSS compared with 9% (n = 6/65) of those treated with danazol (P = .0095). At week 24, 40% of patients treated with momelotinib had a 25% or greater reduction in spleen volume vs 6% of patients in the danazol group (P < .0001). Moreover, reductions of 35% or more occurred in 23% vs 3% (P = .0006), respectively.

Additionally, anemia affected patients treated with danazol at a higher rate (75%) than those treated with momelotinib (61%).

At week 24, transfusion independence occurred in 31% (95% CI, 23%-39%) of patients in the momelotinib group vs 20% (95% CI, 11%-32%) of those in the danazol group (one-sided P = .0064). Transfusion independence rates from baseline increased by 18% vs 5% in the momelotinib and danazol groups, respectively.

“The anemia benefit is what excites me the most as a clinician taking care of patients [with] myelofibrosis,” lead author Srdan Verstovsek, MD, PhD, said in an interview with CancerNetwork.

“[They] can maintain transfusion independence or…become transfusion independent. It’s a big deal not having blood transfusions. A combination of quality-of-life improvement, anemia response, and transfusion independence is the key to my excitement about momelotinib. [It] will probably become a number-one choice in the second-line setting.”

Verstovsek is a hematologist-oncologist, professor of medicine, director of the Hanns A. Pielenz Clinical Research Center for Myeloproliferative Neoplasms, and chief of the section for myeloproliferative neoplasms in the department of leukemia at the University of Texas MD Anderson Cancer Center.

The international, double-blind, randomized, controlled MOMENTUM trial examined 195 patients at 107 sites across 21 countries between April 24, 2020, and December 3, 2021. The most common diagnosis was primary myelofibrosis (64%). Additionally, most patients had intermediate-2 risk disease (57%) and presented with a JAK2 mutation (76%). The mean duration of prior JAK inhibitor therapy was 2.6 years for the overall population.

The median age in the enrolled population was 71 years (interquartile range [IQR], 66-76) at baseline. Most patients were men (63%) and White (81%).

Patients were randomly assigned 2:1 to either the experimental (n = 130) or control (n = 65) group. Those in the experimental group received oral momelotinib at 200 mg daily plus danazol placebo during the 24-week treatment period, and those in the control group received danazol at 300 mg daily plus momelotinib placebo for the same duration.

Dose reductions of both drugs occurred in a stepwise manner. Momelotinib was reduced in 50 mg increments and danazol was reduced by 200 mg in the first step and then in 100 mg increments, thereafter. The lowest permitted doses of momelotinib and danazol were 50 mg and 200 mg, respectively.

The most common any-grade non-hematological treatment-emergent adverse effects (TEAEs) were diarrhea (22%), nausea (16%), and asthenia (13%) among those treated with momelotinib. The most common TEAEs following treatment with danazol were increased blood creatinine (15%), dyspnea (14%), and peripheral edema (14%). The most frequent non-hematological AEs of grade 3 or higher in the momelotinib and danazol groups were acute kidney injury (3% vs 9%) and pneumonia (2% vs 9%).

“For myelofibrosis, we’re good at counteracting the symptoms and the splenomegaly, and now we can counteract the anemia to a degree, but there’s room for more,” Verstovsek concluded. “There are several other drugs, many [with different] mechanisms of action, that may become very useful in combination with the JAK inhibitors. We may even start thinking about doublets or triplets in the future to make myelofibrosis as chronic as clinically possible.”

Reference

Verstovsek S, Gerds AT, Vannucchi AM, et al; MOMENTUM Study Investigators. Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM): results from an international, double-blind, randomised, controlled, phase 3 study. Lancet. 2023;401(10373):269-280. doi:10.1016/S0140-6736(22)02036-0