Background: Momelotinib, a JAK1/JAK2/ACVR1 inhibitor, is approved for treating myelofibrosis with splenomegaly, symptoms, and moderate-to-severe anemia. Evidence on its real-world effectiveness after ruxolitinib failure is limited.
Methods: This study retrospectively analyzed 221 patients who received momelotinib after ruxolitinib failure by assessing spleen, symptom, and anemia responses, safety, and survival. Logistic regression analyses identified the responses' predictors.
Results: Before momelotinib initiation, all patients had received ruxolitinib for a median of 31.5 months and discontinued as a result of resistance (29.9%), intolerance (48.0%), or both (22.1%). At baseline, all patients started at full dose; 97.3% presented with cytopenia, 34.8% presented with large splenomegaly, and 43.9% were highly symptomatic. Most patients (74.7%) switched from ruxolitinib stop to momelotinib within 2 months without tapering, whereas 18.1% waited over a year. After a median exposure of 8.2 months, adverse events occurred in 35.7% of patients, which prompted dose reductions or permanent discontinuation in 12.7% and 19.9% of cases, respectively. At 6 months, 30.0% achieved ≥50% spleen length reduction (SR50), with higher responses in those with prior SR50 to ruxolitinib and shorter transition intervals. Symptom and anemia responses occurred in 39.2% and 63.4% of cases, respectively. After a median follow-up of 10.3 months, 11 patients (5.0%) progressed to blast phase, and 37 patients (16.7%) died. Two-year overall and progression-free survival (including death and blast phase transformation) were 60.9% and 59.0%, respectively.
Conclusions: Momelotinib demonstrated meaningful clinical benefit and acceptable safety in cytopenic patients pretreated with ruxolitinib, which supports its role after ruxolitinib failure.
Keywords: anemia; cytopenia; momelotinib; myelofibrosis; thrombocytopenia.
© 2026 The Author(s). Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.