Francesca Palandri, Monia Marchetti, Elena M. Elli, Alessandro Isidori, Ilaria Gianesello, Chiara Sartor, Novella Pugliese, Maria Di Perna, Erika Morsia, Susanna Gallo, Federico Itri, Vittorio Montefusco, Elena Crisà, Annalisa Biagi, Eloise Beggiato, Olga Mulas, Giulia Benevolo, Elisabetta Abruzzese, Marco Santoro, Alessandra Iurlo, Elisabetta Calistri, Marco Rossi, Bruno Martino, Mario Tiribelli, Carmen Fava, Arbana Dizdari, Monica Crugnola, Andrea Duminuco, Amedeo Votto, Selene Guerzoni, Giovanni Caocci, F Pane, Francesco Lanza, Filippo Branzanti, Alessandra Dedola, Flavia Salvatore, F Heidel, Massimo Breccia, Giuseppe A. Palumbo, Andrew T. Kuykendall, Alessandro Lucchesi, Sara Galimberti
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.