Retromomelo: Real-world use of momelotinib – the french experience from the FIM group

Abstract

Abstract Context: Momelotinib is a novel therapy for myelofibrosis that inhibits JAK1, JAK2, and the activin A receptor type 1 (ACVR1), a regulator of iron metabolism via hepcidin. This dual mechanism contributes to benefits in symptom control, spleen size reduction, hemoglobin increase, and reduced transfusion dependence in both JAK-inhibitor–naïve and previously treated patients. Despite recent regulatory approval, real-world evidence on momelotinib remains limited. The French Intergroup on Myeloproliferative Neoplasms (FIM) therefore initiated the RETROMOMELO study to evaluate the effectiveness and safety of momelotinib in routine clinical practice. Methods: This retrospective multicenter study included patients with myelofibrosis treated with momelotinib (compassionate use) between February 2023 and May 2025 at 12 French centers. Baseline demographics, disease characteristics, prior therapies, transfusion status, treatment duration, clinical and hematological responses, and adverse events were collected. The management of prior JAK inhibitor therapy and transition strategies to momelotinib were also assessed. Categorical variables were summarized as counts and percentages and analysed using Chi-square test. Paired binary variables were analyzed using McNemar's chi-squared test with continuity correction. Continuous variables were expressed as median and interquartile range (IQR), and compared using Student's t-test. Results: The study included 37 patients with myelofibrosis (MF), of whom 57% were male, with a median age of 78 years-old (IQR [interquartile range] 73–82). Diagnoses were primary MF (62%), post essential thrombocythemia MF (24%), and post polycythemia vera MF (14%). Molecular profiling revealed JAK2 V617F mutation in 76% of cases, CALR type 1 mutation in 15% of cases, and MPL mutation in 9.1%. Momelotinib was used as second-line therapy in 47% of cases and as third-line in 33%. A majority of patients (84%) had received prior ruxolitinib therapy, and 54% were transfusion dependent at baseline. DIPSS+ scores showed intermediate-2 risk in 52% of patients and high risk in 42% of patients. Prior JAK inhibitor therapy was stopped abruptly in 83% of cases, with treatment overlap in only 11%, and corticosteroids were not used as bridging therapy. Following treatment initiation, patients experienced a median spleen size reduction of 3.3 cm (IQR 0–4.3; p = 0.0002). Hemoglobin levels increased by a median of 20 g/L (IQR 7–34; p < 0.001). The proportion of patients reporting fatigue decreased from 72% before treatment to 53% after momelotinib, although this difference did not reach statistical significance (p = 0.07). Similarly, a trend toward reduction was observed for other reported symptoms (sweats, early satiety, pruritus, abdominal discomfort, bone pain), but without statistically significant differences. Momelotinib was discontinued in 83% of patients after a median treatment duration of 7.7 months (IQR 4.1–13.6). Among the 19 patients who discontinued momelotinib, reasons included intolerance (n=7), disease relapse or refractory disease (n=7), death (n=3), hematopoietic stem cell transplantation (n=2), and transformation to acute myeloid leukemia (n=1). The most frequent non-hematologic adverse events were gastrointestinal, including diarrhea (n = 10), abdominal pain (n = 10), and nausea (n = 6). Dizziness was reported in 13 patients. The only grade 3 adverse events were diarrhea (n = 2) and abdominal pain (n = 1). Conclusion: In this real-world cohort of patients with myelofibrosis, momelotinib demonstrated meaningful clinical benefit in reducing spleen size and improving anemia, even in heavily pretreated patients. Treatment discontinuation was frequent but primarily due to disease progression or intolerance rather than unexpected safety concerns. Gastrointestinal adverse events were mostly low grade; however, their persistence may have contributed to momelotinib discontinuation in a non-negligible number of cases, highlighting the importance of early symptomatic management at treatment initiation. These findings support the use of momelotinib as an effective therapeutic option in routine practice for advanced MF.