Real World Efficacy and Safety of Momelotinib for Myelofibrosis: Evaluation of a UK-Wide Study Confirms 40% Anaemia Response Rate in a Non-Clinical Trial Cohort
Authors: Rampotas Alexandros , Torre Elena , Carter-Brzezinski Luke , Duminuco Andrea , Cadman-Davies Llywelyn , Chee Ashlyn , Panitsas Fotios , Alimam Samah , Milojkovic Dragana , Kaczmarski Richard , Fraser Louise , Frewin Rebecca , Foley Kate , Hockings Catherine , Khan Alesia , Williams Rhys , Ryan Jennifer , Yip Kawai , Thaw Kyaw Htin , Sheikh Amna , Wadelin Frances , Godfrey Anna L , Teh Chun Huat , Wilson Andrew J. , Lambert Jonathan , Mead Adam J , McLornan Donal P , Innes Andrew J , McGregor Andrew , Somervaille Tim , Harrison Claire , Harrington Patrick , Psaila Bethan 
Published: December 2024

Introduction
Momelotinib (GS-0387) is a small-molecule inhibitor targeting Janus kinase 1 and 2 (JAK1/2) and activin receptor-like kinase 2 (ALK2), developed for myelofibrosis (MF). It inhibits JAK1/2-mediated cytokine signalling and ACVR1-mediated hepcidin production, addressing both myeloproliferative and anemia components of MF. In the UK, Momelotinib was available via a compassionate-access programme from 2023 and approved January 2024 for MF patients with moderate or severe anemia. This study investigates momelotinib's real-world efficacy and safety across the UK.
Methods
Data were collected retrospectively from 16 UK centers. All patients who received momelotinib for MF outside of a clinical trial setting were included. Data on MPN characteristics, transfusion requirements, total symptom scores (TSS), blood tests, and spleen measurements were collected at baseline, 6 weeks, and 3 months post-treatment initiation via clinical examination, US or CT measurement. Anemia and clinical responses were evaluated per ELN response criteria for MF.
Results
The study included 85 patients with MF (62% male, 38% female), median age 72.1 years (IQR: 65.8-76.3 years). Diagnoses were primary MF (52.9%), post-polycythemia vera MF (15.3%), and post-essential thrombocythemia MF (30.6%). Molecular profiling revealed JAK2 V617F (64.7%), CALR (18.8%), MPL (12.9%), and “triple-negative” (5.9%). Most patients (77.6%) had previously received a JAK inhibitor (JAKi), while 22.4% were JAKi naive. Secondary mutations included ASXL1 (30.6%), DNMT3A (10.6%), and TET2 (10.6%). DIPSS+/DIPSS scores were available in 76/85 patients with most being Intermediate-2 or high (77.6%).
Efficacy outcomes in 21 patients who had paired measurements showed that 43% achieved a reduction in spleen size as per ELN response criteria. TSS where paired data were available in 21 patients, improved significantly in 24% of patients, defined as ≥50% symptom score reduction at 3 months. Anemia responses, defined as a ≥20 g/L increase in haemoglobin (Hb) or becoming transfusion independent, were available in 79/85 patients. 36.7% and 43.8% of cases achieved an anaemia response at 6 weeks and 3 months, respectively. Haemoglobin concentration increased significantly at 6 weeks (p&lt;10-4) and 3 months (p&lt;10-4) compared to baseline (matched-pairs Wilcoxon signed-rank test) with a mean increase of 10.8 and 9.2 g/L respectively.
The safety profile was consistent with clinical trial data. 75% of patients continued treatment without significant adverse events after a median follow up of 7.6 months. Discontinuation was due to toxicity (12%), refractory/progressive disease (6%), and HSCT (2.4%). Median overall survival (OS) (censored at HSCT) was not reached (NR), with a 12-month survival rate of 82.5% (95% CI: 67.2%-91.1%). Median event-free survival (EFS) was NR (95% CI: 15.6 months-NE), 6-month EFS 82% (95% CI 70.8-89.2%) (events defined as first occurrence of: permanent discontinuation due to toxicity, disease refractoriness/progression, blast-phase evolution, or death). Grade 3 side effects were reported in 9/85 patients, including thrombocytopenia, fatigue, raised ALT, hyperkalemia, vision loss (cause under investigation), dermatosis, and chest infection. Eleven patients died, 10/11 from AML or progressive disease, and one from a subdural hematoma in the presence of severe thrombocytopenia.
Conclusion
Momelotinib demonstrated significant efficacy in reducing spleen volume, improving anemia, and alleviating symptoms in a substantial proportion of MF patients, including as both a 1st or 2nd line JAKi, with a reasonable safety profile. These real-world results support its use as a viable treatment option for myelofibrosis in routine clinical practice.