Real-World Outcomes of Momelotinib As an Alternative Therapy to Other JAK Inhibitors in Myelofibrosis Patients with Anemia

Momelotinib (MMB) is a first-in-class inhibitor of activin A receptor type 1, JAK1, and JAK2. Unlike previous JAK inhibitors (iJAK), which can exacerbate anemia, MMB has demonstrated significant improvements in anemia while also addressing disease-related symptoms and splenomegaly in myelofibrosis (MF) patients (pts) in clinical trials. Given its recent approval, real-world data on MMB use remain limited.

We conducted a multicenter, observational, retrospective study involving MF pts with splenomegaly or symptoms and anemia, who received MMB through a managed-access program provided by GSK in Spain from March 2023 to July 2024. This study included both JAK inhibitor-naive pts and those who had received prior iJAK.

A total of 154 pts from 74 centers were included, with a median age at MMB start of 72 years (range 42-87). Driver mutations genotypes were JAK2 63%, CALR 23%, MPL 6%, and triple negative 6.5% (1,5% unavailable). Data on additional somatic mutations by NGS was available in 90 cases, showing pathogenic/probably pathogenic mutations in 62 pts (68,8%). High molecular risk (HMR) mutations were found in ASXL1 (37 pts), U2AF1 (12), SRSF2 (9), EZH2 (9), and IDH 1/2 (4). DIPSS-plus score was intermediate-2 (42%), high risk (42%).

Seventy-seven percent of pts had previously received erythropoietin stimulating agents and 11% danazol. Of the 154 pts, 26 received MMB as first-line (1L) therapy. The remaining 128 had a median of 1.2 prior lines (range 1-6), with 91% having received ruxolitinib, 3% fedratinib, 21% hydroxyurea, 8.6% corticosteroids, and 4% thalidomide/lenalidomide. At MMB start, 93.5% had symptoms, and 83% had splenomegaly. Baseline median hemoglobin (Hb) was 8.0 g/dL (range 4.7-13.5), and the median platelet count was 160,000/μL(range 3,000-1,812,000).At baseline, 100/154 pts (64,9%) were transfusion-dependent (TD), requiring a median of 3 red blood cell units (RBC) per month (range: 2-8).

With a median follow-up of 5.0 months (range: 0.1-14), 79% of the pts reported an improvement in symptoms: 75% in pruritus, 76% asthenia, 65% anorexia, 45% weight loss, 75% sweating and 47% abdominal discomfort. Splenomegaly could be evaluated in 14/26 pts treated in 1L and 58/128 in 2L, with 57% showing any degree of spleen reduction in 1L and 50% in 2L. Among patients evaluable for spleen response by 2013 IWG-MRT and ELN criteria (palpable splenomegaly >5cm below the left costal margin (LCM)), 3/9 of 1L patients and 7/32 in 2L met the criteria for spleen response.

In terms of anemia improvement, 133 pts with a follow-up period exceeding one month were evaluated. Median Hb level increased from 8.0 to 8.9 g/dL (range 5-17.2) at last follow up, and 52% of TD pts achieved transfusion independence (TI). This percentage remained consistent across follow-ups at 3 months (n=96, 57% achieving TI), 6 months (n=52, 60%),9 months (n=22, 54%), and 12 months (n=13, 44%). For those maintaining TD, the median number of RBC units required showed a decreasing trend (mean 4.6 vs 4 RBC units, p=0.1). Anemia improved similarly in 1L and 2L patients, with median Hb increases of 0.7 and 0.9 g/dL, and TI rates of 50% and 52%, respectively.

Regarding safety, the most common adverse events (AEs) were diarrhea (11.7%), thrombocytopenia (10%), infections (9%), nausea (6.2%), hepatotoxicity (5.5%), dizziness (6.2%), peripheral neuropathy (4.8%, grade (g.) 1-2 in all cases) and hypotension (2%). Twenty-six pts needed dose reductions, and 10 temporary treatment discontinuations, primarily due to infections or cytopenias. The most frequently reported g. 3-4 AEs were thrombocytopenia (6.2%), infections (2.8%) and hepatotoxicity (2.6%).

At last follow-up, 122/154 pts (79%) continued treatment. Discontinuations were due to hematopoietic stem cell transplantation (3 pts), lack of efficacy (5 pts), progression/transformation (7 pts), toxicity (6 pts; 2 infections, 1 interstitial nephritis, 1 renal failure, 1 hypotension, and 1 diarrhea), and deaths (11 pts, including 5 infections, 3 severe hemorrhages, 2 due to disease progression, 1 cardiorespiratory arrest of unknown cause).

Conclusion: Real-life treatment with MMB confirms its marked effect in improving anemia in MF patients, with high rates of patients achieving TI in both iJAK-exposed and iJAK naïve patients. Additionally, MMB has proven effective in reducing symptoms and controlling splenomegaly in pts previously exposed to ruxolitinib, with an acceptable toxicity profile.