Impact of hemoglobin improvement with momelotinib on survival in patients with myelofibrosis and anemia: Post hoc analyses of the simplify-1 and momentum trials

Abstract

Abstract Introduction: Anemia is associated with poor quality of life and shorter survival in patients with myelofibrosis (MF), as recognized by inclusion of hemoglobin (Hb) <10 g/dL as a negative prognostic factor in all major MF risk assessment tools. Recent analyses of the JAK1/JAK2/ACVR1 inhibitor momelotinib, approved for the treatment of patients with MF who have anemia, have also illustrated the positive overall survival (OS) impact of achieving Hb ≥10 g/dL. In a post hoc analysis of momelotinib-randomized patients in the phase 3 SIMPLIFY-1 and MOMENTUM trials (Palandri F, et al. EHA 2025. Poster PF828), 63% in SIMPLIFY-1 and 36% in MOMENTUM with baseline Hb <10 g/dL achieved Hb ≥10 g/dL by week 24 with momelotinib. OS was longer in patients who achieved this threshold by week 24 than those who did not (SIMPLIFY-1: hazard ratio [HR], 0.54; 95% CI, 0.27-1.06; MOMENTUM: HR, 0.28; 95% CI, 0.09-0.82). This previous analysis assessed achievement of Hb ≥10 g/dL at any time by week 24, which may have included early, transient changes in Hb levels that were not stable through week 24. The present post hoc analyses were conducted using a narrower definition restricting achievement of Hb ≥10 g/dL to week 24± a 2-week window, to further evaluate the OS impact of achieving Hb ≥10 g/dL at week 24 with momelotinib. Methods: SIMPLIFY-1 (NCT01969838; JAK inhibitor–naive patients) and MOMENTUM (NCT04173494; JAK inhibitor–experienced patients) were phase 3, randomized, double-blind trials of momelotinib vs ruxolitinib or danazol, respectively. This post hoc analysis included patients with baseline Hb <10 g/dL in the momelotinib arms of each trial; subgroups with baseline moderate (Hb ≥8 to <10 g/dL) or severe (Hb <8 g/dL) anemia were also defined. As all patients in both trials received open-label momelotinib after week 24, evaluation of long-term outcomes in the comparator arms was precluded. In SIMPLIFY-1, Hb assessments were completed at baseline and every 2 weeks through week 24; in MOMENTUM, Hb assessments were completed at baseline, weeks 2 and 4, and then every 4 weeks through week 24. Achievement of Hb ≥10 g/dL at week 24 ± 2 weeks was determined post hoc using the highest Hb measurement in this window, excluding those within 4 weeks post transfusion. OS from momelotinib treatment initiation was assessed by Kaplan-Meier analysis and Cox models to estimate HRs in patients who achieved vs did not achieve Hb ≥10 g/dL at week 24. Results: Of momelotinib-randomized patients in SIMPLIFY-1 and MOMENTUM, 86 and 126, respectively, had baseline Hb <10 g/dL and were evaluable in this analysis. In SIMPLIFY-1, a total of 23 patients (27%) achieved Hb ≥10 g/dL at week 24; this included 18 of 58 patients (31%) with moderate anemia and 5 of 28 (18%) with severe anemia. In MOMENTUM, a total of 24 patients (19%) achieved Hb ≥10 g/dL at week 24; this included 19 of 64 (30%) with moderate anemia and 5 of 62 (8%) with severe anemia. In both SIMPLIFY-1 (HR, 0.39; 95% CI, 0.16-0.94) and MOMENTUM (HR, 0.14; 95% CI, 0.02-1.05), achieving Hb ≥10 g/dL at week 24 was associated with longer OS. In SIMPLIFY-1, median OS was numerically longer in patients who did vs did not achieve Hb ≥10 g/dL at week 24 (not reached [NR; 95% CI, 37.7-NR] vs 39.9 months [95% CI, 29.3-NR]); median OS was NR both in patients who did or did not achieve this threshold at week 24 in MOMENTUM. Conclusions: These post hoc analyses confirm and expand on previous evidence that, in patients with moderate to severe anemia regardless of JAK inhibitor exposure, achieving Hb ≥10 g/dL at week 24 with momelotinib is associated with longer survival. Early intervention with momelotinib to achieve Hb improvements may support optimal outcomes, as evidenced by the results in JAK inhibitor–naive and moderately anemic patients compared with JAK inhibitor–experienced or severely anemic patients. Overall, achieving Hb ≥10 g/dL at week 24 per the definition applied here (at week 24 ± 2 weeks) may provide stronger predictive information than the previously applied “any time by week 24” definition, further reinforcing the achievement of Hb ≥10 g/dL as a positive factor for OS in MF.