Introduction: The JAK inhibitor ruxolitinib is the first approved drug for the treatment of myelofibrosis (MF), with spleen volume and symptom reduction seen mostly within the first 6 months of treatment. Despite ruxolitinib's early efficacy, factors such as cytopenias, dose reduction, and loss of response lead to discontinuation in many patients, after which overall survival (OS) is poor. The Response to Ruxolitinib After 6 Months (RR6) prognostic model was developed from an analysis of 209 patients with MF in the RUXOREL-MF study (NCT03959371) to identify individuals who have an increased risk of death based on their response to ruxolitinib after 6 months of treatment (Maffioli M, et al. Blood Adv 2022). Although the RR6 model allows early identification of ruxolitinib-treated patients who have worse outcomes following discontinuation, the long-term outcomes in patients who transition to alternate therapies such as momelotinib have not been previously explored. SIMPLIFY-1 (NCT01969838), a phase 3 randomized trial in which JAK inhibitor–naivepatients with intermediate- or high-riskMF were assigned to receive 24 weeks of either momelotinib or ruxolitinib and after which all patients could receive open-label momelotinib, provides a unique opportunity to evaluate this question. This post hoc analysis applies the RR6 model criteria to estimate risk categories for ruxolitinib-randomized patients from SIMPLIFY-1 who crossed over to momelotinib and compares their OS outcomes with those of the previous RUXOREL-MF cohort.

Methods: The analyses were conducted using data from SIMPLIFY-1. Risk categories (low [score 0], intermediate [score 1 to 2], high [score 2.5 to 4]) were calculated according to the RR6 model based on ruxolitinib dose, spleen length reduction, and red blood cell transfusion need. Median OS from 6 months after ruxolitinib initiation for patients who crossed over to momelotinib and hazard ratios (HRs) between risk groups were estimated using Kaplan-Meier analysis and Cox regression, respectively. Descriptive analyses comparing baseline characteristics, risk categorization, and OS were conducted between the ruxolitinib-randomized patients from SIMPLIFY-1 who crossed over to momelotinib and the RUXOREL-MF cohort. Formal comparisons are ongoing.

Results: Among the 216 ruxolitinib-randomized patients in SIMPLIFY-1 (197 of whom crossed over to momelotinib) and 188 patients in RUXOREL-MF, median age was 66 and 67 years and 55% and 63% were male, respectively. In SIMPLIFY-1, according to the International Prognostic Scoring System, 21% had low- or intermediate-1–risk MF and 79% had intermediate-2– or high-risk MF. In RUXOREL-MF, according to the Dynamic International Prognostic Scoring System and the MF Secondary to PV and ET–Prognostic Model, 51% had low- or intermediate-1–risk MF and 45% had intermediate-2– or high-risk MF. In SIMPLIFY-1, 59% started ruxolitinib at the highest dose of 20 mg twice daily vs 37% in RUXOREL-MF.

After applying the RR6 model criteria, the proportion of patients in each risk group was comparable across studies, with 16% (34/216) and 19% (36/188) categorized as low risk, 40% (86/216) and 45% (85/188) categorized as intermediate risk, and 37% (80/216) and 36% (67/188) categorized as high risk in SIMPLIFY-1 and RUXOREL-MF, respectively, with 16 patients in SIMPLIFY-1 missing RR6 classification data. Median OS in SIMPLIFY-1 was longer across all RR6-defined risk categories vs RUXOREL-MF. Median OS was not reached (NR) for low-risk patients in both studies, NR (95% CI, 38.7-NR) vs 61 months (95% CI, 43-80) for intermediate-risk patients, and 43.2 months (95% CI, 31.1-NR) vs 33 months (95% CI, 21-50) for high-risk patients. Univariate analysis showed HRs of 2.37 (95% CI, 0.82-6.84) for intermediate vs low risk and 3.87 (95% CI, 1.37-10.96) for high vs low risk in SIMPLIFY-1, lower than the corresponding HRs in the RUXOREL-MF population, which were 4.27 (95% CI, 1.65-11.07) for intermediate vs low risk and 8.37 (95% CI, 3.19-21.95) for high vs low risk.

Conclusions: Among comparable ruxolitinib-treated cohorts with similar RR6 risk distributions, ruxolitinib-randomized patients in SIMPLIFY-1 who crossed over to momelotinib achieved better OS vs patients following ruxolitinib discontinuation in RUXOREL-MF, suggesting that momelotinib may mitigate risk following ruxolitinib discontinuation and confer a potential survival benefit even in patients with a higher risk of impaired survival.

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2025
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