Clinical Outcomes of Myelofibrosis Patients Following Immediate Transition to Momelotinib from Ruxolitinib

Introduction: Approved JAK inhibitors (JAKi; ruxolitinib [RUX], fedratinib, and pacritinib) provide symptom and spleen benefit in myelofibrosis (MF), but can worsen cytopenias and provoke transfusion dependence. Anemia and transfusion dependence are critical negative prognostic indicators of overall survival (OS) in MF. Momelotinib (MMB) is a potent and selective small-molecule inhibitor of ACVR1, JAK1, and JAK2, resulting in symptomatic and splenic benefits and a restoration of iron homeostasis and erythropoiesis, facilitating anemia benefits including transfusion independence (TI). TI response with MMB has been associated with improved OS (Mesa et al, 2022). A majority of patients are at risk for poor OS after discontinuing RUX (Palandri et al, 2020). Also, prognostic negative risk factors of spleen length, RUX dose reduction, and RBC transfusion requirement predict poor OS following 6 months of RUX treatment (Maffioli et al, 2022). Phase 3 studies of MMB have provided extensive experience with MMB administered immediately post-RUX, without RUX tapering or washout. Here, we describe a retrospective analysis of data focusing upon the timing and clinical experience of directly transitioning patients from RUX to MMB.

Methods: In the Phase 3 SIMPLIFY-1 study (S1), JAKi-naïve patients with MF (n=432) were randomized 1:1 to MMB or RUX. In SIMPLIFY-2 (S2), MF patients previously treated with RUX (n=156) were randomized 2:1 to MMB or best available therapy (BAT). For S2, taper and washout of active MF therapy was prohibited prior to randomization. RUX was included as BAT and 88.5% of S2 control arm received RUX. In both S1 and S2, following the 24-week (6 month) randomized treatment (RT) period, patients could continue MMB (MMB→MMB) and those randomized to RUX or BAT crossed over to open-label (OL) MMB (RUX/BAT→MMB) immediately without the need for tapering or washout.

Results: In S1, 197 patients transitioned from RUX→MMB at week 25, all of whom initiated MMB at the 200 mg daily dose with highly comparable dose intensity between MMB→MMB (171 patients) and RUX→MMB; 81% of the active patients were receiving 200 mg daily 12 weeks following crossover. Of note, over the 4 weeks prior to crossover, 71/197 (36%) patients were receiving an average RUX dose of ≤10 mg BID. At the first assessment following crossover to MMB, there was rapid improvement in mean Hgb (≈1 g/dL), and mean spleen volume was maintained (≈1700 cm³) post-crossover for both MMB→MMB and RUX→MMB patients (Figure 1). Furthermore, of the 92 RUX patients who were not TI responders at Week 24 (W24), 46% became TI responders 12 weeks after RUX→MMB. Of the 71 patients who received a mean of ≤10 mg BID RUX over the 4 weeks prior to crossover, only 10% achieved a spleen response (≥35% volume reduction from baseline) prior to W24 crossover. Post RUX→MMB, 23% achieved or maintained spleen response at Week 48.

Safety observations in S1 during the immediate 2‑week period following RUX→MMB revealed excellent tolerability; new onset Grade 3/4 anemia and thrombocytopenia were experienced by only 3% and 2% of patients respectively and there were no cases of RUX discontinuation syndrome. More broadly, all AE terms of any grade experienced within 2 weeks of RUX→MMB transition occurred at ≤7%. Weight gain associated with RUX was ~4-fold higher than that observed with MMB and did not further increase after cross-over.

Similar to S1, in S2 the crossover at W24 from BAT (mainly RUX) to MMB was associated with a rapid improvement in mean Hgb and stable or improved spleen volume.

MFSAF total symptom scores (TSS) were not collected during OL MMB treatment in S1 or S2; however, S2 provided TSS data on 79 of the 102 patients randomized to MMB who received RUX until the day immediately prior to initiation of MMB. W24 TSS improved by ≥50% from pre-study baseline in 26% of MMB patients, including in 22% of those who were on RUX therapy pre-study, immediately prior to starting MMB.

Conclusion: MMB is a promising new therapy for MF, and data provide confidence in an immediate transition to MMB from RUX without washout or tapering, which is likely to rapidly improve anemia without compromising safety or control of symptoms and spleen. In addition, no withdrawal effects were noted following transition from RUX→MMB. Patients may be better served by timely transition to therapy able to improve anemia while maintaining or improving splenic and symptom responses.