A Prognostic Model to Predict Ruxolitinib Discontinuation and Death in Patients with Myelofibrosis

SIMPLE SUMMARY: Despite significant clinical activity, 50% to 70% of patients discontinue ruxolitinib within 3 to 5 years. The identification of patients who are more likely to discontinue it early has now become of paramount practical importance, given the availability of new drugs that are either approved (i.e., fedratinib, pacritinib, and momelotinib) or undergoing advanced clinical investigation for patients with a suboptimal response or ruxolitinib resistance (i.e., navitoclax, pelabresib, and imetelstat). A retrospective, real-world analysis was performed on 889 MF patients treated with ruxolitinib from the observational “RUX-MF” Italian study. We investigated predictors of early ruxolitinib discontinuation and death on therapy in 889 MF patients. Results confirm that prolonged ruxolitinib administration is associated with improved OS when compared to earlier discontinuation. While this outcome may be expected at the 5-year timepoint, interestingly, the survival advantage was observed also categorizing patients at earlier timepoints. ABSTRACT: Most patients with myelofibrosis (MF) discontinue ruxolitinib (JAK1/JAK2 inhibitor) in the first 5 years of therapy due to therapy failure. As the therapeutic possibilities of MF are expanding, it is critical to identify patients predisposed to early ruxolitinib monotherapy failure and worse outcomes. We investigated predictors of early ruxolitinib discontinuation and death on therapy in 889 patients included in the “RUX-MF” retrospective study. Overall, 172 patients were alive on ruxolitinib after ≥5 years (long-term ruxolitinib, LTR), 115 patients were alive but off ruxolitinib after ≥5 yrs (short-term RUX, STR), and 123 patients died while on ruxolitinib after <5 yrs (early death on ruxolitinib, EDR). The cumulative incidence of the blast phase was similar in LTR and STR patients (p = 0.08). Overall survival (OS) was significantly longer in LTR pts (p = 0.002). In multivariate analysis, PLT < 100 × 10(9)/L, Hb < 10 g/dL, primary MF, absence of spleen response at 3 months and ruxolitinib starting dose <10 mg BID were associated with higher probability of STR. Assigning one point to each significant variable, a prognostic model for STR (STR-PM) was built, and three groups were identified: low (score 0–1), intermediate (score 2), and high risk (score ≥ 3). The STR-PM may identify patients at higher risk of failure with ruxolitinib monotherapy who should be considered for alternative frontline strategies.