Pacritinib Demonstrates Superior Efficacy to Low-Dose Ruxolitinib in Myelofibrosis Patients with Thrombocytopenia

Ruxolitinib (RUX), a JAK1/2 inhibitor, is an approved first-line therapy for patients with myelofibrosis (MF) who have thrombocytopenia; however, the RUX starting dose in patients with platelet counts of 50-100 × 10⁹/L is often reduced and there is no guidance for RUX dosing in patients with platelet counts <50 × 10⁹/L. Pacritinib, a JAK2/interleukin-1 receptor─associated kinase inhibitor, is currently under investigation as a treatment option for patients with thrombocytopenic MF. In the phase 3 PERSIST-2 clinical trial, pacritinib was studied without dose reduction in thrombocytopenic patients (≤100 × 10⁹/L). The data indicated pacritinib was more effective compared with best available therapy as measured by spleen volume reduction (SVR) and modified total symptom score (mTSS) response. A large proportion of patients in the best-available-therapy cohort received RUX. However, the safety and efficacy of pacritinib compared with RUX have not been specifically evaluated.

The current retrospective analysis directly compares the tolerability and clinical effectiveness of pacritinib and RUX as first-line therapies in thrombocytopenic patients who are RUX-naïve. Patients were randomized 1:1:1 to pacritinib (200 mg twice daily or 400 mg once day) or RUX. The pacritinib data analyses exclude the 400-mg dose since it is no longer in development. Most patients treated with pacritinib (200 mg twice daily) maintained full doses throughout the 24-week duration of the trial. Dosing was selected according to prescribing information for patients who received RUX. Patients treated with RUX received a median starting dose of 10 mg daily (interquartile range [IQR], 10-10) at baseline, 10 mg daily at week 12 (IQR, 0-10), and 10 mg daily at week 24 (IQR, 0-20).

Safety was evaluated in all patients treated with 200 mg pacritinib (n = 57) and RUX (n = 12). Nearly all patients on pacritinib (93%) and all RUX-treated patients (100%) experienced adverse events (AEs). The most frequent AE was grade 1 to 2 diarrhea, which occurred more frequently in the pacritinib group (47%) compared with the RUX group (8%). Infection of any grade occurred more frequently on pacritinib (47%) compared with RUX (33%), while grade ≥3 infections were less common (11% vs 17%, respectively). Fatal AEs were more common in patients on RUX (25%) versus 7% in pacritinib. Incidence of cytopenias (thrombocytopenia and anemia), hemorrhagic events at all grades, and cardiac events occurred at similar rates between the pacritinib and RUX cohorts.

Efficacy was determined by the percentage of patients treated with pacritinib (n = 43) and RUX (n = 9) who achieved ≥35% SVR or a ≥50% mTSS response based on the intention-to-treat population randomized at least 22 weeks prior to the study end. In the pacritinib group, higher rates of SVR (28%) and mTSS response (37%) were observed compared with rates in the RUX group (SVR = 11% and mTSS = 11%). The hazard ratio for overall survival for pacritinib compared with RUX was 0.49 (95% confidence interval, 0.13-1.92). Treatment effects observed for SVR, mTSS, and survival persisted after adjusting for baseline age, Dynamic International Prognostic Scoring System risk score, platelet count, and primary or secondary MF.

Observations from the PERSIST-2 trial suggest that 200 mg pacritinib twice daily is as safe as but potentially more effective than RUX as first-line therapy in MF patients with thrombocytopenia. Thus, pacritinib may emerge a beneficial and valid therapeutic option in the MF treatment landscape.

Source: Mascarenhas J, Bose P, Kiladjian J-J, et al. A retrospective head-to-head comparison between pacritinib and ruxolitinib in patients with myelofibrosis and moderate to severe thrombocytopenia. American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021. Abstract 3639.