Revised "iRR6" model in intermediate-1 risk myelofibrosis patients treated with ruxolitinib

Background: The response to ruxolitinib after 6 months (RR6) model allows early identification of ruxolitinib-treated myelofibrosis (MF) patients with poorer overall survival (OS); however, it is less applicable to lower-risk patients. Methods: To further explore this, the authors performed a subanalysis of the "RUX-MF" study (NCT06516406) with an aim to validate the RR6 and to develop a score specific for intermediate-1 DIPSS/MYSEC-PM risk patients. Results: Among the 776 evaluable patients, 34.4%, 47.8%, and 17.8% were at low, intermediate, and high RR6 risk, with 5-year OS of 64.1%, 51.8%, and 44.5%, respectively (p < .001). In the 428 intermediate-1 patients, the RR6 model did not discriminate between intermediate and low-risk patients (5-year OS: 74.4% vs. 72.0%, p = .24). The intermediate-1 specific RR6 (iRR6) model was therefore developed by incorporating new variables: underdosed ruxolitinib with respect to platelet count at one or more time points (hazard ratio [HR], 3.91; p < .001), absence of palpable spleen reduction by ≥50% at 6 months (HR, 1.45; p = .02), and red blood cell transfusion requirement at all time points (HR, 1.85; p = .01). The iRR6 model stratified patients into three risk categories: low (score 0, 20.3%), intermediate (score 1-2, 45.8%), and high-risk (score >2, 33.9%), with 5-year OS of 84.8%, 76.4%, and 56.6%, respectively (p < .0001). The iRR6 model was validated in a cohort of 95 intermediate-1 risk patients from the Moffitt Cancer Center, yielding stratification into the same three risk categories, with 5-year OS of 83.3% (low-risk), 71.7% (intermediate-risk), and 54.5% (high-risk) (p = .01). Conclusions: The iRR6 model provides a more refined tool for the identification of intermediate-1 MF patients who may benefit from early therapy shift.