Efficacy, safety and survival with ruxolitinib in patients with myelofibrosis: results of a median 2-year follow-up of COMFORT-I

Abstract

COMFORT-I is a randomized, double-blind, placebo-controlled trial of the Janus kinase 1/Janus kinase 2 inhibitor ruxolitinib in 309 patients with intermediate-2 or high-risk myelofibrosis. This analysis of COMFORT-I describes the long-term efficacy and safety of ruxolitinib (median follow-up, 2 years). Spleen volume was measured by magnetic resonance imaging, and quality of life was evaluated using the EORTC QLQ-C30. Overall survival was determined according to randomized treatment group. At the time of this analysis, 100 of 155 patients randomized to ruxolitinib were still receiving treatment. All patients randomized to placebo crossed over to ruxolitinib or discontinued within 3 months of the primary analysis (median time to crossover, 41 weeks). Mean spleen volume reductions in the ruxolitinib group were 31.6% at week 24 and 34.9% at week 96; improvements in quality of life measures were also maintained. Improved survival was observed for ruxolitinib (n=27 deaths) versus placebo (n=41 deaths) (hazard ratio=0.58; 95% confidence interval: 0.36, 0.95; P=0.03). The incidence of new-onset grade 3 or 4 anemia and thrombocytopenia decreased over time to levels observed in patients receiving placebo. These data indicate that ruxolitinib treatment provides durable reductions in spleen volume and improvements in quality of life and suggest a continued survival advantage for ruxolitinib over placebo.

Figure 1.

Mean daily dose of ruxolitinib over time in all patients randomized to ruxolitinib and by initial ruxolitinib dose; bid: twice daily; BL; baseline.

Figure 2.

Durability of spleen volume reduction and individual percentage changes from baseline with ruxolitinib therapy. (A) Kaplan-Meier curve of durability of spleen volume reduction. In patients maintaining at least a 35% reduction in spleen volume (dark green line), duration of response was defined as the time from first 35% reduction to less than 35% reduction and 25% increase from nadir. Among patients achieving a 35% reduction in spleen volume, most patients maintained at least a 10% reduction from baseline (light green line), with duration defined as the time from first 35% reduction to less than 10% reduction from baseline. (B) Percentage change in spleen volume in individual patients from original baseline to last available spleen volume measurement in the ruxolitinib group (median follow-up, 24 months) and placebo group after crossover to ruxolitinib treatment (median follow-up after crossover, 14 months).

Figure 3.

Mean percentage changes from baseline in spleen volume at weeks 24 and 48 and mean percentage changes in Total Symptom Score by titrated dose. Titrated dose was defined as the average dose patients received in the last 12 weeks before the time of assessment; bid: twice daily.

Figure 4.

Overall survival by randomized treatment group (intent-to-treat population). CI: confidence interval; HR: hazard ratio.

Figure 5.

Incidence of new-onset grade 3 and 4 anemia and thrombocytopenia over time. The incidence of anemia and thrombocytopenia after 6 months was summarized only for patients originally randomized to receive ruxolitinib because all patients receiving placebo had either crossed over to ruxolitinib or discontinued from the study after the primary analysis. Incidence was calculated using the life table method based on the time to first worsening grade 3 or 4 event censored at the time of discontinuation or data cutoff (earlier of the two); the effective sample size was used as the denominator.

Figure 6.

Mean percentage change (± standard error of the mean) in (A) platelet counts and (B) hemoglobin levels from baseline over time. BL: baseline.