A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 randomized phase III trials of ruxolitinib for the treatment of myelofibrosis

Abstract

Ruxolitinib, a potent Janus kinase 1/2 inhibitor, resulted in rapid and durable improvements in splenomegaly and disease-related symptoms in the 2 phase III COMFORT studies. In addition, ruxolitinib was associated with prolonged survival compared with placebo (COMFORT-I) and best available therapy (COMFORT-II). We present a pooled analysis of overall survival in the COMFORT studies using an intent-to-treat analysis and an analysis correcting for crossover in the control arms. Overall, 301 patients received ruxolitinib (COMFORT-I, n=155; COMFORT-II, n=146) and 227 patients received placebo (n=154) or best available therapy (n=73). After a median three years of follow up, intent-to-treat analysis showed that patients who received ruxolitinib had prolonged survival compared with patients who received placebo or best available therapy [hazard ratio=0.65; 95% confidence interval (95%CI): 0.46-0.90; P=0.01]; the crossover-corrected hazard ratio was 0.29 (95%CI: 0.13-0.63). Both patients with intermediate-2- or high-risk disease showed prolonged survival, and patients with high-risk disease in the ruxolitinib group had survival similar to that of patients with intermediate-2-risk disease in the control group. The Kaplan-Meier estimate of overall survival at week 144 was 78% in the ruxolitinib arm, 61% in the intent-to-treat control arm, and 31% in the crossover-adjusted control arm. While larger spleen size at baseline was prognostic for shortened survival, reductions in spleen size with ruxolitinib treatment correlated with longer survival. These findings are consistent with previous reports and support that ruxolitinib offers a survival benefit for patients with myelofibrosis compared with conventional therapies. (clinicaltrials.gov identifiers: COMFORT-I, NCT00952289; COMFORT-II, NCT00934544).

Figure 1.

Kaplan-Meier analysis of overall survival by (A) intent to treat,^a (B) International Prognostic Scoring System risk status,^b and (C) correcting for crossover from the control arms (rank-preserving structural failure time analysis).^{c a}HR: 0.65; 95%CI: 0.46–0.90; P=0.01. ^bHR: 0.47; 95%CI: 0.33–0.67; P<0.0001. ^cHR: 0.29; 95%CI: 0.13–0.63; P=0.01.

Figure 2.

Overall survival by base-line covariates.^a Patients were required to have platelet counts (PLT) ≥ 100×10⁹/L at baseline. ^bAdjusted for prognostic base-line characteristics and controlled for treatment. Hazard ratio (HR) > 1 indicates an increased risk of death. Higher Hb level, secondary MF subtype, female sex, and higher platelet count were associated with better prognosis while higher base-line WBC, age, and spleen volume were associated with worse prognosis independently of treatment. For the following continuous covariates the risk of death was incrementally lower on each unit increase (Hb, platelet count) or incrementally higher (WBC, age, and spleen volume). Hb: hemoglobin; MF: myelofibrosis; PET: post–essential thrombocythemia; PPV: post–polycythemia vera; WBC: white blood cell count.

Figure 3.

Correlation of (A) spleen volume reduction and (B) spleen length reduction at week 24 with overall survival (landmark analysis at 24 weeks^a). ^aIncludes patients known to be alive at week 24. ^bCategory includes patients with a <10% reduction from baseline in spleen volume at week 24 or no assessment (ruxolitinib, n=64; control, n=189); among these patients, there were 26 deaths (events) in the pooled ruxolitinib group and 63 deaths in the control group. ^cCategory includes patients with no change or an increase from baseline in palpable spleen length at week 24 or no assessment (ruxolitinib, n=23; control, n=95); among these patients, there were 8 deaths (events) in the pooled ruxolitinib group and 28 deaths in the control group. HR: hazard ratio.