Sustained clinical benefit and confirmed longer survival with ruxolitinib in patients with myelofibrosis: 5-year follow-up of COMFORT-II

Previous studies have demonstrated that ruxolitinib, a potent JAK1/JAK2 inhibitor, induces rapid and durable improvements in the splenomegaly of patients with myelofibrosis. Moreover, when compared to best available therapy (BAT), ruxolitinib has been shown to significantly prolong the survival of patients. During ASH 2015, the final 5-year follow-up data of the phase III COMFORT-II study were presented, demonstrating that the immediate benefits of ruxolitinib treatment, such as improvements in spleen size, were maintained with long-term therapy. In addition, the previously reported OS benefit was maintained, although results are confounded by extensive crossover from the BAT arm.

COMFORT-II was a randomized, open-label phase III study in which a total of 219 patients with intermediate-2, or high-risk primary myelofibrosis (MF), post-polycythemia vera MF, or post-essential thrombocythemia MF were randomized 2:1 to receive either ruxolitinib or BAT. Following progressive splenomegaly, patients in the BAT arm were allowed to cross-over to ruxolitinib. In total, 45 patients initially allocated to BAT crossed-over to ruxolitinib over the course of the study. At study completion, the median follow-up was 4.3 years. Overall 132 out of 136 (97.1%) evaluable patients treated with ruxolitinib experienced some degree of spleen reduction. In 78 patients (53.4%) the reduction in spleen volume from baseline was 35% or more at any time during the treatment. Of the 45 patients crossing-over from BAT to ruxolitinib, 34 (75.6%) experienced some degree of spleen reduction with a decrease of 35% or more in 19 patients (42.2%). At approximately 5-years follow-up, 88% of patients (45 out of 51) who remained on treatment had improvements from baseline in spleen volume (in 67% of patients more than 35% improvement). The median duration of maintenance of spleen volume reduction was 3.2 years. The Kaplan-Meier estimated probability of maintaining this reduction was 0.51 (95%CI: 0.38-0.62) at 3 years and 0.48 (95%CI: 0.35-0.60) at 5 years. Approximately one-third of evaluable JAK2 V617F-positive patients had more than 20% reduction in allele burden at 3.2 years (38.3%) and 3.7 years (31.0%). With ruxolitinib therapy, 23 patients (15.8%) had an improved fibrosis (including 4 patients who improved to grade 0 from baseline fibrosis grades of 1 [N=1], 2 [N=2], and 3 [N=1]). In 47 patients (32.2%) stabilization of the fibrosis was reported, while 27 patients (18.5%) had a worsening at their last assessment.

The median overall survival (OS) was not yet reached in the ruxolitinib arm at the time of the final analysis, while in the BAT arm the median OS was 4.1 years. This translates into a 33% reduction in risk of death with ruxolitinib compared to BAT (HR [95%CI]: 0.67 [0.44-1.02]; p = 0.06). The estimated probability of survival at 5 years was 56% with ruxolitinib and 44% with BAT.

With respect to safety, there was no relevant increase in the incidence of adverse events with longer exposure compared with previous reports. The most commonly reported adverse events in patients who received ruxolitinib at any time were thrombocytopenia (52.4%), anemia (49.2%), diarrhea (35.6%), and peripheral edema (33.0%). Grade 3/4 adverse events included anemia (22.5%), thrombocytopenia (15.2%), pneumonia (5.8%), general physical health deterioration (4.2%), and dyspnea (4.2%).

In summary, the immediate benefits of ruxolitinib treatment such as improvements in spleen size, were maintained with long-term therapy. The previously reported OS benefit was maintained, although results are confounded by extensive crossover from the BAT arm. Finally, the long term safety and tolerability was consistent with previous findings.

Reference

Harrison C, Vannucchi A, Kiladjian J-J, et al. Long-Term Efficacy and Safety in COMFORT-II, a Phase 3 Study Comparing Ruxolitinib with Best Available Therapy for the Treatment of Myelofibrosis: 5-Year Final Study Results. Presented at Ash 2015; Abstract #59.