Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial

Abstract

Background: The randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial evaluated the JAK1/JAK2 inhibitor ruxolitinib in patients with intermediate-2/high-risk myelofibrosis. The primary and planned 3-year analyses of COMFORT-I data demonstrated that ruxolitinib-the first myelofibrosis-approved therapy-reduced splenomegaly and prolonged overall survival versus placebo. Here, we present the final 5-year results.

Methods: Patients managed in Australia, Canada, and the USA were randomized centrally (interactive voice response system) 1:1 to oral ruxolitinib twice daily (15 or 20 mg per baseline platelet counts) or placebo. Investigators and patients were blinded to treatment. The secondary endpoints evaluated in this analysis were durability of a ≥35% reduction from baseline in spleen volume (spleen response) and overall survival, evaluated in the intent-to-treat population. Safety was evaluated in patients who received study treatment.

Results: Patients were randomized (September 2009-April 2010) to ruxolitinib (n = 155) or placebo (n = 154). At termination, 27.7% of ruxolitinib-randomized patients and 25.2% (28/111) who crossed over from placebo were on treatment; no patients remained on placebo. Patients randomized to ruxolitinib had a median spleen response duration of 168.3 weeks and prolonged median overall survival versus placebo (ruxolitinib group, not reached; placebo group, 200 weeks; HR, 0.69; 95% CI, 0.50-0.96; P = 0.025) despite the crossover to ruxolitinib. The ruxolitinib safety profile remained consistent with previous analyses. The most common new-onset all-grade nonhematologic adverse events starting <12 versus ≥48 months after ruxolitinib initiation were fatigue (29.0 vs 33.3%) and diarrhea (27.8 vs 14.6%). New-onset grade 3 or 4 anemia and thrombocytopenia both primarily occurred within the first 6 months, with no cases after 42 months. The most common treatment-emergent adverse event-related deaths in the ruxolitinib-randomized group were sepsis (2.6%), disease progression (1.9%), and pneumonia (1.9%).

Conclusion: The final COMFORT-I results continue to support ruxolitinib as an effective treatment for patients with intermediate-2/high-risk MF.

Trial registration: ClinicalTrials.gov, NCT00952289.

Keywords: JAK; Janus kinase; Myelofibrosis.

Figures

Fig. 1

Patient disposition. *Three patients in the placebo group were not evaluable for safety (n = 151); these patients were excluded from the calculation of the percentage of patients who discontinued. (dagger) Limited to patients whose study discontinuation dates matched their dates of death. (double dagger) Including but not limited to the following: received a different therapy, transitioned to commercial ruxolitinib, and loss of response

Fig. 2

Duration of ≥35% reduction from baseline in spleen volume. Duration of spleen response was evaluated for the 92 patients in the ruxolitinib group who achieved a ≥35% reduction from baseline in spleen volume. NE, not evaluable

Fig. 3

Median percentage change from baseline in spleen volume over time. *For patients in the ruxolitinib crossover group, baseline represents the date of crossover to ruxolitinib. BL, baseline

Fig. 4

Overall survival. The overall survival analysis included all patients who died during the study or during long-term follow-up after discontinuation of study treatment. HR, hazard ratio

Fig. 5

Overall survival by IPSS risk status. In both treatment arms, overall survival was significantly longer for patients with int-2 compared with high-risk MF at diagnosis (ruxolitinib, P = 0.002; placebo, P = 0.004). Ruxolitinib was associated with nonsignificant survival advantages compared with placebo for both the int-2 and high-risk patient subgroups. HR, hazard ratio; int-2, intermediate-2; IPSS, International Prognostic Scoring System; MF, myelofibrosis

Fig. 6

Incidence of new or worsening grade 3 or 4 a anemia, b thrombocytopenia, and c leukopenia over time. Anemia, thrombocytopenia, and leukopenia were based on hematologic laboratory abnormalities. (asterisk) Placebo arm data are only shown up to 6 months because all patients randomized to placebo crossed over or discontinued within 3 months of the primary analysis

Fig. 7

Mean blood counts over time in the ruxolitinib randomized and ruxolitinib crossover groups. Blood counts were based on measurements of a hemoglobin level, b platelet counts, and c white blood cell counts. *For patients in the ruxolitinib crossover group, BL represents the date of crossover to ruxolitinib. BL, baseline