Efficacy, safety, and survival with ruxolitinib in patients with myelofibrosis: results of a median 3-year follow-up of COMFORT-I

Abstract

In the phase III COMFORT-I study, the Janus kinase 1 (JAK1)/JAK2 inhibitor ruxolitinib provided significant improvements in splenomegaly, key symptoms, and quality-of-life measures and was associated with an overall survival benefit relative to placebo in patients with intermediate-2 or high-risk myelofibrosis. This planned analysis assessed the long-term efficacy and safety of ruxolitinib at a median follow-up of 149 weeks. At data cutoff, approximately 50% of patients originally randomized to ruxolitinib remained on treatment whereas all patients originally assigned to placebo had discontinued or crossed over to ruxolitinib. At week 144, mean spleen volume reduction was 34% with ruxolitinib. Previously observed improvements in quality-of-life measures were sustained with longer-term ruxolitinib therapy. Overall survival continued to favor ruxolitinib despite the majority of placebo patients crossing over to ruxolitinib [hazard ratio 0.69 (95% confidence interval: 0.46-1.03); P = 0.067]. Exploratory analyses suggest that crossover may have contributed to an underestimation of the true survival difference between the treatment groups. Ruxolitinib continued to be generally well tolerated; there was no pattern of worsening grade ≥ 3 anemia or thrombocytopenia with longer-term ruxolitinib exposure. These longer-term data continue to support the efficacy and safety of ruxolitinib in patients with myelofibrosis. The study is registered at clinicaltrials.gov: NCT00952289.

Copyright© Ferrata Storti Foundation.

Figures

Figure 1.

Patient disposition. *For the placebo arm, there were three patients who were not evaluable for safety (n=151); these patients were excluded from the calculation of the percentage of patients who discontinued (40/151). †Patients in the placebo group could cross over to ruxolitinib prior to the primary analysis based on defined criteria for worsening splenomegaly. After the primary analysis had been completed, the study was unblinded and all remaining patients receiving placebo were allowed to cross over to ruxolitinib. ‡The percentages of patients who discontinued for the reasons listed are based on the number of patients who discontinued within the treatment group and not on the total number of patients in the treatment group. BID: twice a day.

Figure 2.

Mean daily dose of ruxolitinib over time in patients originally randomized to ruxolitinib. BID: twice a day; SEM: standard error of the mean.

Figure 3.

(A) Percentage change in spleen size over time. Mean percentage change from baseline in spleen volume (left panel) and palpable spleen length (right panel). (B) Durability of spleen volume reduction in patients originally randomized to ruxolitinib. The probability of maintaining a spleen volume reduction in patients who achieved a ≥35% decrease in spleen volume over the course of the study is shown. Also shown is the probability of maintaining a ≥10% spleen volume reduction — a spleen volume reduction that has been shown to be associated with meaningful improvements in quality of life and myelofibrosis-related symptoms — in patients who achieved a ≥35% decrease in spleen volume.

Figure 4.

Mean change in quality-of-life (QOL) measures assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30. The figures shown are global health status, two functional domains (role and physical functioning), and symptom scores for fatigue, a key symptom affecting QOL in patients with myelofibrosis. Arrows indicate improvement.

Figure 5.

(A) Overall survival in the intent-to-treat population as assessed by the Kaplan-Meier method. (B) Overall survival in the intent-to-treat population as assessed by the rank-preserving structural fail time (RPSFT) method. CI: confidence interval: HR: hazard ratio.

Figure 6.

(A) Incidence of new-onset or worsening grade 3 or 4 anemia and thrombocytopenia over time. (B) Mean hemoglobin level and platelet count and hemoglobin level over time. *All patients receiving placebo at the primary analysis crossed over or discontinued within 3 months of the primary analysis; therefore, data for patients receiving placebo are shown for up to 6 months only. RUX: ruxolitinib; PBO: placebo.