A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis

Abstract

Background: Ruxolitinib, a selective inhibitor of Janus kinase (JAK) 1 and 2, has clinically significant activity in myelofibrosis.

Methods: In this double-blind trial, we randomly assigned patients with intermediate-2 or high-risk myelofibrosis to twice-daily oral ruxolitinib (155 patients) or placebo (154 patients). The primary end point was the proportion of patients with a reduction in spleen volume of 35% or more at 24 weeks, assessed by means of magnetic resonance imaging. Secondary end points included the durability of response, changes in symptom burden (assessed by the total symptom score), and overall survival.

Results: The primary end point was reached in 41.9% of patients in the ruxolitinib group as compared with 0.7% in the placebo group (P<0.001). A reduction in spleen volume was maintained in patients who received ruxolitinib; 67.0% of the patients with a response had the response for 48 weeks or more. There was an improvement of 50% or more in the total symptom score at 24 weeks in 45.9% of patients who received ruxolitinib as compared with 5.3% of patients who received placebo (P<0.001). Thirteen deaths occurred in the ruxolitinib group as compared with 24 deaths in the placebo group (hazard ratio, 0.50; 95% confidence interval, 0.25 to 0.98; P=0.04). The rate of discontinuation of the study drug because of adverse events was 11.0% in the ruxolitinib group and 10.6% in the placebo group. Among patients who received ruxolitinib, anemia and thrombocytopenia were the most common adverse events, but they rarely led to discontinuation of the drug (in one patient for each event). Two patients had transformation to acute myeloid leukemia; both were in the ruxolitinib group.

Conclusions: Ruxolitinib, as compared with placebo, provided significant clinical benefits in patients with myelofibrosis by reducing spleen size, ameliorating debilitating myelofibrosis-related symptoms, and improving overall survival. These benefits came at the cost of more frequent anemia and thrombocytopenia in the early part of the treatment period. (Funded by Incyte; COMFORT-I ClinicalTrials.gov number, NCT00952289.).

Figure 1. Assessment of Spleen Volume Reduction

Figure 1A represents the intent-to-treat analysis of the percentage of patients in each treatment group achieving the primary endpoint of a ≥35% reduction in spleen volume by magnetic resonance imaging or computed tomography. Patients who discontinued before week 24 or crossed over before week 24 were counted as nonresponders. Only patients with baseline data were included in this analysis. Figure 1B depicts a waterfall plot of percent change in spleen volume from baseline for patients in the ruxolitinib and placebo groups at week 24 (n=139 and n=106, respectively) or the last evaluation before week 24 (n=16 and n=47). One patient with a missing baseline value is not included on the graph. Most patients in the ruxolitinib group (150/155) experienced a reduction in spleen volume, whereas most patients in the placebo group exhibited either an increase (102/153) or no change in spleen volume (15/153). Figure 1C shows the median percent change in spleen size, as measured by volume assessed by magnetic resonance imaging or computed tomography over time. Reductions in spleen volume were apparent at the first on-study measurement at 12 weeks and were maintained over the course of the study. OR denotes odds ratio. CI denotes confidence interval.

Figure 1. Assessment of Spleen Volume Reduction

Figure 1A represents the intent-to-treat analysis of the percentage of patients in each treatment group achieving the primary endpoint of a ≥35% reduction in spleen volume by magnetic resonance imaging or computed tomography. Patients who discontinued before week 24 or crossed over before week 24 were counted as nonresponders. Only patients with baseline data were included in this analysis. Figure 1B depicts a waterfall plot of percent change in spleen volume from baseline for patients in the ruxolitinib and placebo groups at week 24 (n=139 and n=106, respectively) or the last evaluation before week 24 (n=16 and n=47). One patient with a missing baseline value is not included on the graph. Most patients in the ruxolitinib group (150/155) experienced a reduction in spleen volume, whereas most patients in the placebo group exhibited either an increase (102/153) or no change in spleen volume (15/153). Figure 1C shows the median percent change in spleen size, as measured by volume assessed by magnetic resonance imaging or computed tomography over time. Reductions in spleen volume were apparent at the first on-study measurement at 12 weeks and were maintained over the course of the study. OR denotes odds ratio. CI denotes confidence interval.

Figure 1. Assessment of Spleen Volume Reduction

Figure 1A represents the intent-to-treat analysis of the percentage of patients in each treatment group achieving the primary endpoint of a ≥35% reduction in spleen volume by magnetic resonance imaging or computed tomography. Patients who discontinued before week 24 or crossed over before week 24 were counted as nonresponders. Only patients with baseline data were included in this analysis. Figure 1B depicts a waterfall plot of percent change in spleen volume from baseline for patients in the ruxolitinib and placebo groups at week 24 (n=139 and n=106, respectively) or the last evaluation before week 24 (n=16 and n=47). One patient with a missing baseline value is not included on the graph. Most patients in the ruxolitinib group (150/155) experienced a reduction in spleen volume, whereas most patients in the placebo group exhibited either an increase (102/153) or no change in spleen volume (15/153). Figure 1C shows the median percent change in spleen size, as measured by volume assessed by magnetic resonance imaging or computed tomography over time. Reductions in spleen volume were apparent at the first on-study measurement at 12 weeks and were maintained over the course of the study. OR denotes odds ratio. CI denotes confidence interval.

Figure 2. Assessment of Symptom Improvement

Figure 2A shows the intent-to-treat analysis of the proportion of patients achieving at least a 50% reduction in symptom score over time (each value plotted represents the moving average of the prior 7 days). Patients who discontinued or had missing data were considered nonresponders. The majority of responses occurred rapidly, within the first 4 weeks of treatment. Only patients with baseline data were included in this analysis. Figure 2B depicts a waterfall plot of percent change in TSS from baseline for patients in the ruxolitinib and placebo groups at week 24 (n=129 and n=103, respectively) or the last evaluation on randomized therapy (n=16 and n=42). Patients with a baseline score of 0 (n=5), missing baseline values (n=8), and insufficient postbaseline data (n=6) are not included on the graph. Whereas most ruxolitinib-treated patients experienced a reduction in TSS, the majority of placebo-treated patients had a worsening of symptoms (all TSS worsening ≥150% are shown as 150%). Figure 2C illustrates the mean percent change in score for each individual symptom that comprises the modified Myelofibrosis Symptom Assessment Form v2.0. All symptoms improved in the ruxolitinib group and worsened in the placebo group (P<0.01 for ruxolitinib vs. placebo). SEM denotes standard error of the mean.

Figure 2. Assessment of Symptom Improvement

Figure 2A shows the intent-to-treat analysis of the proportion of patients achieving at least a 50% reduction in symptom score over time (each value plotted represents the moving average of the prior 7 days). Patients who discontinued or had missing data were considered nonresponders. The majority of responses occurred rapidly, within the first 4 weeks of treatment. Only patients with baseline data were included in this analysis. Figure 2B depicts a waterfall plot of percent change in TSS from baseline for patients in the ruxolitinib and placebo groups at week 24 (n=129 and n=103, respectively) or the last evaluation on randomized therapy (n=16 and n=42). Patients with a baseline score of 0 (n=5), missing baseline values (n=8), and insufficient postbaseline data (n=6) are not included on the graph. Whereas most ruxolitinib-treated patients experienced a reduction in TSS, the majority of placebo-treated patients had a worsening of symptoms (all TSS worsening ≥150% are shown as 150%). Figure 2C illustrates the mean percent change in score for each individual symptom that comprises the modified Myelofibrosis Symptom Assessment Form v2.0. All symptoms improved in the ruxolitinib group and worsened in the placebo group (P<0.01 for ruxolitinib vs. placebo). SEM denotes standard error of the mean.

Figure 2. Assessment of Symptom Improvement

Figure 2A shows the intent-to-treat analysis of the proportion of patients achieving at least a 50% reduction in symptom score over time (each value plotted represents the moving average of the prior 7 days). Patients who discontinued or had missing data were considered nonresponders. The majority of responses occurred rapidly, within the first 4 weeks of treatment. Only patients with baseline data were included in this analysis. Figure 2B depicts a waterfall plot of percent change in TSS from baseline for patients in the ruxolitinib and placebo groups at week 24 (n=129 and n=103, respectively) or the last evaluation on randomized therapy (n=16 and n=42). Patients with a baseline score of 0 (n=5), missing baseline values (n=8), and insufficient postbaseline data (n=6) are not included on the graph. Whereas most ruxolitinib-treated patients experienced a reduction in TSS, the majority of placebo-treated patients had a worsening of symptoms (all TSS worsening ≥150% are shown as 150%). Figure 2C illustrates the mean percent change in score for each individual symptom that comprises the modified Myelofibrosis Symptom Assessment Form v2.0. All symptoms improved in the ruxolitinib group and worsened in the placebo group (P<0.01 for ruxolitinib vs. placebo). SEM denotes standard error of the mean.

Figure 3. Overall Survival

Figure 3 shows the Kaplan-Meier plot of overall survival, including 4 months of additional follow-up after the primary analysis. There were 13 (8.4%) deaths in the ruxolitinib and 24 (15.7%) in the placebo group (median follow-up, 51 weeks). CI denotes confidence interval.