Ibrutinib Regimens versus Chemoimmunotherapy in Older Patients with Untreated CLL

Humans

Patient Characteristics

Figure 1. Figure 1. Screening, Randomization, and Analysis.

Of the 547 patients who underwent randomization, 23 (4%) were determined to have not met the eligibility criteria at screening and were excluded from the primary analysis, in accordance with the protocol. These patients were included in the intention-to-treat analysis.

Table 1. Table 1. Characteristics of the Patients at Baseline.

From December 2013 to May 2016, a total of 644 patients were preregistered and 547 were enrolled at 219 sites throughout the United States and Canada (Figure 1, and see the Supplementary Appendix). Of the 547 patients who were enrolled in the trial, 183 were randomly assigned to receive bendamustine plus rituximab, 182 to receive ibrutinib, and 182 to receive ibrutinib plus rituximab. The characteristics of the patients were typical of a population with untreated CLL (Table 1, and Table S2 in the Supplementary Appendix); the median age was 71 years (range, 65 to 89), and 367 patients (67%) were men.

With regard to risk factors for CLL, 46% of the patients had intermediate-risk disease and 54% had high-risk disease according to modified Rai stage, 53% had ZAP70-unmethylated disease on central testing (with ZAP70-unmethylated disease status used as a surrogate for IgVH-unmutated disease status), and 27% had disease associated with the presence of del(17p13.1) or del(11q22.3) on local FISH analysis. A separate, central FISH analysis performed with the use of the hierarchical classification method established by Döhner et al.20 revealed the presence of del(17p13.1) in 6% of the patients, del(11q22.3) in 19%, trisomy 12 in 22%, and del(13q14.3) in 36%, as well as the absence of all these abnormalities in 17%. In addition, 29% of the patients had a complex karyotype, with at least three unrelated cytogenetic abnormalities as assessed by central review,21 and 10% had a mutation in TP53 with a variant allele frequency of more than 10%. Of the 360 patients who underwent central sequencing of IgVH genes, 61% had IgVH-unmutated disease. There was no significant difference among the three treatment groups with regard to baseline characteristics, with the exception of a higher percentage of patients with a complex karyotype in the ibrutinib-plus-rituximab group than in the other two treatment groups (P=0.04).

Of the 524 patients who were enrolled in the trial and were determined to have met the eligibility criteria at screening, 389 patients (74%) consented to undergo the geriatric assessment for the correlative analysis, and 369 of those patients (95%) completed the assessment before treatment. The mean (±SD) score for activities of daily living was 13.7±0.8 (range, 9 to 14), and the mean number of coexisting conditions was 2.5±1.9 (range, 0 to 14) (Table S3 in the Supplementary Appendix). There was no significant difference among the three treatment groups with regard to results on the geriatric assessment.

Progression-free Survival and Overall Survival

Figure 2. Figure 2. Primary and Subgroup Analyses of Progression-free Survival.

Panel A shows Kaplan–Meier estimates of progression-free survival for each treatment group. The primary analysis included all patients who underwent randomization and were determined to have met the eligibility criteria at screening. Panel B shows hazard ratios for disease progression or death at the time of data cutoff, according to subgroups that were based on risk factors for chronic lymphocytic leukemia. The subgroup analysis was performed in the intention-to-treat population. Hazard ratios were calculated with univariable Cox proportional-hazards models. NR denotes not reached.

Of the 547 patients who underwent randomization, 524 (96%) were determined to have met the eligibility criteria at screening and were included in the primary analysis. Median progression-free survival was reached only with bendamustine plus rituximab. The estimated percentage of patients with progression-free survival at 2 years was 74% (95% confidence interval [CI], 66 to 80) with bendamustine plus rituximab, as compared with 87% (95% CI, 81 to 92) with ibrutinib and 88% (95% CI, 81 to 92) with ibrutinib plus rituximab (Figure 2A). The hazard ratio for disease progression or death was 0.39 (95% CI, 0.26 to 0.58) for the comparison of ibrutinib with bendamustine plus rituximab (one-sided P<0.001) and 0.38 (95% CI, 0.25 to 0.59) for the comparison of ibrutinib plus rituximab with bendamustine plus rituximab (one-sided P<0.001). There was no significant difference between the ibrutinib-plus-rituximab group and the ibrutinib group with regard to progression-free survival (hazard ratio, 1.00; 95% CI, 0.62 to 1.62; one-sided P=0.49) (Figure 2A). In an intention-to-treat analysis, which included all patients who underwent randomization, the same conclusions were reached (Fig. S1 in the Supplementary Appendix).

In analyses of subgroups that were defined according to risk factors for CLL, progression-free survival was longer with the ibrutinib-containing regimens than with bendamustine plus rituximab in all risk factor–related subgroups, but the difference was not significant among patients with ZAP70-methylated disease (Figure 2B). In exploratory analyses of subgroups that were defined according to cytogenetic factors, there was an interaction between cytogenetics and the effect of treatment on progression-free survival. Progression-free survival was longer with the ibrutinib-containing regimens than with bendamustine plus rituximab in all cytogenetic factor–related subgroups, but the difference was greater among patients with del(17p13.1) (Fig. S2 in the Supplementary Appendix). In an additional analysis, progression-free survival was longer among patients with IgVH-mutated disease than among those with IgVH-unmutated disease (hazard ratio, 0.51; 95% CI, 0.32 to 0.81), but there was no significant interaction between IgVH mutation status and the effect of treatment on progression-free survival. Details regarding this analysis are provided in Tables S4 and S5 and Figure S3 in the Supplementary Appendix.

At the time of data cutoff, 66 deaths had occurred. The estimated percentage of patients with overall survival at 2 years was 95% (95% CI, 91 to 98) with bendamustine plus rituximab, 90% (95% CI, 85 to 94) with ibrutinib, and 94% (95% CI, 89 to 97) with ibrutinib plus rituximab. There was no significant difference among the three treatment groups with regard to overall survival (P≥0.65 for all pairwise comparisons) (Fig. S4 in the Supplementary Appendix).

Treatment and Response

At the time of data cutoff, the median follow-up was 38 months among the 481 patients who were alive. A total of 114 of 182 patients (63%) in the ibrutinib group and 117 of 182 patients (64%) in the ibrutinib-plus-rituximab group were still receiving ibrutinib, and 88 of 183 patients (48%) in the bendamustine-plus-rituximab group were still in remission and undergoing surveillance in the trial after completion of treatment. In the bendamustine-plus-rituximab group, 67% of the patients received six cycles of treatment; the number of cycles received ranged from one to six, with a dose held in 67% of the patients and the dose reduced in 37%. In the ibrutinib group, the median duration of treatment at the time of data cutoff was 32 months (range, 0 to 51), with the dose reduced in 13% of the patients. In the ibrutinib-plus-rituximab group, the median duration of ibrutinib treatment at the time of data cutoff was 32 months (range, 0 to 52), with the dose reduced in 14% of the patients; 92% of the patients received all planned doses of rituximab.

The best response was determined by means of CT and physical examination in 504 patients (92%) and by means of physical examination alone in 18 (3%) and was not evaluated in 25 (5%). Among all the patients, the response rate was lower with bendamustine plus rituximab than with the ibrutinib-containing regimens: 81% (95% CI, 75 to 87) with bendamustine plus rituximab, as compared with 93% (95% CI, 88 to 96) with ibrutinib and 94% (95% CI, 89 to 97) with ibrutinib plus rituximab. However, the complete response rate was higher with bendamustine plus rituximab than with the ibrutinib-containing regimens: 26% (95% CI, 20 to 33), as compared with 7% (95% CI, 4 to 12) and 12% (95% CI, 8 to 18). The percentage of patients with undetectable minimal residual disease was significantly higher with bendamustine plus rituximab than with the ibrutinib-containing regimens: 8% (95% CI, 5 to 13), as compared with 1% (95% CI, <1 to 3) and 4% (95% CI, 2 to 8).

Adverse Events

Table 2. Table 2. Summary of Grade 3, 4, or 5 Adverse Events. Table 3. Table 3. Summary of Grade 3, 4, or 5 Infections.

Because adverse events associated with these treatments have been reported extensively in the literature, we have focused on grade 3 or higher adverse events of special interest (Table 2). These adverse events are reported regardless of attribution and include events that occurred during treatment and follow-up, excluding events that occurred after crossover. The rate of grade 3, 4, or 5 hematologic adverse events was higher with bendamustine plus rituximab (61%) than with ibrutinib or ibrutinib plus rituximab (41% and 39%, respectively), whereas the rate of grade 3, 4, or 5 nonhematologic adverse events was lower with bendamustine plus rituximab (63%) than with the ibrutinib-containing regimens (74% with each regimen). Infections occurred in all three treatment groups, with respiratory tract infections, urinary tract infections, sepsis, and abdominal infections being the most common (Table 3, and Table S6 in the Supplementary Appendix). Atrial fibrillation of any grade occurred in 3% of the patients in the bendamustine-plus-rituximab group, 17% in the ibrutinib group, and 14% in the ibrutinib-plus-rituximab group. Grade 3 or higher hypertension occurred in 14%, 29%, and 34%, respectively. Summaries of all adverse events are provided in Tables S7 through S10 in the Supplementary Appendix.

Death occurred during treatment or within 30 days after treatment discontinuation in 2 patients (1%) in the bendamustine-plus-rituximab group, 13 (7%) in the ibrutinib group, and 13 (7%) in the ibrutinib-plus-rituximab group. Death occurred within the first six cycles of treatment, within 30 days after the sixth cycle among those who completed six cycles, or within 30 days after treatment discontinuation among those who did not complete six cycles in 2 patients (1%) in the bendamustine-plus-rituximab group, 3 (2%) in the ibrutinib group, and 6 (3%) in the ibrutinib-plus-rituximab group. All causes of death are shown in Table S11 in the Supplementary Appendix.

Secondary cancers occurred in 13% of the patients in the bendamustine-plus-rituximab group (excluding events that occurred after crossover), 13% in the ibrutinib group, and 16% in the ibrutinib-plus-rituximab group. Richter’s transformation (CLL that evolved into an aggressive lymphoma) occurred in 1 patient in the bendamustine-plus-rituximab group and in 2 patients in the ibrutinib-plus-rituximab group.

Articles You May Like

Cellecta, Inc. launches DriverMap™ predesigned RNA-Seq panels and analysis software
MIT Scientists Have Turned Wasp Venom Into a Potential Antibiotic
Breast Cancer Risk May Rise After Childbirth, but Is Still Low
Are You Lonely And Don’t Realize It? Try Taking This Quiz
This Is What Mars Sounds Like, As Recorded By NASA’s InSight Robot

Leave a Reply

Your email address will not be published. Required fields are marked *