According to the results of Alliance A041202, an international multicenter phase 3 trial, ibrutinib produces superior progression-free survival (PFS) compared with standard chemoimmunotherapy in older patients with chronic lymphocytic leukemia (CLL) and adding rituximab does not improve the ibrutinib response.
According to the results of Alliance A041202, an international multicenter phase 3 trial, ibrutinib produces superior progression-free survival (PFS) compared with standard chemoimmunotherapy (CIT) in older patients with chronic lymphocytic leukemia (CLL) and adding rituximab does not improve the ibrutinib response. The results were presented as part of the plenary session on the second day of the 60th American Society of Hematology (ASH) Annual Meeting & Exposition, being held December 1-4, in San Diego, California.
Accounting for about 25% to 30% of US leukemia cases, the American Cancer Society reports that nearly 21,000 new cases of CLL were diagnosed this year and the disease was responsible for about 4500 deaths.
CIT has been the gold standard for patients, with bendamustine plus rituximab (BR) being one standard, more aggressive CIT regimen for patients age 65 or older. The Bruton tyrosine kinase inhibitor ibrutinib was FDA approved for untreated CLL in 2016, but it’s only been compared with chlorambucil in this patient population but not with aggressive CIT. Also, the impact of adding rituximab to the ibrutinib treatment has not been evaluated, explained Jennifer A. Woyach, MD, associate professor, The Ohio State University College of Medicine, Columbus, Ohio.
“Older patients are underrepresented in CLL clinical trials unless the trial has been specifically designed for them,” Woyach said.
Data from the RESONATE-2 trial presented at the 2017 ASH annual meeting compared ibrutinib as a single agent and chemoimmunotherapy regimens in treatment-naïve patients with patients with CLL who were receiving various combination treatments. Based on their results, the authors recommended that single-agent ibrutinib could be used in place of the combination chemotherapy regimens.
The Alliance A041202 trial has 3 treatment arms—BR (arm 1), ibrutinib alone (arm 2), and ibrutinib plus rituximab (arm 3)—which are designed to determine whether ibrutinib-containing regimens lead to superior PFS compared with CIT in treatment-naïve older patients. PFS was defined as the time from randomization to first detection of disease progression or death. Additionally, this study sought to determine if adding rituximab to ibrutinib would prolong PFS over ibrutinib alone, Woyach said. The trial design allowed patients on arm 1 who progressed to cross over to arm 2. Data for the presentation at the ASH meeting were locked on October 4, 2018, she added.
For trial inclusion, patients had to be 65 years or older with previously untreated, symptomatic CLL; creatinine clearance had to be at least 40 mL/min; bilirubin ≤1.5 the upper limit of normal; and patients should have no significant life-limiting intercurrent illness or need for warfarin treatment. Of the 644 patients who were screened, 547 were randomized 1:1:1 to the 3 arms. Thirty patients in the BR arm crossed over to the ibrutinib alone arm following analysis.
The median age of trial enrollees was 71 years (range, 65-89) and a majority (67%) were men. High-risk Rai stage (stage III/IV) was detected in 54% of patients, unmethylated Zap-70 in 53%, del(17p) or del(11q) by local FISH analysis in 25%, and complex karyotype in 29%.
PFS was higher in the ibrutinib-alone cohort compared with the ibrutinib plus rituximab cohort, Woyach said. In the eligible patient population, at a median follow-up of 24 months, 74% of patients in the brendamustine and rituximab (arm 1) were alive and progression-free (95% CI, 66%-80%), compared with 87% in the ibrutinib alone (arm 2) (95% CI, 81%-92%), and 88% in the ibrutinib plus rituximab (arm 3) (95% CI, 81%-92%).
No significant difference in PFS were observed in the 2 ibrutinib arms among patients with a complex karyotype, she said. Two-year PFS estimates were 59%, 39%, and 87% in arms 1, 2, and 3, respectively. Overall response rates in the intent-to-treat population were 81%, 93%, and 94% in arms 1, 2, and 3, respectively, and the complete response rates were 26%, 7%, and 12%, respectively.
“We did not observe any significant differences in overall survival [OS] among the arms, which might be due to the crossover or the short follow-up time,” Woyach said. She reported that median OS had not been reached for any arm, and OS estimates were 95%, 90%, and 94% for arms 1, 2, and 3, respectively, at a 38-months follow-up.
Adverse events (AEs) were observed at a significantly high rate in this trial. Hematologic AEs were observed in 61%, 41%, and 38% of patients in arms 1, 2, and 3, respectively. Non-hematologic AEs were observed in 63%, 74%, and 74% of patients, respectively.
“Hematologic AEs were prevalent in the BR arm while non-hematologic AEs were more common in the ibrutinib arms,” Woyach said.
“Unexplained or unwitnessed death over the entire observation period was seen in 2 (1.1%), 7 (3.9%), and 13 (7%) patients in arms 1, 2, and 3 respectively,” Woyach said.
Concluding her presentation, Woyach said that the findings from their trial justify using ibrutinib as a standard of care treatment for patients 65 and older, and that combining it with rituximab does not improve PFS outcomes. “Clinical trials of this patient population are still of high clinical interest, and the cooperative group setting remains a reasonable avenue to complete these large studies,” she added.
Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib alone or in combination with rituximab produces superior progression free survival (PFS) compared with bendamustine plus rituximab in untreated older patients with chronic lymphocytic leukemia (CLL): results of Alliance North American Intergroup Study A041202. In: Proceedings from the American Society of Hematology; December 1-3, 2018; San Diego, CA. Abstract 6.