From December 1 to December 4, more than 25,000 attendees from around the world gathered in San Diego, California, to attend the 60th American Society for Hematology (ASH) Annual Meeting, where the latest developments and new findings in the hematology field were presented. Over the next several weeks, prIME Lines will highlight some of the most interesting data related to the treatment of hematologic malignancies presented during the meeting.
During the Plenary Session, Jennifer Woyach, MD (Ohio State University, Columbus, Ohio, United States), presented results from the phase III Alliance A041202 trial (N = 547), comparing the Brutons kinase inhibitor ibrutinib alone with ibrutinib plus rituximab and with bendamustine plus rituximab (6 cycles) in previously untreated patients over 65 years of age with chronic lymphocytic leukemia (CLL). This study is of great importance as ibrutinib approval for this indication is based on comparison with chlorambucil alone, which is a relatively ineffective therapy, and not with a standard of care chemoimmunotherapy regimen such as bendamustine plus rituximab or chlorambucil plus obinutuzumab. Results from this study were simultaneously published in The New England Journal of Medicine.
The median age of patients was 71 years, and 54% had high-risk disease according to modified Rai staging, 53% had unmethylated Zap-70 disease on central testing, and 27% had identified presence of del(17p) or del(11q) by local FISH testing. Median progression-free survival (PFS) was not reached with ibrutinib-containing regimens and was 43 months for patients receiving bentuxiamb plus rituximab. Treatment with ibrutinib resulted in a significant improvement in 2-year rates of progression-free survival (PFS) over bendamustine plus rituximab. Ibrutinib monotherapy was associated with a 2-year PFS of 87%, compared to 74% with bendamustine plus rituximab (HR 0.39, P<.001). Similar improvements in PFS were seen in patients receiving ibrutinib in combination with rituximab (88% vs 74%; HR 0.38, P<.001). There was no significant difference in PFS with ibrutinib monotherapy versus ibrutinib plus rituximab (HR 1.00, P = .49). The PFS benefit of ibrutinib-containing regimens compared to bendamustine plus rituximab was consistent across all prespecified subgroups defined according to risk factors for CLL, though the difference was not significant in subgroup of patients with methylated Zap-70. Overall survival (OS) did not differ significantly between the three treatment groups (P ≥ .65). However, the crossover design of this study and relatively short follow-up may impact these findings. The response rate was lower with bendamustine plus rituximab (81%) compared to both ibrutinib (93%) and ibrutinib plus rituximab (94%). Interestingly, the complete response rate was higher with bendamustine plus rituximab (26%) than with ibrutinib (7%) or ibrutinib plus rituximab (12%). Similarly, the rate of minimal residual disease was significantly higher with bendamustine plus rituximab (8%) than with ibrutinib regimens (1% and 4%, respectively).
The safety profile was consistent with the known toxicity profile of each regimen. Grade 3-5 hematologic adverse events (AEs) occurred more frequently in patients receiving bendamustine plus rituximab than in patients receiving ibrutinib monotherapy or ibrutinib plus rituximab (61% vs 41% and 39%). In contrast, nonhematologic AEs were more frequent in patients receiving ibrutinib-containing regimens (74% with each regimen vs 63% with bendamustine plus rituximab). Specifically, grade 3-5 atrial fibrillation, hypertension, and unexplained/unwitnessed death rates were higher with ibrutinib regimens.
Dr Woyach concluded, that overall, these results support the use of ibrutinib monotherapy as a standard treatment regimen for older patients with untreated CLL, though careful monitoring for AEs is necessary. Ongoing trials are currently evaluating ibrutinib in combination with obinutuzumab and venetoclax in this population.
For more information on these data and findings from other CLL trials presented at 2018 ASH annual meeting, their critical analysis, and practice application, see prIME Oncology Clinical Update on CLL.