The first-in-class Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib and the B-cell lymphoma 2 (BCL-2)-selective BCL-2 Homology 3 (BH3)-mimetic venetoclax have transformed the therapeutic landscape of chronic lymphocytic leukemia (CLL) in recent years. Studies involving these agents generated much interest at the 2018 American Society of Hematology (ASH) Annual Meeting in San Diego, California.
Ibrutinib and venetoclax complement each other well and synergize with one another in preclinical systems. In patients with CLL, ibrutinib is particularly effective at clearing nodal disease, and venetoclax at clearing the bone marrow compartment. Of note, even as a single agent, venetoclax is able to eradicate measurable residual disease (MRD), an important surrogate for long-term outcome, in a proportion of patients with relapsed CLL — an effect seldom seen with ibrutinib monotherapy.
Based on these considerations, several groups are studying the combination of ibrutinib and venetoclax in patients with CLL. Nitin Jain, MD, of the University of Texas MD Anderson Cancer Center in Houston, presented results of this combination in the frontline setting from an ongoing investigator-initiated trial at the University of Texas MD Anderson Cancer Center.1 Venetoclax was started after 12 weeks of ibrutinib monotherapy (to mitigate tumor lysis syndrome risk) and administered for 24 four-week cycles. Responses improved over time: the rates of complete response (CR)/CR with incomplete count recovery (CRi) were 88% and 96% after 12 and 18 cycles of combination therapy, respectively. The rate of undetectable MRD (defined as <10-4; U-MRD4) in the bone marrow at the corresponding time points were 61% and 69%, respectively.
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Peter Hillmen, MB ChB, PhD, of the University of Leeds and the Leeds Institute of Cancer and Pathology in the United Kingdom, presented results of ibrutinib plus venetoclax in patients with relapsed/refractory (R/R) CLL from the Bloodwise TAP CLARITY study in the United Kingdom.2 In this study, venetoclax was introduced after 8 weeks of ibrutinib monotherapy. The CR/CRi rate after 12 months of combined therapy was 58%, and 41% of patients had achieved undetectable MRD4 in the bone marrow.
The type 2, glycoengineered, anti-CD20 monoclonal antibody obinutuzumab substantially deepened responses to ibrutinib monotherapy in patients with R/R CLL in the UK IcICLLe Extension Study, the results of which were presented by Andy Rawstron, PhD, of the Leeds Teaching Hospitals in Great Britain.3 Kerry Rogers, MD, of the The Ohio State University Comprehensive Cancer Center in Columbus, presented results from her team’s fixed duration (14 cycles) study combining ibrutinib, venetoclax, and obinutuzumab. The team reported overall response rates of 84% and 88%, undetectable MRD4 rates of 67% and 50%, and MRD4-negative CR rates of 28% and 28%, for their treatment-naive and R/R cohorts, respectively, at the end of treatment.4
Results from a number of important studies involving ibrutinib in treatment-naive patients were also presented at ASH 2018. In a plenary presentation, Jennifer Woyach, MD, of The Ohio State University Comprehensive Cancer Center, presented the much anticipated results of the Alliance North American Intergroup A041202 study, a phase 3 randomized controlled trial that compared ibrutinib alone with ibrutinib plus rituximab (IR) and with bendamustine plus rituximab (BR) in 525 previously untreated patients with CLL aged 65 years or older.5 This study confirmed previous observations that have suggested that adding rituximab to ibrutinib does not prolong progression-free survival (PFS) and established the superiority of both ibrutinib regimens over BR in the frontline setting.
