The phase 2 CLL2-BAAG trial evaluated the triple combination of Bruton tyrosine kinase inhibitor (BTKi) acalabrutinib, BCL2 inhibitor venetoclax, and anti-CD20 monoclonal antibody obinutuzumab following an optional bendamustine debulking in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL); with this combination strategy, 75.6% of patients achieved undetectable MRD (uMRD) after approximately 6 months of the triplet therapy in primary analysis.1 We now report efficacy data and circulating tumor DNA (ctDNA) analyses of the CLL2-BAAG trial; additional follow-up, efficacy data and circulating tumor DNA (ctDNA) analyses were reported at the 2023 American Society of Hematology annual meeting and summarized here.
In the induction phase of the CLL2-BAAG trial, patients received obinutuzumab (Cycle 1; days 1, 8, 15, 4-weekly in cycles 2-6) plus acalabrutinib (cycle 2) and venetoclax (cycle 3); maintenance treatment with continuous acalabrutinib and venetoclax and 3-monthly obinutuzumab was administered until uMRD <10-4 in peripheral blood or for up to 24 months.2 Date of data cut was February 2023.
A total of 45 evaluable patients were included in the current analysis with a median age of 60 years.2 In the total cohort, patients received ≥1 prior treatments; 18 patients (40%) had received prior BTKi and/or venetoclax, 14/45 patients (31.8%) had del(17p) and/or TP53 mutations, 34 (75.6%) had unmutated IGHV.2
At a follow-up of 34.4 months, all patients had exited the study, with median treatment duration of 14.7 months.2 Using the MRD- and response-guided strategy, 25 patients (55.6%) discontinued therapy (based on confirmed uMRD) and 9 patients (20.0%) completed all 8 maintenance cycles (based on persisting MRD and/or lack of a complete response).2
As reported, the uMRD rate was 76% with the remaining 10 patients showing detectable MRD ≥10-4.2 In the course of maintenance, 7 of these 10 patients (70%) achieved uMRD, 1 patient had a Richter’s transformation (RT) and 2 patients still had detectable MRD after 8 cycles of maintenance.2 With all patients off-treatment, uMRD <10-4 in peripheral blood (PB) was achieved in 42 of 45 patients (93.3%) at any time point, including 17 of 18 patients (94.4%) previously exposed to venetoclax and/or a BTKi.2 The median time to uMRD in PB was 5.4 months from the start of study treatment.2 In the total cohort, median progression-free survival (PFS) was not reached and estimated 30-month PFS rate was 88.2%.2 The estimated 30-month overall survival was 100%. One patient died of COVID-19 18 months after the end of study treatment.2
A total of 564 paired flow cytometry/ctDNA samples were available. Overall, 17 MRD recurrences occurred; 11 were first detected by ctDNA, and 3 by FCM.2 In patients with earlier detection by ctDNA, a higher proportion had high-risk genetics (unmutated IGHV, complex karyotype), del(11q), and prior exposure to venetoclax/BTKi compared to those with earlier detection by FCM.2
A total of 50 serious adverse events (SAEs) were reported; of these, 33 were of grade 3 severity and 6 were grade 4; one death due to COVID-19 was reported 18 months after the end of study treatment. The most common SAEs were COVID-19, other pneumonias, infusion-related reactions, and neutropenias.2
Based on these results, it was concluded that time-limited MRD-guided triple combination therapy of acalabrutinib, venetoclax and obinutuzumab yielded better efficacy outcomes, deeper remission, and achievement of uMRD in patients with R/R CLL.
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