Great news from this long awaited first published phase 2 study reporting the efficacy of this AVO triplet, which are the most active new drugs approved for patients with CLL.
"In patients with chronic lymphocytic leukemia (CLL) and undetectable minimal residual disease (MRD) in the bone marrow, the frontline combination of acalabrutinib (Calquence), venetoclax (Venclexta), and obinutuzumab (Gazyva) were highly active and well-tolerated, according to phase 3 study results published in The Lancet Oncology."
A subsequent Dana Faber phase 3 study and the very similar ACE-CL-311 phase 3 study which I completed this year differ from this trial, where "alabrutinib plus venetoclax was continued until disease progression or unacceptable toxicity. However, patients had the option to discontinue if they achieved a complete remission." These phase 3 trials have just 14 to 15 cycles.
Matthew Davids, MD, MMSc, (photographed) is the lead investigator and director, Clinical Research, Division of Lymphoma and physician at Dana-Farber Cancer Institute and an associate professor of Medicine at Harvard Medical School. In this interview with Targeted Oncology™ targetedonc.com/view/acalab... Dr. Davids noted the following in what was a challenging group of patients "In terms of cytogenetics at baseline, 13q deletions were most common (49%), and 6q deletion were least common (5%). There were also patients with 17p deletions (27%), 11q deletions (35%), Trisomy 12 (14%), and complex karyotype (19%). Most of the patient population did not have IGHV-mutated disease (73%), and 49% had were negative for ZAP-70. In terms of high-risk factors, 27% of the population had both a TP53 mutation and 17p deletion, and 19% had a NOTCH1 mutation.
All patients received at least 1 dose of each therapy in the study. Thirty-six of the patients were evaluable for the secondary end points. At a median follow-up of 27.6 months (interquartile range, 25.1-28.2), there were no cases of clinical progression and all patients remained alive at data cut off.
The rate of CR with undetectable MRD at the start of cycle 16 was 38% (95% CI, 22-55), missing the primary end point of the study. But, notably, the CR rate increased from 14% at cycle 8% to 35% at cycle 16% and was still 38% by cycle 25. It was also notable, according to the study authors, that those who achieved a CR by cycle 8 all had IGHV-unmutated disease and 5 of them has a TP53 aberration.
Acalabrutinib with venetoclax and obinutuzumab did achieve a 100% ORR in the study with the best CR rate being 46%, and this result was irrespective of IGHV mutation status or the presence of TP53 aberrations.
In the subgroup of patients with undetectable MRD in both the peripheral blood and bone marrow, response status did not appear to impact the rate of undetectability, which was 92% in the peripheral blood, and 86% in the bone marrow. Further, across mutational subgroups, the rate of MRD undetectability in the blood and bone marrow were similar."
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“We have learned since we first designed the study that attaining undetectable MRD is a better predictor of long term PFS than whether a patient achieves a CR, so in retrospect, the primary end point was not optimal. Our triplet therapy achieved one of the highest bone marrow uMRD rates ever reported [86%] despite the fact that our population was enriched for patients with high-risk TP53-aberrant CLL,” Davids explained. “This suggests that the responses with this time-limited therapy are likely to be highly durable. Moreover, the tolerability of this triplet therapy was excellent, suggesting that it may be a regimen that could be used across a broad population of patients with CLL, including those who are older and/or have other medical comorbidities”
Reference
1. Davids MS, Lampson BL, Tyekucheva S, et al. Acalabrutinib, venetoclax, and obinutuzumab as frontline treatment for chronic lymphocytic leukaemia: a single-arm, open-label, phase 2 study. Lancet Oncol. 2021;22(10):1391-1402. doi: 10.1016/S1470-2045(21)00455-1
This is an unlocked post, so non members can find this extremely encouraging news.
Neil
Results on triple combination (A+V+O) for high risk patients -with-chronic-lymphocytic-leukemia-or-small-lymphocytic-lymphoma-cll
