In clinical trials, more than half (56.9%) of older patients with chronic lymphocytic leukemia (CLL) who received 1 year of treatment with venetoclax (Venclexta), an oral drug that blocks B-cell lymphoma-2 protein plus obinutuzumab (Gazyva), a monoclonal antibody that targets CD20 on cancer cells, achieved undetectable minimal residual disease (MRD).1
Researchers are hoping to enhance the efficacy of treatment without increasing the frequency or severity of side effects by adding a newer agent to the combination of venetoclax plus obinutuzumab.2 Compared with ibrutinib (Imbruvica), an older targeted drug for patients with CLL, acalabrutinib (Calquence) is a more selective inhibitor of Bruton tyrosine kinase. Based on results of clinical trials, acalabrutinib is well-tolerated and active when used alone or together with obinutuzumab.2 Researchers, led by Benjamin Lampson, MD, PhD, Professor, Medicine, Oncology Division, Dana-Farber Cancer Institute, Boston, MA, wanted to determine whether using a time-limited triplet regimen of acalabrutinib plus venetoclax plus obinutuzumab (AVO), could achieve a high rate of undetectable MRD in bone marrow with acceptable tolerability.2,3 In their study, patients with CLL received a 28-day lead-in with acalabrutinib (100 mg twice daily) and 6 cycles of obinutuzumab given via intravenous infusion. Venetoclax was started on day 1 of cycle 4 and continued for 15 cycles.3 Patients who were MRD-negative after 15 cycles of AVO were allowed to discontinue therapy. All other patients continued on the combination for 9 more cycles (24 total).3
According to recently published findings from this phase 2 study, AVO resulted in durable responses that improved over time. “The first finding is that the triplet can be safely administered in combination,” said Dr Lampson. “The second finding is that the triplet is highly active in frontline CLL, and thus merits further investigation in the phase 3 setting.”2
After a full course of AVO therapy in this trial, 75% of patients achieved undetectable MRD in their bone marrow, and 100% of patients achieved measurable reductions in their CLL. Responses to AVO were seen regardless of IGHV mutation status or TP53 mutation status.3 Patients with CLL who have specific subtypes of disease based on these 2 mutations have a higher risk for relapse.
Side effects seen with the AVO triplet were similar to each drug’s known side effects when given alone. The most common side effects were fatigue (81%), headache (76%), low white blood cell count (68%), and bruising (43%).3
Researchers are now expanding the phase 2 clinical trial to include more patients who have TP53-mutated disease, which is a high-risk marker. A separate phase 3 trial, CL-311, is enrolling patients with CLL to compare 3 treatments: AVO, acalabrutinib plus venetoclax, and standard chemoimmunotherapy. Researchers hope to demonstrate that the chemotherapy-free AVO combination achieves complete and long-lasting remissions, which would define a new frontline treatment for patients with CLL.2
- Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med.2019;380:2225-2236.
- Seymour C. Acalabrutinib triplet impresses in frontline CLL, advances to phase III study. April 7, 2020. www.onclive.com/web-exclusives/acalabrutinib-triplet-impresses-in-frontline-cll-advances-to-phase-iii-study. Accessed May 3, 2020.
- Lampson BL, Tyekucheva S, Crombie JL, et al. Preliminary safety and efficacy results from a phase 2 study of acalabrutinib, venetoclax and obinutuzumab in patients with previously untreated chronic lymphocytic leukemia (CLL). Blood. 2019;134(Supplement_1):32.