With all of the active agents that are now available for use in CLL, there is interest in how to optimize their use in the frontline setting and thereafter. One approach involves the sequential use of individual novel therapies. For instance, a patient might start on acalabrutinib and continue until progression, at which time they might switch to venetoclax and obinutuzumab. A different, investigational approach involves combining 3 novel agents in succession as part of a time-limited frontline regimen. A phase 2 study conducted at The Ohio State University evaluated such a regimen in the following 2 cohorts: patients with treatment-naive CLL and patients with relapsed or refractory CLL. Obinutuzumab was initiated in cycle 1, ibrutinib was started in cycle 2, and venetoclax began in cycle 3, and combination regimens were given for a total of 14 cycles of fixed-duration therapy. This triplet regimen was active in both cohorts, with the 36-month estimated progression-free survival above 90% in each. Still, combination regimens have greater toxicities (eg, risk of infection, cytopenias, etc) than monotherapies.

We are investigating the use of a second-generation Bruton tyrosine kinase inhibitor in a triplet regimen to see if we may get better tolerability and at least comparable efficacy with a minimal residual disease (MRD)–guided, time-limited approach. We recently reported updated data from our ongoing phase 2 study evaluating a regimen of acalabrutinib, venetoclax, and obinutuzumab (AVO) in frontline CLL. The population was enriched for high-risk TP53-aberrant disease per protocol, with nearly 40% having TP53-aberrant CLL despite being treatment naive. While initial studies evaluating triplets did not restrict for high-risk CLL, more recent studies are shifting the focus to enroll high-risk patients, such as those with 17p deletion and TP53 mutation. There is a feeling that high-risk patients are the most likely to derive the most benefit from triplet combinations. To date, we have treated 44 patients in the AVO study, and the tolerability and efficacy look excellent, with undetectable MRD (uMRD) in the blood in approximately 85% of patients. It is a time-limited therapy, with most individuals requiring approximately 15 months of treatment, although we allow them to go up to 24 months on treatment. Once patients reach a uMRD state, they go on observation.

Another trial evaluating a triplet combination regimen of BGB-3111 (zanubrutinib), venetoclax, and obinutuzumab is also reporting high rates of uMRD. An interesting aspect of this study is that the researchers are allowing patients to discontinue treatment even earlier if they achieve uMRD, so that such individuals would only be receiving treatment for 10 months. It will be interesting to see whether this produces durable responses. Ultimately, we will have to compare triplet-based therapy with other standards of care. Our AVO study has helped to inform the design of an ongoing, 3-arm, phase 3 trial that is comparing the AVO triplet regimen with the AV doublet regimen and with chemoimmunotherapy as frontline therapy for CLL (NCT03836261).

Ultimately, what is also needed are comparisons of these combination regimens to sequential therapy with novel agents in patients with previously untreated CLL. The CLL17 study will be very important because it will compare continuous single-agent ibrutinib vs fixed-duration venetoclax plus obinutuzumab vs fixed-duration ibrutinib plus venetoclax (NCT04608318). However, it will likely be several years before we start seeing any data from this study.