The Bottom Line:
In this ongoing trial, the triple combination therapy using acalabrutinib, venetoclax, and obinutuzumab is highly active. Thus far this drug combination has produced durable remissions as a frontline treatment in patients with TP53 mutation CLL and has been generally well tolerated, with a low 2.9% incidence of atrial fibrillation and zero of the more serious abnormal ventricular heart irregularities.
Who Performed the Research and Where Was it Presented:
Dr. Christine Ryan from Dana-Farber Cancer Institute and colleagues presented the results at the American Society for Hematology (ASH) Annual Meeting in 2022. The principal investigator was Dr. Matt Davids.
Combination therapies are increasingly being tested for the treatment of CLL/SLL. The hope is that combining drugs with different mechanisms of action for a limited time will produce better outcomes for patients. Venetoclax and obinutuzumab have previously been tested in combination with ibrutinib, and while the combination was very effective, 95% had low neutrophils and 85% had high blood pressure. See our previous coverage here.
In this interview, our own Dr. Brian Koffman interviewed Dr. Christine Ryan, a clinical fellow in hematology/oncology at Dana-Farber Cancer Institute. They discussed a triple combination that uses acalabrutinib instead of ibrutinib.
Methods and Participants:
For this ongoing phase 2 clinical trial, 68 treatment-naïve patients with CLL have been enrolled. The first cohort was open to any treatment-naïve patient, and the second cohort specifically enrolled patients with TP53 mutation. Patients with TP53 mutation CLL tend to have worse outcomes on chemoimmunotherapy, and while they respond well to BTK inhibitor monotherapy, the responses tend to not last as long. Patients received triple combination therapy with acalabrutinib, venetoclax, and obinutuzumab for up to 24 cycles (2 years). The results of the first cohort have previously been reported here.
- One of the concerns with combination therapies is increasing toxicity and immunosuppression. In this study, the adverse events seen were typical of what is seen with each drug individually, and there were no safety signals above and beyond that.
- Common adverse events included low white blood cell count (75%), low platelet count (73%), low red blood cell count (49%), headaches (78%), fatigue (76%), bruising (66%), nausea (49%), diarrhea (40%), hypertension (27%), infection (6% with one death from a COVID-19 pneumonia), and atrial fibrillation (2.9%).
- With a median follow-up time of 35 months, 43% of all evaluable patients had achieved a complete response with undetectable measurable residual disease (uMRD) in the bone marrow.
- In the TP53 mutation cohort, 45% of patients had achieved a complete response with uMRD in the bone marrow.
- Thus far, responses have been durable, with 93% experiencing progression-free survival at a median follow-up of nearly 3 years.
- Overall survival thus far is 98%, with one patient death due to COVID-19.
Frontline treatment with the triple combination therapy of acalabrutinib, venetoclax, and obinutuzumab has thus far been highly active and produced durable remissions in those with CLL who have TP53 mutation. While it did lead to low blood counts in most patients, these were not generally clinically significant and more importantly the serious cardiac side effects and infections rates were low. There was one death from COVID-19.
An ongoing phase 3 clinical trial will further evaluate its efficacy in comparison to those receiving the combination of acalabrutinib plus venetoclax. But this phase 3 trial will specifically exclude those with TP53 mutation.
Trials like this will help address what is the optimal combination therapy and whether the potential improved outcome with triplet combination therapy is worth the possibility of increased side effects when they are compared to doublet combination therapies.
The questions about the best sequencing of drugs and how combinations may affect treatment decisions also remain unanswered.
Still, it is encouraging to see such deep and durable remissions in the more difficult to treat patients with TP53 mutations and that treatment with a triplet combination therapy was well tolerated.
Links and Resources:
Watch the interview on the abstract here:
You can read the actual ASH abstract here: Updated Results from a Multicenter, Phase 2 Study of Acalabrutinib, Venetoclax, Obinutuzumab (AVO) in a Population of Previously Untreated Patients with CLL Enriched for High-Risk Disease
Take care of yourself first.
Ann Liu, PhD