Authored by Ann Liu, PhD
Medically Reviewed by Brian Koffman, MDCM (retired), MSEd
The Bottom Line:
Frontline combination acalabrutinib, venetoclax, and obinutuzumab produces high rates of undetectable measurable residual disease (uMRD) in patients with CLL, including those with high-risk features.
Who Performed the Research and Where Was it Presented:
Dr. Jennifer Brown from Dana Farber Cancer Institute and colleagues presented the results at the American Society for Hematology (ASH) Annual Meeting 2024.
Background:
Combination therapies are increasingly being studied in the hopes of getting patients with chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL) into deeper remissions and allowing for time-limited therapy. For high-risk patients with CLL / SLL who have deletion 17p or TP53 mutations or unmutated IGHV (uIGHV), the conventional wisdom has to keep them on continuous BTK inhibitors. However, there is interest in determining whether combination therapies can get these patients into deeper remissions and possibly give them a break from treatment. In this study, researchers looked at the combination of acalabrutinib plus venetoclax and obinutuzumab (AVO) for treatment-naïve CLL.
Methods and Participants:
This was a phase 2 clinical trial of a combination of acalabrutinib, venetoclax, and obinutuzumab in patients with previously untreated CLL. Unlike the AMPLIFY trial, this study included and ultimately enrolled a high number of high-risk CLL patients (deletion 17p / TP53 mutation). Treatment was time-limited (up to 2 years) and measurable residual disease (MRD)- guided.
Results:
- A total of 72 patients enrolled in the study, and 63% had either deletion 17p or TP53 mutation. 75% had higher-risk unmutated IGHV (uIGHV). This was a high-risk group that would usually be treated with continuous BTKi therapy.
- The median follow-up was 55 months.
- By month 16 of treatment, 85% of patients without high-risk mutations had uMRD in the peripheral blood, and 89% had uMRD in the bone marrow.
- Rates were slightly lower in patients with deletion 17p or TP53 mutations: 71% had uMRD in the peripheral blood, and 71% had uMRD in the bone marrow.
- In patients with unmutated IGHV, 80% had uMRD in the peripheral blood, and 78% had uMRD in the bone marrow.
- Four-year progression-free survival was 89% in all patients, 77% in patients with del(17p) or TP53 mutation, and 87% in patients with unmutated IGHV.
- Common side effects included low neutrophil (a type of white blood cell) counts (73%), low platelet counts (72%), headache (76%), bruising (66%), diarrhea (46%), infection (46%), hypertension (34%), infusion-related reactions (28%), and joint stiffness (30%).
Conclusions:
Acalabrutinib – venetoclax – obinutuzumab is a highly active, time-limited frontline therapy for patients with high-risk CLL. It produces high rates of uMRD, and though it is relatively early, responses seem durable thus far. These results suggest that along with choosing continuous BTKi therapy, AVO is a different, safe, and effective limited-duration option for patients with deletion 17p, TP53 mutation, or uIGHV.
This combination has also been tested in the phase 3 AMPLIFY trial, and the hope is that the positive results of this trial will lead to FDA approval of a combination of acalabrutinib, venetoclax, and obinutuzumab in the near future.
Links and Resources:
Watch the interview on the abstract here:
You can read the ASH abstract here: Primary Endpoint Evaluation of a Multicenter, Phase 2 Study of Acalabrutinib, Venetoclax, Obinutuzumab (AVO) in a Population of Previously Untreated Patients with CLL Enriched for High-Risk Disease.
