Authored by Ann Liu, PhD
Medically Reviewed by Brian Koffman, MDCM (retired), MSEd
The Bottom Line:
Adding early obinutuzumab to acalabrutinib and venetoclax significantly increases rates of uMRD in the bone marrow of patients with treatment-naïve CLL.
Who Performed the Research and Where Was it Presented:
Dr. William Wierda from The University of Texas MD Anderson Cancer Center and colleagues presented the results at the American Society for Hematology (ASH) Annual Meeting 2024.
Background:
The combination of acalabrutinib plus venetoclax is an all-oral combination therapy being studied as a first-line treatment for chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Results from the phase 3 AMPLIFY trial demonstrated that acalabrutinib and venetoclax significantly improved progression-free survival compared with chemoimmunotherapy, and it was well-tolerated. Obinutuzumab is an anti-CD20 monoclonal antibody that can potentially improve the depth and duration of remissions when added to limited-duration combination therapies. In this study, researchers examined whether adding early obinutuzumab to acalabrutinib and venetoclax would increase the number of patients who reached undetectable measurable residual disease (uMRD).
Methods and Participants:
This phase 2 clinical trial compares the doublet therapy of acalabrutinib plus venetoclax (AV) with triplet therapy of acalabrutinib plus venetoclax plus obinutuzumab (AVO) in treatment-naïve patients with CLL. Patients received acalabrutinib and venetoclax for 24 months, and obinutuzumab was given for the first 6 months in the AVO group. If patients in either group had detectable MRD at cycle 14, they could receive 6 cycles of obinutuzumab. The primary outcome was the rate of uMRD in the bone marrow.
Results:
- 83 patients enrolled in the study, 42 of whom received AV and 41 received AVO.
- Adding obinutuzumab to AV significantly increased uMRD rates in the bone marrow.
Undetectable measurable residual disease rates in bone marrow
| AV | AVO | |
| Cycle 9 | 14% | 63% |
| Cycle 14 | 24% | 73% |
- The most common moderate to serious side effects were low neutrophil counts (AV 14%, AVO 34%), non-melanoma skin cancers (AV 7%, AVO 15% ), and infections (AV 5%, AVO 32%).
- There have been five deaths, all in the AVO arm: 3 due to COVID-19, one due to sepsis, and one due to progressive Richter transformation.
Conclusions:
Adding early obinutuzumab to acalabrutinib and venetoclax significantly increases rates of uMRD in the bone marrow of patients with treatment-naïve CLL. However, adding obinutuzumab increases the risk of low neutrophil counts and infections. This is similar to what was seen in the AMPLIFY trial, where adding obinutuzumab to AV improved the depth and duration of responses but came with an increased risk of infections and death, mainly due to COVID-19 since the study was conducted during the COVID-19 pandemic. For patients and healthcare providers considering adding obinutuzumab to AV, carefully weigh the increased risks versus the increased benefits.
Links and Resources:
Watch the interview on the abstract here:
You can read the actual ASH abstract here: Early Obinutuzumab Significantly Increases Bone Marrow Undetectable MRD (10-4 sensitivity) (uMRD4) Rate When Combined with Acalabrutinib and Venetoclax in a Randomized Phase II Trial for Treatment Naïve CLL.
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