Authored by Dr. Brian Koffman
Bottom Line:
- MRD guided acalabrutinib, venetoclax and obinutuzumab led to an 88% progression free survival rate in relapsed / refractory chronic lymphocytic leukemia.
- 42 of 45 CLL patients reached undetectable Measurable Residual Disease or uMRD in the peripheral blood.
- Circulating Tumor DNA or ctDNA in the plasma improved early detection of relapses.
Who Performed the Research and Where Was it Presented:
Dr. Moritz Furstenau led a group of German researchers in presenting the abstract “Long-Term Remissions with MRD-Guided Acalabrutinib, Venetoclax and Obinutuzumab in Relapsed / Refractory CLL: Follow-up Efficacy and Circulating Tumor DNA Analysis of the CLL2-Baag Trial” at the American Society of Hematology Annual Meeting in 2023 (ASH 2023) held in San Diego.
Background:
CLL Society previously reported on this phase 2 CLL2-Baag trial that used a combination of acalabrutinib, venetoclax, and obinutuzumab after an optional debulking with bendamustine in patients with relapsed / refractory CLL. It failed to achieve its primary endpoint on a rate of 90% uMRD. 75.6% reached undetectable MRD in peripheral blood at approximately six months of the triplet. For comparison, BOVEN, which used venetoclax plus obinutuzumab and zanubrutinib to achieve 89% uMRD at ten months.
This abstract updates the efficacy data and adds new information on circulating tumor DNA analyses with longer follow-up.
Method and Participants:
- Obinutuzumab was started in cycle 1.
- Acalabrutinib was started in cycle 2.
- Veneotocalx was added in cycle 3.
- Maintenance treatment with continuous acalabrutinib and venetoclax and obinututuzumab every 3 month until achievement of both uMRD <10-4 in the blood and reaching a complete remission, or for up to two years.
- MRD was measured both by flow cytometry in the blood and by digital droplet PCR in that looks for the unique DNA signature of the CLL that is cell free or found floating in the blood plasma.
- uMRD was defined as <1 CLL cell/10,000 leukocytes (<10-4) and no detected ctDNA.
- Patients had to have relapsed / refractory chronic lymphocytic leukemia requiring treatment.
- 46 patients were included in the trial but one was excluded from analysis as he did not meet admission criteria.
- 18 patients (40%) had received a BTK inhibitor (BTKi) and/or venetoclax .
- 14/44 patients (31.8%) had del(17p) and/or TP53 mutations. 34 (75.6%) had unmutated IGHV.
Results:
- Outcomes:
- With a median observation time of slightly less than three year, all 45 patients were off study treatment.
- The time of treatment was 14.7 months.
- Following the MRD and response guided approach, 25 patients (55.6%) discontinued therapy having achieved uMRD while nine (20.0%) completed the maximum of eight maintenance cycles due to persistent MRD and/or lack of a complete response.
- uMRD rate in blood was 75.6% when checked at six months with ten patients still showing detectable MRD ≥10-4.
- However, with the maintenance therapy, seven of those ten patients (70%) achieved uMRD.
- One had a Richter’s transformation and two patients still had detectable MRD after the full eight cycles of maintenance.
- uMRD <10-4 in the blood was therefore achieved in 42 of 45 patients (93.3%) at some time point.
- Results were similar for those who had previous exposure to a BTK inhibitor and/or venetoclax, and for those with del(17p) and/or TP53 mutations.
- Median progression-free survival was not reached.
- The overall survival at 30 months was 100%.
- One patient died of COVID-19 18 months after the end of study treatment.
- Flow Cytometry versus ctDNA for Detection of Relapse:
- 564 paired Flow Cytomety/ctDNA samples were available.
- 17 patients went from undetectable MRD to detectable MRD.
- 11 were first detected by ctDNA, and only three were first discovered by flow cytometry.
- Adverse Events:
- The most common serious adverse events were COVID-19 (n=8), other pneumonias (n=5), infusion-related reactions (n=5) and low neutrophil counts (n=3).
Conclusions:
The triplet of acalabrutinib, venetoclax, and obinutuzumab, sometimes called AVO, has impressive results in terms of helping patients reach uMRD and more importantly high rates of progression free survival and a perfect 100% overall survival for 30 months. However, excellent results are seen with other combinations of two or three drugs. Fewer drugs come with several advantages including reduced immune suppression, lowered risk of side effects, cost savings and the preservation of more future options. Which combination of drugs is best is not known.
This study also introduces the potential power of ctDNA as a way to detect very small amounts of CLL in the peripheral blood. Its role in monitoring disease versus flow cytometry and next generation sequencing (ClonoSEQ) is still to be determined, but it does seem to be another powerful tool to monitor the CLL, especially when the number of cancer cells in the blood is low.
Links and Resources:
Watch my monologue here:
Read the full ASH 2023 abstract that has more results and helpful graphics at: Long-Term Remissions with MRD-Guided Acalabrutinib, Venetoclax and Obinutuzumab in Relapsed / Refractory CLL: Follow-up Efficacy and Circulating Tumor DNA Analysis of the CLL2-Baag Trial.
Stay strong. We are all in this together.
Brian Koffman MDCM (retired) MS Ed (he, him, his)
Co-Founder, Executive VP and Chief Medical Officer
CLL Society, Inc.
