At the 65th American Society of Hematology (ASH) Annual Meeting, Moritz Furstenau, MD, University of Cologne, Cologne, Germany, presented a follow-up analysis of the CLL2-Baag trial on the efficacy of time-limited, measurable residual disease (MRD) guided acalabrutinib, venetoclax, and obinutuzumab combination therapy after optional debulking with bendamustine among patients with R/R chronic lymphocytic leukemia. He also spoke on the tumor DNA analysis from this study. 

Furstenau and coauthors report efficacy data and circulating tumor DNA (ctDNA) analyses with additional follow-up, finding that the addition of ctDNA-based analyses to the conventional MRD assessment by flow cytometry (FCM) demonstrated an improved early detection of relapses.

Transcript: 

Hi, I am Moritz Furstenau from the German CLL study group. I'm also a medical doctor at the University of Cologne. At this year's ASH, we presented some follow-up data of our CLL2-BAG trial in which we tested a [minimal residual disease] (MRD)-guided triplet combination of acalabrutinib, venetoclax, and obinutuzumab in patients with relapsed/refractory chronic lymphocytic leukemia. We also presented some of our data on circulating tumor DNA (ctDNA)-based MRD monitoring this study.

The BAG trial is an investigator-initiated multicenter phase 2 trial that we ran in Germany, that enrolled 45 patients in total. The patient population was a rather high-risk population with many patients with TP53 aberrations, almost all patients with an unmutated [immunoglobulin heavy chain variable region] (IGHV). Almost half of the patients had previously already received [Bruton’s tyrosine kinase] (BTK) inhibitors or venetoclax, or both, in prior lines. 

The patients, when they were included, sequentially started obinutuzumab, acalabrutinib, and venetoclax over the first 3 cycles. Then, the full triplet combination was given for another 6 cycles until the final restaging. Patients went then on into a maintenance phase with the same 3 drugs in the less dense treatment schedule. What's special about the maintenance treatment is that the duration of maintenance was guided by the MRD status. So, measurable residual disease status. If patients had undetectable MRD below 10 to minus 4 in 2 consecutive measurements, they could stop maintenance treatment. Usually in relapse, CLL patients either get continuous BTK inhibitors or a 2-year treatment of venetoclax and rituximab, or at least most patients. In our trial with the MRD-guided concepts, patients had a median treatment duration that was considerably shorter [at] 14.7 months. 

Despite this rather short treatment duration, we saw a very high efficacy and we achieved undetectable MRD in 93% of patients. Almost all patients that were included in the trial achieved undetectable MRD at some point during the study. What we also saw was a 30-month progression-free survival rate of 88%, which is, higher than what we usually see with the established options. The overall survival, at 30 months was 100%. We also did quite an extensive analysis of ctDNA MRD monitoring. We already did a prior analysis in the same study, in which we found out that, ctDNA-based MRD monitoring seems to better reflect, the residual disease in the lymph nodes. What we found, or what we wanted to find out in this analysis now is whether ctDNA-based analysis [is] able to earlier detect relapses. 

We had a few relapses only in the study so far, but what we could see was that the ctDNA-based monitoring was able to earlier detect relapses and molecular relapses compared to flow cytometry-based MRD monitoring. We were going to further explore this ctDNA-based approach. It's still quite experimental and we wouldn't recommend [using] it as a standalone method at the moment, but we can imagine using it together with a cell-based method, already now. 

So, taken together, I think we can state that the triplet combination of acalabrutinib, venetoclax, and obinutuzumab led to very deep remissions in almost all patients with 93% being MRD negative at some point during the study. Despite the rather short treatment duration of a little bit more than 1 year, we achieved a progression-free survival rate of 88% at 30 months.

Source: 

Furstenau M, Giza A, Fink AM, et al. 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. Presented at the ASH 65th Annual Meeting & Exposition; December 9-12 2023; San Diego, California. Abstract 203