Matthew S. Davids, MD, MMSc, on Triplet Therapy of Acalabrutinib, Venetoclax, and Obinutuzumab: Focus on TP53-Aberrant CLL

We are fortunate in CLL that we have several different effective frontline treatment options for our patients. We have continuous therapy with BTK inhibitor drugs like acalabrutinib, and we also have time limited therapies like venetoclax plus obinutuzumab. And at this year's ASH meeting, we saw the phase three AMPLIFY results presented comparing an AVO triplet, all three drugs together versus AV as a doublet versus chemoimmunotherapy. And this is likely to be a registrational study that could lead to FDA approval of these regimens. However, the AMPLIFY study excluded patients with high risk CLL, meaning TP53 aberration, and that was the focus of our study of AVO. So we conducted a phase two multicenter investigator initiated clinical trial of this AVO triplet for patients with previously untreated CLL. We had initially published results in an all comers cohort of 37 patients showing that this regimen was very effective and well tolerated. So we then expanded the study to include 45 additional patients with TP53, aberrant high risk CLL. And at the 2024 ASH meeting, we presented and simultaneously published in Journal of Clinical Oncology the results of this study, which was enriched for patients with high risk disease. So in total with the 72 patients, 63% of the patients had high risk CLL. They were treated with this regimen that introduces acalabrutinib monotherapy followed by combination with obinutuzumab for two months, followed by the triplet therapy for three months, acalabrutinib, venetoclax and obinutuzumab. One little tweak that we made with the venetoclax is that we did a four week dose ramp up instead of the standard five week dose ramp up because these patients were very well debulked for tumor lysis syndrome risk. And this proved to be safe. These patients received 15 cycles of therapy and if they had undetectable minimal residual disease in the bone marrow and were in a complete response, then they could stop therapy at that point. Patients who still had residual disease would go on to get a second year of therapy to go to cycle 24 and then have a restaging assessment at the end of that cycle. And those patients could then also discontinue therapy. Patients who still had residual disease would continue on the AV doublet. Patients who later relapsed after completing time-limited therapy could go back on the AV doublet for re-treatment. In terms of the results of our study, so we've treated now 72 patients with the AVO triplet, and these patients had a median age in their mid sixties. Although we treated patients up to age 80 and the population was enriched for high risk disease, 63% of the patients had TP53 aberration. Despite these high risk features, the primary endpoint of the study, which is CR with bone marrow undetectable MRD at cycle 16 was 42%, both in patients with all comers genetics and the same number 42% in patients with high risk disease. When we look strictly at bone marrow undetectable MRD rates at that same time point cycle 16, 70% of the with high risk disease achieve that milestone and 78% of the patients of all comers achieve that same milestone. So these are very deep responses that we're seeing with triplet based therapy and it's also been very well tolerated. So these patients have had low rates of atrial fibrillation and hypertension. There have been some infectious complications as we expect with CLL, but nothing out of the ordinary and most patients have really tolerated this triplet regimen well, with regard to progression events, there have been 10 progression events on study. These include six progression events due to CLL and four transformation events. Overall, the PFS so far at four years looks very promising. So for those patients with TP53 aberrant disease, it's a 70% PFS at four years, and for those all comers, it's 88% at four years. So we think this is a very effective regimen in the high risk population. The efficacy does look similar to AVO from AMPLIFY in the high risk patients here. And so we think this really does support the use of the AVO triplet as a standard of care option for high risk patients with CLL as a first treatment. We will await the results of ongoing phase three trials, comparing the AVO triplet to venetoclax and obinutuzumab, which could define this as a new standard of care for high risk CLL.