Acalabrutinib, venetoclax and obinutuzumab show high rates of clinical response in previously untreated CLL enriched for high-risk disease

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Published: 15 Dec 2022
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Dr Christine Ryan - Dana-Farber Cancer Institute, Boston, USA

Dr Christine Ryan speaks to ecancer as part of ASH 2022 about updated results from her study looking at the combination of acalabrutinib, venetoclax and obinutuzumab (AVO) in a population of previously untreated patients with CLL enriched for high-risk disease.

She explains that following results from the all-comer cohort where similar results were seen across all patients (even those with high-risk disease), a new cohort was enrolled specifically to observe results in this high-risk group.

Dr Ryan reports that very high rates of clinical response and MRD negativity were seen with the triplet regimen in this high-risk cohort.

In this study we looked at the combination of three different drugs, acalabrutinib, venetoclax and obinutuzumab, and really there is a strong rationale for triplet combinations in CLL that stems from using three drugs that have three distinct mechanisms of action. We know each of these drugs is effective in targeting CLL cells. Additionally, there have been studies investigating triplet novel agent regimens, specifically of ibrutinib, venetoclax and obinutuzumab, in CLL. While those studies showed very high rates of clinical responses, as well as MRD negativity, there were characteristic toxicities of ibrutinib seen, particularly with regard to cardiovascular side effects and some GI and musculoskeletal side effects as well. So, in this study we sought to employ a better-tolerated BTK inhibitor, acalabrutinib, in a triplet regimen.

What was the methodology used in the study?

Briefly, to review the treatment scheme of our study design, the three agents involved, as I said, are acalabrutinib, venetoclax and obinutuzumab. Very briefly, patients started with one cycle alone of acalabrutinib, then the obinutuzumab was started on cycle 2 and given for a total of six cycles, and then venetoclax was added at cycle four. We actually included an abbreviated ramp-up so patients received 50mg on day 2 of that cycle.

Then at cycle 16, so after 15 cycles on study, patients were assessed for the primary endpoint with full restaging as well as MRD testing. At that juncture there was a decision regarding treatment continuation. So if patients had achieved a complete response with undetectable MRD in the bone marrow they had the option of discontinuing therapy. Otherwise, patients who continued on therapy received an additional nine cycles of acalabrutinib and venetoclax before restaging again at cycle 25.

In total, in terms of the results that we presented at ASH, there are 68 patients enrolled at the time of data cut-off; 37 of those patients had been part of an initial all-comer cohort and 31 were part of an expansion cohort. One of the really notable findings in the results from the initial all-comer cohort was that we saw similar clinical outcomes in patients regardless of their TP53 status. So we enrolled a second cohort specifically for patients with high risk disease, so only those patients with TP53 aberrant disease. At ASH that was the first time we were reporting on results including specifically that cohort of high risk patients.

What were the updated findings?

Very encouragingly we saw very high rates of clinical response and MRD negativity with this triplet regimen. As I was discussing about the primary endpoint, in this study we set the primary endpoint as the rate of complete response with undetectable MRD in the bone marrow. In all patients 43% of them achieved that primary endpoint and, specifically in the subset of patients with TP53 aberrant disease, 45% also achieved that primary endpoint of a complete response with undetectable MRD in the bone marrow.

Across the board we saw high rates of undetectable MRD both in the peripheral blood and in the bone marrow, as measured by multicolour flow cytometry: rates over 80% in both blood and bone marrow, and, again, really no significant difference with regard to TP53 status.

What are the next steps for the study?

That’s a great question. We, at this point, are reporting on a median follow-up of just under three years and at this point we are seeing very high rates of progression free survival, so a 93% progression free survival at that median follow-up of just under three years. We are continuing to gather information on longer term follow-up for these patients and really our study provides a foundation for this time limited triplet in patients with high risk CLL. There is an ongoing phase III trial which you may be aware of that is investigating… it’s a randomised study investigating a doublet combination, so acalabrutinib and venetoclax, versus this triplet, acalabrutinib, venetoclax and obinutuzumab, versus standard chemoimmunotherapy. So that will provide head-to-head data on the doublet versus triplet. But, notably, that study only enrols patients with non-high risk CLL. So, while that study will provide very important and foundational results to establishing a potential role for this triplet in standard of care, our study really will provide the foundation for that specifically in patients with high risk CLL.