ASH 2024 | A trial of acalabrutinib, lenalidomide, and rituximab or obinutuzumab in treatment-naïve MCL

At this meeting, we reported our Phase II study, which used a combination of novel agents without chemotherapy. That is acalabrutinib plus lenalidomide plus rituximab or obinutuzumab as a triplet regimen for patients with previously untreated mantle cell lymphoma. As you know, the initial therapy for mantle cell lymphoma is continued to be under development And now that there’s more and more evidence suggesting that novel agents’ combination without chemotherapy has been very effective. So previously, we reported the doublet, which is the rituximab plus lenalidomide. And based on that result, we evaluate to add additional BTK inhibitor acalabrutinib as a triplet combination. We hope that the combination has synergistic activity and can achieve deep remission measured by MRD assay. And the second point is in doing so, perhaps we can use MRD response as a response adapted strategy so that we can minimize prolonged maintenance and therefore reduce toxicity. So this study enrolled 24 patients for the ALR cohort and they’re fairly typical mantle cell-informed patients that you would encounter in the community practice. There’s a male predominance, they have advanced stage disease and they have median age in the range of 64 to 65 years. We also looked at risk factors such as MIPI score or Ki-67 or TP53 mutational status by sequencing. And it’s fairly typical. We saw about maybe 25 to 30% TP53 mutated patient in this cohort. It turns out this combination is quite well tolerated. The hematological toxicity included grade 3 asymptomatic thrombocytopenia, anemia, and neutropenia. All of those were expected. We did not see febrile neutropenia. We also saw common infection, grade 1 to 2, generally managed and resolved in the outpatient setting. Some patients end up with COVID-19 infection or pneumonia, but that happened during the COVID-19 omicron wave. We did not see that subsequent to it. And as far as the effectiveness, we measured the response by Lugano criteria. We also looked at cell-based clonal-seq assay for MRD analysis. And with the triple combination of ALR, we saw the molecular response rate about 50% after six rounds of treatment of induction and close to 67% at the end of the induction, which is 12 cycles, and improved to about 76% after 24 cycles of treatment. So based on those data, we were able to treatment de-escalate 13 patients after 24 cycles of treatment. So they stopped oral agent and they could also stop all treatment, which is including the rituximab maintenance after 36 cycles of treatment. And now they’re being monitored off treatment for clinical remission status as well as MRD analysis. And in addition, we started a feasibility ALO cohort, which replaced rituximab with obinutuzumab, we enrolled 10 patients. And this regimen has very similar adverse event profile compared to the ALR regimen. And also very notably, we saw a very rapid molecular response during induction with the ALO combination. So I think even though it’s very early, it looks quite promising that we could consider obinutuzumab as a component of the novel agent combination. And, you know, finally, we also looked at cell-free DNA analysis in the ALR cohort. I think the advantage of cell-free analysis with that not only, you know, it provides MRD information, but also more specific mutational profile in a real-time fashion. So that provides some insights as to the mechanism of treatment progression or treatment resistance. We discovered that there are new TP53 subclones at the time of disease progression. So we’re quite excited to share our Phase II study data with ASH 2024 and we look forward to long-term results with longer follow-up. Thank you.

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