ICML 2025 | Acalabrutinib, lenalidomide, and rituximab in previously untreated indolent B-cell lymphoma

This year at ICML we will present the results of a Phase II study of the combination of acalabrutinib, lenalidomide and rituximab, also referred to as AR2, in patients with previously untreated advanced stage and high tumor burden per GALL criteria, indolent lymphoma, including overall 50 patients with follicular lymphoma and 10 patients with marginal zone lymphoma. This was a multi-center Phase II study, including not only MD Anderson, but also a community hospital located in Houston called LBJ Hospital, and so overall a trial able to represent diversity. In this trial, Acalabrutinib was given at the dose of 100 milligrams by mouth twice a day in a 28-day cycle as a monotherapy for the first cycle. And R-squared was added from cycle 2 to cycle 13, so overall 13 cycles, and the standard dose of lenalidomide 20 milligrams by mouth on days 1 to 21, still in a 28-day cycle. 

So what we saw in this trial is that first of all, I need to emphasize the population included was a very high risk population with very large median largest diameter, more than five centimeters, baseline SUV maximum above 10, and about 75 percent of patients had a high or intermediate FLIPI score. The treatment was quite safe when we looked into treatment emergent adverse events. We didn’t see, with all the limitation of interstudy comparison, any synergy in terms of toxicity as compared to R-squared alone. Of course, we saw some adverse events more typical of Acalabrutinib such as headache, but it was mostly low grade grade one or grade two and mainly during the first cycle. 

But what was really impressive was the efficacy. When we look into the all population, so including the all 60 patients with either follicular or marginal zone lymphoma, the complete response rate was higher than 90 percent and when limited to marginal zone lymphoma was actually 100 percent. We now have a median follow-up of almost two years. Median PFS and overall survival haven’t been reached yet and the two-year PFS rate is higher than 80 percent and the two-year overall survival rate is higher than 90 percent. These are very promising data now in a quite large data set and hopefully they’re going to represent the basis for future trials where we’re going to enroll more marginal zone lymphoma patients but most importantly where hopefully we will be able to compare in a randomized fashion six cycles of AR-squared to the standard treatment which is currently in the US mainly represented by BR for six cycles and hopefully finally challenge the paradigm that frontline chemoimmunotherapy is the only standard treatment option for high tumor burden and advanced stage in indolent lymphoma patients.

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