Dr Dreyling on the Efficacy of Frontline Acalabrutinib Plus BR in High-Risk MCL

"The ECHO regimen of chemotherapy plus a BTK inhibitor has greater benefits [vs chemotherapy alone] in the high-risk patients."

Martin Dreyling, MD, PhD, a full professor in the Department of Medicine and head of the Medical Clinic III at University Hospital/Ludwig-Maximilians-University Munich, contextualized the efficacy of acalabrutinib (Calquence) plus bendamustine and rituximab (Rituxan; BR) within the larger research paradigm for patients with high-risk mantle cell lymphoma (MCL).

The phase 2 ENRICH study (NCT01880567) investigated whether chemotherapy could be omitted entirely in favor of the BTK inhibitor ibrutinib (Imbruvica) combined with rituximab in older patients with previously treated MCL. The trial demonstrated that, among patients classified as having a low-risk disease profile, avoiding chemotherapy and instead using ibrutinib plus rituximab yielded superior outcomes compared with the standard-of-care chemotherapy regimens. This finding was significant, as it highlighted the advantages of a simpler, less toxic, oral-based therapy compared with the historically effective but highly toxic chemotherapy strategies that had been the standard for decades, according to Dreyling. He noted that these results prompted an important question: How should treatment be approached for patients with high-risk first-line MCL, and could the benefits of targeted therapy extend to this population?

In the ENRICH trial, data revealed that high-risk patients derived greater benefit from chemotherapy compared with a BTK inhibitor plus rituximab alone. Consequently, the phase 3 ECHO trial (NCT02972840) was designed to evaluate the combination of chemotherapy with a BTK inhibitor—BR plus acalabrutinib—in this higher-risk group. High-risk disease was defined by the presence of specific biological features, including blastoid variant histology, a Ki-67 proliferation index above 30%, or the presence of TP53 mutations. The identification of at least 1 of these features was sufficient to classify a patient as high risk.

The ECHO regimen had notable clinical benefits in this population, Dreyling explained. The complete response rate reached 66.6% in the acalabrutinib-treated overall study group (n = 299) and 67.9% among high-risk patients treated with acalabrutinib (n = 187). This improvement in response translated into a progression-free survival (PFS) advantage across the entire cohort. Subgroup analyses provided further insight: patients with blastoid morphology in the acalabrutinib arm (n = 41) achieved a more pronounced PFS benefit, with a HR of 0.59 (95% CI, 0.33-1.07; P = .0775) compared with 0.73 (95% CI, 0.57-0.94; P = .0160) in the overall study population. Similarly, patients with a Ki-67 index of at least 50% benefitted from the addition of acalabrutinib (n = 62), with an HR of 0.69 (95% CI, 0.42-1.09; P = .1138). The divergence of the PFS curves emphasized that chemotherapy alone was insufficient for managing high-risk disease, a clinical reality that had long been suspected and is now validated through this randomized trial evidence, Dreyling emphasized. However, due to the trial's small sample size, conclusions regarding patients with TP53 mutations could not be drawn, he concluded.