Research Summary

Phase 2 MRD-Driven Acalabrutinib Triplets Show Molecular Complete Responses in Frontline MCL

Edited by:
Anthony Calabro, MA

Key Highlights

  • This open-label, multicenter phase 2 study evaluated acalabrutinib and lenalidomide with rituximab or obinutuzumab as initial therapy for previously untreated mantle cell lymphoma.
  • After 12 cycles of induction, the ALR cohort had a 100% overall response rate, 83% complete response rate, and 67% molecular complete response rate.
  • In the ALO feasibility cohort, overall response, complete response, and molecular complete response rates were 90% after induction.
  • Longitudinal MRD monitoring by clonoSEQ supported response-adapted treatment de-escalation in patients achieving molecular complete response.

MRD-driven initial therapy with acalabrutinib and lenalidomide plus rituximab (ALR) or obinutuzumab (ALO) was feasible and associated with high rates of durable molecular response in patients with previously untreated mantle cell lymphoma (MCL), according to findings from an open-label, multicenter phase 2 study. The journal name was not provided in the source material.

The study evaluated whether adding the next-generation Bruton tyrosine kinase inhibitor acalabrutinib to lenalidomide and anti-CD20 antibody therapy could support a response-adapted, time-limited treatment approach. The primary objective was molecular complete response (CR) after 12 cycles of induction, defined as CR by Lugano criteria with undetectable minimal residual disease at less than 10⁻⁶ (uMRD6) by clonoSEQ.

Researchers enrolled patients with previously untreated MCL who had measurable disease and required systemic therapy. Eligible patients had an Eastern Cooperative Oncology Group performance status of 2 or lower and adequate organ function. Key exclusions included central nervous system lymphoma, known HIV infection, active hepatitis B or C, and invasive malignancies within 5 years.

The study included 24 patients treated with ALR and 10 patients treated with ALO. Acalabrutinib was administered at 100 mg twice daily continuously. Lenalidomide was given during induction cycles 1 through 12, with dose escalation if tolerated, followed by dose reduction during maintenance. Patients in molecular CR were eligible to discontinue acalabrutinib plus lenalidomide after 24 cycles, and all patients received a minimum of 36 cycles of anti-CD20 antibody treatment. Responses were assessed by Lugano criteria, and longitudinal MRD monitoring was performed using clonoSEQ in peripheral blood and cell-free DNA analysis by cancer personalized profiling by deep sequencing.

Study Findings

A total of 34 patients with previously untreated MCL requiring therapy were enrolled. Median age was 64 years in the ALR cohort and 65 years in the ALO cohort. All patients had stage III/IV disease, and approximately 60% had intermediate- or high-risk MCL International Prognostic Index scores. TP53 mutations were detected in 25% of patients in the ALR cohort and 30% in the ALO cohort.

In the ALR cohort, all 24 patients completed induction and entered maintenance. After 12 cycles, the overall response rate was 100% and the CR rate was 83% by Lugano criteria. Peripheral blood uMRD6 was achieved in 16 of 24 patients, or 67%, after 12 cycles. Four additional patients achieved uMRD6 later, resulting in a best molecular CR rate of 83%. At a median follow-up of 53 months, 4-year overall survival was 91% and 4-year progression-free survival was 76%. TP53 mutations were adversely associated with progression-free survival (P = .026).

In the ALO cohort, 9 of 10 patients entered maintenance after induction. Overall response, CR, and molecular CR rates were 90% after induction. At a median follow-up of 25 months, 2-year overall survival and progression-free survival were both 100%.

Treatment was described as overall well tolerated, with expected adverse events. In the ALR cohort, grade 3/4 hematologic toxicities included neutropenia, thrombocytopenia, and anemia. Nonhematologic toxicities included rash, fatigue, nausea, and vomiting. Infections were mostly grade 1/2, except for COVID-19 infection and pneumonia requiring hospital care in some patients during the Omicron period; all recovered with supportive care.

Clinical Implications

According to the study authors, these findings suggest that ALR and ALO are feasible as chemotherapy-free, MRD-driven, time-limited initial therapy strategies for patients with MCL. The authors stated that longitudinal MRD monitoring provided a noninvasive approach for tracking molecular response and mutational evolution, supporting response-adapted treatment strategies.

The authors noted that the small sample size limited extrapolation and that larger studies are needed to validate outcomes of the response-adapted strategy. They also stated that TP53 mutations continued to challenge effective treatment strategies and were associated with inferior prognosis.

Expert Commentary

“This safe and active regimen is feasible as a time-limited initial therapy for patients with MCL and warrants further evaluation in response-adapted strategy,” the researchers concluded.

Reference
Ruan J, Bond DA, Shah B, et al. MRD-driven initial therapy of acalabrutinib and lenalidomide plus rituximab or obinutuzumab for mantle cell lymphoma. Published online 2025. PMID:41289154. PMCID:PMC12927050