MRD-driven Initial Therapy of Acalabrutinib and Lenalidomide plus Rituximab (ALR) or Obinutuzumab (ALO) for Mantle Cell Lymphoma Open Access

• Time-limited initial therapy with ALR or ALO is feasible and has high rates of durable molecular responses in MCL.

• Longitudinal MRD provides non-invasive monitoring of molecular response and mutational evolution for response-adapted treatment strategy.

This phase 2 study evaluated the efficacy and safety of combining acalabrutinib (A) and lenalidomide (L) with either rituximab (ALR) or obinutuzumab (ALO), with longitudinal minimal residual disease (MRD) monitoring in frontline MCL treatment (ClinicalTrials.gov - NCT03863184). The primary objective was molecular CR after 12 cycles of induction, defined by Lugano criteria and undetectable MRD <10-6 (uMRD6) by clonoSEQ. Secondary objectives included safety, responses and survival. Exploratory objectives included tumor mutation profiles and cell-free DNA (cfDNA) by CAPP-Seq. Patients in uMRD6 molecular CR were eligible for discontinuation of A+L after 24 cycles; all patients received a minimum of 36 cycles of anti-CD20 antibody treatment. In the ALR cohort, grade 3-4 hematologic toxicities included neutropenia (38%), thrombocytopenia (4%) and anemia (4%). Non-hematologic toxicities included rash (42%), fatigue (4%), nausea (4%), and vomiting (4%). The ORR was 100%, CR 83% and molecular CR 67% after 12 cycles of induction, with best molecular CR at 83%. At a median follow-up of 53 months (range 46-60), the 4-yr OS and PFS for ALR were 91% and 76%, respectively. TP53 mutations were adversely associated with PFS (p=0.026). For ALO, ORR, CR and molecular CR were 90% following induction, and 2-yr OS and PFS were both at 100%. Longitudinal cfDNA analysis in ALR revealed clonal evolution during response and progression. This safe and active regimen is feasible as a time-limited initial therapy for MCL patients and warrants further evaluation in response-adapted strategy.