Combination Treatment of Acalabrutinib-Lenalidomide-Rituximab and Observing MRD in Patients With Treatment-Naïve MCL: Phase 2 Trial Results

Combination Treatment of Acalabrutinib-Lenalidomide-Rituximab and Observing MRD in Patients With Treatment-Naïve MCL: Phase 2 Trial Results


The study included induction and maintenance therapy, with acalabrutinib provided at 100 mg two times a day, continuously. Lenalidomide was administered at 15 mg daily on days 1-21 of a 28-day cycle for 12 cycles during induction. Dose escalation reached 20 mg if tolerated, then the dose reduced to 15 mg during maintenance. Rituximab was administered weekly x 4 during cycle 1, then once every other cycle throughout induction and maintenance. Peripheral blood MRD (PB-MRD) was measured with AdaptiveBiotech ClonoSeq assay, and genomic mutation profile was assessed by CAPP-Seq NGS.

The primary objective is MRD-negative (<10-6) complete response (CR) rate at the conclusion of induction therapy. A sample size of 24 is required to achieve at least 20% of CR improvement with the acalabrutinib-lenalidomide-rituximab triplet from a historical CR of 60% with the lenalidomide-rituximab doublet (alpha=10%, power=80%). Acalabrutinib and lenalidomide could be discontinued after 24 cycles of treatment for subjects achieving MRD-negative CR.

From 10/2019 to 10/2021, 24 patients were enrolled, and the acalabrutinib-lenalidomide-rituximab study met its accrual. At entry, the median age was 64 years (range 35-77), and the M:F ratio was 3.8:1. All patients had stage III/IV disease, 21% had elevated lactate dehydrogenase (LDH), and 96% had bone marrow involvement. The Mantle Cell Lymphoma International Prognostic Index (MIPI) scores were 37% low-, 42% intermediate-, and 21% high-risk. The Ki67 index was <30% in 63% of subjects, and TP53 mutations were detected in 29% of subjects. At a median follow-up of 19 months in July 2022, all 24 patients remained in the study without evidence of progression, including 21 who have completed 12 cycles of induction and 11 who have completed 24 cycles of treatment.

Of the 21 patients who were evaluable for primary endpoint, the overall response rate was 100% and the CR was 90.5% after 12 cycles of treatment. PB-MRD was undetectable in 50% of patients after 6 cycles, 71% after 12 cycles, and 82% after 24 cycles. This included 80% of patients with TP53 mutations achieving MRD-negative CR after 12 cycles. To date, seven patients in MRD-negative CR have discontinued acalabrutinib and lenalidomide. Mutational status was determined in 21 patients; the most frequent mutations included IGLL5, ATM, CCND1, TP53, BCL6, NSD2, SF3B1, STAG2, and ZFHX4. MIPI score, Ki67 index, or TP53 mutational status had no impact on the response, whether assessed with Lugano criteria or PB-MRD.

Overall, treatment was well tolerated with the expected side effects. Grade 3-4 hematologic toxicities included asymptomatic neutropenia (38%), thrombocytopenia (4%), and anemia (4%). Grade 3-4 non-hematologic toxicities included rash (42%), fatigue (4%), nausea (4%), vomiting (4%), and hyponatremia (4%). Sixteen patients (67%) experienced COVID-19 infection during the Omicron wave and all made a full recovery with supportive care. Four incidences of a 2nd malignancy were reported, including one renal cell carcinoma requiring removal and three non-melanomatous skin cancers.

Dr Ruan et al concluded, “Real-time MRD analysis facilitates response-adapted treatment de-escalation during maintenance to minimize toxicity, which warrants further evaluation. An expansion cohort of acalabrutinib-lenalidomide-obinutuzumab is being launched.”


Ruan J, Leonard JP, Chen GZ, et al. Phase 2 trial of acalabrutinib-lenalidomide-rituximab (ALR) with real-time monitoring of MRD in patients with treatment-naïve mantle cell lymphoma. Abstract presented at: ASH Annual Meeting; Dec 10-13, 2022; New Orleans, Louisiana, and virtual. Abstract 73.