MRD-Driven Time-Limited Therapy of Acalabrutinib and Lenalidomide Plus Rituximab (ALR) or Obinutuzumab (ALO) in Patients with Treatment-Naïve Mantle Cell Lymphoma: Phase 2 Trial Outcomes with MRD and cfDNA Analyses
Authors: Ruan Jia , Bond David A. , Shah Bijal D , Allan John N. , Rutherford Sarah C. , Gribbin Caitlin , Chen Zhengming , Hobbie Brittany , Harbhajan Melinda , Sahni Tejasvi , Tam Wayne , Bhinder Bhavneet , Sigouros Michael , Inghirami Giorgio , Chen-Kiang Selina , Elemento Olivier , Maddocks Kami J. , Leonard John P. , Martin Peter 
Published: December 2024

BACKGROUND: Initial treatment for mantle cell lymphoma (MCL) continues to evolve with the optimization of targeted agents. We previously reported durable efficacy of the lenalidomide and rituximab (LR) regimen as frontline MCL therapy (NEJM 2015:373:1835; Blood 2018:132:2016). We hypothesized that the addition of acalabrutinib (A), a next-generation BTK inhibitor, to LR (ALR) would accelerate molecular CR, allowing response-adapted and time-limited treatment. We also explored feasibility of the obinutuzumab-based triple combination of ALO. We report the mature finding of the triplet ALR, as well as preliminary data on ALO.
METHODS: The study included induction and maintenance, with acalabrutinib provided at 100 mg BID continuously. Lenalidomide was administered at 15 mg during induction (cycles 1-12), with dose escalation to 20 mg if tolerated, then dose reduced to 15 mg during maintenance. For ALR (n=24), rituximab was administered weekly x 4 during cycle 1, then once every other cycle throughout induction and maintenance. For ALO (n=10), obinutuzumab was administered weekly x 3 during cycle 1, monthly for cycles 2-6, then once every other cycle for study duration. Acalabrutinib and lenalidomide could be discontinued after 24 cycles of treatment for subjects achieving MRD-undetectable CR. All treatment could be discontinued after 36 cycles. The primary objective was MRD-undetectable (&lt;10-6) CR rate at the conclusion of ALR induction therapy. Secondary objectives included safety, response rates by Lugano criteria, survival. Exploratory objectives included peripheral blood MRD (PB-MRD) and cfDNA. PB-MRD was measured with AdaptiveBiotech ClonoSeq assay. Tumor genomic mutation profile and cfDNA were assessed by CAPP-Seq NGS with bioinformatic pipeline for variant calling.
RESULTS: 24 subjects were enrolled for ALR, 10 for ALO, and the study met its accrual. At study entry, median age was 64 years (range 35-82), and the M:F ratio was 4:1. All patients had stage III/IV disease, 38% had elevated LDH, and 91% had bone marrow involvement. MIPI scores were 38% low-, 32% intermediate-, and 29% high-risk. Ki67 index was &lt;30% in 65% subjects. TP53 mutations were detected in 29% of subjects. Treatment was associated with 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%), and vomiting (4%). Routine infections were mostly grade 1/2; COVID-19 infection was common (88%) due to the Omicron wave. For ALR, all 24 (100%) patients completed induction and moved onto maintenance. The ORR was 100% (90%CI=88%-100%) and CR 83% (90%CI=66%-94%) after 12 cycles of induction. PB-MRD was undetectable (&lt;10-6) in 50% patients (12 of 24) after 6 cycles, 67% (16 of 24) after 12 cycles, and 77% (17 of 22) after 24 cycles. 83% patients (5 of 6) with TP53 mutations achieved molecular CR after 12 cycles. Three patients progressed while on maintenance therapy, including 2 with TP53 mutations. 16 (67%) patients in molecular remission discontinued all study treatment including at least Acala-Len x24 cycles and R maintenance x36 cycles, and stayed in remission. At a median follow-up of 41 months (range 37-51), the 3-yr OS and PFS for ALR were 95.2% (95%CI=86%-100%) and 87.5% (95%CI=74%-100%), respectively. MIPI score, Ki67 index, TP53 mutations, or MRD status had no impact on survivals. For ALO (n=10), both ORR and CR were 90% (90%CI=61%-100%) following induction. PB-MRD was undetectable (&lt;10-6) in 89% patients (8 of 9) after 6 cycles, 100% (9 of 9) after 12 cycles. At a median follow-up of 17 months (range 13-19), the 1-yr OS and PFS were both 100% (95%CI=100%-100%). Biomarker study with longitudinal cfDNA analysis in ALR revealed clonal evolution of pre-existing as well as new TP53 mutation subclones at time of relapse as possible resistance mechanisms.
CONCLUSIONS: This study demonstrates that the ALR regimen has high rates of durable complete and molecular responses, and is feasible as a time-limited initial therapy for patients with both TP53 wild type and mutant MCL. The ALO regimen is feasible with encouraging initial safety and efficacy. MRD and cfDNA analyses provide real-time and non-invasive monitoring of molecular response and mutational evolution, which warrants further evaluation in response-adapted strategy (ClinicalTrials.gov - NCT03863184).