Phase 2 Trial of Acalabrutinib-Lenalidomide-Rituximab (ALR) with Real-Time Monitoring of MRD in Patients with Treatment-Naïve Mantle Cell Lymphoma

BACKGROUND: Initial treatment for mantle cell lymphoma (MCL) continues to evolve with the introduction 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). Acalabrutinib, a next-generation BTK inhibitor, has shown high response rates in R/R MCL. We hypothesized that addition of acalabrutinib to LR regimen would synergize activity and accelerate MRD-negative CR, allowing response-adapted adjustment of treatment intensity to minimize toxicity. We report the preliminary finding of the triplet ALR as initial treatment for MCL.

METHODS: The study includes induction and maintenance, with acalabrutinib provided at 100 mg BID continuously. Lenalidomide is administered at 15 mg daily on days 1-21 of a 28-day cycle for 12 cycles during induction, with dose escalation to 20 mg if tolerated, then dose reduced to 15 mg during maintenance. Rituximab is administered weekly x 4 during cycle 1, then once every other cycle throughout induction and maintenance. Peripheral blood MRD (PB-MRD) is measured with AdaptiveBiotech ClonoSeq assay. Genomic mutation profile is assessed by CAPP-Seq NGS. The primary objective is MRD-negative (<10^-6) CR rate at the conclusion of induction therapy. Secondary objectives include safety, response rates by Lugano criteria, survival. A sample size of 24 is required to achieve at least 20% of CR improvement with the ALR triplet from a historical CR of 60% with the LR doublet (alpha=10%, power=80%). Acalabrutinib and lenalidomide can be discontinued after 24 cycles of treatment for subjects achieving MRD-negative CR.

RESULTS: From 10/2019-10/2021, 24 subjects were enrolled, and the ALR study met its accrual. At study entry, 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 LDH, and 96% had bone marrow involvement. MIPI scores were 37% low-, 42% intermediate-, and 21% high-risk. Ki67 index was <30% in 63% subjects. TP53 mutations were detected in 29% subjects. Treatment was well tolerated 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%), vomiting (4%) and hyponatremia (4%). Routine infections included URI (8%), UTI (4%), cellulitis (4%), sinusitis (8%), and zoster (8%). Sixteen patients (67%) experienced COVID-19 infection during the Omicron wave, including 6 (25%) grade 3 COVID-19 pneumonia, and 1 (4%) PE; all made full recovery with supportive care. Four incidences of 2^nd malignancy were reported, including 1 renal cell carcinoma requiring removal, and 3 non-melanomatous skin cancer. As of July 2022, at a median follow-up of 19 months, all 24 (100%) patients remain on study without evidence of progression, including 21 who have completed 12 cycles of induction, and 11 completed 24 cycles of treatment. Of the 21 patients evaluable for primary endpoint (other 3 premature for such), the ORR is 100% (90% CI = 87%-100%), and CR 90.5% (90% CI = 73%-98%) after 12 cycles of treatment. PB-MRD was undetectable (<10^-6) in 50% patients (12 of 24) after 6 cycles, 71% (15 of 21) after 12 cycles, 82% (9 of 11) after 24 cycles, including 80% patients (4 of 5) with TP53 mutations achieving MRD-neg CR after 12 cycles. To date seven patients in MRD-negative CR have discontinued acalabrutinib and lenalidomide. Mutational status was determined in 21 patients, and the most frequent mutations included IGLL5 (43%), ATM (38%), CCND1 (33%), TP53 (29%), BCL6 (24%), NSD2 (19%), SF3B1 (14%), STAG2 (14%), and ZFHX4 (14%). MIPI score, Ki67 index, or TP53 mutational status had no impact on response, assessed with Lugano criteria or PB-MRD.

CONCLUSIONS: This study demonstrates that triple chemo-free combination of acalabrutinib-lenalidomide-rituximab (ALR) is well tolerated, highly effective, and produces high rates of MRD-negative CR as initial treatment for MCL, including high risk patients with TP53 mutations. 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 (ClinicalTrials.gov - NCT03863184).

Ruan:Kite Pharma: Consultancy; Pharmacyclics: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; AstraZeneca: Research Funding; Seattle Genetics: Consultancy; Daiichi Sankyo: Consultancy, Research Funding. Leonard:Second Genome: Consultancy; Regeneron: Consultancy; BMS/Celgene: Consultancy; Novartis: Consultancy; Constellation: Consultancy; Epizyme: Consultancy; Eisai: Consultancy; Roche/Genentech: Consultancy; Sutro: Consultancy; Karyopharm: Consultancy; Genmab: Consultancy; Janssen: Consultancy; Gilead/Kite: Consultancy; Grail: Consultancy; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy; AstraZeneca: Consultancy; Bayer: Consultancy; Beigene: Consultancy; Astellas: Consultancy; AbbVie: Consultancy; Bristol-Myers Squibb: Consultancy; Mustang Bio: Consultancy; Merck: Consultancy; MEI Pharma: Consultancy; Lilly: Consultancy; Pfizer: Consultancy; Calithera: Consultancy; Incyte: Consultancy; Miltenyi: Consultancy. Allan:Epizyme: Consultancy; ADC Therapeutics: Consultancy; Ascentage: Consultancy; Celgene: Research Funding; TG Therapeutics: Consultancy, Research Funding; BeiGene: Consultancy, Speakers Bureau; PCYC: Consultancy, Speakers Bureau; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau. Rutherford:Kite Pharma: Consultancy; Celgene/Juno: Consultancy; Dova: Consultancy; Karyopharm: Consultancy, Research Funding; Genentech: Research Funding; ADC Therapeutics: Consultancy. Shah:Servier: Other: grants and investigator-initiated trials; PeproMene Bio: Other: Steering committee; Autolus: Consultancy; Century Therapeutics: Consultancy; Adaptive: Consultancy; Pharmacyclics: Consultancy; Beigene: Consultancy; Acrotech: Consultancy; Jazz: Consultancy, Other: grants and investigator-initiated trials; Precision Biosciences: Consultancy; Kite/Gilead: Consultancy, Other: grants and investigator-initiated trials; BMS/Celgene/Juno: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Amgen: Consultancy. Maddocks:Morphosys: Consultancy; Lilly: Consultancy; Beigene: Consultancy; AstraZeneca: Consultancy; Acerta: Consultancy; Janssen: Consultancy; Pfizer: Research Funding; Abbvie: Consultancy; Pharmacyclics: Consultancy, Research Funding; BMS: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Celgene: Consultancy; Genentech: Consultancy; Incyte: Consultancy; Kite: Consultancy; Genmab: Consultancy; Gilead: Consultancy. Elemento:Volastra Therapeutics: Consultancy, Current equity holder in publicly-traded company, Research Funding; Johnson and Johnson: Research Funding; Freenome: Consultancy, Other: Current equity holder in a privately-held company; One Three Biotech: Consultancy, Current equity holder in publicly-traded company; Owkin: Consultancy, Current equity holder in publicly-traded company; Champions Oncology: Consultancy; Janssen: Research Funding; Eli Lilly: Research Funding; AstraZeneca: Research Funding. Martin:ADCT: Consultancy; AstraZeneca: Consultancy; Beigene: Consultancy; BMS: Consultancy; Daiichi Sankyo: Consultancy; Epizyme: Consultancy; Genentech: Consultancy; Janssen: Consultancy; Regeneron: Consultancy; Takeda: Consultancy.

Lenalidomide and acalabrutinib for first-line use in mantle cell lymphoma