Type: Oral
Session: 623. Mantle Cell, Follicular, Waldenstrom’s, and Other Indolent B Cell Lymphomas: Clinical and Epidemiological: Updates on Drug Treatments for Mantle Cell Lymphoma, and CAR-T and Transplants for Indolent Lymphomas
Hematology Disease Topics & Pathways:
Research, Clinical trials, Lymphomas, Clinical Research, B Cell lymphoma, Diseases, Lymphoid Malignancies, Measurable Residual Disease
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 (<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 <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 (<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 (<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).
Disclosures: Ruan: AstraZeneca: Honoraria, Research Funding; Genentech: Research Funding; BMS: Honoraria, Research Funding; Janssen: Honoraria. Bond: Kite/Gilead: Research Funding; BMS: Research Funding; Accutar: Research Funding; Nurix Therapeutics: Consultancy, Research Funding; GenMab: Research Funding; ADC Therapeutics: Consultancy; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Incyte: Research Funding. Shah: Kite Pharma: Consultancy; Autolus, Beigene, Century Therapeutics, Deciphera, Jazz, Kite/Gilead, Pfizer, Precision Biosciences, Novartis, Takeda: Consultancy; Jazz Pharmaceuticals: Consultancy; Eli Lilly: Consultancy; Adaptive Biotechnologies: Consultancy; Pepromene Bio: Other: DSMB; Jazz Pharmaceuticals, Kite-Gilead, Servier: Research Funding; Amgen: Consultancy; AstraZeneca: Consultancy; Bristol Myers Squibb: Consultancy. Allan: TG Therapeutics: Consultancy, Research Funding; Epizyme: Consultancy; BeiGene: Consultancy, Speakers Bureau; AstraZeneca: Consultancy; AbbVie: Consultancy, Speakers Bureau; ADC Therapeutics: Consultancy; Janssen: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Speakers Bureau. Rutherford: Seagen: Consultancy; Karyopharm: Consultancy, Other: DSMB, Research Funding; ADC Therapeutics: Consultancy; BMS: Consultancy; Pfizer: Consultancy; Genmab: Consultancy; Kite: Consultancy; Genentech: Research Funding; Constellation: Research Funding. Inghirami: Daiichi Sankyo: Consultancy. Maddocks: Janssen: Consultancy; Incyte: Consultancy; Lilly: Consultancy; Gilead/KITE: Consultancy; BMS: Consultancy; Genentech: Consultancy; AbbVie: Consultancy; ADC Therapeutics: Consultancy; AstraZeneca: Consultancy; Genmab: Consultancy; MorphoSys: Consultancy. Leonard: AbbVie, AstraZeneca, Astellas, Bayer, BeiGene,BMS, Calithera, Caribou Bioscences, Constellation, Eisai, Epizyme,GenMab, Grail, Incyte, Janssen, Karyopharm, Lilly, Merck, Mustang Bio, Novartis, Pfizer, Roche/Genentech, Seagen, Second Genome, Sutro, Treelin: Consultancy, Honoraria. Martin: AbbVie, AstraZeneca, Beigene, Daiichi Sankyo, Genentech, Janssen, Merck, Pepromene: Consultancy.
OffLabel Disclosure: Acalabrutinib, lenalidomide, obinutuzumab for frontline treatment of mantle cell lymphoma