Complex Karyotype Is a Significant Predictor for Worst Outcomes in Patients with Mantle Cell Lymphoma (MCL) Treated with BTK Inhibitors - Comprehensive Analysis of 396 Patients

Introduction: Complex karyotype (Cx) refers to ≥3 unrelated cytogenetic abnormalities in addition to t(11;14) in MCL patients (pts). In limited pts treated with chemotherapy, pts with Cx exhibited poor outcomes compared to non-Cx group. Prognostic impact of Cx in pts treated with BTKi is unclear. We present the largest and most comprehensive analysis on the prognostic impact of Cx in MCL pts. Methods: We analyzed charts from 396 MCL pts with karyotype data. (271 were non-Cx and 125 were Cx). Karyotype status at initial MCL diagnosis was denovo (DN) while previously treated pts were secondary (S). Among Cx, n=80 pts were DN-Cx and 45 were S-Cx while in non-Cx group, 224 were DN-non-Cx and S-non-Cx were 47 pts. TP53 mutation/FISH data was available (n=134; 46 positive, 88 negative). Pt characteristics were obtained from the time of karyotype testing (at initial diagnosis in DN and at the time of testing in S group). Overall survival (OS) was calculated from test date to the last follow up and progression free survival (PFS) after first line therapy from treatment date to date of progression/death. Univariate and multivariate logistic regression modeled the risk of event and treatment response. Results: Cx pts had significant differences compared to non-Cx, including median Ki-67 (40 vs 20%), sMIPI (median 6 vs 4), poor performance status (p.s.), CNS involvement (7 vs 2%), blastoid (22 vs 7%), pleomorphic (12 vs 3%), higher LDH, WBC, ALC and β2M levels and low Hb and platelet counts, prior BTKi (35 vs 15%), TP53 positive (75 vs 17%), shorter median follow up from the test date (18 vs 33 months). Overall, 70 (56%) in Cx and 70 (26%) in non-Cx had died. Univariate analysis for OS showed, advanced age, higher values of Ki-67, WBC, LDH, β2M, MIPI scores, number of chromosomal aberrations, B symptoms, splenomegaly, CNS involvement, poor p.s., prior BTKi, blastoid/pleomorphic histology, TP53 positive status, non-responder to first line therapy and Cx (median 35 months vs 101 months in non-Cx respectively; p In addition to other factors, Cx was associated with shorter PFS in univariate (median 12 vs 48 months for non-Cx; p Among the 107 pts with Cx and 221 with non-Cx with available treatment data, 31 in Cx (1-C) and 101 in non-Cx were treated with BTKi with/without chemo-immunotherapy. Median PFS in both Cx and non-Cx groups was significantly longer with BTKi based therapies compared to R-HCVAD, R-Chemo and other therapies (excluding CAR-T and 1 pt with venetoclax-BTKi). PFS in S-Cx category (n=36), the worst category for survival outcomes, was not influenced by BTKi but was improved with CAR-T therapy (1-D). BTKi therapy improved PFS and OS in Cx and DN-Cx categories compared to R-HCVAD, R-chemo, other therapies (with/without SCT) but did not impact on S-Cx category with the worst outcomes. Response rate to BTKi were (92% vs 74%; p=0.01) in pts with non-Cx and Cx respectively. Conclusions: Cx pts remain a high risk MCL cohort in the BTKi era. Within Cx pts, DN-Cx had better outcomes compared to S-Cx category with the worst outcomes. Outcomes and treatment responses in non-Cx were significantly superior compared to Cx pts. CAR-T therapy holds a great promise for improving outcomes in S-Cx karyotype MCL patients. Download : Download high-res image (620KB) Download : Download full-size image Disclosures Westin: BMS: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Curis: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; 47: Research Funding; Novartis: Consultancy, Research Funding; Amgen: Consultancy. Nastoupil: Bayer: Honoraria; Gamida Cell: Honoraria; Gilead/KITE: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Karus Therapeutics: Research Funding; Genentech, Inc.: Honoraria, Research Funding; LAM Therapeutics: Research Funding; TG Therapeutics: Honoraria, Research Funding; Merck: Research Funding; Celgene: Honoraria, Research Funding. Vega: NCI: Research Funding. Flowers: Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; V Foundation: Research Funding; AbbVie: Consultancy, Research Funding; Bayer: Consultancy; BeiGene: Consultancy; Celgene: Consultancy, Research Funding; TG Therapeutics: Research Funding; Millennium/Takeda: Consultancy, Research Funding; Acerta: Research Funding; Spectrum: Consultancy; Pharmacyclics/Janssen: Consultancy; Karyopharm: Consultancy; OptumRx: Consultancy; Gilead: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Denovo Biopharma: Consultancy; Cancer Prevention and Research Institute of Texas: Research Funding; Kite: Research Funding; Leukemia and Lymphoma Society: Membership on an entity's Board of Directors or advisory committees. Wang: Acerta Pharma: Research Funding; Juno: Consultancy, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Oncternal: Consultancy, Research Funding; Lu Daopei Medical Group: Honoraria; Dava Oncology: Honoraria; Guidepoint Global: Consultancy; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; BioInvent: Research Funding; InnoCare: Consultancy; OMI: Honoraria, Other: Travel, accommodation, expenses; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; VelosBio: Research Funding; Verastem: Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; MoreHealth: Consultancy; Nobel Insights: Consultancy; Beijing Medical Award Foundation: Honoraria; OncLive: Honoraria; Targeted Oncology: Honoraria; Loxo Oncology: Consultancy, Research Funding; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Pulse Biosciences: Consultancy; Molecular Templates: Research Funding.