Favorable Overall Survival Following First and Second Relapse of MCL with Availability of Novel Therapies: Results from the Lion Prospective Observational Registry

Background: Mantle cell lymphoma (MCL) is an uncommon type of non-Hodgkin lymphoma (NHL) associated with a high rate of relapse following frontline treatment, but with expanding treatment options for relapsed/refractory (RR) disease. Historically, outcomes for RR MCL have been unfavorable compared with indolent NHL subtypes, however survival data with more recently approved therapies is less well characterized. We report survival data following 2nd and 3rd line therapy for RR MCL in a large contemporary prospective cohort.

Methods: We included patients (pts) with RR MCL enrolled in the Lymphoma Innovations ORIEN Network (LION) prospective observational registry at one of seven participating centers. The LION Cohort is a 7-center cohort project which enrolls patients with relapsed/refractory NHL. All patients signed written consent. Clinical data were abstracted from medical records using a standardized protocol. Event free survival was estimated using the method of Kaplan-Meier and defined as time from start of 2nd (EFS2) or 3rd (EFS3) line treatment until progression, subsequent treatment, or death censoring pts alive and without further treatment or relapse at last follow-up. Overall survival was estimated using Kaplan-Meier and defined as time from start of 2nd (OS2) or 3rd (OS3) line treatment until death, censoring pts alive at last follow-up. Comparisons of EFS and OS were performed using the log-rank test.

Results: A total of 128 eligible pts with RR MCL consented between 2/5/2020 and 7/8/2022. Pts received 2^nd line treatment between 2002- 2021; 84% (107/128) after November 2013. Baseline characteristics included male sex in 95 pts (77%), stage III/IV disease in 110 pts (91%), progression within 24 months (mo) of initial treatment (POD24) in 43 pts (34%). Median age at first relapse was 65 years. Second line treatments included BTK inhibitors (BTKi) in 61 pts (50%), bendamustine based therapy in 14 pts (12%), lenalidomide and/or bortezomib based therapy in 14 pts (12%), venetoclax in 3 pts (3%), and other classes of treatment in 30 pts (25%). After a median follow-up of 45 mo, the estimated median EFS2 was 26 mo (95% confidence interval [CI] 15-38), with a 24-month estimated EFS2 of 51% (95% CI 41-60) and 5-year estimated EFS2 of 24% (95% CI 14-34). The estimated 24-month OS2 was 91% (95% CI 84-96) and 5-year estimated OS2 was 84% (95% CI 74-90). Third line treatments included BTKi in 36 pts (47%), chimeric antigen receptor T-cell (CAR-T) in 10 pts (13%), bendamustine based therapy in 5 (7%), venetoclax in 3 (4%), lenalidomide and/or bortezomib in 3 (4%), and other treatments in 20 (26%). After a median follow-up of 34 mo from 2nd relapse, the estimated median EFS3 was 19 mo (95% CI 12-49), with a 24-month EFS3 of 47% (95% CI 34-58) and 5-year EFS3 of 29% (95% CI 16-43). The estimated 24-mo OS3 was 84% (95% CI 72-91) and 5-year estimated OS3 of 73% (95% CI 57-84). POD24 was associated with inferior EFS2, with estimated median EFS2 9.7 mo (95% CI 5.1-23.6) vs 34.4 mo (95% CI 18.4-45.9) for non-POD24 pts (p=0.0025). POD24 from frontline treatment was also associated with inferior EFS3 among pts with indexed third line therapy with median EFS3 15.6 mo (95% CI 8-37) for POD24 and 49.1 mo (95% CI 11-84) for non-POD24 pts (p=0.04). No significant differences were observed in EFS2 between pts treated with BTKi, with median EFS2 21 mo (95% CI 10-34), compared with other classes of second-line treatment with median EFS2 of 35 mo (95% CI 14-46, p=0.37). Likewise, EFS3 was not significantly different between patients treated with third-line BTKi with estimated median EFS3 of 54 mo (95% CI 11-not reached) compared to CAR-T with estimated median EFS3 of 9 mo (95% CI 3-19), compared to other third line treatments with median EFS3 of 20 mo (95% CI 10-49, p=0.4).

Conclusions: We observed a median EFS2 of 26 mo and median EFS3 of 19 mo in a contemporary prospective cohort of pts with RR MCL. We did not observe an association between class of treatment received and EFS2 or EFS3, but observed inferior EFS2 and EFS3 for patients with POD24 following frontline therapy compared with patients with later first relapse highlighting the higher risk nature of this population. The observed OS2 and OS3 outcomes in this prospective cohort exceed historical estimates for relapsed MCL prior to availability of newer therapies, provide context for interpreting single arm trial results, and may inform future clinical trial design.

Bond:Kite/Gilead: Consultancy, Honoraria; Nurix: Research Funding; Novartis: Research Funding; SeaGen: Consultancy, Honoraria. Romancik:AstraZeneca: Membership on an entity's Board of Directors or advisory committees. Farooq:MorphoSys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite, a Gilead Company: Honoraria; Caribou pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Checkmate Pharma: Research Funding. Ayyappan:abbvie: Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; beigene: Membership on an entity's Board of Directors or advisory committees; Fate therapeutics: Membership on an entity's Board of Directors or advisory committees; Intellisphere: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle genetics: Membership on an entity's Board of Directors or advisory committees; TG therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Total CME: Speakers Bureau. Churchman:M2Gen: Current Employment. 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:Abbvie: Consultancy; Incyte: Consultancy; Kite: Consultancy; Genentech: Consultancy; AstraZeneca: Consultancy; Genmab: Consultancy; Pfizer: Research Funding; Janssen: Consultancy; Gilead: Consultancy; Pharmacyclics: Consultancy, Research Funding; BMS: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Acerta: Consultancy; Beigene: Consultancy; Celgene: Consultancy; Lilly: Consultancy; Morphosys: Consultancy. Link:Bristol-Myers Squibb: Research Funding; Jannsen: Research Funding; Novartis: Research Funding; MEI: Consultancy; Genentech / Roche: Consultancy, Research Funding. Cohen:BMS/Celgene: Research Funding; Aptitude Health: Consultancy; Lilly Oncology/Eli Lilly: Consultancy, Research Funding; Janssen: Consultancy; Kite Pharma/Gilead: Consultancy; HutchMed: Consultancy, Research Funding; Takeda: Research Funding; BeiGene: Consultancy, Research Funding; Astrazeneca: Consultancy, Research Funding; Novartis: Research Funding; Genentech: Research Funding. Stephens:Arqule: Research Funding; Karyopharm: Research Funding; Mingsight: Research Funding; Acerta: Research Funding; JUNO: Research Funding; Newave: Research Funding; Novartis: Research Funding; Epizyme: Consultancy; AbbVie: Consultancy; AstraZeneca: Consultancy; TG Therapeutics: Consultancy; CSL Behring: Consultancy; Beigene: Consultancy; Celgene: Consultancy; Genentech: Consultancy; Lilly: Consultancy.

Patients treated with off label venetoclax for mangel cell lymphoma included in observational analysis