Background: Event-free survival at 24 months (EFS24) after frontline immunochemotherapy (IC) is an important endpoint in diffuse large B-cell lymphoma and follicular lymphoma, and patients who achieve EFS24 have similar survival compared to age- and sex-matched general population. The role of EFS24 in predicting subsequent survival has not been established in mantle cell lymphoma (MCL), possibly due to perceived poor survival historically. In the last decade, the outcomes of MCL are improving in the evolving treatment landscape. In this international multicenter study, we investigated conditional survival and cause of death in patients with MCL who achieved EFS24 after frontline IC in the older and more recent eras.
Methods: Outcomes after frontline IC were evaluated in 5 independent cohorts that included over 3000 patients in total: Mayo/Iowa MER prospective cohort, BC Cancer retrospective population-based cohort, US 12-center retrospective cohort, Swedish Lymphoma Registry, and Danish National Lymphoma Registry. For each cohort, 2 treatment eras were defined based on cohort-specific shifts in treatment patterns (Table 1). Overall survival (OS) after diagnosis and after achieving EFS24 were compared to the background age- and sex-matched general population using a standardized mortality ratio (SMR). Cumulative incidences of cause-specific deaths were analyzed using a competing risk model.
Results: In the MER cohort, patients treated in Era M1 (2002-2009; n=147) and Era M2 (2010-2015; n=153) both had inferior OS compared to the general US population. A lower SMR in Era M2 vs M1 (2.25 vs 3.46) suggests a narrower gap in OS compared to the general US population. Lymphoma was the leading cause of death in both eras. In Era M1, patients who achieved EFS24 still had inferior OS compared to the general US population (SMR=2.40, 95% CI 1.76-3.19), and lymphoma remained the leading cause of death. For patients in Era M2 who achieved EFS24, the difference in OS compared to the general US population was not statistically significant with current follow-up (SMR=1.43, 95% CI 0.93-2.09), and lymphoma was no longer the leading cause of death (Table 2).
In the BC cohort, patients treated in Era B2 (6/2013-2019; n=188) vs Era B1 (2003-5/2013; n=250) had a narrower gap in OS compared to the general British Columbia population (SMR 4.53 vs 6.69). Lymphoma was the leading cause of death in both eras. For patients achieving EFS24, the gap in OS was narrower in Era B2 vs B1 (SMR 3.56 vs 4.99). After achieving EFS24, lymphoma was the single leading cause of death for patients in Era B1 but not in Era B2 (Table 2).
In the US 12-center cohort, patients treated in Era U1 (2002-2011; n=312) and Era U2 (2012-2016; n=417) both had inferior OS compared to the general US population (SMR 2.68 and 2.92, respectively). In patients who achieved EFS24, with current follow up, the difference in OS compared to the general US population was statistically significant in Era U1 (SMR=2.01, 95% CI 1.50-2.64) but not in Era U2 (SMR=1.44, 95% CI 0.82-2.34). Lymphoma was not the leading cause of death after achieving EFS24 (Table 2).
In the Swedish cohort, the gap in OS compared to the general Swedish population was narrower in Era S2 (2013-2018; n=439) vs S1 (2006-2012; n=442), both after frontline IC (SMR 4.8 vs 5.4) and after achieving EFS24 (SMR 2.6 vs 3.4). After achieving EFS24, lymphoma was the leading cause of death for patients in Era S1 but not in Era S2 (Table 2).
In the Danish cohort, patients treated in Era D2 (2014-2020; n=370) vs Era D1 (2004-2013; n=461) had a slightly narrower gap in OS compared to the general Danish population (SMR 1.90 vs 2.10). For patients who achieved EFS24, those in Era D1 still had inferior OS compared to the general Danish population (SMR=1.44, 95% CI 1.22-1.68), but the OS difference compared to the general Danish population in Era D2 was not statistically significant (SMR=1.27, 95% CI 0.92-1.72) with current follow-up (Table 2). Cause of death data were not available in this cohort.
Conclusion: Survival in patients with MCL who achieved EFS24 after frontline IC improved in the more recent treatment era and moved closer to the background expected survival. After achieving EFS24, lymphoma-related mortality was no longer the leading cause of death in the more recent era. EFS24 following frontline treatment may become a critical endpoint for predicting subsequent outcomes in patients with MCL in the modern era.
Disclosures
Wang:TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Genmab: Research Funding; Morphosys: Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Genentech: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Innocare: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy. Farooq:MorphoSys: Consultancy; Kite, a Gilead Company: Honoraria; Caribou: Consultancy, Honoraria; Regeneron: Research Funding. Ekstroem Smedby:AbbVie: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding. Niemann:Carsten Niemann has received research funding and/or consultancy fees from AstraZeneca, Janssen, AbbVie, Beigene, Genmab, CSL Behring, Octapharma, Takeda, and Novo Nordisk Foundation.: Consultancy, Research Funding. Bond:Nurix Therapeutics: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; SeaGen: Consultancy; Incyte: Research Funding. Bachanova:BMS: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; ADC: Membership on an entity's Board of Directors or advisory committees; Allogene: Membership on an entity's Board of Directors or advisory committees; Miltenyi: Other: DSMB; Citius: Research Funding; Incyte: Research Funding; Gamida Cell: Research Funding. Barta:Acrotech: Consultancy; Affimed: Consultancy; Janssen: Consultancy; Daiichi Sankyo: Consultancy. Hill:Kite, a Gilead Company: Consultancy, Honoraria, Other: travel support, Research Funding; Genentech: Consultancy, Other: Advisory board, Research Funding; Bristol Myers Squibb: Consultancy; BeiGene: Consultancy; AbbVie: Consultancy, Other: Advisory board, Research Funding; AstraZeneca: Consultancy; Pharmacyclics: Consultancy, Other: Advisory board, Research Funding; Incyte: Consultancy; Gilead: Other: Advisory board. Martin:AbbVie, AstraZeneca, Beigene, Epizyme, Genentech, Gilead, Janssen, Pepromene, Daiichi Sankyo: Consultancy. Danilov:Cyclacel: Research Funding; Janssen: Consultancy; Astra Zeneca: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Bayer: Research Funding; Lilly Oncology: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; MEI: Consultancy, Research Funding; Nurix: Consultancy, Research Funding; Bristol Meyers Squibb: Consultancy, Research Funding; Genentech: Consultancy; GenMab: Consultancy, Research Funding; Merck: Consultancy. Grover:Seattle Genetics: Consultancy; Sangamo: Current holder of stock options in a privately-held company; Novartis: Honoraria; Tessa Therapeutics: Research Funding; Caribou Biosciences: Honoraria; Seagen: Honoraria; Genentech: Honoraria; Kite: Honoraria; ADC Therapeutics: Consultancy, Honoraria. Karmali:Kite/Gilead: Consultancy, Honoraria, Research Funding; Calithera: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Miltenyi: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; BeiGene: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding; Genentech/Roche: Consultancy, Honoraria; Lilly: Consultancy, Honoraria; Morphosys: Consultancy, Speakers Bureau; Janssen: Consultancy. Ghosh:AstraZeneca, Janssen, Pharmacyclics, Kite pharma, BMS, Epizyme: Speakers Bureau; Roche NHL solutions panel: Membership on an entity's Board of Directors or advisory committees; Seagen, TG Therapeutics, AstraZeneca, Phamacyclics, Janssen, Bristol Myers Squibb, Gilead Sciences, Kite Pharma, Beigene, Incyte, Lava Therapeutics, Incyte, Roche/Genentech, Novartis, Loxo Oncology, AbbVie, Genmab, Adaptive Biotech, ADC Therapeutics, Morp: Honoraria; TG Therapeutics, Genentech/Roche, Bristol Myers Squibb, Gilead, Morphosys, AbbVie, Pharmacyclics: Research Funding; Seagen, TG Therapeutics, AstraZeneca, Phamacyclics, Janssen, Bristol Myers Squibb, Gilead Sciences, Kite Pharma, Beigene, Incyte, Lava Therapeutics, Incyte, Roche/Genentech, Novartis, Loxo Oncology, AbbVie, Genmab, Adaptive Biotech, ADC Therapeutics: Consultancy. Fenske:TG Therapeutics: Consultancy, Speakers Bureau; Servier Pharmaceuticals: Consultancy, Speakers Bureau; Beigene: Consultancy, Speakers Bureau; Kite (Gilead): Consultancy, Speakers Bureau; MorphoSys: Consultancy, Speakers Bureau; Pharmacyclics (AbbVie): Consultancy, Speakers Bureau; SeaGen: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Astrazeneca: Consultancy, Speakers Bureau; Adaptive Biotechnologies: Consultancy, Speakers Bureau. Kahl:Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; ADCT: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Genmab: Consultancy, Honoraria; Lilly: Consultancy, Honoraria. Glimelius:Takeda, Janssen, Cilag, Lokon Pharma: Other: Educational Contributions, Support to Department; Lokon Pharma: Membership on an entity's Board of Directors or advisory committees. Stauffer Larsen:BMS: Consultancy; Gilead: Consultancy; Novartis: Consultancy; Roche: Consultancy. Maddocks:AbbVie: Consultancy; Pharmacyclics: Consultancy, Research Funding; Morphosys: Consultancy; Janssen: Consultancy, Honoraria; GenMab: Consultancy; Genentech: Consultancy; Incyte: Consultancy, Honoraria; ADC Therapeutics: Consultancy; Celgene: Consultancy, Research Funding; BMS: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Gilead/Kite: Consultancy; BeiGene: Consultancy; Epizyme: Consultancy; Eli Lilly and Company: Consultancy; Seattle Genetics: Consultancy; Novartis: Research Funding; Merck: Research Funding. Paludo:Biofourmis: Research Funding; Karyopharm: Research Funding; AbbVie: Consultancy. Nowakowski:Kite Pharma: Consultancy; Blueprint Medicines: Consultancy; TG Therapeutics: Consultancy; Abbvie: Consultancy; Celgene Corporation: Consultancy; Debiopharm: Consultancy; F Hoffmann-La Roche Limited: Consultancy; Genentech: Consultancy; Kymera Therapeutics: Consultancy; Karyopharm Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy; Incyte: Consultancy; Curis: Consultancy; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fate Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ryvu Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Consultancy; Bantam Pharmaceutical LLC: Consultancy; MorphoSys: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seagen: Consultancy; Selvita Inc: Consultancy; Zai Lab Limited: Consultancy. Habermann:Genentech: Research Funding; sorrento: Research Funding; BMS: Research Funding. Maurer:Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Research Funding; GenMab: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Research Funding. Villa:Roche, AstraZeneca, Abbvie, Janssen, Kite/Gilead, BMS/Celgene, BeiGene, Merck: Consultancy, Honoraria; Roche, AstraZeneca: Research Funding. Cohen:BMS/Celgene: Research Funding; Novartis: Research Funding; Genentech: Research Funding; BioInvent: Research Funding; Lam Therapeutics: Research Funding; Takeda,: Research Funding; ADCT: Consultancy; AstraZeneca: Consultancy, Research Funding; Abbvie: Consultancy; Janssen: Consultancy; BeiGene: Consultancy; Loxo/Lilly: Consultancy, Research Funding. Jerkeman:Kite/Gilead: Honoraria; Pierre Fabre: Honoraria; Genmab: Honoraria; Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; BMS: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Cerhan:BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Protagonist: Other: Safety Monitoring Committee; NanoString: Research Funding; Genmab: Research Funding; Genentech: Research Funding.
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