Treatment Patterns and Predictors of Survival after First Line Therapy in Large B-Cell Lymphoma in a Real-World US Cohort

Introduction:

Patients with large B cell lymphoma (LBCL) have a number of choices of front line (1L) therapies, however relapsed and refractory disease are common, suggesting an unmet medical need. As the utilization of new effective treatments such as chimeric antigen receptor T-cell (CAR T) increases, given the NCCN Guidelines category 1 recommendation in second-line (2L), the potential benefits of introducing access in earlier lines of therapy could reduce the burden of disease for patients who do not survive long enough to have access in later lines of therapy. The objectives of this study are to: 1) understand LBCL treatment patterns, 2) describe cumulative incidence of 2L therapy, and 3) identify patient characteristics and clinical factors associated with death after 1L completion and prior to the start of 2L therapy.

Methods:

This retrospective study used the US nationwide Flatiron Health electronic health record-derived de-identified database. Patients were eligible if they had chart confirmed pathological diagnosis of LBCL between 1 Jan 2011 to 30 April 2024 and were considered relapsed or refractory, implemented as having at least one line of therapy, and did not receive hematopoietic cell transplant or a clinical study drug before or as a part of 1L therapy. After completion of 1L therapy, cumulative incidence of 2L initiation, as well as overall survival, with 2L initiation as a competing event, were assessed. Descriptive statistics (frequencies and percentages) were generated. To identify prediction factors for survival, we used a competing risk regression model of death (without initiating 2L), having 2L initiation as a competing risk.

Results:

The cohort included 10,016 patients with LBCL who completed 1L therapy. The median age was 68 years (IQR 58-76), 56% were male, and 30% had an Ann Arbor Stage IV diagnosis. ECOG performance statuses of 0 (18%), 1 (23%), and 2+ (11%) were observed (48% of patients had missing performance statuses).

1L treatment was predominantly anti-CD20 antibody plus anthracycline-containing regimen (84%) and 18% died within 12 months of completing 1L and did not start 2L therapy. We found 30% of patients initiated 2L therapy at any point after 1L completion.

Therapies used in the full 2L population included anti-CD20 + platinum regimens (10.7%), anti-CD-20 + other chemotherapies (9.9%), and anti-CD20 + anthracycline (6.6%), and CAR T (0.5%). Among 2L patients who were NCCN guideline eligible (after April 2022) for CAR T (815), 3.9% were known to receive CAR T treatment.

Based on a competing risk regression model, the predictors of all-cause mortality prior to starting 2L treatment among relapsed or refractory patients, ordered by strongest to weakest association, included ECOG ≥2, triple-hit status, double-hit status, B symptoms, activated B-cell origin, older age, lower socioeconomic status (SES), higher stage at initial diagnosis, and male sex.

Conclusions:

Although some patients will have curative benefit from 1L therapy, a significant portion of all patients who completed 1L therapy later died before continuing on to a 2L therapy. We identified key factors predicting all-cause death before 2L, including low SES. These findings suggest a significant unmet medical need for more effective and timely curative therapies in a 1L setting. While capture of CAR T therapy may be incomplete for some patients who leave the Flatiron network after completion of 1L, the low observed rate of 2L CAR T use in this cohort is unexpected given its category 1 recommendation in NCCN guidelines. Further research can help understand the factors associated with barriers to 2L therapy initiation in the hopes of addressing access challenges.

McGuirk:Legend biotech: Consultancy; Kite: Consultancy; BMS: Consultancy; Novartis: Consultancy; Sana technologies: Consultancy; Caribou bio: Consultancy; CRISPR therapeutics: Consultancy; NEKTAR therapeutics: Consultancy; Autolus: Consultancy; Allo Vir: Consultancy; Envision: Consultancy. Ramsey:Curta Consulting: Current Employment, Current holder of stock options in a privately-held company; Bayer: Consultancy, Honoraria, Research Funding; Biovica: Consultancy; Flatiron Health: Consultancy; Genentech: Consultancy, Research Funding; GRAIL: Consultancy. Proli:Flatiron: Current equity holder in publicly-traded company. Hsu:Amgen Inc: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Kite, A Gilead Company: Current Employment, Current equity holder in publicly-traded company. Patel:Kite, a Gilead Company: Current Employment, Current equity holder in publicly-traded company. Perales:Omeros: Current Employment, Current equity holder in publicly-traded company; NexImmune: Current Employment, Current equity holder in publicly-traded company; Nektar: Research Funding; Novartis: Research Funding; OrcaBio: Current equity holder in private company; Biotec: Research Funding; Allogene: Research Funding; Incyte: Research Funding; Kite/Gilead: Research Funding; Miltenyi: Research Funding. Adamson:Flatiron: Current equity holder in publicly-traded company. Fu:Flatiron: Current equity holder in publicly-traded company. Snider:Flatiron: Current equity holder in publicly-traded company.