Patterns of Survival in Patients with Aggressive B-Cell Lymphoma Treated with CD19-Directed Chimeric Antigen Receptor T-Cell Therapy (CART) As Second Versus Later Line of Therapy

Introduction

Chimeric antigen receptor T-cell therapy (CART) leads to similar response rates in trials evaluating treatment as 2^nd (2L) vs 3^rd line (3L) and beyond in patients (pts) with relapsed/refractory (R/R) aggressive B-cell non-Hodgkin lymphoma (ZUMA-7 and TRANSFORM for 2L vs ZUMA-1 and TRANSCEND for 3L and beyond). Whether earlier vs later use of CART improves survival has not been established. We performed a multicenter retrospective analysis evaluating survival outcomes with CART according to line of therapy, specifically 2L vs 3L vs 4^th line and beyond (4L+) to inform better practice.

Methods

Adult pts with R/R de novo diffuse large B-cell lymphoma (DLBCL) or transformed follicular lymphoma (tFL) treated with CD19-directed CART from 2015-2024 across 13 US centers were identified. Baseline characteristics compared between cohorts included: age, sex, histology, IPI, ECOG, LDH at CART collection, double hit (DHL) and double expressor status (DEL), prior autologous stem cell transplant (autoHCT), lines of therapy pre-CART, bridging therapy (BT), receipt of CART < 12 months from diagnosis, primary refractory disease (PRD) defined as refractory or relapse < 12 mo from frontline therapy, CART on clinical trial, CART construct, and toxicity. Median progression free (mPFS) and overall survival (mOS) were estimated via Kaplan-Meier. Cox regression was used to assess impact of clinical variables on survival. A p-value <0.05 was considered significant.

Results

713 pts were included (n=142 [2L], 281 [3L], 290 [4L+]). Demographic and clinical features were similar between groups including CART construct and prevalence of pts with DHL/DEL or PRD. Exceptions included: more 2L pts received CART < 12 mo from diagnosis (51.4 [2L], 40.1 [3L], 26.6% [4L+], p<0.001), and more 3L pts received autoHCT prior to CART (7 [2L], 18 [3L], 7% [4L+], p<0.001); 4L+ line pts had longer lasting neurotoxicity (4.5 [2L], 2 [3L], 6 days [4L+], p=0.01); 2L pts trended towards more tFL histology (26 [2L], 19 [3L], 17% [4L+], p=0.07) and use of BT (54 [2L], 49 [3L], 43% [4L+], p=0.07). Median follow up from CART infusion was 25.1 mo. CART response rates were similar for 2L, 3L, and 4L+ (ORR 70 [2L], 67 [3L], 64% [4L+], p=0.6; CR 59 [2L], 51 [3L], 48% [4L+], p=0.1). From CART infusion, three-year PFS and OS were similar in 2L vs 3L but shorter in 4L+ pts (PFS 39.5 [2L], 35.9 [3L], 28.1% [4L+], p<0.001; OS 47.4 [2L], 51.8 [3L], 37.7% [4L+], p<0.001), as was mPFS and mOS (mPFS 8.2 [2L], 10.3 [3L], 4.4 [4L+] mo, p<0.001; mOS 29.7 [2L], 36.8 [3L], 20.5 [4L+], p<0.001).

In PRD pts, mPFS and mOS were similar for 2L vs 3L but shorter in 4L+ pts (mPFS 7.2 [2L], 6.0 [3L], 3.0 mo [4L+], p=0.04; mOS 27.4 [2L], 31.6 [3L], 14.9 mo [4L+], p=0.04). In pts receiving BT, mPFS and mOS were similar for 2L vs 3L but shorter in 4L+ pts (mPFS 7.8 [2L], 7.4 [3L], 3.0 mo [4L+], p<0.001; mOS 53.6 [2L], 25.7 [3L], 14.5 mo [4L+], p=0.003). 2L pts who received BT had similar mPFS and mOS to 3L pts who did not receive BT (mPFS 7.8 [2L with BT], 12.5 mo [3L without BT], p=0.7; mOS 53.6 [2L with BT], 69.4 mo [3L without BT], p=0.4).

After CART failure, CART line of therapy did not impact mPFS with next line therapy (3.8 [2L], 2.7 [3L], 2.3 mo [4L+], p=0.3) nor mOS (14.6 [2L], 11.3 [3L], 9.9 mo [4L+], p=0.4).

On Cox regression, pts with PRD, irrespective of line of CART, were more likely to have a PFS/OS event (PFS: HR 1.7 [1.2-2.7], p=0.02; OS: HR 1.7 [1.2-2.7], p=0.02), as were pts who received CART < 12 mo from diagnosis (PFS: HR 2.3 [1.5-3.3], p<0.001; OS: HR 2.3 [1.5-3.3], p<0.001). Age, LDH at time of CART, and DHL/DEL status did not impact survival. When comparing the interaction between CART line (2L and 3L only) and PRD or DHL, 3L pts with PRD were more likely to have a PFS/OS event than 2L (PFS: HR 2.5 [1.7-3.7], p<0.001; OS: HR 2.5 [1.7-3.7], p<0.001); 2L and 3L pts with DHL had similar risk for PFS/OS events (PFS: HR 1.2 [0.9-1.6], p=0.2; OS: HR 1.2 [0.9-1.6], p=0.2).

Conclusions

This multicenter analysis is the first to compare outcomes in DLBCL/tFL pts according to CART line of therapy and demonstrates that survival with 2L or 3L CART is similar but superior to CART 4L+, irrespective of use of BT. The 2L cohort was enriched with pts who received CART < 12 mo from diagnosis, a characteristic associated with poor survival, and suggests the inclusion of more pts with aggressive disease in our 2L cohort. When comparing 2L vs 3L CART, PRD pts may have improved survival with earlier use of CART.

Epperla:Novartis: Consultancy; Ispen: Other: Advisory Board; Lilly: Other: Advisory Board; Beigene: Speakers Bureau; Genetech: Speakers Bureau. Grover:Seagen: Honoraria; Novartis: Honoraria; Regeneron: Honoraria, Research Funding; ADC Therapeutics: Honoraria; BMS: Honoraria, Research Funding; Caribou: Honoraria; Ono Pharma: Honoraria; Genentech: Honoraria; Cabaletta: Research Funding; Janssen: Honoraria; Kite: Honoraria; Sangamo: Current holder of stock options in a privately-held company. Romancik:Astra Zeneca: Consultancy; Kite: Consultancy; ADC Therapeutics: Consultancy. Moyo:Century Therapeutics: Research Funding; J&J: Research Funding; Genmab: Research Funding; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Kenkre:Ipsen: Research Funding. Ollila:Lilly: Research Funding; Ono Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees. Shouse:Astra Zeneca: Honoraria; Abbvie: Consultancy; Beigene, Inc: Consultancy, Honoraria, Speakers Bureau; Kite Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau. Matasar:Pharmacyclics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; AstraZeneca: Honoraria; Genentech: Consultancy, Honoraria, Research Funding; Immunovaccine Technologies: Research Funding; Pfizer: Honoraria; Roche: Consultancy, Honoraria, Research Funding; Regeneron Pharmaceuticals, Inc.: Honoraria; Epizyme: Honoraria; IMV Therapeutics: Honoraria; Kite: Honoraria; BMS/Celgene: Honoraria; Takeda: Honoraria; GM Biosciences: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Honoraria, Research Funding; Genmab: Membership on an entity's Board of Directors or advisory committees; Allogene: Membership on an entity's Board of Directors or advisory committees; Merck: Current equity holder in publicly-traded company; Bayer: Consultancy, Honoraria, Research Funding. Davis:Janssen Biotech: Speakers Bureau. Lin:Genmab: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau. Ma:AbbVie: Consultancy, Honoraria, Research Funding; Juno: Research Funding; Janssen: Consultancy; Lilly: Research Funding, Speakers Bureau; BeiGene: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau. Winter:Merck: Consultancy, Research Funding; BMS: Consultancy; Genetech: Consultancy. Danilov:Genentech: Consultancy; Cyclacel: Research Funding; GenMab: Consultancy, Research Funding; Incyte: Consultancy; Janssen: Consultancy; Lilly Oncology: Consultancy, Research Funding; Merck: Consultancy; Morphosys: Consultancy; Takeda Oncology: Research Funding; Bristol Meyers Squibb: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; TG Therapeutics: Research Funding; ADCT: Consultancy; AstraZeneca: Consultancy, Research Funding; BeiGene: Consultancy; Bayer Oncology: Research Funding; Abbvie: Consultancy, Research Funding; Nurix: Consultancy, Research Funding; Prelude: Consultancy. Shah:Tundra Therapeutics: Current holder of stock options in a privately-held company; Miltenyi Biomedicine, Lilly Oncology: Research Funding; Gilead-Kite, BMS-Juno, Miltenyi, Lilly Onclogy, Novartis, Seattle Genetics, Janssen, Abbvie, Cargo, Beigene, Galapagos, AstraZeneca: Honoraria. Barta:BMS: Consultancy; Acrotech: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy; Kyowa Kirin: Consultancy. Gordon:nanoparticles for cancer therapy (HDL NP As Inducers of Ferroptosis in Cancer, PCT/US2020/051549; b) Nanostructures for Treating Cancer and Other Conditions, PCT/UlllllLS2013/027431): Patents & Royalties: nanoparticles for cancer therapy (HDL NP As Inducers of Ferroptosis in Cancer, PCT/US2020/051549; b) Nanostructures for Treating Cancer and Other Conditions, PCT/UlllllLS2013/027431); Janssen: Other: data and safety monitoring board ; Ono Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb, Kite Pharmaceuticals: Other: Advisory board. Stephens:AstraZeneca, Beigene, Novartis: Research Funding; Abbvie, AstraZeneca, Beigene, BMS, Celegene, Eli Lilly, Genentech, Janssen, Pharmacyclics: Consultancy. Karmali:Ipsen: Speakers Bureau; Abbvie: Honoraria; Genentech/Roche: Honoraria; BMS: Honoraria; BeiGene: Speakers Bureau; Genmab: Honoraria; AstraZeneca: Speakers Bureau; Incyte: Speakers Bureau.