Circulating Tumor DNA Dynamics as Early Outcome Predictors for Lisocabtagene Maraleucel as Second-Line Therapy for Large B-Cell Lymphoma from the Phase 3 TRANSFORM Study

Background: While the prognostic value of MRD using ultrasensitive circulating tumor DNA (ctDNA) assays after first-line immunochemotherapy for DLBCL has been shown (Roschewski M, et al. Blood 2022;140[suppl 1]:785), its relevance to outcomes after second-line (2L) treatment with CD19-directed CAR T cell therapy remains unclear. The phase 3 TRANSFORM study (NCT03575351) showed statistically significant and clinically meaningful improvements in event-free survival (EFS), CR rate, and PFS for lisocabtagene maraleucel (liso-cel) compared with standard of care (SOC) for patients (pts) with primary refractory or early relapsed large B-cell lymphoma (LBCL) eligible for autologous HSCT (Kamdar M, et al. Lancet 2022; Abramson JS, et al. Blood 2023). Here, we report longitudinally measured ctDNA levels from TRANSFORM as a prospective measure of disease burden and describe the predictive value of ctDNA after 2L liso-cel therapy for LBCL. Methods: From the original randomized population (n = 184), 551 plasma samples from 160 pts (liso-cel, n = 79; SOC, n = 81) were used for ctDNA assessment in a blinded manner by Phased Variant (PV) Enrichment and Detection Sequencing (PhasED-Seq) at Foresight Diagnostics. Tumor-derived PVs were identified directly from baseline plasma samples taken at screening without use of tumor tissue; matched DNA from peripheral blood mononuclear cells was used to censor germline variants and clonal hematopoiesis. PVs were used to longitudinally assess ctDNA on the day of liso-cel infusion; at Day 15; and Months 1, 2, 3, and 12 after infusion. For the SOC arm, only pretreatment samples were evaluated. ctDNA levels were compared with baseline characteristics, responses by Lugano 2014 criteria, and EFS. Pts/samples were reported as having detectable MRD when ctDNA levels exceeded a detection threshold (≈1:10 6 cell-free DNA molecules) corresponding to 98% specificity. Results: PVs were identified from 136 of 160 pts (85%) with evaluable pretreatment samples from the liso-cel and SOC treatment arms. The remaining samples had lower disease burden (sum of product of diameters[SPD]; 13%) or failed quality check (2%). Pretreatment ctDNA levels varied widely (median [IQR]: 136 [35‒696] haploid genome equivalents/mL) and were correlated with disease indices portraying higher-risk disease, including stage ( P = 0.02), age-adjusted International Prognostic Index ( P < 0.0001), disease burden (SPD; P < 0.0001), and LDH ( P < 0.0001). Serial ctDNA levels we