Clinical Lymphoma, Myeloma & Leukemia, Vol.22, Suppl.2 - October 2022

S106 E XABS- 2 13-CT DE BAT E : CAR T-Cell or Autologous Ste m Cell Tra n spla n tatio n (ASCT) for Relapsed L BC L - Pro ASCT Craig S. Sauter, M D 1, * 1 Cleveland Clinic, 10201 Carnegie Ave, CA-60, Cleveland, OH 44195, USA *Correspo n di n g author: sauterc@ccf.org Keywords diffuse large B-cell lymphoma, second line, autologous transplant, CAR T-cells, bridging therapy Since the early-mid 1990s, the standard of care (SoC) for relapsed and primary refractory (r/r) diffuse large B-cell lymphoma (DLBCL) in the second line of therapy (2L) has been platinum- containing salvage chemotherapy followed by high-dose therapy and autologous stem cell transplantation (HDT-ASCT) in chemotherapy-sensitive remission. 1 With the advent of novel cellular immunotherapy in the form of chimeric antigen receptor (CAR) modified T-cells directed against CD19, three multicenter, randomized phase 3 studies have reported out as of ASH 2021 to challenge the SoC in 2L. These three studies and associated CAR T-cell products: ZUMA- 7 (axicabtagene ciloleucel [axi- cel]), BELINDA (tisagenlecleucel [tisacel]) and TRANSFORM (lisocabtagene maraleucel [liso-cel]) all randomized subjects in a 1:1 manner to CAR T-cells or SoC. All three studies had a primary endpoint of event-free survival (EFS). Two of the studies (Zuma- 7 and TRANSFORM) were positive toward the primary endpoint in favor of CAR T-cells, with one published in peer-reviewed manuscript form (Zuma- 7 ). 2,3 The BELINDA study has been reported in manuscript form as negative. 4 While the three studies have notable similarities, including enrolling physiologically transplant-eligible patients with primary refractory large B-cell lymphoma (LBCL, including DLBCL and high-grade B-cell lymphoma) or disease relapsing within 12 months of the completion of initial chemoimmunotherapy, key differences exist that deserve discussion toward consideration of replacing SoC in the context of this debate. Based upon the results of the ZUMA- 7 study favoring axi-cel over SoC in 2L with median EFS of 8.3 months and 2 months, respectively (hazard ratio [HR] 0.40 with 95% CI: 0.31-0.51), the FDA approved axi-cel for use in 2L for early r/r LBCL. ZUMA- 7 was the largest of the three studies, enrolling >350 subjects, with the longest reported follow-up of >24 months. In contrast to the other two studies, only subjects that were randomized to the experimental arm underwent leukapheresis and no bridging therapy (outside of corticosteroids) were allowed prior to infusion of axi-cel. Ninety-four percent of subjects randomized to the experimental arm underwent axi-cel infusion. Given the prevalence and intention of disease controlling bridging therapy prior to CAR T-cell infusion in the real-world setting, 5 selection bias should be considered. Events on ZUMA- 7 included change in lymphoma therapy (in addition to death and progressive disease). Of the subjects enrolled on the SoC arm, 80 were deemed by investigators to have either a partial (PR) or complete response (CR) to platinum-containing salvage chemotherapy although only 62 underwent HDT-ASCT. Upon reflection of personal experience in practice, the nearly 1 in 4 patients with platinum-containing salvage chemotherapy sensitive response not proceeding to HDT-ASCT on ZUMA- 7 appears high. Additionally, with treating investigators assessing chemotherapy sensitivity in SoC, it is important to consider whether cases of stable disease (SD) could have been formal Deauville score (DS) = 4 PRs without a protocol mandated central radiology review. Contemporary single-center and multicenter registry data of patients with PR to salvage therapy by PET proceeding to HDT- ASCT have a cure fraction approximating 45-50%. 6, 7 Lastly, no overall survival (OS) was observed in the two arms without formal crossover to axi-cel built-in for SoC arm experiencing treatment failure. Despite the lack of formal crossover on study, 56% of subjects in SoC arm eventually proceeded to cellular immunotherapy, a fraction comparable to the formal crossover designs in BELINDA and TRANSFORM studies wherein 51% of SoC subjects crossed over to tisacel and liso-cel, respectively. Of the three studies presented at ASH, BELINDA was reported negative toward the primary EFS endpoint with a HR of 1.0 7 (95% CI: 0.82-1.40) and median EFS of 3 months in both arms. Potential reasons have been speculated for this result including, but not limited to, prolonged time to infusion of tisacel in the experimental arm (52 days from randomization) and an additional “shot-on-goal” for the SoC arm with the requirement of a second salvage 8 prior to crossing over to tisacel. Lastly, the TRANSFORM study was reported positive for liso-cel over SoC with a 6-month EFS of 63.3% and 33.4%, respectively (HR 0.35, 95% CI: 0.23- 0.53). The follow-up for this study is relatively short at ~6 months and has not been reported in peer-reviewed manuscript form. The majority of subjects in the liso-cel arm received bridging therapy with standard platinum-containing salvage chemotherapy. This could potentially limit the interpretation of the primary endpoint of EFS liso-cel versus SoC.