Lines of Therapy before Autologous Stem Cell Transplant (ASCT) and CAR-T Infusion Affect Outcomes in Aggressive Non-Hodgkin's Lymphoma (NHL)
Authors: Khurana Arushi , Hathcock Matthew A , Habermann Thomas M. , Al Saleh Abdullah S. , Gandhi Sangeetha , Truong Tuan A , Bennani Nabila , Paludo Jonas , Villasboas Jose C , Ansell Stephen M. , Inwards David J. , Porrata Luis F. , Johnston Patrick B. , Micallef Ivana , Lin Yi 
Published: February 2021

Background: Anti CD-19 chimeric antigen receptor T-cell therapy (CAR-T) is approved to treat relapsed/refractory (R/R) aggressive NHL after 2 or more lines of therapy. Randomized clinical trials are ongoing comparing CAR-T and autologous stem cell transplant (ASCT) in second line. In standard of care practice, patients refractory to second line chemotherapy are sometimes treated with third line chemotherapy and taken to ASCT if disease is chemo-sensitive. Current study aims to evaluate the impact of prior lines of therapy on the efficacy of CAR-T and ASCT.
Methods: A retrospective review of patients who received ASCT and/or axicabtagene ciloleucel (axi-cel) for R/R aggressive NHL from June 2016 - January 2020 at Mayo Clinic, Rochester was performed. The lymphoma types included in the study were DLBCL, transformed lymphoma (TFL), high grade B-cell lymphoma (HGBL), and primary mediastinal large B-cell lymphoma (PMBCL). Response to all lymphoma-directed therapy was evaluated using 2014 Lugano criteria. Overall survival (OS) was defined as time from CAR-T or ASCT infusion to death, and progression free survival (PFS) was defined as time from CAR-T or ASCT infusion to disease progression, or next treatment. Categorical data was analyzed as Chi-square or fishers exact test as appropriate. Continuous variables were analyzed using Wilcoxon Rank Sum test. Analysis was performed in R3.6.3.
Results: A total of 105 patients underwent ASCT and 53 patients underwent CAR-T therapy in the study period with at least 6 months follow-up. Of the 105 ASCT patients, 87 received ASCT after 2 lines of chemotherapy, ASCT(2), and 18 received ASCT after 3 lines of chemotherapy, ASCT(3). Twenty six of the ASCT [n=19, ASCT(2) and n=7, ASCT(3)] patients received CART in subsequent therapy. Baseline characteristics were comparable between the two groups except ASCT(3) had higher percent of refractory disease after first line (table 1). With a median follow up of 17.4 months, the PFS was significantly longer for the ASCT(2) group with a trend toward longer OS (Figure 1; PFS @ 1 year: ASCT(2) 67%, 95%CI 58-79%; ASCT(3) 27%, 95%CI 27-74%; p = 0.036).
Among the CAR-T recipients, only 18 (33%) patients received CAR-T in the earliest possible indication, CAR-T(2): after 2 lines of chemotherapy (n=12) and/or after ASCT(2) (n=6), table 1. Compared to patients who received CAR-T in later lines (CAR-T 3+), OS was significantly longer for patients who received CAR-T(2), with a trend toward longer PFS (Figure 1; OS @ 1 year: CAR-T (2) 82%, 95%CI 65-100%; CAR-T later lines 62%, 95%CI 47-82%; p = 0.05). Additionally, 12 (23%) of patients received CAR-T immediately after ASCT (9 after ASCT(2), 3 after ASCT(3)). Baseline demographics in these 12 patients, CAR-T(ASCT), were comparable to the others who had chemoimmunotherapy as the last salvage therapy prior to CAR-T [CAR-T(chemo)], except a smaller proportion received bridging therapy (33% vs. 73%, p = 0.01). The CAR-T (ASCT) group had significantly prolonged PFS (median PFS - not reached [95%CI 3-not reached (NR)] vs. 3 months [95% CI 3-4 months]), and OS (median OS - NR, [95%CI 10.34-NR] vs. 15.1 months, [95%CI 11.9 - NR], p = 0.03). Updated analysis will be presented at the meeting with longer follow up (Figure 1).
Conclusion: CAR-T use at the earliest current approved indication may confer survival advantage. Referral for earlier use of CAR-T remains low at only one third of our CAR-T practice volume. CAR-T use for relapse immediately after ASCT appear to have longer PFS and OS than after other systemic salvage therapy, although contributing parameters such as the need for bridging therapy requires further study. While patients who are chemo-refractory to second line chemotherapy may demonstrate chemo sensitivity with third line chemotherapy, PFS is shorter for ASCT(3). Comparison between ASCT(3) and CAR-T (2, chemorefractory) require larger cohorts with longer follow-up.

Disclosures
Bennani: Affimed: Research Funding; Purdue Pharma: Other: Advisory Board; Kite/Gilead: Research Funding; Verastem: Other: Advisory Board. Ansell:Takeda: Research Funding; ADC Therapeutics: Research Funding; Trillium: Research Funding; Bristol Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; AI Therapeutics: Research Funding. Lin:Juno: Consultancy; Legend BioTech: Consultancy; Merck: Research Funding; Takeda: Research Funding; Gamida Cells: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vineti: Consultancy; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding.