Outcomes in ZUMA-5 with axicabtagene ciloleucel (axi-cel) in patients (pts) with relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL) who had the high-risk feature of progression within 24 months from initiation of first anti-CD20–containing chemoimmunotherapy (POD24).
Authors: Jacobson Caron A. , Chavez Julio C. , Sehgal Alison , William Basem M. , Munoz Javier , Salles Gilles A. , Casulo Carla , Munshi Pashna N. , Maloney David G. , De Vos Sven , Reshef Ran , Leslie Lori Ann , Yakoub-Agha Ibrahim , Oluwole Olalekan O. , Chi Hang Fung Henry , Plaks Vicki , Yang Yin , Lee Jennifer , Avanzi Mauro P. , Neelapu Sattva Swarup 
Published: June 2021

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Background: POD24 is an indicator of poor survival in iNHL (Casulo & Barr. Blood. 2019). In the ZUMA-5 Phase 2 study of axi-cel anti-CD19 CAR T-cell therapy in pts with R/R iNHL, overall response rates (ORR) after 17.5 months median follow-up were similarly high in those with and without POD24 (93% and 92%; Jacobson et al. ASH 2020. #700). Here, we report updated outcomes with longer follow-up in pts with POD24 in ZUMA-5. Methods: Adults with R/R follicular lymphoma (FL) or marginal zone lymphoma (MZL) after ≥2 lines of therapy underwent leukapheresis followed by conditioning therapy and axi-cel infusion (2×106 CAR T cells/kg). Axi-cel–treated pts with available data on progression after an anti-CD20 mAb + alkylating agent were included. The updated efficacy analysis occurred when ≥80 treated pts with FL had ≥18 months follow-up. Results: Of 129 pts at baseline, 81 pts (63%; 68 FL, 13 MZL) had POD24 and 48 pts (37%; 40 FL, 8 MZL) did not have POD24. Median prior lines of therapy in pts with and without POD24 were 3 and 3.5, respectively. High-risk characteristics of pts with and without POD24 included stage III/IV disease, 83% and 94%; ≥3 FLIPI, 44% and 43%; high tumor bulk (GELF), 51% and 44%; and refractory disease, 77% and 63%, respectively. With 23.3 months median follow-up, ORR among efficacy-evaluable pts with POD24 (n = 61) and without POD24 (n = 37) was 92% each (complete response rates, 75% and 86%). At data cutoff, 52% of pts with POD24 and 70% without POD24 had ongoing responses. Median duration of response, progression-free survival, and overall survival were not reached in pts with and without POD24; 18-month estimated rates were 60% and 78%, 55% and 84%, and 85% and 94%, respectively. Incidences of Grade ≥3 adverse events were similar in pts with and without POD24 (84% and 88%), including cytopenias (69% and 65%) and infections (15% and 21%). Grade ≥3 cytokine release syndrome (CRS) occurred in 9% and 2% of pts with and without POD24, respectively; Grade ≥3 neurologic events (NEs) occurred in 17% of pts each. Median times to onset were similar in pts with and without POD24 for CRS (4 days each) and NEs (8 days and 7 days); median durations of CRS (7 days and 5 days) and NEs (11 days and 13 days) were also similar between groups. In efficacy-evaluable pts with FL, median peak CAR T-cell levels were similar in pts with and without POD24 (35.8 cells/μL and 34.5 cells/μL). Peak levels of key inflammatory biomarkers and axi-cel product attributes were generally similar in pts with and without POD24. Conclusions: Axi-cel showed a high rate of durable responses in pts with POD24 iNHL, a population with high-risk disease. Efficacy results, as well as safety and pharmacological profiles, appeared largely comparable between groups, with the exception of PFS rates. Clinical trial information: NCT03105336.