Retreatment With Axicabtagene Ciloleucel (Axi-Cel) in Patients With Relapsed/Refractory Indolent Non-Hodgkin Lymphoma in ZUMA-5
Authors: Chavez Julio C. , Jacobson Caron A. , Sehgal Alison R. , Neelapu Sattva S. , Maloney David G. , Salles Gilles , William Basem M. , Yang Yin , Goyal Lovely , Chou Justin , Plaks Vicki , Avanzi Mauro P. 
Published: November 2020

Background: ZUMA-5 (NCT03105336) is a multicenter Phase 2 study of axi-cel, an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy, in patients with relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). In an interim analysis of ZUMA-5, axi-cel demonstrated high rates of durable responses (Jacobson CA, et al. ASCO 2020. #8008). Although most patients achieved a durable response, a few patients in ZUMA-5 relapsed. CAR T cell retreatment has resulted in limited responses for aggressive NHL (Locke FL, et al. ASCO 2020. #8012); however, the clinical efficacy of retreatment in iNHL is unknown. Here, we report outcomes of patients with R/R iNHL retreated with axi-cel in the primary analysis of ZUMA-5.
Methods: In ZUMA-5, eligible adults (≥ 18 years) with iNHL, specifically follicular lymphoma (FL) or marginal zone lymphoma (MZL), had R/R disease after ≥ 2 lines of therapy. Patients were eligible for retreatment if they progressed after achieving a complete response (CR) or partial response (PR) at the month 3 post-infusion assessment, had no evidence of CD19 loss in progression biopsy, and had no Grade 4 cytokine release syndrome (CRS) or neurologic events (NEs) with first treatment. At both first treatment and retreatment, patients received conditioning chemotherapy followed by axi-cel at a target dose of 2 × 106 CAR T cells/kg.
Results: As of March 12, 2020, 11 patients (9 with FL and 2 with MZL) were retreated with axi-cel. Before first treatment, 82% of patients had stage 3 - 4 disease, 91% had ≥ 3 FLIPI, and 91% had high tumor bulk (by GELF criteria). The median prior lines of therapy was 4 (range, 2 - 7); 60% of patients progressed &lt; 2 years after initial anti-CD20 mAb-containing therapy (POD24), and 82% had refractory disease. Patients with iNHL who were retreated had significantly higher tumor burden before first treatment (median sum of product diameters) than those who were not retreated (3981 vs 2303 mm2; P = .014).
After first treatment, 10 patients achieved a CR, and 1 patient achieved a PR. The first median DOR was 8.3 months (range, 1.9 - 11.8). CRS occurred in 7 patients (4 had Grade 1 and 3 had Grade 2) and NEs occurred in 4 patients (3 had Grade 1 and 1 had Grade 3). Among patients with FL, those who received retreatment (n = 9) had lower median peak CAR T cell levels at first treatment versus other patients with FL (n = 115) who did not receive retreatment (13.2 vs 41.9 cells/µL; P = .024); median peak CAR T cell levels were also lower when normalized by tumor burden (0.003 vs 0.023 cells/µL × mm2; P = .006). Similar trends in CAR T cell expansion were observed in patients with MZL.
All 11 patients with iNHL also responded to axi-cel retreatment, with 10 patients achieving a CR and 1 achieving a PR. With a median follow-up of 2.3 months, the median DOR to retreatment was not reached (range, &lt; 1 - 8.4 months). Responses were ongoing for 9 patients (82%) at data cutoff. Comparable instances of CRS and NEs were observed with retreatment as with first treatment; CRS occurred with retreatment in 8 patients (6 had Grade 1, 2 had Grade 2), and NEs occurred in 4 patients (3 had Grade 1, 1 had Grade 2). No patient experienced Grade ≥ 3 CRS or NEs with retreatment. Median peak levels of IL-6, IL-2, and IFN-γ, cytokines typically associated with severe CRS and NEs, were numerically similar at retreatment and first treatment (IL-6, 5.4 vs 5.5 pg/mL; IL-2, 1.8 vs 0.9 pg/mL; IFN-γ, 62.9 vs 64.2 pg/mL).
At retreatment, median tumor burden by sum of product diameters was lower than that before first treatment (674 vs 3981 mm2; P = .004). In concordance, median levels of TNFα and IL-2Ra, cytokines typically associated with tumor burden, appeared lower before retreatment than before first treatment in patients with FL (TNFα, 1.4 vs 5.3 pg/mL; IL-2Ra, 1.6 vs 19.4 ng/mL). Median peak CAR T cell levels were similar for patients with FL at retreatment as at first treatment (9.0 vs 13.2 CAR-positive cells/µL blood) and remained similar when normalized to tumor burden (0.006 vs 0.003 cells/µL × mm2).
Conclusions: Based on a limited sample, axi-cel retreatment exhibited high response rates in patients with R/R iNHL. Similar safety profiles and CAR T cell expansion were observed at retreatment and first treatment, and a lower tumor burden was observed before retreatment than before first treatment. Confirmatory analyses with more patients and longer follow-up are needed.

Disclosures
Chavez: Kite, a Gilead Company: Consultancy, Speakers Bureau; Novartis: Consultancy; Celgene: Consultancy; AstraZeneca: Speakers Bureau; Gilead: Consultancy; Epizyme: Speakers Bureau; Genentech: Speakers Bureau; AbbVie: Consultancy; Karyopharm: Consultancy; BeiGene: Speakers Bureau; Bayer: Consultancy; Verastem: Consultancy; Pfizer: Consultancy; Morphosys: Consultancy, Speakers Bureau; Merck: Research Funding. Sehgal:Juno Therapeutics: Research Funding; Prothena: Research Funding; Gilead Sciences: Research Funding; Bristol-Myers Squibb: Research Funding; TP Therapeutics: Research Funding; Merck: Research Funding. Neelapu:Incyte: Other: personal fees; Karus Therapeutics: Research Funding; Bristol-Myers Squibb: Other: personal fees, Research Funding; Merck: Other: personal fees, Research Funding; Kite, a Gilead Company: Other: personal fees, Research Funding; Novartis: Other: personal fees; N/A: Other; Cellectis: Research Funding; Poseida: Research Funding; Unum Therapeutics: Other, Research Funding; Calibr: Other; Takeda Pharmaceuticals: Patents & Royalties; Acerta: Research Funding; Legend Biotech: Other; Allogene Therapeutics: Other: personal fees, Research Funding; Pfizer: Other: personal fees; Precision Biosciences: Other: personal fees, Research Funding; Adicet Bio: Other; Cell Medica/Kuur: Other: personal fees; Celgene: Other: personal fees, Research Funding. Maloney:Bioline Rx: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Juno Therapeutics: Consultancy, Honoraria, Patents & Royalties: Patents are pending, but not issued, licensed, no royalties, no licensees., Research Funding; A2 Biotherapeutics: Consultancy, Current equity holder in publicly-traded company, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Gilead Sciences: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Salles:Abbvie, Amgen, Celgene, Gilead, Janssen, Kite, Morphosys, Novartis, F. Hoffmann-La Roche, Takeda: Honoraria; Abbvie, Amgen, Celgene, Gilead, Janssen, Kite, Morphosys, Novartis, Roche, Takeda: Other: Participation to educational events; Abbvie, Autolus, BMS/Celgene, Debiopharm, Genmab, Kite/Gilead, Epizyme, Janssen, Karyopharm, Morphosys, Novartis, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees; Abbvie, Autolus, BMS/Celgene, Debiopharm, Genmab, Kite/Gilead, Epizyme, Janssen, Karyopharm, Morphosys, Novartis, F. Hoffmann-La Roche, Takeda: Consultancy. William:Seattle Genetics: Research Funding; Dova: Research Funding; Guidepoint Global: Consultancy; Incyte: Research Funding; Kyowa Kirin: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Merck: Research Funding. Yang:Kite, a Gilead Company: Current Employment. Goyal:Kite, a Gilead Company: Current Employment. Chou:Gilead Sciences: Current Employment, Other: stock or other ownership; Five Prime Therapeutics: Other: stock or other ownership , Patents & Royalties; Kite, a Gilead Company: Other: travel support. Plaks:Gilead Sciences: Other: stock or other ownership ; Kite, a Gilead Company: Current Employment, Other: travel support. Avanzi:MSKCC: Patents & Royalties; Gilead Sciences: Other: stock or other ownership ; Kite, a Gilead Company: Current Employment, Other: travel support.