Outcomes and Factors Impacting Use of Axicabtagene Ciloleucel in Refractory and Relapsed Large B-Cell Lymphoma: An Intent-to-Treat Analysis
Authors: Mian Agrima , Wei Wei , Winter Allison M. , Khouri Jack , Jagadeesh Deepa , Anwer Faiz , Gerds Aaron T. , Dean Robert M. , Sobecks Ronald , Pohlman Brad , Kalaycio Matt , Hamilton Betty K. , Majhail Navneet S. , Hill Brian T. 
Published: November 2019

Background:
Axicabtagene Ciloleucel (Axi-cel), the first chimeric antigen receptor T-cell therapy (CAR-T), is approved for refractory/relapsed (R/R) aggressive B-cell lymphoma with the ZUMA-1 trial reporting an objective response in 83% and complete response in 58% patients at a median duration of 27 months (Locke et al. 2019). The availability to successfully deliver CAR-T therapy may be restricted by socio-economic, technical/manufacturing challenges and comorbidities related to aggressive B-cell lymphoma and its treatment. In this intent-to treat (ITT) analysis, we compared the outcomes of patients at our center with R/R B-cell lymphoma who received Axi-cel with those for whom Axi-cel therapy was intended but not administered, in order to identify factors that may limit its use in this population.
Methods:
We reviewed medical records of consecutive adult patients with R/R diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma (tFL) and primary mediastinal B-cell lymphoma (PMBCL) for whom letters of medical necessity (LMN) were sent to request approval for Axi-cel, from March 2018 to May 2019 at our center. Patients were grouped according to whether or not they ultimately received Axi-cel. Baseline characteristics between Axi-cel and Non-Axi-cel group were compared using Fischer's exact test for categorical and Wilcoxon rank sum test for continuous variables. Comorbidities were assessed using the Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) (Sorror 2013). Time-dependent outcomes were calculated from the date of LMN. Overall survival (OS) was estimated using the Kaplan-Meier method.
Results:
LMNs were sent for a total of 38 patients, 27 male (71%) with a median age of 63 (range, 25-77) years. 24 patients (63%) had an ECOG PS of 0 or 1 at study entry, while median IPI at diagnosis was 2 (range, 0-5). The most common histology was DLBCL in 25 patients (66%) and 18 (47%) had a germinal center B-cell (GCB) subtype. Four patients had double/triple hit lymphoma. The median number of prior therapies was 4 (range, 2-6) and 21 patients (55%) underwent prior autologous transplant. Forty-seven percent had relapsed and 53% had refractory disease. Patient characteristics are shown in Table 1.
Twenty seven (71%) patients received Axi-cel, while 11 patients (29%) were considered candidates for but could not receive Axi-cel. The median time from LMN to cell infusion was 62 (range, 33-248) days. A higher HCT-CI score was observed in the Non-Axi-cel group as compared to the Axi-cel group (median score of 4 vs 2, P=0.04). The two groups did not differ with respect to age, ECOG PS, IPI, number of prior therapies or transplant status.
Median follow- up was 5 (range, 2-16) months. At the time of last follow-up, 8 out of 27 patients (30%) in the Axi-cel and 10 out of 11 (91%) in the Non-Axi-cel group had died. The median OS for the entire cohort was 10 months (95% CI, 3.7 to 13), Axi-cel group was 13 months (95% CI, 7.7 to N.R.) and Non-Axi-cel group was 1 month (95% CI, 0.4 to 3.7) (Figure 1). In the Non-Axi-cel group, 3 patients underwent leukapheresis but died prior to infusion (including 1 manufacturing failure and 2 patients with rapid systemic progression). The other 7 deaths in this group were prior to leukapheresis (3 due to sepsis, 3 due to rapid progression including 1 case of active CNS disease and 1 patient could not receive therapy due to caregiver and financial barriers). The one surviving patient in the Non-Axi-cel group had refractory CNS relapse at the time of last follow-up.
Conclusions:
In this retrospective ITT analysis, approximately one third of patients with R/R aggressive B-cell lymphoma for whom CAR-T therapy was intended were unable to receive it and had extremely short median OS. Patients who could not receive Axi-cel had a higher comorbidity index at the time of decision to proceed with CAR-T therapy; the majority of them died before leukapheresis from disease progression or complications of prior treatment. Improved strategies are needed to safely bridge patients with aggressive B-cell lymphoma intended to receive Axi-cel. New targeted agents such as polatuzumab vedotin and tafasitamab (formerly MOR208) may increase the proportion of patients with aggressive B-cell lymphoma who ultimately receive and benefit from CAR-T therapy.

Disclosures
Anwer: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; In-Cyte: Speakers Bureau. Gerds:Incyte: Consultancy, Research Funding; Imago Biosciences: Research Funding; CTI Biopharma: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pfizer: Consultancy; Roche: Research Funding. Majhail:Anthem, Inc.: Consultancy; Incyte: Consultancy; Atara Bio: Consultancy; Nkarta: Consultancy; Mallinckrodt: Honoraria. Hill:TG therapeutics: Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria; Celegene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding; Amgen: Research Funding.