Eligibility for CAR T‐cell therapy: An analysis of selection criteria and survival outcomes in chemorefractory DLBCL
Authors: Stephen D. Smith, Prathima Reddy, Alexandra Sokolova, Victor A. Chow, Ryan C. Lynch, Mazyar A. Shadman, Brian G. Till, Andrei R. Shustov, Edus H. Warren, Chaitra S. Ujjani, Manoj P. Menon, Yolanda D. Tseng, Ajay K. Gopal
Journal: American Journal of Hematology (2019)

Chemorefractory diffuse large B-cell lymphoma (DLBCL) is associated with poor outcomes. Recent clinical trials testing chimeric antigen receptor T-cell (CAR T-cell) therapy, including ZUMA-1 leading to the first regulatory approval in DLBCL, demonstrate sustained complete remission, disease control, and long-term survival in a proportion of patients.1, 2 Despite the success of CAR T-cell therapies, trial outcomes must be interpreted in context of study definitions and eligibility parameters. A recent analysis of demonstrated poor outcomes in chemorefractory DLBCL, including a 2-year survival of 20%, but lacked detail on comorbidities which could impact clinical trial eligibility and survival expectations.3 Without understanding patient selection and comorbidities, interpretation of results—and optimal design of future trials—in chemorefractory DLBCL remains challenging. We postulated that clinical trial eligibility requirements could independently correlate with outcomes for patients with relapsed/refractory DLBCL. To evaluate this hypothesis, we examined chemorefractory DLBCL patients seen in the modern era from our center, applying key eligibility criteria from ZUMA-1 and describing the proportion likely to be excluded from trials, along with reasons for exclusion and survival outcomes. Patients with DLBCL seen at our institution from 2011 to 2015 were reviewed under IRB approval to determine chemorefractory status based on ZUMA-1 definition, and evaluate whether they would meet eligibility criteria.1 Chemorefractory status per ZUMA-1 was defined as stable disease (lasting 6 months or less) or progressive disease as best response to most recent chemotherapy, or disease progression within 12 months of autologous stem cell transplant. "Chemorefractory date" was identified by clinical assessment, biopsy, or imaging showing failure of DLBCL treatment (lack of response/progression), and served as the reference date for reviewing potential ZUMA-1 eligibility in detail, as well as the baseline date for survival estimates. Specifically, clinical data (ECOG, labs, organ function) within 8 weeks of chemorefractory date were examined to estimate potential ZUMA-1 eligibility. On occasion, more remote studies (eg, an echocardiogram >8 weeks prior) were included when relevant. Descriptive statistics and Kaplan-Meier overall survival (OS) estimates were performed, comparing patients potentially ZUMA-1 eligible with others. No attempt was made to compare outcomes among pts receiving specific therapies for chemorefractory DLBCL. The specific eligibility factors examined were: histology (DLBCL, PMBCL and tFL); prior therapy including history of allogeneic SCT; CNS involvement, performance status (ECOG 01- vs 2 or higher), laboratory parameters, cardiac disease, infectious comorbidities; history of second malignancy other than nonmelanoma skin cancer/in situ cancer or FL; need for urgent therapy due to tumor mass effect or rapid progression (a need for "bridging therapy"). Of 404 in our DLBCL database from 2011 to 2015, 163 had received at least two therapies and were examined. Thirty six had inadequate follow up, leaving 127 for detailed analysis. Of these, 78 were determined chemorefractory as per ZUMA-1 but an additional 12 patients who received CAR T-cell therapy on institutional trials were excluded. Thus, 66 chemorefractory DLBCL patients not treated with CAR T-cells were examined in depth. Median age was 63 (range, 19-77), 17 had transformed lymphoma. All had received and failed therapy with an anthracycline and a CD20-directed antibody. Fourteen relapsed within 1 year of autologous transplant, and 22 had primary refractory disease. A total of 39 patients (58%) were deemed ineligible for ZUMA-1 by retrospective review, with the most common exclusionary factors being need for urgent therapy, transformation from histology other than follicular lymphoma, and poor performance status (Table S1, Supplementary online materials). The median age of our ZUMA-1 "eligible" cohort was 59 years, and 64 years for "ineligible" patients. Figure 1 shows survival. Among eligible pts vs not: Median OS was 19 vs 7 months (eligible vs not, P = 0.06). 1-year OS was 55% vs 27%, 2-year OS 40% vs 23%. Univariate analysis of ZUMA-1 eligibility criteria indicated that only ECOG status 2 or higher (=0.05) predicted inferior OS. When applied to a historical cohort, fewer than half of chemorefractory DLBCL pts at our center met eligibility criteria for ZUMA-1. This finding resembles two recent studies describing use of axicabtagene ciloleucel in accordance with US Food and Drug Administration labeling ("real-world" use), projecting 49% to 60% of chemorefractory DLBCL patients to be ineligible for ZUMA-1. 4, 5 Our data, excluding patients treated with CAR T-cells but otherwise treated heterogeneously, found a trend toward improved survival patients meeting main inclusion criteria for the ZUMA-1 trial. The two compared groups (ZUMA-1 eligible/ineligible) could be imbalanced for additional factors impacting outcomes, including first remission duration and MYC gene dysregulation, so the comparison of outcomes based on eligibility for ZUMA-1 is exploratory. Nonetheless, the median and 2-year OS rates in each group (40% in eligible, vs 23%)—neither receiving CAR T-cell therapy—are thought-provoking. The eligible patients in our cohort experience comparable OS to that achieved among CAR T-cell study recipients in prospective trials, whereas ZUMA-1 ineligible patients face outcomes resembling those described in Scholar-1.3 Our data, suggesting a significant role of patient selection in the Zuma-1 trial, are supported by recent real-world data using axicabtagene ciloleucel. In those reports, treated patients who failed to meet eligibility criteria for ZUMA-1 had a lower complete response rate4 and nonsignificantly inferior OS.5 The most common exclusionary feature in our cohort was a need for urgent therapy ("bridging" therapy). Bridging therapy between leukoplasias and CAR T-cell administration was prohibited in ZUMA-1, but commonly reported (30%-56% of patients) in the real-world datasets.4, 5 Notably, of seven patients requiring urgent therapy in our series, five had additional features which would rendered them ineligible for ZUMA-1. Permitting bridging therapy, and intention-to-treat survival analysis, in the study of tisagenleceucel2 results in numerically inferior response and survival rates. An exclusionary performance status (ECOG 2 or higher) was present in 15% of our chemorefractory DLBCL cohort, a similar frequency to recent real-world datasets.4, 5 Advanced performance status was historically associated with chemotherapy toxicity and mortality in solid tumors (eg, colorectal cancer), but interobserver agreement at a cutoff of 2 is relatively poor, and data suggesting relevance in hematologic malignancies is limited.6, 7 While ECOG 2 or higher predicted inferior OS in our data and SCHOLAR-1,3 a recent study of real-world use of axicabtagene ciloleucel found these patients did not experience excess toxicity.5 Other major reasons for exclusion in our cohort—non-FL transformation and CNS involvement—may portend higher-risk disease, but without any anticipated impact on the safety of CAR T-cell therapy. Notably, CAR T-cells can cross the blood-brain barrier, and a case report of activity and safety in DLBCL involving CNS has been reported.8 This dataset has several limitations. First, clinical data were often incomplete around the chemorefractory date, resulting in small subsets evaluable for each ZUMA-1 eligibility factor. Patients received heterogenous therapies for chemorefractory DLBCL, including investigational therapies and allogeneic transplant, making generalization of results (and relevance outside of a tertiary care setting) less certain. Data regarding cause of death was unavailable for many patients, critical to distinguishing the impact of patient comorbidities and disease behavior. In conclusion, we found that a minority of patients with chemorefractory DLBCL appear to meet eligibility criteria for the pivotal ZUMA-1 trial. In addition, these criteria appear to select for lower-risk chemorefractory DLBCL risk patients and interpretation of survival outcomes is a challenge. A need for urgent or "bridging" therapy, non-FL transformation, ECOG performance status of 2, and CNS involvement are common exclusionary criteria, but may relate more to high-risk disease than safety of CAR T-cell therapy. In future clinical trials, eligibility criteria should be modified to permit evaluation of promising therapies among chemorefractory DLBCL patients with the greatest need. This work was supported by 5K24CA184039, STTR, The Seattle Cancer Care Alliance, donations from Frank and Betty Vandermeer and Sonya and Tom Campion. Stephen Smith has served as a consultant for Merck & Company; served on the Advisory board for AstraZeneca; and has received Research Funding from Acerta Pharma BV, AstraZeneca, De Novo Biopharma, Genentech, Incyte, Merck & Company, Pharmacyclics, Portola Pharmaceuticals, Seattle Genetics; and his spouse receives Research Funding from Ayala Pharma, Bristol-Meyers Squibb, and Ignyta. Ryan Lynch has received Research Funding from Juno Therapeutics, Incyte, Rhizen Pharmaceuticals, Takeda, TG Therapeutics. Mazyar Shadman has served as a Consultant for AbbVie Pharmaceutical, Genentech, and Sound Biologics; served on the Advisory Board for AbbVie Pharmaceutical, ADC Therapeutics, Atari Therapeutics, Genentech, and Verastem Oncology; and has received Research Funding from Acerta Pharma BV, Beigene, Celgene, Emergent Biosolutions, Genentech, Gilead Sciences, Merck & Company, Mustang Biopharma, Pharmacyclics, and TG therapeutics. Ajay Gopal has served on the Advisory Board for Gilead Sciences and has received Research Funding from them. All other authors have no relevant conflicts of interest. Specific contributions include: Smith SD performed the research, designed the research study, and wrote the article. Reddy P performed the research. Sokolova A performed the research. Gopal AK designed the research study and wrote the article. All other authors assisted with critical review and writing of the article. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.