Intention to treat versus modified intention-to-treat analysis in B-cell maturation antigen and CD19 chimeric antigen receptor trials: A systematic review and meta-analysis

Abstract

IntroductionChimeric antigen receptor T-cell therapy (CART) has revolutionised treatment of haematological malignancies; however, current reporting uses a modified intention-to-treat analysis (mITT) which over-estimates efficacy.We assessed what proportion of CD19 and B-cell maturation antigen (BCMA) CART trials report the number of patients not receiving CART after being enrolled by performing meta-analysis of the mITT and intention-to-treat (iTT) overall response rate (ORR). MethodsPubMed/MEDLINE, EMBASE and Cochrane databases were searched. All prospective clinical trials of CD19 and BCMA-targeting CART enrolling two or greater patients from 1st January 2013 to 1st November 2020 were included. ResultsA total of 28 BCMA CART and 74 CD19 CART trials were identified. These included 10 BCMA CART (35.7%) and 52 (70.2%) CD19 CART trials reporting total number of patients enrolled and number of patients treated with CART. For this cohort of trials, the mITT ORR for BCMA CART was 78.0% (95% confidence interval (CI) = 67.0–89.0%), and the iTT ORR was 70.0% (95% CI = 59.0–80.0%). For CD19 leukaemia CART, the mITT ORR was 87.2% (95% CI = 83.1–91.2), and the iTT ORR was 74.9 (95% CI = 64.8–85.0). For CD19 lymphoma CART, the mITT ORR was 70.7% (95% CI = 63.9–77.5), and the iTT ORR was 58.7% (95% CI = 49.7–67.7). ConclusionAcross BCMA and CD19 CART trials, there is a difference of up to 8–12% in the ORR between modified and iTT analyses and a paucity of information regarding reasons why patients did not receive the intended study treatment.