The essential role of randomised controlled trials.

We read the Viewpoint by Nicholas J Short and Hagop Kantarjian with interest. 1 Short NJ Kantarjian H Using immunotherapy and novel trial designs to optimise front-line therapy in adult acute lymphoblastic leukaemia: breaking with the traditions of the past. Lancet Haematol. 2023; 10: e382-e388 Summary Full Text Full Text PDF PubMed Scopus (1) Google Scholar Although we share enthusiasm for novel agents in the treatment of acute lymphoblastic leukaemia, we caution against abandoning randomised controlled trials (RCTs). Single-arm phase 2 studies establish the activity of novel approaches, but not their efficacy. Without confirmatory RCTs, we will continue to repeat the errors of the past. Single-arm trials are often laden with limitations including selection bias, dependence on surrogate endpoints that do not consistently predict overall survival, small sample sizes, short follow-up, and frequent protocol modifications making it impossible to draw definitive conclusions. History is rife with examples of treatments for acute lymphoblastic leukaemia that looked promising in phase 2 studies but later failed to improve survival when studied in an adequately designed phase 3 RCT. Notable examples include SWOG S1203 (IA regimen), 2 Garcia-Manero G Othus M Pagel JM et al. SWOG S1203: a randomized phase III study of standard cytarabine plus daunorubicin (7+3) therapy versus idarubicin with high dose cytarabine (IA) with or without vorinostat (IA+V) in younger patients with previously untreated acute myeloid leukemia (AML). Blood. 2016; 128: 901 Crossref Google Scholar AALL1131 and CoALL 08–09 (clofarabine), 3 Escherich G Zur Stadt U Borkhardt A et al. Clofarabine increases the eradication of minimal residual disease of primary B-precursor acute lymphoblastic leukemia compared to high-dose cytarabine without improvement of outcome. Results from the randomized clinical trial 08–09 of the cooperative acute lymphoblastic leukemia study group. Haematologica. 2022; 107: 1026-1033 PubMed Google Scholar and UKALL14 (rituximab). 4 Marks DI Kirkwood AA Rowntree CJ et al. Addition of four doses of rituximab to standard induction chemotherapy in adult patients with precursor B-cell acute lymphoblastic leukaemia (UKALL14): a phase 3, multicentre, randomised controlled trial. Lancet Haematol. 2022; 9: e262-e275 Summary Full Text Full Text PDF PubMed Scopus (5) Google Scholar As the famous quote goes, those who do not learn history are doomed to repeat it. Using immunotherapy and novel trial designs to optimise front-line therapy in adult acute lymphoblastic leukaemia: breaking with the traditions of the pastMultidrug chemotherapy has historically been the cornerstone of therapy for both children and adults with acute lymphocytic leukaemia. However, in the past decade, several novel immunotherapies have proven to be highly effective in the treatment of acute lymphocytic leukaemia, including the anti-CD22 antibody–drug conjugate inotuzumab ozogamicin, the CD3 × CD19 bispecific antibody blinatumomab, and two CD19-directed chimeric antigen receptor T-cell products. These agents are all approved in the USA as monotherapy for relapsed or refractory B-cell acute lymphocytic leukaemia. Full-Text PDF