Use of Endpoints in Phase III Randomized Controlled Trials for Acute Myeloid Leukemia over the Last 15 Years: A Systematic Review

Background: The use of objective endpoints is critical for the generalization and clinical implications of a study. Overall survival (OS) has traditionally been used as the gold standard for demonstrating the true clinical benefit of therapy or intervention. We systematically evaluated the proportion of different primary and secondary endpoints used in phase III randomized controlled trials (RCTs) for acute myeloid leukemia (AML), and their trends over time. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, a comprehensive literature search was conducted on three databases (PubMed, Cochrane, and Clinical trials.gov) using MeSH terms and keywords for "Leukemia, Myeloid, Acute" AND "Randomized Controlled Trials as Topic" from January 2006 to March 2021. We screened 3290 articles. After excluding duplicates, reviews, and irrelevant articles, 241 articles reporting only phase III RCTs with primary and secondary endpoints on AML or its subtypes were included for our systematic review. Primary and secondary endpoints data were extracted from the included studies, and the frequency of various endpoints as well as their yearly frequencies were calculated. Disease-free survival (DFS) was used to represent similar outcomes including event-free survival (EFS), progression-free survival (PFS), leukemia-free survival (LFS), and relapse-free survival (RFS). Results: Our study included 241 phase III RCTs on AML. OS was the primary endpoint in 114 (47%) studies, while DFS and complete remission (CR) were reported as primary endpoints in 67 (28%) and 41 (17%) studies, respectively. Safety/adverse events, relapse rate (RR), graft versus host disease (GvHD) free survival, hematological improvement (HI), minimal residual disease (MRD), and non-relapse mortality (NRM) were used as primary endpoints in 10 (4%), 8 (3%), 5 (2%), 4 (2%), 3 (1%), and 2 (1%) studies respectively. Incidence of hospitalization, fungal disease, lung infiltrates, chronic GvHD, and allogeneic stem cell transplant each were used as primary endpoints in 1 (0.4%) study. (Table 1) Secondary endpoints followed a similar pattern as detailed in Table 2. OS (n=74, 31%), DFS (n=77, 32%) and CR (n=73, 30%) were commonly reported secondary endpoints. Safety/adverse effects, RR, mortality, quality of life (QoL), HI, MRD, incidence/length of hospitalization, and acute/chronic GvHD were used as secondary endpoints in 35 (14.5%), 15 (6%), 13 (5%), 9 (4%), 9 (4%), 7 (3%), 7 (3%), 5 (2%), and 4 (2%) studies, respectively. After 2013, increase in the use of OS (31% to 52%) and CR (15% to 17%) as a primary endpoint was noted, while the use of DFS as a primary endpoint decreased from 52% to 21%. (Table 1) For secondary endpoints, a higher trend in the use of DFS (19% to 35%) and OS (31% to 45%) and a lower trend in the use of CR (35% to 29%) was observed after 2013. (Table 2) Conclusion: Overall survival and disease-free survival were the most used primary and secondary endpoints in phase III randomized controlled trials for AML. There has been an increase in the use of clinically meaningful and objective endpoint of OS over the past 15 years in AML phase III RCTs. Figure 1 Figure 1. Disclosures Yacoub: Cara: Current equity holder in publicly-traded company; Dynavex: Current equity holder in publicly-traded company; Agios: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ACCELERON PHARMA: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Ardelyx: Current equity holder in publicly-traded company; Seattle Genetics: Honoraria, Speakers Bureau; Hylapharm: Current equity holder in publicly-traded company. Lin: AbbVie, Aptevo Therapeutics, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad, Genentech-Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Novartis, Ono Pharmaceutical, Pfizer, Prescient Therapeutics, Seattle Genetics, Tolero, Trovagene: Research Funding. McGuirk: Pluristem Therapeutics: Research Funding; Novartis: Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Gamida Cell: Research Funding; EcoR1 Capital: Consultancy; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Fresenius Biotech: Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Bellicum Pharmaceuticals: Research Funding; Astelllas Pharma: Research Funding.