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We investigated the benefit of adding all-trans retinoic acid (ATRA) to chemotherapy for younger patients with nonacute promyelocytic acute myeloid leukemia and high-risk myelodysplastic syndrome, and considered interactions between treatment and molecular markers. Overall, 1075 patients less than 60 years of age were randomized to receive or not receive ATRA in addition to daunorubicin/Ara-C/thioguanine chemotherapy with Ara-C at standard or double standard dose. There were data on FLT3 internal tandem duplications and NPM1 mutations (n = 592), CEBPA mutations (n = 423), and MN1 expression (n = 195). The complete remission rate was 68% with complete remission with incomplete count recovery in an additional 16%; 8-year overall survival was 32%. There was no significant treatment effect for any outcome, with no significant interactions between treatment and demographics, or cytarabine randomization. Importantly, there were no interactions by FLT3/internal tandem duplications, NPM1, or CEBPA mutation. There was a suggestion that ATRA reduced relapse in patients with lower MN1 levels, but no significant effect on overall survival. Results were consistent when restricted to patients with normal karyotype. ATRA has no overall effect on treatment outcomes in this group of patients. The study did not identify any subgroup of patients likely to derive a significant survival benefit from the addition of ATRA to chemotherapy.

Original publication




Journal article



Publication Date





948 - 956


Adolescent, Adult, Antineoplastic Combined Chemotherapy Protocols, CCAAT-Enhancer-Binding Proteins, Child, Child, Preschool, Cytarabine, Daunorubicin, Female, Gene Expression Regulation, Leukemic, Genotype, Humans, Infant, Infant, Newborn, Leukemia, Promyelocytic, Acute, Male, Middle Aged, Mutation, Nuclear Proteins, Reverse Transcriptase Polymerase Chain Reaction, Thioguanine, Treatment Outcome, Tretinoin, Young Adult, fms-Like Tyrosine Kinase 3