The impact on outcome of the addition of all-trans retinoic acid to intensive chemotherapy in younger patients with nonacute promyelocytic acute myeloid leukemia: overall results and results in genotypic subgroups defined by mutations in NPM1, FLT3, and CEBPA.
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.
Burnett
Alan K
AK
Department of Haematology, Cardiff University School of Medicine, Cardiff, UK. BurnettAK@Cardiff.ac.uk
Hills
Robert K
RK
Green
Claire
C
Jenkinson
Sarah
S
Koo
Kenneth
K
Patel
Yashma
Y
Guy
Carol
C
Gilkes
Amanda
A
Milligan
Donald W
DW
Goldstone
Anthony H
AH
Prentice
Archibald G
AG
Wheatley
Keith
K
Linch
David C
DC
Gale
Rosemary E
RE
D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003561:Cytarabine / Q000008:administration & dosage; D003630:Daunorubicin / Q000008:administration & dosage; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D000090243:Nucleophosmin; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013866:Thioguanine / Q000008:administration & dosage; D016896:Treatment Outcome; D014212:Tretinoin / Q000008:administration & dosage; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D003561:Cytarabine; D000090243:Nucleophosmin; D014212:Tretinoin; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D013866:Thioguanine; D003630:Daunorubicin