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

Abstract

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. This study is registered at http://www. controlled-trials.com under ISRCTN17833622. (Blood. 2010;115:948-956)

Genetic Alterations and Their Clinical Implications in Acute Myeloid Leukemia

“…(Levis, et al 2002, Metzelder, et al 2009, Stone, et al 2005, Zhang, et al 2008 An ongoing international intergroup trial (10603 RATIFY), incorporating midostaurin into induction, consolidation or maintenance setting is currently underway. All-trans retinoic acid in combination with chemotherapy was found to be beneficial for NPM1-mutated patients (Burnett, et al 2010); however this preliminary result was not confirmed by the other study done on younger patients. (Schlenk, et al 2009) Tyrosine kinase inhibitor, such as imatinib, might be of clinical value in treatment of patients with KIT mutations.…”

Nucleophosmin and its complex network: a possible therapeutic target in hematological diseases

“…These data were, however, not confirmed when studying younger patients (Burnett et al, 2009). The molecular basis of this response remains elusive, but it may correlate with the reported role of NPM as co-repressor of AP2a during retinoic acid-induced differentiation, including the NPM1 promoter itself (Liu et al, 2007a).…”

Disease evolution and outcomes in familial AML with germline CEBPA mutations

“…Germline CEBPA mutations were verified in affected individuals from pedigrees A to E, using bidirectional sequencing as previously described. 18 The sources of germline (constitutional) DNA included peripheral blood (PB) or bone marrow (BM) during remission (A. The index case in pedigree C was C.III.1, who presented in 2012 at 18 years of age.…”