tretinoin and lestaurtinib

Topics: Adenine; Adenine Nucleotides; Aminoglycosides; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Arabinonucleosides; Carbazoles; Clofarabine; Cytarabine; Dasatinib; Daunorubicin; fms-Like Tyrosine Kinase 3; Furans; Gemtuzumab; Humans; Leukemia, Myeloid, Acute; Naphthalimides; Organophosphonates; Prognosis; Protein Kinase Inhibitors; Pyrimidines; Sesquiterpenes; Staurosporine; Stem Cell Transplantation; Thiazoles; Tretinoin

Topics: Antineoplastic Agents; Azacitidine; Biomedical Research; Carbazoles; Carboplatin; Cytarabine; Daunorubicin; Decitabine; Enzyme Inhibitors; Etoposide; Flavonoids; Furans; Humans; Leukemia, Myeloid, Acute; Mitoxantrone; Piperidines; Quinolones; Staurosporine; Topotecan; Tretinoin

The prognostic significance of FLT3 mutations in acute promyelocytic leukemia (APL) is not firmly established and is of particular interest given the opportunities for targeted therapies using FLT3 inhibitors. We studied 203 patients with PML-RARA-positive APL; 43% of the patients had an FLT3 mutation (65 internal tandem duplications [ITDs], 19 D835/I836, 4 ITD+D835/I836). Both mutations were associated with higher white blood cell (WBC) count at presentation; 75% of the patients with WBC counts of 10 x 10(9)/L or greater had mutant FLT3. FLT3/ITDs were correlated with M3v subtype (P < .001), bcr3 PML breakpoint (P < .001), and expression of reciprocal RARA-PML transcripts (P = .01). Microarray analysis revealed differences in expression profiles among patients with FLT3/ITD, D835/I836, and wild-type FLT3. Patients with mutant FLT3 had a higher rate of induction death (19% vs 9%; P = .04, but no significant difference in relapse risk (28% vs 23%; P = .5) or overall survival (59% vs 67%; P = .2) at 5 years. In in vitro differentiation assays using primary APL blasts (n = 6), the FLT3 inhibitor CEP-701 had a greater effect on cell survival/proliferation in FLT3/ITD+ cells, but this inhibition was reduced in the presence of ATRA. Furthermore, in the presence of CEP-701, ATRA-induced differentiation was reduced in FLT3/ITD+ cells. These data carry implications for the use of FLT3 inhibitors as frontline therapy for APL.

Topics: Adolescent; Adult; Antineoplastic Agents; Carbazoles; Child; Child, Preschool; Female; fms-Like Tyrosine Kinase 3; Furans; Gene Expression Profiling; Humans; Indoles; Infant; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Mutation; Oligonucleotide Array Sequence Analysis; Prognosis; Survival Analysis; Tretinoin