Impact of Cytogenetics and New Molecular Markers On the Achievement of Complete Remission in Patients with Primary Acute Myeloid Leukemia. On Behalf of CETLAM Cooperative Group. Spain.

To analyze the prognostic impact of cytogenetics and main molecular abnormalities on the achievement of complete remission (CR), in patients with primary (de novo) AML (M3 excluded).

Between december-2003 and july-2009, 605 patients up to 70 years-old were included in the CETLAM AML-03 protocol. Induction therapy consisted in one or two courses of idarubicin, intermediate dose ara-C and etoposide, in addition to G-CSF priming from day 0. Cytogenetics classification was as in the MRC studies: Favorable prognosis (FP), intermediate (IP) and adverse (AP). In the IP group, molecular analysis of NPM1 (NPM1+) mutations, CEBPA mutations and internal tandem duplication of FLT3 gene (ITD/FLT3) was performed. In the AP group, the absence (MK-) or presence of monosomal karyotype (MK+) was studied; MK+ was defined as 2 or more autosomal monosomies, or one monosomy and ≥1 structural alteration.

Median age of the series was 53 years (range, 16-73). In 538 (89%) patients cytogenetic data were available; of them, 64 (10,5%) had FP, 375 (61,8) IP (included 255 with normal cytogenetics) and 99 (16,3%) AP. In the FP group, 33 (5,4%) had the AML1/ETO fusion and 31 (5,1%) the CBF/MYH11. In the IP group, 121 (31%) of 279 patients studied were NPM1+, 100 (26,7%) of 346 were DIT/FLT3+ and 22 (6%) of 235 analyzed were CEBPA+. In patients with AP, 47 were MK- and 33 MK+. Overall, 447 (73,8%) of 588 patients evaluable at the moment of the analysis achieved a CR. CR rates according cytogenetics were: FP 92,2%, IP 76,5% and AP 69,4%, p=0.01. In AML, with AML1-ETO+ and CBF/MYH11+, CR rates were 91% and 93.5%, respectively; of note no chemorefractory cases were observed. In the IP group, CR rates according to mutational status were: NPM1+/FLT3- 91.2%, CEBPA+/FLT3- 94.4%, no mutations 79.1% and DIT/FLT3+ 69.7% (p=0.003). Again, no refractoriness was observed in patients in IP patients belonging to the two groups with favourable molecular profile (p=0.003). In patients with AP, CR rate was 76.1% if MK- and 65.6% if MK+ (p=0.46). The prognostic impact of the herein described cytogenetic and molecular findings was confirmed in multivariate analyses.

Genetic characterization is nowadays mandatory in AML. CR rate is high and refractoriness exceptional in the presence of AML1-ETO or CBF/MYH11 rearrangements, or NPM1 or CEBPA mutations without DIT/FLT3. In contrast, CR probability is lower in AP group patients, mainly in those with MK+. These patients require new strategies within clinical trials.

Supported in part by grants: GR1-01075, ECO07/90065, PI080672 and RD06/0020/0101.

No relevant conflicts of interest to declare.