Treatment Outcome of Acute Myeloid Leukemia Patients From Brazil According to Karyotype, Presence or Not of FLT3-ITD and NPM1 Mutations, and BAALC Gene Expression.
Authors: Benício Mariana Tereza Lira , Ribeiro Ana Flávia Leonardi Tibúrcio , Glória Ana Beatriz Firmato , Lucena-Araujo Antonio R , Santana-Lemos Bárbara A , Jacomo Rafael , Assumpcao Juliana Godoy , Oliveira Fabio Morato , Xavier Sandra Guerra , Fagundes Evandro , Rego Eduardo M. 
Published: October 2019

Abstract
Abstract 3836
Current results regarding AML treatment in developed countries have shown that the estimate five-year overall survival (OS) is around 40–50%. In contrast, the few existing studies concerning the outcome of AML patients in developing countries reported OS values around 18–25%, despite the fact that there is a relative excess of acute promyelocytic leukemia (APL) cases, which are associated with favorable prognosis. In addition, the studies conducted in developing countries have not taken into account recently reported molecular markers, such as mutations in the NPM1 gene and expression levels of the BAALC gene, which were demonstrated to impact on outcome. The present study aimed to evaluate the effects of karyotype, NPM1 and FLT3-ITD mutations, and BAALC gene expression on the outcome of AML Brazilian patients. One hundred and fifty-eight patients were enrolled in two University Hospitals of the Southeast Region of the country. The median age was 43 years (range:12–92 y) with 78 males (49%). Patients were treated with conventional chemotherapy consisting of daunorubicin (60mg/m2/d for 3 days) and cytarabin (200mg/m2/d for 7 days) as induction, followed by two or three cycles of consolidation therapy with high doses of cytarabin (above 1g/m2/d). The following variables were analyzed: age, gender, WBC count, karyotype, NPM1 and FLT3-ITD mutations, and the quantitative evaluation of the BAALC gene expression. Pretreatment bone marrow samples were analyzed by G-banding cytogenetic, of which 143 were successful, and so allowed the stratification of patients in groups according to prognosis, as proposed by the Medical Research Council (MRC) in: favorable (n=48), intermediate (n=77) and adverse (n=18). A combination of ASO-RT-PCR and sequencing was performed to detect NPM1 mutations. FLT3-ITD detection was performed by PCR. The relative expression levels of BAALC gene were measured by RQ-PCR, according to the comparative cycle threshold (Ct) method and patients were classified as presenting high or low expression using the median as the cut-off value. The estimated five-year OS for all patients was of 15.3% (S.D.: ± 3.4%). The median OS according to cytogenetic stratification was of 1234, 593 and 230 days for favorable, intermediate and adverse groups, respectively (p=0.04). Univariate analysis detected as significant the following variables: age, cytogenetic risk group and presence of FLT3-ITD (p=0.03). Indeed, patients harboring FLT3-ITD patients presented a mean OS of only 300 days (range: 116–485 days) in comparison with 770 days (531 – 1010) in patients without FLT3 mutations. Besides, FLT3-ITD was associated with genre (more common in females, p=0.02) and with cytogenetics (more frequent in the favorable and intermediate cytogenetic risk groups). When only cytogenetically normal patients were analyzed (n=55), NPM1 mutations were significantly associated with longer OS (mean: 1058 days, range: 449–1666 days vs. 276 days, range: 145–406 days; p=0.03). Patients expressing high BAALC levels presented shorter OS (p=0.04). The multivariate analysis revealed FLT3-ITD as an independent prognostic factor for OS (p=0.007). Our results provide important insights into the characterization of AML patients in Brazil, suggesting that the frequency of cytogenetic abnormalities and FLT3-ITD mutations are similar to those in developed countries, whereas NPM1 mutations are less frequent. Importantly, the outcome was inferior to that reported in Europe and US, thus suggesting that multicentric collaborative efforts are urgently needed.

Disclosures:
No relevant conflicts of interest to declare.