Treatment Outcome of Brazilian Patients with Acute Myeloid Leukemia According to the New European LeukemiaNet Recommendations
Authors: Benício Mariana Tereza Lira , Ribeiro Ana Flávia Leonardi Tibúrcio , Lucena-Araujo Antonio R , Glória Ana Beatriz Firmato , Oliveira Fabio Morato , Santos Silvana Maria Eloi , Falcao Roberto P. , Fagundes Evandro , Rego Eduardo M. 
Published: October 2019

Abstract
Abstract 3146
Although scarce, the results on the outcome of patients with acute myeloid leukemia (AML) in developing countries point to significant disparities compared to studies conducted in US and Europe. We have previously shown that AML patients in Brazil have shorter five-year overall survival (OS) in comparison to patients in developed countries, even considering the relative excess of acute promyelocytic leukemia cases. In addition, AML patients in developing countries have been poorly characterized for genetic abnormalities, despite their relevance. Our aim was to use the new European LeukemiaNet (ELN) recommendations (Döhner et al., 2010) to stratify Brazilian patients with AML and address its applicability to determine treatment outcome. Two hundred and twenty-one consecutive patients treated at two University Hospitals (University of São Paulo and Federal University of Minas Gerais) between 2001–2010 with age between 15 and 65 years were studied. Age, gender, WBC count, karyotype, NPM1, FLT3-ITD and MLL-PTD mutations, and the BAALC gene expression levels were analyzed. 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 courses of consolidation therapy with high dose cytarabin (above 1g/m2/d). Median follow-up time for surviving patients was 20 months (range: 4 – 110 mo). The median age was 42 years and 101 (46%) were male. Patients were assigned to the proposed genetic groups from the ELN recommendations as follows: favorable (n=82), intermediate I (n=66), intermediate II (31) and adverse (n=20). Direct sequencing of PCR products was performed to detect NPM1 mutations. FLT3-ITD detection was performed by PCR. MLL-PTD was detected by RQ-PCR. The relative expression levels of BAALC gene were measured by RQ-PCR, according to the comparative cycle threshold method, and patients were dichotomized in high or low expression groups using the median as cut-off value. The estimated five-year OS for all patients was 18±3% (mean±standard deviation). Univariate analyses determined that age, genetic risk group, FLT3-ITD, and MLL-PTD were significant risk factors. Patients older than 45 years presented shorter OS (18 mo; CI95%, 11 – 26) in comparison to those ≤ 45 years (31 mo, 22 – 39; P=0.01). The mean OS for favorable, intermediate I, intermediate II, and adverse groups were 41, 12, 17 and 13 months, respectively (P=0.02). Mean OS for patients harboring FLT3-ITD was shorter (12 mo; 7 – 17) in comparison to patients with wild-type FLT3 (27 mo; 20 – 34; P=0.04). Besides, FLT3-ITD was associated with NPM1 mutations (twice as often in NPM1mut as in NPM1wt, P=0.02) and higher percentage of bone marrow blasts (p=0.05). Finally, patients harboring MLL-PTD presented shorter OS (4 mo; 0.4 – 7) in comparison to patients with wild-type MLL (31 mo; 24 – 39; P=0.002). Multivariable analysis revealed that only MLL-PTD was an independent prognostic factor for OS. When only cytogenetically normal (CN-AML) patients were analyzed (n=77), NPM1 mutations predicted longer OS (34 mo; 17 – 50 vs. 11 mo; 7 – 14; P=0.03). The beneficial impact of NPM1 mutations on OS was seen independently of FLT3-ITD detection. Patients harboring MLL-PTD presented shorter OS (1.5 mo; 0 – 4) in comparison to patients with wild-type MLL (23 mo; 14 – 32; P=0.02). Finally, mean OS for patients presenting WBC count >50×109/L at diagnosis was shorter (9 mo; 2 – 15) in comparison to those with WBC <50×109/L (22.5 mo; 14 – 31; P=0.007). Multivariable analysis showed that MLL-PTD and WBC counts were independent prognostic factors for OS. In our cohort, the ELN recommendations were able to identify patients with more favorable outcome. However, patient stratification into intermediate I, intermediate II, and adverse groups failed to translate into clinical outcome. Molecular markers revealed significant prognostic information and should be routinely screened, at least in CN-AML cases. Our findings provide important insights into the characterization of AML patients in developing countries. Regardless the higher frequency of patients with favorable prognostic risk, which would not be diminished by the inclusion of CEBPA mutations results, treatment outcome for Brazilian patients was poorer than for those in US and Europe. Our results reinforce the necessity of multicentric collaborative initiatives involving developing countries.

Disclosures:
No relevant conflicts of interest to declare.