FLT3-ITD and CEBPA Mutations Predict Prognosis in Acute Myelogenous Leukemia Irrespective of Hematopoietic Stem Cell Transplantation

Abstract

Cytogenetic and genetic changes have prognostic significance in acute myelogenous leukemia (AML). In our study, we compared the cytogenetic changes and gene mutations (NPM1, CEBPA, DNMT3A, FLT3-ITD, FLT3-TKD, and C-KIT) with clinical outcomes in 1132 patients with AML enrolled at our center over a 10-year period. A total of 977 patients provided gene mutation data. There were subsets of patients who exhibited mutations in NPM1 (17.9%), CEBPA (16.4%), FLT3-ITD (18.5%), FLT3-TKD (3.9%), DNMT3A (8.6%), and C-KIT (8.8%). A total of 557 patients (49.2%) underwent hematopoietic stem cell transplantation (HSCT) as consolidation therapy. Multivariate analysis identified an adverse karyotype (hazard ratio [HR], 1.48; P = .001), the presence of FLT3-ITD (HR, 1.90; P < .001), and receipt of nonstandard first-line induction chemotherapy (HR, 1.45; P = .003) as significant risk factors for poor overall survival (OS), and the presence of CEBPA mut (HR, .42; P < .001) and receipt of HSCT (HR, .35; P < .001) as prognostic factors for favorable OS. In addition, the presence of FLT3-ITD mut (HR, 2.11; P < .001) was identified as an independent risk factor for poor disease-free survival (DFS), and receipt of HSCT was correlated with improved DFS (HR, .74; P = .046). Compared with chemotherapy as consolidation therapy, HSCT improved the prognosis and overcame the prognostic effect of karyotype from the initial diagnosis; however, the presence of FLT3-ITD or CEBPA mutation can predict prognosis in AML irrespective of HSCT.

CEBPA are independent good prognostic factors in pediatric acute myeloid leukemia

“…Our survival analysis showed that FLT3/ITD mutation was identified for inferior EFS and OS rates compared with FLT3/ITD wild‐type, and receipt of SCT was correlated with improved EFS and OS when compared with those who did not receive SCT. These findings are consistent with the concept that SCT is indicated for FLT3/ITD mutations AML patients 34,35 . In the current research, CEBPA mutations were frequent in patients with normal karyotype and were more common combined with FLT3‐ITD wild‐type.…”

“…These findings are consistent with the concept that SCT is indicated for FLT3/ITD mutations AML patients. 34,35 In the current research, CEBPA mutations were frequent in patients with normal karyotype and were more common combined with FLT3-ITD wild-type. In recent years, some studies [36][37][38] had demonstrated that coexistence of CEBPA and FLT3/ITD mutations confers inferior outcomes in several large cohort adult AML cases.…”

Poor outcome of pediatric patients with acute myeloid leukemia harboring high FLT3/ITD allelic ratios

“…In the entire study, our analysis showed that SCT recipients of mutant FLT3/ITD could significantly improve EFS and OS when compared with those who did not receive SCT. These findings were consistent with the concept that SCT was indicated for AML patients with FLT3/ITD mutation 32 , 33 . When we focused on the impact of FLT3/ITD AR on the clinical outcome in pediatric AML, especially in the subgroup of chemotherapy-only patients, high FLT3/ITD AR was apparently associated with poorer EFS and OS when compared with low AR.…”

Clinical implications of recurrent gene mutations in acute myeloid leukemia

“…Among those recurrent gene mutations, the most adverse prognosis was observed in patients with DNMT3A and FLT3-ITD co-mutation, whose survival could be significantly improved with allo-HSCT [7,34]. Recurrent gene mutations analysis showed JAK2, FLT3-ITD high , and KIT high mutations were identified as significant prognostic factors for OS in multivariate analysis [35].…”