Improved outcomes among newly diagnosed patients with FMS-like tyrosine kinase 3 internal tandem duplication mutated acute myeloid leukemia treated with contemporary therapy: Revisiting the European LeukemiaNet adverse risk classification

Abstract

Mutations in fms-like tyrosine kinase 3 (FLT3) gene are common genomic alterations in acute myeloid leukemia (AML). FLT3 internal tandem duplication mutations (FLT3-ITD) have consistently been shown to be adversely prognostic, particularly those with high allelic ratio (AR). Current AML treatment strategies, including high dose cytarabine, purine analogs, FLT3 inhibitors (FLT3i), and with or without allogeneic stem cell transplant (SCT) have been shown to improve the outcomes in patients with FLT3 mutations. We analyzed a consecutive cohort of newly diagnosed patients with AML treated at a large academic medical center from January 2012 to January 2020. A total of 1576 patients with a new diagnosis of AML were reviewed. Among these, 1438 (91%) had molecular testing for FLT3 mutations and 21% (304/1438) had an FLT3 mutation, including 17% with an FLT3-ITD mutation. We show that FLT3-ITD high AR with NPM1 wild-type have significantly improved survival compared with other European LeukemiaNet (ELN) adverse risk disease. In multivariable cox proportional hazards model of patients receiving intensive or low-intensity induction regimens, FLT3 mutations did not have prognostic significance. The use of allogeneic SCT in CR1 for patients with FLT3 mutations appears to improve survival, particularly in those with ELN adverse risk disease. Overall, this data highlights the changing prognostic impact of FLT3 mutations in a contemporary era with appropriate use of induction therapy combined with targeted agents and allogenic SCT.

Figure 1:. Prognostic Impact of FLT3-ITD high/NPM1 WT

A. Overall survival of the full cohort stratified by ELN risk. ELN adverse risk patients were divided into FLT3-ITD high allelic ratio and NPM1 WT and all other ELN adverse risk patients. B. Overall survival of patients treated with intensive induction therapy stratified by ELN risk with FLT3-ITD high allelic ratio/NPM1 WT separated from other ELN adverse risk disease. C. Overall survival of patients treated with low intensity induction therapy stratified by ELN risk with FLT3-ITD high allelic ratio/NPM1 WT separated from other ELN adverse risk disease.

Figure 2:. Prognostic value of FLT3 mutations in patients treated with intensive or low intensity therapy

A. Overall survival of patients treated with intensive induction stratified by presence or absence of FLT3 mutation (ITD or TKD). B. Overall survival of patients treated with intensive induction stratified by of FLT3 mutation. FLT3-ITD high allelic ratio is ≥ 0.5. C. Overall survival of patients treated with intensive induction stratified by FLT3/NPM1 co-mutational status. D. Overall survival of patients treated with low intensity induction stratified by presence or absence of FLT3 mutation (ITD or TKD). E. Overall survival of patients treated with low intensity induction stratified by of FLT3 mutation. FLT3-ITD high allelic ratio is ≥ 0.5. F. Overall survival of patients treated with low intensity induction stratified by FLT3/NPM1 co-mutational status

Figure 3:. Role of SCT

A. Landmark survival analysis including patients treated with intensive induction, responded to induction therapy, were alive at the median time to SCT, and did not have core binding factor leukemia stratified by FLT3 mutation and receipt of SCT in first remission. B. Landmark survival analysis including patients treated with low intensity induction, responded to induction therapy, were alive at the median time to SCT, and did not have core binding factor leukemia stratified by FLT3 mutation and receipt of SCT in first remission. C. Overall survival of all patients with ELN adverse risk disease. Landmark survival analysis including patients that responded to induction therapy, were alive at the median time to SCT, and did not have core binding factor leukemia stratified by FLT3-ITD high allelic ratio and NPM1 WT and all other ELN adverse risk patients.