Impact of NPM1/FLT3-ITD genotypes defined by the 2017 European LeukemiaNet in patients with acute myeloid leukemia

Abstract

Patients with acute myeloid leukemia (AML) harboring FLT3 internal tandem duplications (ITDs) have poor outcomes, in particular AML with a high (≥0.5) mutant/wild-type allelic ratio (AR). The 2017 European LeukemiaNet (ELN) recommendations defined 4 distinct FLT3-ITD genotypes based on the ITD AR and the NPM1 mutational status. In this retrospective exploratory study, we investigated the prognostic and predictive impact of the NPM1/FLT3-ITD genotypes categorized according to the 2017 ELN risk groups in patients randomized within the RATIFY trial, which evaluated the addition of midostaurin to standard chemotherapy. The 4 NPM1/FLT3-ITD genotypes differed significantly with regard to clinical and concurrent genetic features. Complete ELN risk categorization could be done in 318 of 549 trial patients with FLT3-ITD AML. Significant factors for response after 1 or 2 induction cycles were ELN risk group and white blood cell (WBC) counts; treatment with midostaurin had no influence. Overall survival (OS) differed significantly among ELN risk groups, with estimated 5-year OS probabilities of 0.63, 0.43, and 0.33 for favorable-, intermediate-, and adverse-risk groups, respectively (P < .001). A multivariate Cox model for OS using allogeneic hematopoietic cell transplantation (HCT) in first complete remission as a time-dependent variable revealed treatment with midostaurin, allogeneic HCT, ELN favorable-risk group, and lower WBC counts as significant favorable factors. In this model, there was a consistent beneficial effect of midostaurin across ELN risk groups.

AML risk stratification models utilizing ELN-2017 guidelines and additional prognostic factors: a SWOG report

“…Thus, the results may not be generalizable to patients receiving therapy outside of evaluated clinical trials, low-intensity regimens (e.g., azacytidine), or targeted agents (e.g., midostaurin). Nonetheless, some recent biomarker studies suggest that previously recognized prognostic factors remain highly informative and predictive for responses to more “targeted’ agents [ 57 – 59 ], and as such, there likely remains some role for the identification of prognostic biomarkers that are applicable across a variety of therapies.…”

Host immune genetic variations influence the risk of developing acute myeloid leukaemia: results from the NuCLEAR consortium

“…Regulome score 2b. 4 – 7 IL8_ IVS1 + 230 (+396) rs2227307 G Associated with IL8 at both transcriptional and translational levels and with increased transmigration of primary neutrophils. Associated with follicular lymphoma patient survival 6 , 7 CXC-Chemokine receptor 2 (IL8RB) CXCR2_Ex3-1010 rs1126580 G Associated with CXCR2 and CXCR1 levels in whole blood (GTEx).…”

“…Even though cytogenetic analysis have allowed the stratification of AML patients into favourable, intermediate and unfavourable classes and has improved our ability to predict clonal evolution and disease progression 3 , many AML patients (~ 45%) have a normal karyotype, which suggests that additional genetic alterations are needed to develop the disease. Sequencing studies identified genes frequently mutated in AML, some of which predict poor prognosis ( NPM1 wt / FLT3-ITD high , RUNX1 , ASXL1 and TP53 ) 4 . Furthermore, it is increasingly evident that host immunity might also be implicated in AML risk and survival 5 .…”

Therapy for acute myelogenous leukemia revisited: moving away from a one-size-fits-all approach

“…in AML compared to other cancers, these mutations can be combined in complex ways in different subclones, making each patient almost unique in its genetic profile. Even taken into account the two most common mutations in AML; insertion in the NPM1 gene and internal tandem duplication (ITD) in the FLT3 gene, the combination of these two mutations with consideration of differing allele burdens can lead to different prognostic subgroup classifications with treatment-related consequences [12]. Furthermore, incorporating other currently targetable mutations, such as IDH1 and IDH2 mutations [10,11], the picture becomes even more complex.…”