Next Generation Mutational Profiling Improves Prognostication in Younger Patients with Acute Myeloid Leukemia
Authors: Sloan Caroline E , Gimotty Phyllis A. , Boccuti Anne , Sehgal Alison R. , Zhao Jianhua , Daber Robert , Morrissette Jennifer JD , Luger Selina M. , Bagg Adam , Carroll Martin P. 
Published: October 2019

Abstract
Background: Cytogenetics-based prognostication systems are well described in acute myeloid leukemia (AML). In younger patients (<60 years), mutations in FLT3, NPM1 and CEBPA have consistently been shown to affect AML prognosis and have been integrated with cytogenetics to improve prognostication. Patel et al. (NEJM 2012) recently used data from patients <60 years enrolled in a randomized controlled trial to create a new integrated genetic profile (IGP) model using cytogenetics and mutations in 9 genes. The IGP model improved risk stratification compared to cytogenetics alone in these patients. However, this model has not been evaluated in clinical practice or in patients over 60 years old.
Methods: We conducted a retrospective study of 2 cohorts of patients with newly diagnosed de novo AML for whom clinical, cytogenetic and genetic data were available. We included 187 patients from the University of Pennsylvania and 166 patients from Washington University (The Cancer Genome Atlas). We excluded patients with karyotype t(15;17). We evaluated survival outcomes using the 4 mutational profiles (MP) defined by Patel et al. We estimated survival rates in the 4 MP categories from Kaplan-Meier survival curves. Log-rank tests were used to compare survival curves for patients with intermediate MP to those in the 3 other categories.
Results: Clinical characteristics and outcomes were similar in both cohorts so they were combined for further analysis (n=353). Median age of the total cohort was 57 years, with 207 patients <60 years (59%). Among younger patients, 136 had intermediate cytogenetics (66%) and the remaining had favorable (28, 14%), unfavorable (33, 16%), and unknown (10, 5%) cytogenetics. The 136 patients <60 years with intermediate-risk cytogenetics were further classified, according to the IGP model, as having favorable, intermediate or unfavorable MP (Table 1). The survival curve for patients reclassified as having favorable MP was significantly different from the curve for patients with intermediate MP (p=0.027) and similar to the curve for patients with favorable cytogenetics (p=0.751). The survival curve for patients who were FLT3-ITD positive with unfavorable MP was significantly different from the curve for patients with intermediate MP (p=0.014) and similar to the curve for patients with unfavorable cytogenetics (p=0.526). However, the survival curves for patients who were FLT3-ITD negative with unfavorable MP and patients with intermediate MP were similar (p=0.707). Survival rates are in Table 1. In patients >60 years, overall survival was similar among patients with favorable, intermediate and unfavorable MP (Table 2).
Conclusions: Using the IGP model to stratify patients with de novo AML treated at 2 academic institutions, 38% of patients ≤60 years and 45% of patients >60 years with intermediate-risk cytogenetics were reclassified as having favorable, intermediate, or unfavorable MP. Among patients >60 years, the IGP model did not improve prognostication compared to cytogenetics alone. Among patients <60 years, however, we found that the IGP model is applicable for most patients. Our analysis demonstrates that incorporation of 6 out of 9 mutations (FLT3-ITD, DNMT3A, NPM1, CEBPA, IDH1, IDH2) into clinical testing at diagnosis improves characterization of survival for these patients. Other common mutations that are not incorporated in the IGP model may affect prognosis in older patients.
Table 1. Integrated genetic profiles of patients <60 years with intermediate-risk cytogenetics Mutational profile (MP) Prognosis n 1-year overall survival (OS) 3-year OS Adjusted p-value FLT3-ITD negative with mutant NPM1 and IDH1/2 Favorable 13 92% 55% 0.027 FLT3-ITD negative with MLL-PTD or mutant TET2, ASXL1 or PHF6 Unfavorable 13 92% 62% 0.707 FLT3-ITD positive with trisomy 8, MLL-PTD, or mutant TET2 or DNMT3A Unfavorable 28 38% 15% 0.014 Mutant CEBPA or other MP Intermediate 82 69% 35% Reference
Table 2. Integrated genetic profiles of patients >60 years with intermediate-risk cytogenetics Mutational profile (MP) Prognosis n 1-year overall survival (OS) 3-year OS Adjusted p-value FLT3-ITD negative with mutant NPM1 and IDH1/2 Favorable 3 100% 0% 0.470 FLT3-ITD negative with MLL-PTD or mutant TET2, ASXL1 or PHF6 Unfavorable 20 52% 13% 0.851 FLT3-ITD positive with trisomy 8, MLL-PTD, or mutant TET2 or DNMT3A Unfavorable 17 9% 0% 0.448 Mutant CEBPA or other MP Intermediate 48 35% 15% Reference

Disclosures
No relevant conflicts of interest to declare.