A clinically applicable gene expression-based score predicts resistance to induction treatment in acute myeloid leukemia

Abstract

Prediction of resistant disease at initial diagnosis of acute myeloid leukemia (AML) can be achieved with high accuracy using cytogenetic data and 29 gene expression markers (Predictive Score 29 Medical Research Council; PS29MRC). Our aim was to establish PS29MRC as a clinically usable assay by using the widely implemented NanoString platform and further validate the classifier in a more recently treated patient cohort. Analyses were performed on 351 patients with newly diagnosed AML intensively treated within the German AML Cooperative Group registry. As a continuous variable, PS29MRC performed best in predicting induction failure in comparison with previously published risk models. The classifier was strongly associated with overall survival. We were able to establish a previously defined cutoff that allows classifier dichotomization (PS29MRCdic). PS29MRCdic significantly identified induction failure with 59% sensitivity, 77% specificity, and 72% overall accuracy (odds ratio, 4.81; P = 4.15 × 10-10). PS29MRCdic was able to improve the European Leukemia Network 2017 (ELN-2017) risk classification within every category. The median overall survival with high PS29MRCdic was 1.8 years compared with 4.3 years for low-risk patients. In multivariate analysis including ELN-2017 and clinical and genetic markers, only age and PS29MRCdic were independent predictors of refractory disease. In patients aged ≥60 years, only PS29MRCdic remained as a significant variable. In summary, we confirmed PS29MRC as a valuable classifier to identify high-risk patients with AML. Risk classification can still be refined beyond ELN-2017, and predictive classifiers might facilitate clinical trials focusing on these high-risk patients with AML.

Graphical abstract

Figure 1.

Consort diagram. APL, acute promyelocytic leukemia; MDS, myelodysplastic syndrome; MPS, myeloproliferative syndrome.

Figure 2.

Comparison of different predictive classifiers of induction failure in AML. Receiver operating curves (A) and precision-recall curves (B) comparing the prediction of induction failure of PS29MRC, the clinical score of Walter et al, and the retrained response LSC17 score.

Figure 3.

PS29MRCdic identifies patients with AML with inferior prognosis. Kaplan-Meier curve showing outcomes of patients according to the PS29MRC risk groups. (A) Outcomes of all patients. (B) Outcomes of patients younger than 60 years. (C) Outcomes of patients ≥60 years of age. (D) Comparison of patients with TP53 mutations and patients without a TP53 mutation, but with high PS29MRC values (top 10%). (E) Proportions of RD in groups defined by 4 risk factors (ELN-2017, complex karyotype, age, TP53 ), and the PS29MRCdic high-risk group within each risk category. The striped bar represents the high-risk category for each risk factor. adv, adverse risk; fav, favorable risk; int, intermediate risk; KT, karyotype; mut, mutated, wt, wild-type.

Figure 4.

Individual risk prediction in patients with AML. Plot showing the probability of induction failure with a cutoff at PS29MRCcont = 0.4 (blue dashed line).