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Genetics and outcomes in AML patients ≥75 years
(Online Supplementary Figure 7D). Patients with TP53 muta- tions showed trends towards shorter EFS (P=0.079) (Online Supplementary Figure S9A) and OS (P=0.073) (Figure 3D), and had a significantly shorter RFS (P=0.041) (Online Supplementary Figure S9B), compared to TP53-wildtype patients. TP53-mutated patients who achieved CR had a significantly shorter OS (calculated from the day of achieving CR) compared to that of TP53-wildtype patients in CR (P=0.005) (Online Supplementary Figure S9C).
IDH1 mutations: impact on event-free and overall survival, association with patients’ pretreatment characteristics and other gene mutations
In our cohort of old AML patients, the only gene signif- icantly associated with OS in univariate analysis was IDH1 (Online Supplementary Table S1). None of the IDH1 codon R132-mutated patients (13/151, 9%) reached CR/CRi (P<0.001). Consequently, IDH1-mutated patients had a significantly shorter EFS (P<0.001) (Online Supplementary Figure S10A) and OS (P≤0.001) Figure 4A) than IDH1-wildtype patients.
Within this elderly cohort of patients, IDH1-mutated patients showed a trend towards older age (P=0.08) (Online Supplementary Table S2). Furthermore, IDH1- mutated patients tended to have higher platelet counts (P=0.20) and lower WBC counts (P=0.10) than IDH1-wild- type patients. There was no difference in peripheral blood or bone marrow blast counts between IDH1-wildtype and IDH1-mutated patients. IDH1 mutations were associated
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with cytogenetically normal AML (P=0.069): 10/13 IDH1- mutated patients had a normal karyotype, whereas one patient had a 7q deletion, one had trisomy 8, and kary- otype was unknown for one patient. Further information on clinical characteristics of the 13 IDH1-mutated patients are shown in Online Supplementary Table S3. IDH1 and IDH2 mutations were mutually exclusive (P=0.2), and IDH2 mutations, found in 15% of patients (23/151), had no impact on OS (P=0.5). TET2 mutations were mutually exclusive with IDH1 mutations (P=0.001), and with mutated IDH2 (P=0.002).
Five IDH1-mutated patients also carried NPM1 muta- tions. While patients with NPM1 mutations overall tend- ed to have favorable OS (Figure 3A), IDH1 mutations had a dominant negative prognostic effect even when co- occurring with mutated NPM1 (Figure 4B). Four IDH1- mutated patients had simultaneous FLT3-TKD mutations, an association that almost reached statistical significance (P=0.051). There was no association between IDH1 and FLT3-ITD mutations (P=0.5).
Multivariate analysis of prognostic factors in old, intensively treated acute myeloid leukemia patients
We used a multivariate Cox regression model to identify the most relevant predictors of OS in this cohort of inten- sively treated AML patients ≥75 years (Table 2). In this multivariate model, using the MRC classification, ECOG PS, and IDH1, NPM1 and TP53 mutations as covariates, only IDH1 mutations and the MRC adverse cytogenetic
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Figure 3. Overall survival according to gene mutations. (A) NPM1 mutations: overall survival in NPM1-mutated (green) compared to NPM1-wildtype patients (red). (B) NPM1-mutated/FLT3-ITD-negative patients: overall survival in NPM1-mutated/FLT3-ITD-wildtype patients (green) compared to other patients (red). (C) FLT3-ITD muta- tions: overall survival in FLT3-ITD-mutated (red) compared to FLT3-ITD-wildtype patients (green). (D) TP53 mutations: overall survival in TP53-mutated patients (red) compared to TP53-wildtype patients (green). “Mut” denotes mutated and “wt” wildtype.
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