Page 115 - 2018_11-Haematologica-web

Genetics and outcomes in AML patients ≥75 years
mostly because of an increased risk of early death within 60 days from starting treatment (26% for patients with an ECOG PS of 0-1, 40% for those with a PS of 2, and 75% for patients with an ECOG PS of 3 or 4). Patients random- ized to HAM induction tended to have longer OS com- pared to patients randomized to TAD induction (median OS: TAD, 3.1 months versus HAM, 7.8 months; P=0.09) (Online Supplementary Results and Online Supplementary Figure S3).
Impact of cytogenetics on survival
Since only three patients had favorable-risk cytogenetics
according to the MRC classification, the favorable- and intermediate-risk groups were analyzed jointly. Patients in the favorable- or intermediate-risk categories had a non- significantly higher remission rate than adverse-risk patients (CR/CRi, 51% versus 27%; P=0.2). The EFS, RFS, and OS of favorable- and intermediate-risk patients were significantly longer than those for adverse-risk patients (EFS: P=0.001; RFS: P=0.006; OS: P=0.001) (Figure 1A and Online Supplementary Figure S4).
Gene mutations and patients’ pretreatment characteristics
We identified a total of 622 driver mutations affecting 64 genes, with a median number of four mutated genes per patient (range, 1-10 mutations/patient) (Online Supplementary Figure S5). Older age (81-86 years versus 75- 80 years) was not associated with a higher number of driv- er gene mutations (P=0.5, data not shown). The most fre- quently mutated genes in this age group were TET2 (63/151, 42%), DNMT3A (53/151, 35%), NPM1 (48/151, 32%), FLT3 (45/151, 30%), SRSF2 (38/151, 25%), ASXL1 (31/151, 21%), and RUNX1 (28/151, 19%) (Table 1, Figure 2A). Compared to previously studied patients aged <60 or 60-74 years12, those aged ≥75 years had a higher frequency of TET2, SRSF2 and ASXL1 mutations. TP53 mutations occurred in 14% of patients (21/151) and were strongly associated with complex karyotypes (P<0.001). Eighty- three percent of patients (126/151) harbored one or more
A
B
Figure 1. Overall survival according to the MRC and ELN risk classifications. (A) Overall survival for patients in the favorable- and intermediate-risk groups (green) compared to the adverse-risk group (red) according to the MRC cytogenetic risk cat- egory. (B) Overall survival for patients in the favorable-(green), intermediate- (orange) and adverse-risk groups (red) according to the ELN 2017 genetic category.
Table 1. Patients’ baseline characteristics. Variable
Age [years], median (range)
Male sex
Disease type
De novo AML
Secondary AML Therapy-related AML MDS (10%-<20% blasts)
ECOG performance statusa 0
1 2 ≥3
WBC [×109/L], median (range)
Blast count at diagnosis
% bone marrow blasts, median (range)
% peripheral blood blasts, median (range)
MRC cytogenetic risk categoryb Favorable
Intermediate
Adverse
ELN 2017 genetic groupc Favorable Intermediate
Adverse
Remission status after induction CR
CRi
Persistent AML
Death during induction
Most commonly mutated genes
TET2 DNMT3A NPM1 SRSF2 ASXL1 RUNX1 FLT3-ITD NRAS IDH2 TP53 FLT3-TKD IDH1
Total cohort (n=151)
76 (75 – 86)
81 (54%)
122 (81%) 22 (15%) 4 (3%) 3 (2%)
13 (10%) 70 (51%) 42 (31%) 12 (9%)
14.2 (0.1 – 318.1)
80 (10 – 100)
26 (0 – 100)
3 (2%) 112 (82%) 22 (16%)
37 (28%) 32 (24%) 65 (49%)
66 (44%) 6 (4%) 25 (17%) 54 (35%)
63 (42%) 53 (35%) 48 (32%) 38 (25%) 31 (21%) 28 (19%) 27 (18%) 25 (17%) 23 (15%) 21 (14%) 18 (12%) 13 (9%)
ECOG: Eastern Cooperative Oncology Group; WBC: white blood cell count; MRC: British Medical Research Council; ELN: European LeukaemiaNet; CR: complete remis- sion; CRi: complete remission with incomplete blood count recovery; ITD: internal tandem duplication; TKD: tyrosine kinase domain. aNo data available for 14 patients; bNo karyotype was available for 14 patients; cClassification was not possible for 17 patients due to lack of karyotype or FLT3-ITD allelic ratio.
haematologica | 2018; 103(11)
1855