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Genetics and outcomes in AML patients ≥75 years
and intermediate-risk cytogenetics remain associated with a relatively favorable OS in a comparison with adverse- risk cytogenetics. This finding is in agreement with that of a retrospective analysis by Heiblig and colleagues.31 In their study, older age (≥75 years in a cohort with an age range of 70-93 years) was also a strong prognostic factor in terms of OS whereas according to our own data, higher age (80-86 years versus 75-79 years) did not associate with OS, potentially due to the fact that only very fit octagenar- ians were enrolled in a trial of induction chemotherapy. Patients in the cohort reported by Heiblig and colleagues received three different treatment modalities: intensive chemotherapy, less intensive treatment (i.e. low-dose AraC, azacitidine or decitabine) or best supportive care only.31 The median OS in patients aged ≥75 years, regard- less of therapy type, was 4.3 months with a 3-year OS rate of 14%, compared to a median OS of 10 months and a 3- year OS rate of 20% in patients aged <75 years. In patients ≥75 years of age who all received intensive chemotherapy, Heiblig and colleagues reported a 3-year OS rate of 24%, which is comparable to the 3-year OS rate of 21% found in our retrospective analysis. Importantly, the analysis by Heiblig and colleagues also showed that long-term sur- vival beyond 3 years was exceedingly rare in patients treated with hypomethylating agents, while survival times exceeding 10 years were observed in intensively treated patients.
Our previous analysis of the mutational landscape in 664 intensively treated AML patients included 288 patients ≥60 years of age at primary diagnosis.12 We reported that the mutational spectrum in older AML patients differed from that in younger patients (<60 years). In this study, we extend this finding to very old patients aged ≥75 years. The five most frequently mutated genes were TET2, DNMT3A, NPM1, SRSF2 and ASXL1.12 The high incidence of TET2, DNMT3A, SRSF2, ASXL1, TP53 and SF3B1 mutations in our patients is in agreement with reports showing that these genes are frequently mutated in age-associated clonal hematopoiesis.26,32 Overall, 83% (126/151) of AML patients ≥75 years carried at least one mutation in one of these six genes.
Recently, Baldus and colleagues published data on the genetic and epigenetic landscape in 93 elderly AML patients (65-90 years) enrolled in a Study Alliance Leukemia (SAL) registry.33 Similar to our results, they iden- tified a high frequency of mutations in DNMT3A, TET2, SRSF2, ASXL1 and RUNX1. Strikingly, NPM1 mutations were much less common (16.1% of patients) than in our cohort (32%). This difference remains unexplained, since there are no obvious differences regarding, for example, the proportion of patients with de novo versus secondary AML which could affect the frequency of NPM1 muta- tions.
We unexpectedly identified IDH1 mutations as the strongest genetic predictor of shorter survival in this age group. The prognostic value of IDH1 and IDH2 mutations in AML has been studied by multiple groups but is still controversial.34,35 While some analyses found no impact on OS,36 others demonstrated associations with poor37-40 or favorable prognosis.28 A recently published meta-analysis of 33 studies found that IDH1 and IDH2 mutations, ana- lyzed jointly, do not affect OS or EFS.34 IDH1 mutations, when analyzed separately, are associated with lower CR rates, shorter EFS and shorter OS. A negative impact of IDH1 mutations on outcomes has also been described in
younger NPM1-mutated/FLT3-ITD-negative patients.37,39 These findings are generally compatible with the results of our study. This meta-analysis also revealed that IDH2- mutated patients had a longer OS than IDH2-wildtype patients, while in our study there was no impact of IDH2 mutations on OS (P=0.53). This discrepancy may be explained by our focus on very old AML patients, among whom the prognostic relevance of gene mutations may differ from that among younger patients. It remains unclear why mutations in two related genes with appar- ently similar functional consequences21,41,42 might have varying or even opposite impacts on OS. The poor out- come of old AML patients with mutated IDH1 needs to be validated in additional cohorts. If the negative prognostic effect of IDH1 mutations in old patients is confirmed in other studies, these patients should not be considered can- didates for induction chemotherapy. Targeted inhibitors of the mutant IDH1 enzyme, which are currently being tested in clinical trials, may become a preferred therapeu- tic approach for these patients in the future.
In our multivariate analysis, results of cytogenetic analy- sis (classified according to the MRC system) were a strong predictor of outcomes. Compared to the MRC risk cate- gories, application of the new ELN-2017 genetic risk clas- sification led to an expansion of the favorable- and adverse-risk categories (Table 1). The inclusion of RUNX1, ASXL1 and TP53 mutations in the ELN adverse-risk cate- gory, in particular, affects the risk classification of this cohort of very old patients in whom these mutations are common. Many patients who were classified as interme- diate-risk based on cytogenetic results alone according to the MRC recommendations are now re-classified into the adverse-risk group. At least in our cohort, however, the MRC cytogenetic risk classification appears to provide better prognostic stratification compared to the ELN-2017 system. Thus, further validation of the ELN-2017 classifi- cation in larger cohorts of elderly patients seems warrant- ed to define its applicability in this age group.
Our finding that in patients aged 75 or older, the prog- nosis of ELN-2017 favorable-risk patients was not better, and may in fact be worse, than that of the intermediate- risk group suggests that favorable molecular markers established in younger patients (e.g., mutated NPM1 without or with a low FLT3-ITD allelic ratio, biallelic CEBPA mutations) have weaker prognostic relevance in elderly patients. Indeed, in our cohort, the NPM1-mutat- ed/FLT3-ITD-negative genotype did not associate with favorable outcomes. NPM1 mutations alone were associ- ated with significantly longer EFS, but there were only trends towards longer RFS and OS. Among patients who achieved CR after induction therapy, those with mutated NPM1 had a significantly longer OS, suggesting that these patients might have benefited from cytarabine-based con- solidation and prolonged monthly maintenance therapy as used in the AML-CG 1999 trial. In contrast, the MRC adverse-risk group, defined by cytogenetic alterations only, had significantly shorter OS compared to the cytoge- netic favorable- and intermediate-risk groups. In contrast to the ELN-2017 adverse-risk group, no MRC adverse-risk patient survived beyond 2.1 years. Thus, karyotype rather than gene mutations appears to be the major factor defin- ing the prognosis in very old, intensively treated AML patients.43
One limitation of our study is that all patients were treated with the same treatment modality - intensive
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