TP53 mutation defines a unique subgroup within complex karyotype de novo and therapy-related MDS/AML

Abstract

A subset of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) show complex karyotype (CK), and these cases include a relatively high proportion of cases of therapy-related myeloid neoplasms and TP53 mutations. We aimed to evaluate the clinicopathologic features of outcome of 299 AML and MDS patients with CK collected from multiple academic institutions. Mutations were present in 287 patients (96%), and the most common mutation detected was in TP53 gene (247, 83%). A higher frequency of TP53 mutations was present in therapy-related cases (P = .008), with a trend for worse overall survival (OS) in therapy-related patients as compared with de novo disease (P = .08) and within the therapy-related group; the presence of TP53 mutation strongly predicted for worse outcome (P = .0017). However, there was no difference in survival between CK patients based on categorization of AML vs MDS (P = .96) or presence of absence of circulating blasts ≥1% (P = .52). TP53-mutated patients presented with older age (P = .06) and lower hemoglobin levels (P = .004) and marrow blast counts (P = .02) compared with those with CK lacking TP53 mutation. Multivariable analysis identified presence of multihit TP53 mutation as strongest predictor of worse outcome, whereas neither a diagnosis of AML vs MDS nor therapy-relatedness independently influenced OS. Our findings suggest that among patients with MDS and AML, the presence of TP53 mutation (in particular multihit TP53 mutation) in the context of CK identifies a homogeneously aggressive disease, irrespective of the blast count at presentation or therapy-relatedness. The current classification of these cases into different disease categories artificially separates a single biologic disease entity.

Graphical abstract

Figure 1.

Heatmap of most frequent mutations divided by AML (red) and MDS status (blue). TP53 allelic status is indicated by dark gray (multihit) and light gray (monoallelic), and white is absence of TP53. All other mutations are indicated by black (present) and white (absent). MK is also indicated by black (present) and white (absent).

Figure 2.

Overall survival (OS) of patients based on therapy related status, AML vs. MDS, bone marrow blast percentage strata, and TP53 status in all patients and in the MDS and AML subsets. (A) OS of all patients based on therapy-related (median, 10.2 months) vs de novo status (median, 12.2 months), P = .08. (B) OS of all patients based on MDS (median OS, 13.0 months) vs AML (median, 9.4 months, P = .52). (C) OS of all patients based on BM blasts 0% to 4% (median, 14 months) vs 5% to 9% blasts (median, 15.5 months) vs 10% to 19% blasts (median, 10.5 months) vs >20% blasts (median, 9.5 months) (P = .52). (D) OS of all patients based on TP53 mutation status; no mutation (median, 33.9 months) vs TP53 monoallelic (median, 12.5 months) vs TP53 multihit (median, 9.4 months), P < .0001. For TP53 monoallelic vs multihit, P = .05. (E) OS of MDS patients based on TP53 mutation status; no mutation (median, 36.5 months) vs TP53 monoallelic (median, 15.4 months) vs TP53 multihit (median, 10.2 months), P < .0001. For TP53 monoallelic vs multihit, P = .02. (F) OS of AML patients based on TP53 mutation status; no mutation (median, 23.2 months) vs TP53 monoallelic (median, 5.2 months) vs TP53 multihit (median, 9.0 months), P = .003. For TP53 monoallelic vs multihit, P = .68.