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. 2022 Apr 14;139(15):2347-2354.
doi: 10.1182/blood.2021014472.

Molecular characterization of mutant TP53 acute myeloid leukemia and high-risk myelodysplastic syndrome

Tim Grob  1 , Adil S A Al Hinai  1   2 , Mathijs A Sanders  1 , François G Kavelaars  1 , Melissa Rijken  1 , Patrycja L Gradowska  1 , Bart J Biemond  3 , Dimitri A Breems  4 , Johan Maertens  5 , Marinus van Marwijk Kooy  6 , Thomas Pabst  7 , Okke de Weerdt  8 , Gert J Ossenkoppele  3 , Arjan A van de Loosdrecht  3 , Gerwin A Huls  9 , Jan J Cornelissen  1 , H Berna Beverloo  10 , Bob Löwenberg  1 , Mojca Jongen-Lavrencic  1 , Peter J M Valk  1
Affiliations

Molecular characterization of mutant TP53 acute myeloid leukemia and high-risk myelodysplastic syndrome

Tim Grob et al. Blood. .

Abstract

Substantial heterogeneity within mutant TP53 acute myeloid leukemia (AML) and myelodysplastic syndrome with excess of blast (MDS-EB) precludes the exact assessment of prognostic impact for individual patients. We performed in-depth clinical and molecular analysis of mutant TP53 AML and MDS-EB to dissect the molecular characteristics in detail and determine its impact on survival. We performed next-generation sequencing on 2200 AML/MDS-EB specimens and assessed the TP53 mutant allelic status (mono- or bi-allelic), the number of TP53 mutations, mutant TP53 clone size, concurrent mutations, cytogenetics, and mutant TP53 molecular minimal residual disease and studied the associations of these characteristics with overall survival. TP53 mutations were detected in 230 (10.5%) patients with AML/MDS-EB with a median variant allele frequency of 47%. Bi-allelic mutant TP53 status was observed in 174 (76%) patients. Multiple TP53 mutations were found in 49 (21%) patients. Concurrent mutations were detected in 113 (49%) patients. No significant difference in any of the aforementioned molecular characteristics of mutant TP53 was detected between AML and MDS-EB. Patients with mutant TP53 have a poor outcome (2-year overall survival, 12.8%); however, no survival difference between AML and MDS-EB was observed. Importantly, none of the molecular characteristics were significantly associated with survival in mutant TP53 AML/MDS-EB. In most patients, TP53 mutations remained detectable in complete remission by deep sequencing (73%). Detection of residual mutant TP53 was not associated with survival. Mutant TP53 AML and MDS-EB do not differ with respect to molecular characteristics and survival. Therefore, mutant TP53 AML/MDS-EB should be considered a distinct molecular disease entity.

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Figures

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Graphical abstract
Figure 1
Figure 1
Overview of cytogenetic aberrations and concurrent mutations in mutant TP53 AML/MDS-EB (n = 230). Each column represents an individual patient, and the presence of the aberration is indicated in blue. The upper panel shows the cytogenetic aberrations, and the lower panel shows the concurrent mutations. Patients with MDS-EB or bi-allelic TP53 mutant status are also indicated in blue. In case of failed cytogenetics, the cytogenetic aberrations were considered negative.
Figure 2
Figure 2
Overall survival of patients with AML and MDS-EB (n = 2200). (A) Overall survival of AML/MDS-EB patients by the ELN 2017 risk classification. Patients in the adverse risk category are segregated by TP53 wild-type and TP53 mutant. (B) Overall survival of AML and MDS-EB disease classification at diagnosis stratified according to patients with TP53 wild-type and TP53 mutant.
Figure 3
Figure 3
Overall survival of molecular characteristics in mutant TP53 AML/MDS-EB (n = 230). Overall survival of TP53 mutant allelic status (mono-allelic versus bi-allelic) (A), the number of TP53 mutations (B), and the presence or absence of concurrent mutations (C).
Figure 4
Figure 4
Overall survival of patients with AML/MDS-EB by CK. Overall survival of patients with mutant TP53 AML/MDS-EB by CK (n = 220) (A) and for mutant TP53 AML/MDS-EB patients who received allogeneic HSCT (n = 59) (B). Of note, the survival time starts at the date of transplant. (C) Overall survival of patients with AML/MDS-EB by CK and mutant TP53 status (n = 2101).
Figure 5
Figure 5
Overall survival of patients with AML/MDS-EB by TP53 mutations detected in CR (n = 62).
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