TP53 Mutation Defines a Unique Subgroup Within MDS/AML with Complex Karyotype

Take-aways:

• TP53 mutations, rather than disease ontogeny (therapy-related vs de novo), determine MDS or AML patient outcomes with CK.
• Among patients with MDS or AML with CK, the presence of TP53 mutation (in particular, multihit TP53 mutation) identifies a homogeneously aggressive disease, irrespective of the blast count at presentation.
• TP53-mutated MDS and AML with CK should be considered a single biologic disease entity.

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TP53 mutation, rather than how the disease originates, is a stronger indicator of patient outcomes in myelo­dysplastic syndromes (MDS) and acute myeloid leukemia (AML) with complex karyotype (CK), according to a study published in Blood.

CK is prevalent in 10% to 12% of AML patients and in 10% to 30% of MDS patients and is associated with TP53 mutations. Both AML and MDS with CK are linked to therapy-related disease (t-AML and t-MDS).

“Our findings underscore the importance of TP53 mutations rather than disease ontogeny in determining outcome of MDS and AML patients with CK,” the authors, led by Olga K. Weinberg, MD, of the University of Texas Southwestern Medical Center in Dallas, wrote.

The presence of TP53-mutated MDS and AML with CK points to a single aggressive disease, the authors noted, arguing against the current state of disease classification, which they said “artificially separates a single biologic disease entity” depending on the blast count at presentation or whether it is related to therapy.

“Our data suggest that CK, TP53-mutated [myeloid neoplasms (t-MN)] represents a unique entity with very poor prognosis, irrespective of whether the blast percentage indicates MDS or AML or whether the disease is therapy-related or de novo in its ontogeny,” the authors wrote.

The current practice of the World Health Organization is to classify t-AML and t-MDS as a single group of t-MN linked to therapy independent of their morphologic features or designation as MDS or AML based on blast count.

Study Cohort and Findings

Researchers reviewed pathology cases with a confirmed diagnosis of AML or MDS between 2012 and 2020 from Massachusetts General Hospital, Yale, University of Texas Southwestern, Weill Cornell, and Stanford Medical Center.

The analysis included confirmed cases of AML or MDS in which at least three independent cytogenetic ab­­normalities were present, and targeted next-generation sequencing (NGS) panels were performed as part of the clinical workup.

The NGS data were used to classify genetic variants according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology recommendations, and only “pathogenic” or “likely pathogenic” mutations were included in the analysis.

In each case, the bone marrow (BM) blast percentage was recorded based on manual count of the BM aspirate smear, and CK was identified from G-banded metaphase cells prepared from unstimulated BM aspirate cultures.

Patient electronic health records were used to document demographic and clinical characteristics, including treatments administered, patient follow-up, and outcome measures. Overall survival (OS) was calculated from the date of diagnosis to the date of death or last follow-up.

The cohort included 299 patients (144 AML and 155 MDS) with a median age of 69.7 years. Within the cohort, 118 patients (45 AML and 73 MDS) were classified as having therapy-related disease.

Mutations were present in 287 patients (96%), with the most common mutation in the TP53 gene (n=247; 83%). Of these, 180 patients (63%) had multihit TP53 mutation, defined as either two different TP53 mutations, a single TP53 mutation with variant allele frequency >60%, or a single TP53 mutation with 17p loss on karyotype.

Cytogenetic analysis identified CK in all 299 patients and monosomal karyotype (MK) in 181 patients.

A comparison of the 118 therapy-related patients to the 81 de novo MDS/AML patients revealed no difference in gender distribution or age at presentation. OS was worse for therapy-related patients (median, 10.2 months) compared with de novo patients (median, 12.2 months; P=.08).

Therapy-related patients had lower peripheral and BM blast counts (P=.002 and P=.0003, respectively) and a higher proportion of MK and TP53 mutations (P=.07 and P=.008, respectively) compared with de novo cases.

TP53-Mutated Cases

A comparison of patients harboring TP53 mutations (n=247) to patients with CK and wild-type TP53 (n=52) revealed that the former presented with older age (P=.06) and lower hemoglobin (P=.004) and BM blast counts (P=.02).

When comparing OS among TP53-mutated patients, there was no significant difference between therapy- related (median, 8.5 months) versus de novo (median, 10.7 months) disease (P=.19). However, comparing OS among all patients based on TP53 mutation status showed a highly significant difference between the categories no TP53 mutation (median, 33.9 months) versus TP53 mono­allelic (median, 12.5 months) versus TP53 multihit (median, 9.4 months; P<.0001).

Implications

The study confirmed the high incidence and poor prognosis of TP53 mutations in CK MDS and AML patients, with TP53 mutations present in 84% of the study cohort and predictive of significantly shorter OS (P<.0001). Presence of multihit TP53 mutation was identified as the strongest predictor of worse outcomes.

However, among TP53-mutated patients, no significant difference emerged between therapy-related versus de novo disease, a finding that underscores the importance of TP53 mutations rather than disease ontogeny in determining outcome of MDS and AML patients with CK. No difference in OS was found between CK patients based on categorization of AML versus MDS (P=.96) or presence of absence of circulating blasts ≥1% (P=.52).

The study was limited in assessing allelic imbalances of the TP53 locus, as most NGS platforms used in clinical practice do not assess for loss of heterozygosity required to definitively determine the TP53 allelic state. In addition, a subset of the cases lacked information on TP53 variant allele frequency.

“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,” they concluded. “The current classification of these cases into different disease categories artificially separates a single biologic disease entity.”

Reference

Weinberg OK, Siddon A, Madanat YF, et al. TP53 mutation defines a unique subgroup within complex karyotype de novo and therapy-related MDS/AML. Blood Adv. 2022;6(9):2847-2853.