Validation of the 5th edition of the World Health Organization and International Consensus Classification guidelines for TP53-mutated myeloid neoplasm in an independent international cohort

Abstract

The World Health Organization (WHO-5) and International Consensus Classification (ICC) acknowledge the poor prognosis of TP53-mutated (TP53^mut) myeloid neoplasm (MN). However, there are substantial differences between the two classifications that may lead to under- or overestimation of the prognostic risk. We retrospectively applied WHO-5 and ICC to 603 MN cases harboring TP53^mut (variant allele frequency, VAF ≥ 2%). WHO-5 and ICC would not classify 64% and 20% of these cases as TP53^mut MN, respectively. Moreover, of those classified, 67.5% would be classified discrepantly. Primary drivers of discrepancies included: (i) prognostic importance of TP53^mut acute myeloid leukemia (AML), (ii) interaction of the blast percentage and allelic status, (iii) 17p.13.1 deletion detected by cytogenetics, (iv) complex karyotype (CK) as multi-hit equivalent, and (v) TP53^mut VAF threshold, we analyzed survival outcomes of each of these groups with an aim to provide clarity. TP53^mut AML was associated with significantly poor survival compared to TP53-wild type TP53^wt AML, myelodysplasia-related (AML, MR 4.7 vs. 18.3 months; P < 0.0001), supporting its inclusion within TP53^mut MN as a distinct subentity. Secondly, the survival of TP53^mut with blast 10-19% was poor regardless of the allelic status. Thirdly, for cases with a single TP53^mut with VAF < 50%, 17p13.1 del or CK serve as practical surrogates of biallelic inactivation, obviating the need for an additional copy number analysis. Finally, TP53^mut AML, MDS multi-hit/multi-hit equivalent with VAF < 10% had significantly poorer survival compared to TP53^mut MDS VAF < 10% without CK and 17p del, and were comparable to those with VAF ≥ 10% (14.1 vs. 48.8 vs.7.8 months, P < 0.0001). Collectively, these findings address key areas of contention and provide valuable insights that will guide future revisions of the WHO and ICC classifications.

Fig. 1. TP53-mutated (TP53^mut) myeloid neoplasm (MN) classified by World Health Organization 5^th edition (WHO-5) and International Consensus Classification (ICC).

A Consort diagram summarizing the classification of TP53^mut MN by WHO-5 (blue) and ICC (green) criteria, along with disease subcategories presently excluded from each classification system, respectively (purple). B Percentage of MN with TP53^mut that can be classified, and C not classified using WHO-5 and ICC criteria.

Fig. 2. Concordance and divergence in the WHO-5 and ICC classification of TP53-mutated (TP53^mut) myeloid neoplasm (MN).

A Sankey plot depicting the divergences between the two classifications of TP53^mut MN. B heterogeneity in the overall survival (OS) of WHO-5 classified monoallelic TP53 when reclassified using ICC criteria. C According to WHO-5, 90.9% of TP53^mut acute myeloid leukemia (AML) were classified as AML-myelodysplasia related (MR), followed by acute erythroid leukemia (AEL, 7%). D OS of AML with TP53^mut with variant allele frequency (VAF) ≥ 10% was significantly poorer compared to AML TP53^mut with VAF < 10%; and E OS of TP53^mut AML was significantly worse than TP53 wild type (TP53^wt) AML-MR.

Fig. 3. Interaction between blast cut-off and WHO-5 allelic status of TP53-mutated myelodysplastic syndrome (MDS).

A Within the WHO-5 biallelic/presumptive biallelic inactivation group, the median overall survival (OS) of MDS with 10–19% blasts was significantly poorer compared to MDS 0–9% blasts. B Within the WHO-5 monoallelic group, the median OS of MDS 10–19% blasts was significantly poorer compared to MDS 0–9% blasts. C In the MDS 10–19% blast group, the median OS of biallelic/presumptive biallelic inactivation was comparable to that of monoallelic mutations. D While in the MDS 0–9% blast group, the median OS of biallelic/presumptive biallelic inactivation was significantly poorer compared to monoallelic mutations.

Fig. 4. Interactions between blast percentage, TP53 mutation (TP53^mut) variant allele frequency (VAF), and allelic status based on the ICC criteria and survival of TP53^mut myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).

A Adverse risk cytogenetic features. BTP53^mut multi-hit and multi-hit equivalent. C Higher TP53^mut VAF were more prevalent in TP53^mut MDS 10–19% blasts and AML compared to MDS 0–9% blasts. D overall survival (OS) of TP53^mut MDS 10–19% blast and AML was significantly poorer compared to MDS 0–9% blasts. Overall survival of patients with a marrow/blood blast count of E 0–9%, F ≥20%, and G 10–19% according to allelic status.

Fig. 5. Validation and prognostic significance of 17p13.1 deletion and complex karyotype (CK) in TP53-mutated (TP53^mut) myeloid neoplasm (MN).

A Copy number variation (CNV) analysis confirmed 17p13.1 deletion in 94% of cases where it was observed on metaphase cytogenetics. Additionally, CNV analysis identified loss of heterozygosity (LOH) or copy-neutral LOH (CnLOH) across the TP53 locus in 26.9% of cases without 17p13.1 deletion on metaphase cytogenetics. B In cases without 17p13.1 deletion detected on karyotype, LOH/CnLOH was significantly enriched in the presence of CK compared to those without CK. C Median overall survival (OS) of patients with a single TP53^mut with variant allele frequency (VAF) < 50% with either 17p13.1 deletion or CK was comparable to cases with biallelic/presumptive biallelic TP53 inactivation.

Fig. 6. The median OS of biallelic or single TP53^mut VAF < 10% plus CK was significantly shorter compared to that of single TP53^mut VAF < 10% without CK and was comparable to TP53^mut VAF ≥ 10%.

A The median OS of AML or multi-hit/multi-hit equivalent MDS was significantly worse compared to MDS cases with a single TP53^mut VAF < 10% without 17p loss or CK, and was comparable to TP53^mut VAF ≥ 10%. B In a TP53^mut VAF < 10% MDS, the median OS of biallelic or monoallelic with CK was significantly poor. While the median OS of monoallelic TP53^mut VAF < 10% without CK was comparable to TP53 wild type (TP53^wt) MDS.