Comparison of World Health Organization and International Consensus Classification Guidelines for Myeloid Neoplasms Harboring TP53-Mutations Using an Independent International Cohort

BACKGROUND: Recently proposed World Health Organization (WHO, 5^th edition) and International Consensus Classification (ICC) recognized myeloid neoplasms (MN) harboring TP53-mutated (TP53^mut) as a separate entity. However, there are critical differences between the two classifications regarding allelic-status, variance allele frequency (VAF) cut-off and blast categories, that may lead to under- or overestimation of the risk.

METHODS: We analyzed MN harboring TP53^mut (VAF ≥2%, n=536) managed at Mayo Clinic (USA) and South Australia Health Network (Australia). ICC (Arber et al, Blood 2022) and WHO (Bluebook, Beta v2) definitions were used to stratify MN harboring TP53^mut.

RESULTS: Of 536 cases, 379 (71%) had myelodysplastic syndromes (MDS) (<20% blasts) and 157 (29%) had acute myeloid leukemia (AML). Using WHO, 160 (42%) of 379 were classified as MDS-biTP53 as they harbored 2 TP53^mut (n=115; 30%) or 1 TP53^mut plus confirmed loss of heterozygosity (LOH) or copy neutral LOH (cnLOH) of TP53 locus (n=45; 12%). Sixty-two (16%) TP53^mut MDS with VAF >49% were classified as presumptive MDS-biTP53. Of the 157 cases with 1 TP53^mut VAF ≤49%, 17 confirmed to have an intact wild-type TP53 copy and were classified as monoallelic. While 140 (89%) cases did not have copy number variation (CNV) analysis.

We next evaluated the number of TP53^mut cases classified differently by WHO and ICC. As WHO does not recognize TP53^mut AML as a separate entity, 157 (29%) TP53^mut AML were not classifiable. 46% (174/379) of the TP53^mut MDS including 48 (30%), 12 (19%) and 79 (65%) of biTP53, presumptive biTP53, and monoallelic TP53^mut MDS according to WHO were classified differently by ICC (Figure 1A). Discordance between the two classifications were predominantly driven by:

(i) The difference in VAF cut-off. Sixty patients (11%) with TP53^mut VAF <10% were excluded from the ICC classification of TP53^mut MN as it mandates TP53^mut VAF cut-off ≥10%. 11 (18%) and 41 (68%) of these had biTP53, monoallelic TP53^mut MDS by WHO criteria while 8 (13%) had AML. Importantly, within the VAF <10% cohort, median overall survival (OS) of 2 TP53^mut or 1 TP53^mut with 17p13.1 (hereafter 17p) deletion or complex karyotype (CK, n=30) was significantly poor compared to 1 TP53^mut VAF <10% (11.6 vs 32.4 months; P =0.002, Figure 1B), suggesting that ICC may underestimate the poor prognosis of multi-hit or multi-hit equivalent TP53^mut MN with VAF <10%.

(ii) The difference in bone marrow blast cut-off. The underlying assumption by WHO is that prognosis of biTP53^mut MDS is poor irrespective of blast percentage category (0-9% vs 10-19%). In contrast, ICC considers that TP53^mut MDS/AML (blasts 10-19%) is associated with poor prognosis irrespective of TP53 allelic status. Median OS of TP53^mut MDS with 10-19% blasts was significantly poor compared to blast 0-9% (6.4 vs 11.6 months, P <0.0001). Second, median OS of biTP53^mut was significantly poor than monoallelic TP53^mut in MDS- blast 0-9% (10.1 vs 15.9 months; P =0.0001) but not in blasts 10-19% (6.8 vs 6.2 months; P =0.19). Hence, exclusion of monoallelic TP53^mut MDS with blast 10-19% as TP53^mut MN from the WHO classification may underestimate the poor prognosis.

(iii) The difference in the definition of biallelic and multi-hit TP53 loss. 35 cases with 1 TP53^mut VAF ≤49%, had 17p deletion but did not have CNV analysis to confirm the loss of TP53 locus and could not be classified further using WHO. ICC classified 18 (50%) of these cases as multi-hit. Median OS of 1 TP53^mut VAF ≤49%, and 17p deletion on karyotype was significantly poor than 1 TP53^mut (VAF ≤49%without 17p deletion on karyotype (6.4 vs 14.6 months, P =0.001).

(iv) The difference in the definition of multi-hit equivalent. 32% (33/104) WHO defined monoallelic cases without available CNV data, were classified as multi-hit-equivalent by ICC as they harbored CK. However, WHO does not consider CK as presumptive evidence of biTP53. Median OS of 1 TP53^mut VAF ≤49% with CK was significantly poor compared to 1 TP53^mut without CK (8.2 vs 26.9 months, P =0.0008).

CONCLUSION: Our study provides evidence that poor prognosis of ‘multi-hit’ TP53 with VAF <10% is underestimated by ICC. On the other hand, poor prognosis of monoallelic TP53 MDS with 10-19% blasts as well as 1 TP53^mut VAF ≤49% in the presence of CK is underestimated by WHO. These data suggest that both classifications can be further refined.