Validation of the WHO-5 and ICC guidelines for TP53-mutated myeloid neoplasm in an independent international cohort

Although both the 5th edition of the WHO guidelines (WHO-5) and ICC guidelines acknowledge the poor prognosis of TP53 mutations (TP53^mut) in myeloid neoplasms (MN), there are discrepancies between their classifications of TP53^mut MDS and AML. For example, TP53^mut AML is recognized as a distinct entity by the ICC, but not by WHO-5. Differences between the classifications may lead to under- or over-estimation of the prognostic risk.

A retrospective analysis of 603 MN cases harboring TP53^mut (MDS, n = 374; AML, n = 229), compared outcomes with those of TP53 wild type (TP53^wt) MN cases (n = 600), to validate the WHO-5 and ICC classifications and assess how the differences may impact clinical practice. Primary drivers of discrepancies were identified and survival outcomes of each were analyzed. Findings were published in Blood Cancer Journal by Shah et al.¹

Key learnings

Of the 603 patients with TP53^mut (VAF ≥ 2%), 64% and 20% would not meet the WHO-5 and ICC criteria, respectively, to be classified as TP53^mut MN. There was discrepancy in classification of 67.5% of patients classified as TP53^mut MN.

The primary drivers of discrepancies were the prognostic significance of TP53^mut AML; interaction of the blast percentage and allelic status; 17p.13.1 deletion detected by cytogenetics; CK as multi-hit equivalent; and TP53^mut VAF threshold.

Regarding the primary driver of discrepancy, TP53^mut AML was associated with significantly poorer survival than TP53^wt AML (AML-MR; 4.7 vs 18.3 months; p < 0.0001), indicating that TP53^mut AML should be classified as a distinct sub-entity within TP53^mut MN.

The discrepancies and differences in survival outcomes identified in this analysis highlight the importance of developing consistent classification systems, and provide insights into which areas could be revisited to inform subsequent iterations of the WHO and ICC guidelines.