Spectrum, prevalence, and clinical correlates of PPM1D mutations in patients with clonal hematopoiesis and clonal cytopenias. Open Access

• PPM1D mutations dominate t-CH/t-CCUS, show shortest latency post-genotoxic therapy, and are enriched in this subgroup.

• While the median PPM1D VAF was relatively lower, a higher VAF (≥13%) was linked to inferior overall survival.

TP53 and PPM1D are key regulators of DNA damage response and repair and somatic mutations in these genes often co-occur in hematopoietic cells, expanding under genotoxic stress. Unlike with TP53 mutations, where mechanisms of progression are defined, pathways underlying clonal fitness and transformation in PPM1D mutant cells remain unclear. In collaboration with 5 academic institutions, we analyzed the clinical and molecular landscape of 337 patients with clonal hematopoiesis (CH) and clonal cytopenia of undetermined significance (CCUS) across four genotypes: PPM1Dmt/TP53wt (n= 170 [50%]), PPM1Dmt/TP53mt (n= 25 [7%]), TP53mt/PPM1Dwt (n=17 [5%]), and TP53wt/PPM1Dwt (n= 125 [38%]). All PPM1D variants were truncating, located in exon 6 of the gene, with a median variant allele frequency (VAF) of 6% (0.3-64%). The PPM1Dmt/TP53mt genotype was most frequently encountered in therapy related (t)CH/CCUS (80%, 66.5%, 76.5% and 19%; p= <0.001) and had a shorter time interval to detection from last genotoxic exposure (6.2, 5.9, 11.25, and 24.5 months; p= <0.001), in comparison to PPM1Dmt/TP53wt, TP53mt/PPM1Dwt and TP53wt/PPM1Dwt genotypes, respectively. Acknowledging the short follow-up duration, rates of malignant transformation were lower in PPM1Dmt/TP53wt (2%) and PPM1Dmt/TP53mt (4%) groups, in comparison to PPM1Dwt/TP53wt (12%) and PPM1Dwt/TP53mt (17%) groups (p= <0.001), respectively. In summary, PPM1D mutations are frequently observed in t-CH/CCUS, with low median VAFs and are associated with low rates of progression, even when co-mutated with TP53.