PPM1D Somatic Mutations in Myeloid Neoplasms: Clinical Profile, Clonal Characteristics and Impact of Concurrent Somatic TP53 Mutations

Background:

Therapy-related myeloid neoplasms (t-MN) occur after exposure to DNA-damaging agents including cytotoxic chemo and radiation therapy and are associated with dismal outcomes. TP53 and PPM1D (protein phosphatase Mn²⁺/Mg²⁺-dependent 1D) mutations (MT) disrupt the DNA damage response and repair (DDR) pathway, are often co-mutated (25-35%), and although enriched in t-MN (20%), can also be seen in age-related clonal hematopoiesis (CH) (5-10%). While progressive genomic instability with biallelic inactivation has been described as a mechanism of MN progression with TP53 MT, similar mechanisms remain to be elucidated for PPM1D MT. We conducted this study to assess the clinical phenotype and outcomes of TP53 and PPM1D co-mutated (PPM1D^TP53m) versus PPM1D MT and wild type TP53 (PPM1D^TP53wt) CH and MN.

Methods:

After approval from the Mayo Clinic IRB, the CH and MN databases were queried and 119 pts with PPM1D MT (CH= 26, clonal cytopenia of unknown significance [CCUS]= 64, myelodysplastic syndrome [MDS]=16, myeloproliferative neoplasm [MPN]=8, acute myeloid leukemia [AML]= 5) were identified. We analyzed baseline characteristics, karyotypic changes, somatic mutations, and survival outcomes between the PPM1D^TP53m (n= 22) and PPM1D^TP53wt (n= 97) groups (gp).

Results:

Baseline characteristics

The median age in years (yrs) was 68.5 (range [R], 43-89) and 71 (R,30-92) in the PPM1D^TP53m and PPM1D^TP53wt gp (p= 0.65). 22% vs 18% (p=0.78), 58% vs 32% (p=0.03), 9% vs 32% (p=0.01), 7% vs 4.5% (p=>0.99) and 3% vs 14% (p=0.07) pts met criteria for CH, CCUS, MDS, MPN and AML in the PPM1D^TP53wt and PPM1D^TP53m gp, respectively. Similarly, 19% vs 18% (p=>0.99), 47% vs 32% (p=0.23), 7% vs 36% (p=0.001), 2% vs 0% (p=>0.99) and 2% vs 14% (p=0.04) of pts met criteria for t-CH, t-CCUS, t-MDS, t-MPN and t-AML in the PPM1D^TP53wt and PPM1D^TP53m gp, respectively. All PPM1D variants were truncating, located in exon 6 of the gene, with median variant allele frequency (VAF) (8% [R,1-64] vs 5.5% [R,2-24], p= 0.10) and number of PPM1D MT (1 [R,1-5] vs 1 [R, 1-3], p=>0.99) being similar between the two gp. While proportion of pts with t-MN were similar between the two gps (77% vs 86%, p= 0.40), cytogenetic (CG) abnormalities (67% vs 31%, p= 0.006), including monosomies (28% vs 2%, p= <0.001) and complex CG (53% vs 4%, p= <0.001) were more frequent in PPM1D^TP53m gp compared to PPM1D^TP53wt gp, respectively. The median TP53 MT VAF was 14% (R, 1-14); 50% had multi-hit TP53 MT.

Somatic mutations in PPM1D MT myeloid neoplasm with and without TP53 MT

Somatic co-mutations excluding TP53 were seen in 71% of pts; 73.5% in PPM1D^TP53wt and 59% in PPM1D^TP53m gp (p= 0.20). Apart from CBL (0% vs 9%,p=0.03), MT involving DNMT3A (20% vs 14%, p= 0.56), TET2 (15% vs. 14%, p= >0.99), IDH1 (6% vs 19%, p= 0.07), splicing factors (8% vs 14%, p=0.08), ASXL1 (11% vs 4.5%, p=0.46), and JAK2 (9% vs 0%,p=0.20) were comparable between PPM1D^TP53wt and PPM1D^TP53m gps, respectively. The proportion of pts with ≥ 2 somatic co-mutations excluding TP53 MT were numerically higher in PPM1D^TP53wt gp (43%) compared to PPM1D^TP53m gp (23%) (p= 0.09). In the PPM1D^TP53wt gp, other somatic driver mutations included RUNX1 (n= 7 [7%]; CH [n=1], CCUS [n=2], MDS [n=3], MPN [n=1]), NRAS (n=1 [1%]; CCUS), BCOR (n=1 [1%]; CCUS), and PTPN11 (n=1 [1%]; CCUS).

Leukemic transformation and survival

With a median follow up of 6.43 months (mo) (R, 0.23-36.4), median overall survival (mOS) in mo among high-risk MDS/AML (16.4 vs 15.0, p= 0.66) and CHIP/CCUS pts (35.79 vs 26.28, p= 0.93) was similar between PPM1D^TP53wt and PPM1D^TP53m gps, respectively. CHIP/CCUS pts harboring multiple vs single PPM1D MT had an inferior mOS (23.9 vs 36.7 mo, p= 0.05). Three (2.5%) MDS pts underwent AML transformation; 1 (1%) and 2 (10%) in PPM1D^TP53wt and PPM1D^TP53m gp, respectively (p= 0.07).

Conclusions

In our study, 18% of pts had concurrent TP53 and PPM1D MT (82% t-MN), with the PPM1D^TP53wt genotype being more frequent in CCUS, while the PPM1D^TP53m genotype was more frequent in MN. The PPM1D^TP53m genotype had a higher frequency of CG abnormalities, including complex CG. Survival outcome was inferior and comparable in PPM1D MT MN with or without TP53 MT. While 73.5 % of the PPM1D^TP53wt gp had somatic driver MT and 31% had karyotypic abnormalities, 22% had no additional MT or CG changes (all CH/CCUS), underscoring the need to understand how PPM1D MT contribute to hematopoietic dysfunction and MN.