TP53-Mutated Therapy-Related Myeloid Neoplasms Are Associated with a Long Latency and Are More Prevalent in Patients with Primary Hematological Cancers Compared to Solid Tumors

Background: TP53 mutations (TP53^mut) are highly prevalent in therapy-related myeloid neoplasms (t-MN) compared to de novo MN (35–40% vs 7–13%) and are associated with a poor outcome. Understanding the risk factors involved in the pathogenesis of TP53^mut t-MN is critical to prevent its development.

Methods: We characterized t-MN cases by examining primary cancer type vs autoimmune disease diagnosis vs solid organ transplantation, treatment modality, and latency (interval between primary cancer/disease and t-MN diagnosis) to identify patient and disease-related factors associated with TP53^mut t-MN. Allelic loss of TP53^mut MN was defined according to International Consensus Classification (ICC) criteria (Arber et al., Blood 2022).

Results: Of 587 t-MN patients, 33% (n=194) had acute myeloid leukemia (t-AML) and 67% (n=393) had myelodysplastic syndrome (t-MDS, blasts<20%). Primary diagnosis comprised of 243 (41.6%) solid cancers and 300 (51.4%) hematological malignancies, while 7% (n=41) of t-MN cases had autoimmune disease or underwent solid organ transplant.

Overall, 94 (16.1%) patients received prior radiotherapy (RT) alone and 75.6% (n=444) received chemotherapy (CT) with/without RT. 109 patients (18.7%) underwent autologous stem cell transplant (ASCT). The median latency from primary diagnosis to t-MN was 83.2 months (IQR 41.3, 153.2), and there was a trend towards shorter latency in t-AML compared to t-MDS (70.5 vs 85.8 months; P=0.07). Of the t-MN patients, 280 (47.7%) harbored TP53^mut, which was associated with significantly poorer survival compared to wild-type (TP53^wt) t-MN (9.7 vs 21.9 months; P <0.001). In contrast to TP53^wt (59.0% vs 41.0%), the majority of TP53^mut t-MN presented with t-MDS vs t-AML (75.7% vs 24.3%; P <0.001).

According to ICC criteria, multi-hit MDS (n=131; 47.8%) was the most common entity, followed by AML (n=68; 24.8%), MDS/AML (n=34; 12.4%), and single-hit MDS (n=8, 2.9%). Poor prognostic karyotype changes e.g., del 5q, del 7q, complex karyotype and monosomal karyotype, were more prevalent in TP53^mut compared to TP53^wt t-MN. Co-mutations in other genes were enriched in TP53^wt t-MN.

As TP53^mut t-MN is associated with a dismal outcome, we assessed the factors associated with its development. There were no significant differences in median age at primary cancer/disease diagnosis (59.0 vs 59.9 years; P=0.4) or gender (females 43.3% vs 39.3%; P=0.3) between TP53^mut and TP53^wt t-MN. However, TP53^mut patients were older at t-MN diagnosis (69 vs 67.4 years; P=0.05). Correlations between gene mutations and prior malignancies revealed a significant association between TP53^mut and hematological primary cancers (odds ratio [OR] 1.6; P=0.006), especially multiple myeloma (MM, OR 4.9; P<0.001) and lymphoproliferative disease (LPD, OR 2.0; P=0.013). Among solid cancers, head and neck malignancies were significantly associated with increased risk of developing TP53^mut t-MN (OR 7.7; P=0.01). Compared to RT alone, ASCT (OR 2.2; P=0.004) and CT (OR 2.0; P=0.008) were associated with an increased risk of TP53^mut t-MN.

Recent studies indicate that CT/RT confer a selective advantage to preexisting TP53^mut hematopoietic stem and progenitor cells, allowing clonal expansion/evolution and progression to t-MN. We hypothesized that TP53^mut t-MN with high-risk disease features is a function of TP53^mut clonal expansion/evolution rate and would predict latency between primary cancer and t-MN. Indeed, the latency between primary cancer and t-MN diagnosis was longer in TP53^mut (87.8 months, IQR 45.5, 154.1) compared to TP53^wt (74.7 months, IQR 37.5, 146.9 months) t-MN (P=0.05). Interestingly, 54% and 29% of TP53^mut t-MN had a latency of ≥5 and ≥10 years, respectively. There were no correlations between latency and TP53 variant allele frequency (VAF) (r=0.38 and P=0.7) or between TP53^mut t-MDS and t-AML (85.2 vs 109.3 months; P=0.9). Together, latency between primary cancer and t-MN was not associated with TP53^mut t-MN phenotype, VAF or other poor-risk disease features.

Conclusion: Hematological malignancies, especially MM and LPD treated with high-dose CT, were strongly associated with TP53^mut t-MN development, highlighting the importance of careful and ongoing screening in this population. Also, the long latency of TP53^mut t-MN provides an opportunity to devise effective surveillance strategies and preventative interventions long before TP53^mut t-MN development.