Clinical outcomes in <i>TP53</i> -mutated clonal hematopoiesis: Single-center retrospective study.

Abstract

6594 Background: Clonal hematopoiesis (CH), including CH of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS), is defined by myeloid neoplasm (MN)-associated somatic mutations in the absence of known hematologic malignancy and may precede MNs, such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). TP53 -mutated ( TP53 m) CH has been assumed to be high risk, but clinical outcomes are poorly characterized. Methods: We retrospectively evaluated patients (pts) with TP53 m CH seen at a tertiary cancer center. Inclusion required pathogenic or likely pathogenic TP53 mutations of presumed hematopoietic origin identified on bone marrow, peripheral blood, or plasma next-generation sequencing. Results: 62 pts with TP53 m CH were included; 26 (42%) CHIP and 36 (58%) CCUS. Median age was 68 years (range, 23–81) with 30 male pts (48%). History of tobacco, alcohol, and illicit drug use was noted in 30 (48%), 31 (50%), and 7 (11%) pts, respectively. Common comorbidities included cardiovascular disease (n=51, 82%), diabetes (n=17, 27%), and rheumatologic disorders (n=13, 21%). 53 pts (85%) had a history of non-myeloid malignancy, with 41 (77%) receiving prior cytotoxic chemotherapy, 20 radiation (32%), and 13 (21%) stem cell transplant/cellular therapy (SCTCT). By CH Risk Score (CHRS), 4 (7%), 38 (61%), and 20 (32%) pts were considered low-, intermediate-, and high-risk of myeloid transformation. The 36 CCUS pts were classified as 10 (28%) low, 9 (25%) intermediate, and 17 (47%) high risk by Clonal Cytopenia Risk Score (CCRS). Median TP53 VAF was 5% (range, 1–54), and 30 pts (46%) had additional somatic mutations. 12 pts (19%) were TP53 double-hit. Median time from prior malignancy to CH detection was 42.3 months (mo; range, 0.2–365.0). With a median follow-up time of 60.1 mo (95% confidence interval [CI], 43.0–70.5), median overall survival (mOS) from CH detection was 67.5 mo (95% CI, 59.0–not estimable [NE]). A total of 15 pts (24%) progressed to MNs (12 MDS [80%], 3 AML [20%]) with a median time to transformation of 20.2 mo (95% CI: 6.8–53.9). mOS from time of MN diagnosis was 20.1 mo (95% CI, 7.3–NE) for MDS and 0.3 mo (95% CI, 0.3–NE) for AML pts. Pts who transformed to MNs were more likely to have had tobacco (p=0.026) or illicit drug use (p=0.031), higher comorbidity burdens (p=0.031), rheumatologic disorders (p=0.016), previous SCTCT (p=0.042), and CCUS (p=0.035). No differences were observed by TP53 VAF. Of those who transformed, 7 (47%) were intermediate- and 8 (53%) high-risk by CHRS. CCRS showed low, intermediate, and high risk in 4 (33%), 1 (9%), and 7 (58%) of the 12 TP53 m CCUS pts who progressed to MNs, respectively. Conclusions: TP53 m CH is associated with significant comorbidity burdens and oncologic history. Existing risk stratification tools poorly predict myeloid transformation in these pts. Further clinicopathologic characterization of TP53 m CH is warranted.