Abstract
Background: Clonal hematopoiesis (CH) refers to acquired myeloid neoplasm (MN)-associated mutations that are detectable in blood by next generation sequencing (NGS). CH is more common with older age. People with cancer and those who had prior treatment have higher rates of CH. Clonal cytopenia of undetermined significance (CCUS) refers to CH with an unexplained cytopenia. CH and CCUS can lead an increased risk of developing a MN and an increased risk of cardiovascular disease. In the Clonal Hematopoiesis Risk Score (CHRS) used to assess risk of CH/CCUS transforming to MN, TP53 mutations are included as a high risk mutation for progression risk due to their adverse nature in MN, though these mutations were not noted to be high risk in the analysis. Real world TP53 CH outcomes are understudied.
In clinical practice, CH is detected incidentally though genetic testing for another reason or during work up for cytopenia. The CH clinic at Memorial Sloan Kettering Cancer Center (MSK) was established in 2018, and performs yearly NGS testing on patients in the clinic, along with counseling and cardiology referrals. The MSK Heme-IMPACT (Integrated Mutation Profiling of Actional Cancer Targets) NGS test uses matched blood and fingernails to detect 468 genes associated with hematologic malignancies. As several years of follow up with serial NGS testing is available in our CH clinic patients, we sought to assess the changes in TP53 clones and myeloid transformation patterns in TP53 CH cases seen in our clinic.
Method: Retrospective chart review of patients with TP53 clonal hematopoiesis that were seen in the MSK CH clinic between July 2018 and February 2025 was conducted. Data collected included demographics, blood count parameters, and NGS data as available in the electronic medical record. Statistical analysis was performed with descriptive statistics. This retrospective study was approved by the MSK Institutional Review Board.
Results: In available data from 430 patients seen in CH clinic, a total of 45 patients with TP53 CH were identified (10.5% of CH clinic population). In these 45 patients, the median age at CH diagnosis was 66. About half of the study population were women (N=25, 55%). The majority of patients were White (N=37, 82%). Other races included Black (N=3, 7%), Asian (N=1, 2%), and Unknown/decline to identify (N=4, 9%). Most patients identified as non-Hispanic (Non-Hispanic (N=41, 91%)), Hispanic (N=3, 7%), Unknown (N=1, 2%)). The majority have another cancer diagnosis (N=42, 93%), most commonly solid tumor (N=33, 79%), lymphoma/myeloma (N=7, 17%), or both (N=2, 5%). Most patients previously received chemotherapy or radiation (N=31, 69%), while fewer had surgical management alone (N=8, 18%) or observation only (N=6, 13%). 11 patients (24%) were undergoing active therapy. There were 3 patients without cancer (7%). 7 patients (16%) had pre-existing coronary artery disease. About half had CH (N=24, 53%) and half had CCUS (N=21, 47%) at presentation.
The most common CH TP53 mutations were single nucleotide variants (N=41, 91%), with 3 duplications (7%) and 1 deletion (2%). The most common TP53 CH mutation was c.524G>A (N=7, 16%). Most patients had co-occurring mutations (co-mut) (N=32, 71%), while 13 patients (29%) had a single TP53 CH without co-mut. Of those with co-mut, the majority had 1 (N=15, 47%) or 2 (N=11, 32%), with up to 6 co-mut in 1 patient (3%). The most common co-mut were DNMT3A (N=12, 38%) and ASXL1 (N=4 ,13%), and 2 patients (6%) had 2 TP53 co-mut.
Most patients (N=36, 80%) have at least 2 annual NGS performed, with median follow up 16.5 months. 6 patients (13%) have annual follow up with yearly NGS for 5-7 years. One third (N=15, 33%) had BMA confirming CH/CCUS diagnosis. Most patients seen after 2023 (N=32) when CHRS scores were available were documented intermediate risk (N=23, 72%), with fewer low (N=3, 9%) and high risk (N=6, 19%). 7 patients (15%) developed new co-mut over serial NGS, including RUNX1, DNMT3A, ASXL1, NRAS, and TP53, without blood count changes. One patient lost TP53 and two PPM1D co-mut over serial testing. Transformation to MN occurred in 3 patients (7%), all of whom developed myelodysplastic syndrome (2 with new deletion 5q), had no new co-mut, and remain on observation. 6 (13%) patients died, none with MN.
Conclusions: This retrospective study describes characteristics of the TP53 CH population at a single center. Continued prospective monitoring is needed.
