Real world experience of patient outcomes in a dedicated clonal hematopoiesis hematology clinic

Abstract Introduction: Clonal hematopoiesis (CH) is a pre-malignant entity associated with increased risk of myeloid neoplasm (MN), cardiovascular disease, and all-cause mortality. CH encompasses both clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of uncertain significance (CCUS) and is being increasingly recognized due to widespread use of high-throughput DNA sequencing. In response, dedicated hematology clinics have been established to help in evaluation and management of these patients (pts). The Ohio State University's (OSU's) HALT (Hematologic Abnormalities at risk of Leukemic Transformation) Clinic evaluates pts with suspected CH or germline disorders. Methods: We performed a retrospective study of pts referred to HALT Clinic between March 2022 and March 2025. We collected demographic data, personal and family medical history, complete blood counts, and molecular testing, and performed descriptive statistics stratified by diagnosis (CHIP or CCUS). We further analyzed the mutational profile of these pts and risk stratified them per the Clonal Hematopoiesis Risk Score (CHRS) and Clonal Cytopenia Risk Score (CCRS), when applicable. Results: The HALT clinic received 143 referrals over three years, of which 80 were for suspected CH. After clinic evaluation, 76 pts (95%) had CHIP/CCUS, 3 had myelodysplastic syndrome, and 1 had a benign mutation. Remaining referrals were for suspected inherited predisposition or idiopathic cytopenias. Seventy-five percent of referrals came from hematology or medical oncology, 11% from genetic counselors and 9% from internal or family medicine. In the 76 pts with CH, the median age was 66 and 46.1% were male. 43.4% had a history of chemotherapy exposure and 13.2% had prior radiation. The most commonly identified CH mutations were TET2 (19.8%), TP53 (18.2%), DNMT3A (15.7%), ASXL1 (9.1%), PPM1D (9.1%), and splicing mutations (5.8%). The median number of mutations seen was 1 (range, 1-4) and median variant allele frequency (VAF) of 12.6%. On initial evaluation, baseline hemoglobin (Hgb) was under 10 g/dL in 13.2% of pts and less than 8 g/dL in 1.3% of pts with CH. After a median follow-up of 8.75 months (range, 0-38.2 months), Hgb was <10 g/dL and <8 g/dL in 14.5% and 6.6%, respectively. Baseline platelet count was <50 x 109/L in 7.9% and <20 x 109/L in 1.3% of patients, and the proportion remained similar during follow up (6.6% and 2.6%, respectively). CHRS score was calculated for 70/76 pts with CHIP or CCUS. Missing CHRS scores were due to unknown VAF or presence of mosaic chromosomal alterations. Of these pts, 26 (37.1%) were classified as low risk, 30 (42.9%) as intermediate, and 14 (20.0%) as high risk. In the 43 CCUS pts , CHRS stratified 12 (27.9%) as low risk, 20 (46.5%) as intermediate, and 11(25.6%) as high. The corresponding CCRS stratification resulted in 19 (44.2%) considered low risk, 14 (32.6%) intermediate risk, and 10 (23.3%) as high risk. Three pts in our cohort progressed to acute myeloid leukemia (AML), all having preceding TP53-mutated CCUS. One patient had a concurrent PPM1D mutation and 2 of 3 were undergoing concurrent treatment for another malignancy (multiple myeloma and metastatic breast cancer). All 3 pts were high risk by CHRS, 2 were intermediate risk by CCRS. No other pts have progressed to MN. Eight pts of the 76 with CH (10.5%) are now deceased; 3 were related to complications from AML, 1 due to bleeding from thrombocytopenia, and 4 from complications related to non-myeloid malignancies. Conclusion: The overall rate of progression from CH to myeloid neoplasm is typically thought to be 0.5 to 1% per year. However, our experience in a dedicated CH clinic suggests that pts referred may be at a higher risk of progression, with nearly half having prior chemotherapy or radiation exposure and up to 25% of pts considered high risk by current prognostic models. All pts with high risk CCUS in HALT clinic are screened for the IMPACT study, a multi-center, randomized, placebo-controlled trial of canakinumab to prevent the progression to overt MN with 25 pts currently enrolled nationally, with 17 pts at OSU (NCT05641831). Thus, CH clinics serve a valuable role in identifying the highest risk pts who may benefit from ongoing research into strategies to prevent progression to overt MNs.