Introduction Clonal hematopoiesis (CH) is enriched in patients with cancer and has been linked to adverse outcomes. Although often identified in routine diagnostic testing, prospective data remain limited. To guide risk stratification and therapeutic decisions, our institution launched a multidisciplinary tumor board (CH-MTB) in 2022 to review cases of clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS).

Methods Patients with a history of cancer and incidental CH detection were referred from either (1) plasma cell-free DNA (cfDNA) sequencing using the FoundationOne Liquid CDx assay (NCT04932525) covering CH-related genes (ASXL1, DNMT3A, IDH1, IDH2, JAK2, MPL, MYD88, SF3B1, TET2, and U2AF1), performed for cancer management. Patients with a somatic mutation in one of these genes and variant allele frequency (VAF) ≥ 10%, or any VAF for JAK2, MPL, or MYD88, were assigned to the cfDNA cohort (all had solid tumors); or (2) presence of unexplained clonal cytopenia assessed by a 174-gene peripheral blood (PB) next-generation sequencing (NGS) panel. These patients were assigned to the PB-NGS cohort (62% solid tumors, 38% lymphoma or multiple myeloma). The Clonal Hematopoiesis Risk Score (CHRS) was calculated for mutations with VAF ≥ 2%; mutations with VAF < 2% were classified as micro-CHIP.

ResultsFrom June 2022 to June 2024, 591 patients were prospectively enrolled: 374 in the cfDNA cohort and 217 in the PB-NGS cohort. Median age was 69 years; 52% were female. A history of ≥ 2 primary cancers was reported in 25%. Lung cancer (25%) and non-Hodgkin lymphoma (NHL) (32%) were the most common in the cfDNA and PB-NGS cohorts, respectively. Median treatment lines were 2 (range: 0-12). Compared to the cfDNA group, the PB-NGS patients showed higher rates of thrombocytopenia (39% vs. 6%, p < 0.01), neutropenia (15% vs. 2%, p < 0.01), anemia (59% vs. 36%, p < 0.01), macrocytosis (21% vs. 8%, p < 0.01), and elevated red cell distribution width (RDW) (34% vs. 17%, p = 0.03).

Top mutations in the PB-NGS cohort included DNMT3A (47%), PPM1D (27%), TET2 (26%), TP53 (22%), and ASXL1 (12%). In the cfDNA cohort, DNMT3A (61%), TET2 (33%), ASXL1 (25%), JAK2 (25%), and MYD88 (6%) mutations predominated. Based on the CHRS, patients were low-risk (25% vs. 35%), intermediate-risk (36% vs. 22%), and high-risk (12% vs. 1%) in the PB-NGS vs. cfDNA cohorts (p < 0.001). Micro-CHIP was observed in 18% and 17%, respectively.

Concordance between cfDNA and PB-NGS was assessed in 67 patients (11%) with both tests (84% collected within 1 year). Of the 132 mutations covered by both panels, 74 (56%) were detected by both, 51 (39%) only in cfDNA, and 7 (5%) only in PB-NGS. Most cfDNA-only mutations (82%) had a VAF < 2%. For mutations with VAF ≥ 2%, VAFs correlated strongly between cfDNA and PB-NGS (r = 0.77), specifically for DNMT3A (r = 0.92) and TET2 (r = 0.69).

After a median follow-up of 18 months (range: 0-35), 20 new hematologic malignancies were diagnosed: 7 at first CH-MTB visit (myelodysplastic syndrome [MDS]: 2; myeloproliferative neoplasm [MPN]: 2; chronic myelomonocytic leukemia [CMML]: 1; chronic myeloid leukemia: 1; NHL: 1) and 13 during follow-up (MDS: 9; MPN: 1; MDS/MPN: 2; NHL: 1). Among the 12 with MDS or CMML, 8 had clonal evolution, 4 acquired new mutations, and 4 had TP53 alterations. Of those progressing to MDS, 64% had a high or very high IPSS-M score.

Univariable analysis adjusted for cohort affiliation showed that patients with ≥ 2 treatment lines (hazard ratio [HR] = 1.8), presence of CCUS (HR = 1.8), elevated RDW (HR = 2.3), and CHRS high-risk (HR = 3.5) were at risk for shorter overall survival (OS) (p < 0.01). In multivariable analysis of CHRS components adjusted for cohort affiliation, presence of CCUS (HR = 1.7) and elevated RDW (HR = 2.1) independently predicted shorter OS (p ≤ 0.01). Competing risk analysis showed that CHRS high-risk group (HR = 11, p = 0.03), presence of ≥ 2 CHIP mutations (HR = 9.3, p < 0.01), and VAF ≥ 20% (HR = 5.7, p < 0.01) were associated with progression to hematologic malignancies.

Conclusion Our MTB dedicated to CH proved the importance of early detection of hematologic malignancies in patients with cancer. CHRS high-risk group, high VAF, and multiple CHIP mutations were associated with progression to hematologic malignancies. These findings highlight the need for oncology-specific CH risk models to identify patients warranting early CHIP interception.

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2025
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