Fitness Landscape of Clonal Hematopoiesis Under Selective Pressure of Immune Checkpoint Blockade

JCO Precis Oncol. 2020 Sep 9:4:PO.20.00186. doi: 10.1200/PO.20.00186. eCollection 2020.


Purpose: Conventional cytotoxic therapies increase the risk of clonal hematopoiesis and select for TP53-mutant clones, which carry a high risk for transformation to therapy-related myelodysplastic neoplasms. In contrast, the effect of immune checkpoint blockade (ICB) on clonal hematopoiesis is unknown.

Methods: Paired peripheral-blood samples taken before and after treatment with ICB were obtained for 91 patients with either cutaneous melanoma or basal cell carcinoma. Error-corrected sequencing of a targeted panel of genes recurrently mutated in clonal hematopoiesis was performed on peripheral-blood genomic DNA.

Results: The average interval between acquisition of the paired samples was 180 days. Forty-one percent of the patients had clonal hematopoiesis at a variant allele frequency (VAF) > 0.01 in the pretreatment sample. There was near-complete agreement in the distribution and burden of clonal hematopoiesis mutations in the paired blood samples, with 87 of 88 mutations identified across the cohort present in paired samples, regardless of the duration between sample collection. The VAF in the paired samples also showed a high correlation, with an R 2 = 0.95 (P < .0001). In contrast to cytotoxic therapy, exposure to ICB did not lead to selection of TP53- or PPM1D-mutant clones. However, consistent with the known effects of DNA-damaging therapy, we identified one patient who had eight unique TP53 mutations in the posttreatment blood sample after receiving two courses of radiation therapy.

Conclusion: There was no expansion of hematopoietic clones or selection for clones at high risk for malignant transformation in patients who received ICB, observations that warrant further validation in larger cohorts. These findings highlight an important difference between ICB and conventional cytotoxic therapies and their respective impacts on premalignant genetic lesions.