Immune Checkpoint Inhibitor Therapy and Associations with Clonal Hematopoiesis

Area of Science:

• Hematology
• Oncology
• Immunotherapy

Background:

• Cancer patients often exhibit clonal hematopoiesis (CH), characterized by mutations in hematopoietic stem cells.
• Immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment but its effect on hematopoiesis is unclear.
• Understanding ICB's impact on CH is crucial given the rising incidence of secondary leukemias.

Purpose of the Study:

• To characterize the hematopoietic compartment in melanoma and non-small cell lung cancer (NSCLC) patients.
• To investigate if ICB therapy influences hematopoietic clonal architecture and expansion.
• To explore the potential of CH as a biomarker for ICB response and predictor of myeloid malignancy risk.

Main Methods:

• Analysis of peripheral blood samples from 142 patients with melanoma and NSCLC.
• Evaluation of serial samples (n=25) from patients before and after ICB exposure.
• Error-corrected sequencing of genes recurrently mutated in CH (e.g., DNMT3A, TET2).

Main Results:

• High prevalence of CH observed in melanoma and NSCLC cohorts.
• In melanoma patients, mutations in DNMT3A and TET2 increased in size with longer ICB exposure, showing statistically significant VAF changes.
• Similar, though not statistically significant, epigenetic expansion trends were noted in NSCLC patients post-ICB.

Conclusions:

• ICB therapy may exert selective pressure on hematopoietic stem cells, promoting clonal expansion in epigenetic modifier genes.
• DNMT3A/TET2 CH mutations may serve as predictive biomarkers for ICB response in melanoma and NSCLC.
• Long-term ICB therapy may increase the risk of myeloid malignancy due to sustained clonal expansion.