Incipient clonal hematopoiesis is accelerated following CD30.CAR-T therapy

Area of Science:

• Hematology
• Oncology
• Immunotherapy

Background:

• Chimeric antigen receptor (CAR) T-cells are a novel therapy for refractory lymphomas.
• Clonal hematopoiesis (CH), characterized by mutated bone marrow progenitors, is frequently observed in lymphoma patients undergoing CAR-T therapy.
• Conditioning chemotherapy and inflammatory responses associated with CAR-T treatment can promote CH clone expansion.

Purpose of the Study:

• To investigate the hypothesis that pre-existing CH clones expand during CAR-T cell treatment.
• To longitudinally track CH clone dynamics in patients receiving CD30.CAR-T therapy for CD30+ lymphomas.

Main Methods:

• Longitudinal measurement of CH at 154 timepoints from 26 patients undergoing CD30.CAR-T therapy.
• Tracking of single CH clones and analysis of their expansion dynamics post-treatment.
• Assessment of CH clone presence in the CAR-T product and its impact on product characteristics.

Main Results:

• Pre-treatment CH was detected in 54% of patients and did not correlate with survival or toxicity.
• Initially small CH clones (VAF <1%) exhibited significant expansion (3.37-fold) after CAR-T administration, unlike larger clones (1.20-fold).
• Matched CH clones were found at low levels in the CAR-T product without affecting its immunophenotype or transduction efficiency.

Conclusions:

• CAR-T therapy recipients may have an increased prevalence of CH.
• Longitudinal studies are warranted to further investigate CH complications in patients receiving CAR-T therapy.
• Understanding CH dynamics is crucial as cellular immunotherapies become frontline treatments for hematological malignancies.