CHIP amplifies the risk of lymphoid malignancies in individuals with monoclonal B-cell lymphocytosis (MBL)

Monoclonal B-cell lymphocytosis (MBL) and clonal hematopoiesis of indeterminate potential (CHIP) are prevalent clonal precursors associated with increased risk of lymphoid malignancies. However, the relationship between MBL and CHIP and their combined impact on lymphoid malignancy risk remains poorly understood. We screened participants from the Mayo Clinic Biobank to identify MBL using eight-color flow cytometry; CHIP was detected using whole-exome sequencing of whole-blood DNA in 291 genes related to myeloid or lymphoid malignancies. Incident myeloid or lymphoid hematological malignancies were identified using ICD codes and confirmed via medical record review. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Cox regression was used to estimate hazard ratios (HR). Analyses were adjusted for age and sex. In 10,067 participants, 15% had MBL, and 9% had CHIP. No evidence of an association between MBL and CHIP (OR = 1.00; 95% CI: 0.82-1.20) was observed. With a median follow-up of 5.4 years, 138 participants developed hematological malignancies (94 lymphoid). MBL (HR = 3.48; 95% CI: 2.27-5.34; P < 0.001) and CHIP (HR = 1.89; 95% CI: 1.10-3.27; P = 0.022) were each associated with incident lymphoid malignancy. Compared to individuals with no precursors, the combined presence of MBL and CHIP significantly amplified lymphoma risk (HR = 7.18; 95% CI: 3.33-15.47; P < 0.001), more than doubling the risk among individuals with MBL alone (HR = 3.30; 95% CI: 2.06-5.30; P < 0.001). In contrast, the risk associated with CHIP alone was attenuated and no longer statistically significant (HR = 1.63; 95% CI: 0.77-3.47; P = 0.20). MBL and CHIP are independent hematological precursor conditions. While their combined presence amplifies the risk of lymphoid malignancy, CHIP alone may not be a strong independent risk factor.