816MO - Two hematological precursors and their impact on hematological malignancies

Background

Monoclonal B-cell lymphocytosis (MBL) is a precursor to chronic lymphocytic leukemia (CLL) but also a risk factor for other lymphoid malignancies. Clonal hematopoiesis of indeterminate potential is a precursor to myeloid or lymphoid malignancies, depending on if the mutation is in a gene associated with lymphoid (L-CHIP) or myeloid (M-CHIP) disease, respectively. Little is known about the association between CHIP and MBL and their joint effect on risk of hematological malignancies (HM).

Methods

Study participants were from the Mayo Clinic Biobank. Using whole-exome sequencing, M-CHIP and L-CHIP were, respectively, defined based on mutations in 56 genes associated with myeloid malignancies or mutations in 235 genes associated with lymphoid malignancies. MBL screening was done using eight-color flow cytometry, and 575 individuals provided a second blood sample for MBL screening ∼10 years later. Incident HM 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), with time defined as date between MBL sample and the first of incident HM, death, or 12/31/2023. Analyses were adjusted for age and sex.

Results

In 9,328 individuals screened, 15% were positive for MBL, 7% were positive for M-CHIP, and 2% were positive for L-CHIP. We found no evidence of an association between MBL and M-CHIP (OR=1.0, 95% CI:0.85-1.3) or between MBL and L-CHIP (OR=0.9, 95% CI:0.58-1.4). When investigating the association between CHIP and MBL at the second timepoint, we found no evidence of an association with the development or growth of the MBL clone. We next modeled the combined effect of these precursors on incident HM and found that those individuals with both MBL and M-CHIP had a 2.8% 10-year cumulative incidence of myeloid disease, similar to that of 3.2% for those with M-CHIP only. Conversely, individuals with both MBL and L-CHIP had a 10-year cumulative incidence of 36% for lymphoid malignancy compared to 0.7% among those with no precursor condition (HR= 40; 95% CI: 13.6-117.3).

Conclusions

MBL and CHIP are independent precursor conditions. Individuals with both MBL and L-CHIP had a 40-fold increase risk of lymphoid malignancy.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Mayo Clinic.

Funding

National Institutes of Health.

Disclosure

All authors have declared no conflicts of interest.