Dynamics of Clonal Hematopoiesis of Indeterminate Potential and Clinical Outcomes Following Chemotherapy in Lymphoma Patients

Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) is a potentially premalignant condition of aging that arises upon the expansion of somatically mutated hematopoietic stem/progenitor cells in hematological malignancy-free individuals. CHIP can be detected in 10-15% of healthy older patients and can lead to dysfunctional hematopoiesis and dysregulation of immune functions of mature blood cells. In lymphoma patients treated with front-line chemotherapy, CHIP can be detected in 20% of patients. However, this is not routinely considered, nor does it currently alter treatment plans. Rates of various chemotherapy-related complications such as febrile neutropenia, grade 3-4 anemia, leukopenia, and hospital admissions are higher in elderly lymphoma patients. Clinicians remain unsure as to why some older lymphoma patients go through chemotherapy treatment rather uneventfully while others of comparable performance status and comorbidity suffer repeated complications that can necessitate dose reductions/delays. We hypothesized that CHIP may be a risk factor for chemotherapy complications in older lymphoma patients related to the dysfunctional bone marrow and blood cells caused by CHIP. We performed targeted next-generation sequencing for a cohort of older lymphoma patients prior to their commencement of chemotherapy and at three treatment time points. This revealed that the prevalence and variant allele frequency (VAF) of CHIP variants, particularly variants in DNA damage response genes (DDR), increased during chemotherapy treatment. We then compared the CHIP profiles of these patients with clinical records tracking chemotherapy-related complications and found DDR CHIP to be significantly associated with respiratory toxicities. Additionally, univariate analysis showed CHIP to be associated with altered blood cell parameters including hemoglobin, eosinophils, basophils, platelets, red blood cell distribution width (RDW), mean corpuscle volume (MCV), whether RDW or MCV increased during treatment, and the number of MCV increases. Through multivariable analysis, associations between CHIP and number of MCV increases, platelet count, RDW, and whether RDW increased remained significant. We plan to expand this study to a larger cohort, performing further sequencing and clinical analysis. This may provide early insight into which patients might be most at risk for chemotherapy complications and blood count alterations, allowing for the development of personalized treatment plans and the optimization of patient outcomes.