During normal aging, individual hematopoietic stem cells (HSCs) steadily accumulate somatic mutations. By age 60, it is estimated that each HSC harbors almost 10 mutations affecting its coding genome. While most of these mutations do not measurably alter stem cell function or cause disease, some confer a competitive advantage over normal HSCs and contribute to the development of mature blood cells. This phenomenon, when occurring in otherwise healthy individuals, is termed Clonal Hematopoiesis of Indeterminate Potential (CHIP). CHIP affects at least 10% of persons over 70 years of age, and has been linked to increased risks of developing hematologic malignancies and cardiovascular disease.
Autologous and allogeneic stem cell transplantation (auto-SCT and allo-SCT) can be curative therapies for patients with high-risk hematologic cancers. Both procedures rely on the transfer of healthy hematopoietic cells to recipients after administration of a pre-transplant conditioning regimen, and their success is fundamentally dependent on engraftment of normal hematopoiesis. We recently completed two studies that evaluated the clinical impact of CHIP in stem cells used for auto- and allo-SCT.
In work published this year in the Journal of Clinical Oncology 1, we found that CHIP is present in about 30% of patients with non-Hodgkin lymphoma who undergo autologous stem cell transplants, reflecting a rate more than 5 times higher than healthy adults of similar age spectrum. In this population of lymphoma patients, the presence of CHIP was associated with inferior overall survival and a significantly increased risk of developing therapy-related myeloid malignancies. As such, these patients constitute a high-risk group to consider for future clinical trials aimed at improving outcomes with auto-SCT.
In a study published this year in Blood 2, we found that CHIP can be transferred from healthy stem cell donors to recipients during allo-SCT. We showed that allo-SCT recipients who develop new, unexplained cytopenias despite high donor chimerism following transplantation almost all have CHIP engrafted from their donor stem cells. We are now conducting an analysis of a large cohort of 2,000 donors in order to validate our findings and understand the full spectrum of clinical consequences of donor-engrafted CHIP. Identifying CHIP as a biomarker in this population could improve donor selection, thereby improving transplant outcomes, while also expanding our understanding of CHIP's effects on immune function more broadly.
