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— Coleman Lindsley, MD, PhD, and Christopher Gibson, MD
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.
Divergent clinical and clonal evolution in a donor-recipient pair. We identified SF3B1 and ASXL1 mutations in the donor stem product. Both were detectable in the recipient bone marrow one year after HSCT. At the time of DCL diagnosis, the recipient’s bone marrow still harbored the initial SF3B1 mutation, as well as new mutations in ASXL1, SETBP1, and SUZ12, but the original ASXL1 mutation was not detectable. In a contemporaneous sample from the donor, the SF3B1 and ASXL1 mutations had expanded without any evidence of genetic or clinical evolution.
Coleman Lindsley, MD, PhD
Christopher Gibson, MD