Clonal hematopoiesis and its emerging effects on cellular therapies

Abstract

The accumulation of somatic mutations in hematopoietic stem cells during aging, leading to clonal expansion, is linked to a higher risk of cardiovascular mortality and hematologic malignancies. Clinically, clonal hematopoiesis is associated with a pro-inflammatory phenotype of hematopoietic cells and their progeny, inflammatory conditions and a poor outcome for patients with hematologic neoplasms and solid tumors. Here, we review the relevance and complications of clonal hematopoiesis for the treatment of hematologic malignancies with cell therapeutic approaches. In autologous and allogeneic hematopoietic stem cell transplantation native hematopoietic and immune effector cells of clonal origin are transferred, which may affect outcome of the procedure. In chimeric antigen receptor modified T-cell therapy, the effectiveness may be altered by preexisting somatic mutations in genetically modified effector cells or by unmodified bystander cells harboring clonal hematopoiesis. Registry studies and carefully designed prospective trials will be required to assess the relative roles of donor- and recipient-derived individual clonal events for autologous and allogeneic cell therapies and to incorporate novel insights into therapeutic strategies.

Molecular and phenotypic blueprint of the hematopoietic compartment reveals proliferation stress as a driver of age-associated human stem cell dysfunctions

“…For instance, the functional decline of the lymphoid compartment, responsible for a defective adaptive immunity in old age, has been observed also in human-aged HSPC leading to the common interpretation that, likewise in mice, human HSPC aging is associated with a prominent myeloid skewing 19–21 . Additionally, the increased incidence of myeloproliferative disorders and hematopoietic myeloid malignancies in aged individuals 22–26 further supports the above-mentioned shift in myeloid output during aging. Moreover, there is evidence in humans that aging is associated with anemia 27 and clonal hematopoiesis 23 which may act as additional cofactors in the development of myelodysplasia and hematopoietic malignancies 28,29 .…”

Prevalence and variation of CHIP in patients with aggressive lymphomas undergoing CD19-directed CAR T-cell treatment

“…Nevertheless, other cellular therapies in patients with lymphoma were reported to be influenced negatively by CHIP, which we did not observe. 11 In the future, larger studies with longitudinal single-cell analysis of various immune cells, including the CAR T cells themselves, are necessary to perform reliable multivariate analyses and to elucidate the influence of CHIP-associated somatic mutations on the outcome of CAR T-cell treatment.…”

“…The relevance of CHIP in the context of CAR T-cell treatment is widely unknown. 11,12 Therefore, we longitudinally evaluated the prevalence of CHIP in patients with r/r B-cell non-Hodgkin lymphoma undergoing CAR T-cell treatment and assessed the influence on clinical inflammation syndromes (CRS/ICANS), cytopenia after CAR T-cell therapy, and outcome.…”

Cardiac-Related Lesions in Newly Diagnosed Patients With Acute Leukemia: A Chinese Population-Based Real-World Study

“…However, most scholars only focus on heart damage caused by anti-tumor therapy ( 25 , 26 ). Cardiotoxicity during the treatment of AL patients has been extensively reported ( 27 ), including radiotherapy ( 28 , 29 ), conventional chemotherapies (e.g., anthracyclines, antimetabolites, and cyclophosphamide) ( 30 – 32 ), immune checkpoint inhibitors (programmed cell death 1, programmed death ligand 1, or CTL-associated protein 4) ( 33 , 34 ), and many targeted therapies, particularly monoclonal antibodies and tyrosine kinase inhibitors ( 35 , 36 ), CART therapy ( 37 – 39 ), natural killer cell immunotherapy ( 40 ), and hematopoietic stem cell transplantation ( 41 – 43 ). Possible mechanisms are mediated by reactive oxygen species generated in iron-dependent chemical reactions ( 44 ), mitochondrial dysfunction ( 45 ), increased calcium flux in cardiomyocytes ( 46 ), and disorders of DNA topoisomerase 2-beta metabolism ( 47 ).…”