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.

Fig. 1. Contrasting hematopoiesis with clonal hematopoiesis.

CH, which describes the accumulation of somatic mutations through aging and stress over an individual’s lifetime, may result in clonal hematopoiesis of indeterminate potential, CHIP. Various pathological conditions have been associated with CH dominance. Pictograms: BioRender.com.

Fig. 2. Conceivable effects of clonal hematopoiesis on CAR T-cell therapy.

CH might theoretically impact CAR T-cell processing and treatment (gray text) at all stages. Already observed effects attributed to CH (black text). Pictograms: BioRender.com.

Fig. 3. Impact of clonal hematopoiesis on outcome of hematopoietic cell transplantation.

The presence of CH in the graft has been associated with various findings in allogeneic, as well as autologous hematopoietic stem cell transplantation. The potential influence of different mobilization procedures on CH recovery within the graft is not depicted. Image showing blood transfusion: scraffitto at the University Hospital Dresden by Alfred Hesse, photo: T. Albrecht.