Toward Safer CD34+ Megadose T-Cell-Depleted Transplants Following Reduced Intensity and Nonmyeloablative Conditioning Regimens

Haploidentical hematopoietic cell transplantation (haplo-HCT) offers a curative procedure for patients with malignant and nonmalignant hematological diseases, as well as an expanding number of inherited disorders. Haplo-HCT is likely the best HLA-related unmatched source of hematopoietic cell transplantation (HCT). Over the past decade, haplo-HCT has emerged as an important clinical option in the treatment of neoplastic hematologic diseases, especially for patients who lack a HLA-matched sibling donor (MSD). The risk of graft-versus-host disease (GvHD) and graft rejection associated with such transplants has been markedly reduced by extensive T-cell depletion (TCD) for GvHD prevention and escalated doses of CD34+ progenitors (i.e., megadose) to overcome graft rejection. Haplo-HCT in the context of TCD and nonmyeloablative (NMA) conditioning is associated with minimal risk for GvHD but with risk of higher rates of graft rejection. Thus new approaches to address this challenge are being developed. If successful, non-myeloablative haplo-HCT potentially could offer a highly attractive and safer treatment modality for patients with different hematological diseases or a platform for organ transplantation and cell therapy by addition of CD34+ cell megadose. In this chapter, we describe novel approaches for chimerism induction with CD34+ megadose in settings of TCD and NMA conditioning regimens, based on insights regarding the mechanism by which CD34+ megadose transplants overcome graft rejection.