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INTRODUCTION

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Haploidentical stem cell transplantation (haploSCT) from a first-degree-related haplotype-mismatched donor (siblings, children, parents) could expand allogeneic stem cell transplantation (SCT) to a large proportion of patients with hematologic malignancies without an HLA-matched donor (1). As the average family size continues to shrink, the likelihood of finding an HLA-matched related sibling donor continues to decrease (2). Moreover, as the population continues to age, finding a young, healthy sibling donor becomes increasingly less likely. The use of matched unrelated donors (MUDs) is limited by the long time to SCT (median 3-4 months), which makes it difficult to treat patients with more advanced disease in rapid need of SCT. The ethnicity/race of the recipient can also limit MUD transplantation as approximately 30% of Caucasians, 70% of Hispanics, and 90% of African Americans do not have a MUD in the worldwide registries (3).

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In contrast to unrelated donor stem cells, haploidentical (or “half-matched”) donors can be available immediately, and there are no costs associated with an unrelated donor search, maintaining a registry, or coordinating logistics with distant donor centers. This is an especially valuable option for the non-Caucasian and mixed-race individuals (3). This approach might also be particularly useful in developing countries that may not have the resources to procure unrelated donor transplants or maintain complex unrelated donor registries. Moreover, haploidentical donors offer the possibility to easily collect donor cells for cellular therapy posttransplant. Over the recent decade, significant breakthrough advances in controlling alloreactivity have been made and important steps taken toward graft engineering and posttransplant cellular therapy, approaches that changed dramatically the landscape of haploSCT. Improved haploidentical transplant outcomes represent a major advance in SCT that has practically eliminated the limitation of donor availability for allogeneic SCT.

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COMPLETE T-CELL DEPLETION: CONTROL OF GRAFT-VERSUS-HOST DISEASE WITH A HIGH TREATMENT-RELATED MORTALITY

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Historically, unmanipulated T-cell-replete haploSCT grafts with conventional graft-versus-host-disease (GVHD) prophylaxis used in the late 1970s were associated with intense bidirectional alloreactivity and unacceptably high morbidity and mortality rates due to hyperacute GVHD and graft rejection (4,5,6). This led in the 1980s to the development of complete ex vivo depletion of T cells using CD34-selected grafts. Complete T-cell depletion has been associated with a lower incidence of acute GVHD (aGVHD); however, this caused delayed immune recovery and was associated with a high nonrelapse mortality (NRM) from infections and higher disease relapse rates given the decreased graft-versus-leukemia effect, as well as a higher rate of graft rejection (7,8,9). While graft rejection was partially overcome with “megadoses” of CD34 cells (typically >107 CD34+ cells/kg) and a myeloablative conditioning regimen (including total-body irradiation [TBI], cyclophosphamide, thiotepa) with severe T-cell depletion of the graft, immune recovery remained delayed, leading to high NRM rates in excess of 40% (10). Improved results with this approach have been reported in ...

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