Alternative-Donor Hematopoietic Stem Cell Transplantation with Post-Transplantation Cyclophosphamide for Nonmalignant Disorders

Abstract

Allogeneic (allo-) hematopoietic stem cell transplant (HSCT) is curative for many nonmalignant pediatric disorders, including hemoglobinopathies, bone marrow failure syndromes, and immunodeficiencies. There is great success using HLA-matched related donors for these patients; however, the use of alternative donors has been associated with increased graft failure, graft versus host disease (GVHD), and transplant-related mortality (TRM). HSCT using alternative donors with post-transplantation cyclophosphamide (PT/Cy) for GVHD prophylaxis has been performed for hematologic malignancies with engraftment, GVHD, and TRM comparable to that seen with HLA-matched related donors. There are limited reports of HSCT in nonmalignant pediatric disorders other than hemoglobinopathies using alternative donors and PT/Cy. We transplanted eleven pediatric patients with life-threatening nonmalignant conditions using reduced intensity conditioning (RIC), alternative donors, and PT/Cy alone or in combination with tacrolimus and mycophenolate mofetil. We observed limited GVHD, no TRM, and successful engraftment sufficient to eliminate manifestations of disease in all patients. Allo-HSCT using alternative donors and PT/Cy shows promise for curing nonmalignant disorders; development of prospective clinical trials to confirm these observations is warranted.

Haploidentical Related Donor Hematopoietic Stem Cell Transplantation for Dedicator-of-Cytokinesis 8 Deficiency Using Post-Transplantation Cyclophosphamide

“…Klein et al recently reported on their experience with 11 pediatric patients carrying a host of life-threatening nonmalignant diseases, who all received reduced-intensity–conditioned transplantation with alternative donors (including 4 haploidentical donors) and PT/Cy alone or in combination with tacrolimus and mycophenolate mofetil [46]. In their series, there was only limited acute GVHD, no transplantation-related mortality, and successful engraftment, leading to reversal of the disease manifestations in all patients [46].…”

“…Klein et al recently reported on their experience with 11 pediatric patients carrying a host of life-threatening nonmalignant diseases, who all received reduced-intensity–conditioned transplantation with alternative donors (including 4 haploidentical donors) and PT/Cy alone or in combination with tacrolimus and mycophenolate mofetil [46]. In their series, there was only limited acute GVHD, no transplantation-related mortality, and successful engraftment, leading to reversal of the disease manifestations in all patients [46]. Parta et al also described a child with chronic granulomatous disease who underwent haploidentical transplantation utilizing PT/Cy for GVHD prophylaxis who had successful engraftment and limited acute GVHD (grade 2) and CMV viremia, both of which were well controlled [23].…”

“…However, there are only a few reports of transplantations using haploidentical related donors in DOCK8 deficiency [9,14,15]. The success of haploidentical transplantation in other primary immunodeficiency syndromes suggested the feasibility of this approach in patients with DOCK8 deficiency [16-19]. Paramount to the success of haploidentical HSCT is the ability to prevent graft-versus-host disease (GVHD).…”

“…This can be addressed using in vitro techniques with T cell depletion by CD34 + selection or selective T cell depletion (eg, depletion of T cell receptor, depletion of TCRab + (T cell receptor alpha beta) T cells, associated with depletion of CD19 + B lymphocytes) [19,20]. Alternately, in vivo depletion of T cells can be accomplished by pretransplantation serotherapy [21,22] or by using post-transplantation cyclophosphamide (PT/Cy) [16,23]. …”

In vivo engineering of bone tissues with hematopoietic functions and mixed chimerism

“…Successful allogeneic HSC or BM transplantation relies heavily on the ability of the HLA-matched donor cells to replace the recipient's hematopoietic functions by homing and engrafting into the host BM niche (7)(8)(9). Currently, all transplantations require recipient conditioning, which involves cytoreductive agents and/or irradiation to improve donor cell engraftment (10)(11)(12). The conditioning provides immunosuppression and allows for donor cells to engraft in the recipient HSC niche (12,13).…”