Matched versus Haploidentical Hematopoietic Stem Cell Transplantation as Treatment Options for Primary Immunodeficiencies in Children.

Primary immunodeficiencies (PIDs) are inherited disorders of the immune system with allogeneic hematopoietic stem cell transplantation (HSCT) as the only curative treatment in some of them. In case an HLA-matched donor is not available, HSCT from a haploidentical family donor may be considered. We compared the outcomes of HSCT from HLA-matched unrelated or related donors (MUDs or MRDs) and mismatched related haploidentical donors (MMRDs) in patients with a variety of PIDs in 2 centers. A total of 44 pediatric patients were evaluated. We reviewed the outcomes of 25 children who underwent transplantation with HLA-matched grafts (MRD, n = 13; MUD, n = 12) and 19 patients receiving haploidentical stem cells. Bone marrow (BM) was transplanted in 85% (MRD) and 75% (MUD) of the matched cohort and peripheral blood stem cells (PBSCs) in 15% (MRD), 25% (MUD), and 100% (MMRD). All but 9 patients (MRD, n = 6; MMRD, n = 3) with severe combined immunodeficiency (SCID) received a chemotherapy-based conditioning regimen. Immune reconstitution of T, B, and natural killer cells was comparable for all groups with an advantage of recipients of MRD grafts in early CD4 reconstitution. However, deaths due to viral infections occurred more often in the haploidentical cohort. The disease-free survival was 91.7% (MRD), 66.7% (MUD), and 62.7% (MMRD), respectively. Grade II to IV acute graft-versus-host disease (GVHD) occurred in 15% (MRD), 8% (MUD), and 21% (MMRD) of the patients. Only 1 patient had severe grade IV GVHD in the MRD group, whereas no grade >II GVHD was observed in the MUD or MMRD cohort. These data indicate that in the absence of a suitable HLA-identical family donor, haploidentical HSCT may be a viable option for patients with life-threatening disease and urgent need of HSCT.

High-dose iodine-131-metaiodobenzylguanidine with haploidentical stem cell transplantation and posttransplant immunotherapy in children with relapsed/refractory neuroblastoma.

We evaluated the feasibility and efficacy of using high-dose iodine-131-metaiodobenzylguanidine ((131)I-MIBG) followed by reduced-intensity conditioning (RIC) and transplantation of T cell-depleted haploidentical peripheral blood stem cells (designated haplo-SCT) to treat relapsing/refractory neuroblastoma (RRNB). Five RRNB patients were enrolled: 4 with relapse (3 after autologous SCT) and 1 with induction therapy failure. The preparative regimen included high-dose (131)I-MIBG on day -20, followed by fludarabine (Flu), thiotepa, and melphalan (Mel) from day -8 to -1. Granulocyte-colony stimulating factor (G-CSF)-mobilized, T cell-depleted haploidentical paternal stem cells were infused on day 0 together with cultured donor mesenchymal stem cells. A single dose of rituximab was given on day +1. After cessation of short immunosuppression (mycophenolate, OKT3), 4 children received donor lymphocyte infusion (DLI). (131)I-MIBG infusion and RIC were well tolerated. All patients engrafted. No primary acute graft-versus-host disease (aGVHD) was observed. Four children developed aGVHD after DLI and were successfully treated. Analysis of immunologic recovery showed fast reappearance of potentially immunocompetent natural killer (NK) and T cells, which might have acted as effector cells responsible for the graft-versus-tumor (GVT) effect. Two children are alive and well, with no evidence of disease 40 and 42 months after transplantation. One patient experienced late progression with new bone lesions (sternum) 38 months after haplo-SCT, and is being treated with local irradiation and reinstituted DLI. One patient rejected the graft, was rescued with autologous backup, and died of progressive disease 5 months after transplantation. Another child relapsed 7 months after transplantation and died 5 months later. High-dose (131)I-MIBG followed by RIC and haplo-SCT for RRNB is feasible and promising, because 2 of 5 children on that regimen achieved long-lasting remission. Further studies are needed to evaluate targeted therapy and immune-mediated tumor control in high-risk neuroblastoma.