Successful Allogeneic Stem Cell Transplantation in Nuclear Factor-Kappa B Essential Modulator Deficiency Syndrome After Treosulfan-Based Conditioning: A Case Report.

BACKGROUND: X-linked EDA-ID1 (ectodermal dysplasia, anhidrotic, with immunodeficiency 1, Online Mendelian Inheritance in Man [OMIM] 300291), or NEMO (nuclear factor kappa B essential modulator) deficiency syndrome, is caused by mutations in the IKBKG/NEMO gene. We report the case of a boy with EDA-ID1 who underwent allogeneic stem cell transplantation. METHODS: In early infancy, the patient developed an atypical, severe, initial manifestation resembling Omenn syndrome with infections, and he underwent allogeneic stem cell transplantation from an unrelated 9 of 10 HLA matched donor with a mismatch in the DQB1 allele after conditioning with treosulfan, fludarabine, thiotepa, and antithymocyte globulin (Grafalon). The post-transplant period was complicated by cytomegalovirus replication and mild, grade 2 graft vs host disease. Because of NEMO deficiency syndrome-associated enteropathy and continuous weight loss, parenteral nutrition was started and the patient was fed an elemental formula and a gluten-free diet. Over a period of 3 years, the patient had 7 incidents of blood stream infections caused by Staphylococci or gut-derived Gram-negative flora, with 1 incident of septic shock caused by Escherichia coli. The blood stream infection stopped after gastrointestinal tract decontamination was done once per month for 7-day courses alternately with rifaximin, vancomycin, and gentamicin sulfate. CONCLUSIONS: Patients with NEMO deficiency syndrome require very complex, multidisciplinary care, and immunodeficiency correction can only be observed as one of the critical points in patient care. Developmental problems, enteropathy with the need for intravenous hyperalimentation, and specific interventions for other clinical manifestations of multifaceted syndrome are needed for proper care.

Successful Salvage Haploidentical Alpha-Beta T Cell-Depleted Stem Cell Transplantation After Busulfan-Based Myeloablation in a Patient With IPEX Syndrome: A Case Report.

BACKGROUND: X-linked immunodysregulation syndrome with polyendocrinopathy and enteropathy (IPEX) is caused by FOXP3 gene mutations that block the generation of regulatory T lymphocytes. We report an 18-month-old boy with classic IPEX who underwent 2 hematopoietic stem cell transplantations (HSCTs). METHODS: The first HSCT from an unrelated 8/10 HLA-matched umbilical cord blood donor (UCB) was performed after a conditioning regimen consisting of treosulfan, fludarabine, thiotepa, and thymoglobulin. Due to complete rejection of the UCB transplant, a second transplantation from a 6/10 HLA-matched mother was performed after alpha-beta T-cell depletion. The second conditioning regimen consisted of busulfan, fludarabine, a single dose of cyclophosphamide 1 g/m2, and Grafalon (Neovii Pharmaceuticals, Rapperswil, Switzerland). The T-cell depletion product contained 15.06 x 106 CD34+ cells per kilogram body weight (BW) and 4.19 x 105 alpha-beta T lymphocytes per kilogram BW. Due to acute graft rejection, the boy was treated with thymoglobulin, and full donor chimerism in both T lymphocytes and mononuclear cells was achieved. The immunosuppressive therapy was stopped 1 year after transplantation. To date, the patient remains free from graft-vs-host disease (GVHD) and immunosuppression. CONCLUSIONS: HSCT after busulfan-based reduced-toxicity conditioning in patients with IPEX syndrome is feasible and well tolerated and can result in full donor engraftment. Monitoring of chimerism and aggressive therapy in cases of graft rejection are warranted due to the high reactivity of residual autologous T lymphocytes. T-cell depletion reduces the risk of GVHD and the need for steroid therapy, which is especially challenging in patients with diabetes.

Pediatric unmanipulated haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide and reduced intensity, TBI-free conditioning regimens in salvage transplantations.

BACKGROUND: Unmanipulated haploidentical stem cell transplantation (haploSCT) with post-transplant cyclophosphamide is an option for patients with advanced hematologic malignancies. It offers a platform both for non-major histocompatibility complex-restricted alloimmunity due to killer-like immunoglobulin receptor (KIR)-mediated mechanisms of natural killer lymphocyte regulation and for classical T-cell mediated antileukemic effects. OBJECTIVES: The devastating long-term sequelae after total body irradiation (TBI) in children are encouraging omission of irradiation techniques in pediatric stem cell transplantations (SCT). MATERIAL AND METHODS: Five children, 4 with acute leukemia and 1 with hemophagocytic lymphohistiocytosis, aged from 1 to 10 years, underwent haploSCT with post-transplantation cyclophosphamide. In all children, the conditioning regimen consisted of chemotherapy without TBI. The graft material was bone marrow (BM) in 4 cases and peripheral blood stem cells in 1 case. Three out of 5 leukemic patients showed better KIR haplotype associated with augmented alloreactivity. RESULTS: Engraftment with complete donor chimerism was achieved in 4 patients, and 1 recipient died before leukocyte recovery. Three patients developed skin acute graft-versus-host-disease (aGvHD), 1 gut aGvHD and 1 liver aGvHD. In 2 recipients, chronic graft-versus-host-disease (cGvHD) was observed (1 limited and 1 extensive). The 4 engrafted patients were alive and in complete remission 3, 9, 32, and 36 months after transplantation. A T-cell count of 200 cells/uL was reached 90 days after haploSCT in all patients. CONCLUSIONS: HaploSCT with TBI-free protocols can be a viable option for heavily pretreated patients with advanced malignancies.

Feasibility and Safety of Treosulfan, Melphalan, and Thiotepa-Based Megachemotherapy with Autologous or Allogeneic Stem Cell Transplantation in Heavily Pretreated Children with Relapsed or Refractory Neuroblastoma.

The prognosis of resistant or relapsing children with neuroblastoma remains very poor, and the search for new therapies is ongoing. In this analysis, we assessed the toxicity of a treosulfan, melphalan, and thiotepa (TMT) regimen in 17 children with recurrent or refractory neuroblastoma who underwent stem cell transplantation (SCT). For allogeneic SCT, fludarabine and antithymocyte globulin were added. The stem cell source was autologous in 8 patients, haploidentical in 8 patients, and a matched unrelated donor in 1 patient. The reported nonhematologic toxicities included grade 3 mucositis, grade 1 to 3 hypertransaminasemia, and in 3 patients, veno-occlusive disease. No neurologic, cardiac, or dermatologic toxicities were observed. The probability of overall survival (OS) in patients with primary resistance was superior to that in patients with relapsed disease (100% versus 22.6%; P = .046). Post-transplantation dinutuximab beta immunotherapy was associated with superior 5-year OS (66.7% versus 11.4%; P = .0007). The use of an allogeneic donor, previous autologous SCT with busulfan and melphalan, and pretreatment with high-dose metaiodobenzylguanidine therapy demonstrated no effect on outcomes. In 4 patients, TMT megatherapy alone was enough to achieve complete remission. The TMT conditioning regimen was well tolerated in heavily pretreated patients with neuroblastoma. The manageable toxicity and addition of new anticancer drugs with optional post-SCT immunotherapy or chemotherapy support further trials with the TMT regimen in patients with neuroblastoma.

Allogeneic Stem Cell Transplantation after Fanconi Anemia Conditioning in Children with Ataxia-Telangiectasia Results in Stable T Cell Engraftment and Lack of Infections despite Mixed Chimerism.

Ataxia-telangiectasia (A-T) syndrome is an autosomal recessive chromosomal breakage syndrome caused by mutation of the ataxia-telangiectasia mutated gene manifested by progressive neurodegeneration, telangiectasias of sclera and skin, immune deficiency with sinopulmonary infections, and increased incidence of lymphoid malignancies and solid tumors. Three children with A-T underwent allogeneic stem cell transplantation (SCT) using protocols for Fanconi anemia. All 3 patients were engrafted with a mixed donor-recipient chimerism, but the full donor engraftment was observed in the T lymphocyte compartment. Immunologic recovery resulted in T cell production and lack of symptomatic infections. Regular intravenous immunoglobulin supplementation was needed until IgG production recovered, which depended on pretransplant serotherapy. During the observation period patients did not require hospital admission, and none of the transplanted patients developed sinopulmonary infections. Neurologic functions in reported patients were impaired and slowly deteriorated after transplantation, but no immediate toxicities were observed. The following hallmark features of A-T were present after SCT: neurologic symptoms, growth failure, telangiectasia formation, or increased serum alpha fetoprotein. SCT can help control immune deficiency constituting 1 of the features of A-T, and elimination of autologous hematopoiesis reduces the risk of lymphoid malignancies. Resolving crucial problems with qualification for SCT depends on balancing the risk and benefits of transplant therapy.