Matched unrelated bone marrow transplantation for combined immunodeficiency

Divisions of Immunology/Allergy, Haematology/Oncology, The Infection, Immunity, Injury and Repair Programme, Research Institute, The Hospital for Sick Children and The University of Toronto, Canada.
Bone Marrow Transplantation (Impact Factor: 3.57). 04/2000; 25(6):613-21. DOI: 10.1038/sj.bmt.1702215
Source: PubMed


Bone marrow transplantation (BMT) from siblings is the treatment of choice for severe combined immunodeficiency (SCID). The objective of this study was to evaluate the efficiency of BMT from matched unrelated donors (MUD) in congenital immunodeficiencies when a sibling donor is unavailable. Sixteen consecutive patients with SCID (n = 9) and CID (n= 7), were referred for an unrelated donor search. Acceptable donors were found for all patients. Fifteen patients received busulfan and cyclophosphamide pretransplant conditioning. One patient had an early loss of graft and was reconditioned using cyclophosphamide and total body irradiation. The graft-versus-host disease (GVHD) prophylaxis used was methylprednisolone, cyclosporin A with or without methotrexate. Neutrophil engraftment was rapid and was achieved in all patients within a mean of 15.4 days. Only 13 episodes of fever were recorded shortly after BMT. GVHD of grade II or more was apparent in 2/9 (22%) of SCID patients and in 4/7 (57%) of CID patients. Overall survival was 75% with a mean follow-up of 47.4 months (range 18-101). Six out of nine SCID patients (67%) and 6/7 (86%) of CID patients are alive and well. Eleven patients had normal humoral immunity, and cell-mediated immunity as measured by flow cytometry and mitogenic responses, was intact in all patients. Intradermal candida skin test was positive in 9/10 patients tested. We conclude that BMT from MUD results in rapid engraftment and is therefore associated with a low rate of infection contributing to the improved survival rate. The protocol used is especially favorable for patients with combined immunodeficiency.

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    • "Overall survival rates of 67 – 100% are superior to that observed following HFD , with the advantages of more rapid and complete immune recon - stitution and a lower incidence of graft failure ( Table IV ) ( Filipovich et al , 1992 ; Dalal et al , 2000 ) . However , the risk of acute GVHD following URD HSCT remains high at around 50% and is associated with a high rate of non - relapse mortality ( Dalal et al , 2000 ; Filipovich et al , 2001 ; Grunebaum et al , 2006 ) . In addition , a suitable unrelated donor is unavailable for many patients and the duration of the search process may be prohibitive , particularly in SCID . "
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    ABSTRACT: Allogeneic haemopoietic stem cell transplantation has provided curative therapy for life-threatening malignant and non-malignant diseases in children for over 40 years. Only 25% of children in whom an allograft is indicated have the ideal option of a human leucocyte antigen-identical sibling donor. Substantial advances in the use of alternative donors (unrelated volunteer donors, haploidentical family donors and unrelated umbilical cord blood donors) now make it possible for almost all children to benefit from this life-saving treatment. Each donor choice is associated with distinct advantages and disadvantages, which have greater or lesser importance in different diseases. We review the current status of alternative donor transplantation for haematological malignancies, primary immunodeficiencies, inherited metabolic disorders and bone marrow failure syndromes and outline the current UK consensus donor selection algorithms for these disease groups.
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    ABSTRACT: Severe combined immunodeficiency disease (SCID) refers to a heterogeneous group of rare (1/100,000 live births), lethal, congenital disorders that result in the inability of T cells to respond to mitogens, alloantigens, and specific antigens and B cells to produce specific antibodies.1 Before the early 1990s, patients with this disorder were characterized primarily by the phenotype and function of their circulating lymphocytes, mode of inheritance, and presence or absence of enzyme deficiencies known to be associated with SCID, such as adenosine deaminase. In this original classification, three main types of SCID were described2 and include the following: (1) classical SCID, characterized by T and B lymphopenia, with or without natural killer (NK) cells, and agammaglobulinemia, (2) the more common SCID with B lymphocytes, and (3) SCID secondary to adenosine deaminase (ADA) deficiency, which may present with either of the preceding lymphoid phenotypes.3 and 4 Less often, children with SCID present with Omenn's syndrome,5 in which affected infants have scaling erythroderma, leukocytosis, eosinophilia, hepatosplenomegaly, and lymphadenopathy with replacement of nodal architecture by Langerhans and reticulum cells,6 reticular dysgenesis,7 in which SCID is associated with severe neutropenia and often bilateral sensorineural deafness,8 or SCID with short-limbed dwarfism and ectodermal dysplasia.9 Multiple variants of SCID have been described in which patients have nonfunctional T cells that demonstrate capping defects,10 lack CD711 or possess abnormal CD3 subunit expression,12 or have CD8 deficiency with nonfunctional CD4+ cells.13 and 14 Despite this phenotypic heterogeneity, the distribution of SCID phenotypes reported in four separate studies performed in Europe and the United States was surprisingly similar.15, 16, 17 and 18 Approximately 40% of patients presented as SCID with B cells, 25% as classical SCIDs (B−T−), 15% with ADA deficiency, 10% as SCIDs with nonfunctional T cells, and 2% to 3% with reticular dysgenesis. Inheritance of these disorders are either autosomal recessive (ADA deficiency,4 and 19 short-limbed dwarfism,9 Omenn's syndrome,5 capping defects,10 CD8 deficiency,13 and 14 or as either an X-linked or autosomal recessive disorder (classical SCID, SCID with B cells, reticular dysgenesis).14 and 20Although first trimester diagnosis of adenosine deaminase deficiency has been possible for many years by measurement of enzyme activity in cultured amniocytes or chorionic villi samples,21 children with ADA+ SCID, until recently, required fetal blood sampling to ascertain the presence or absence of T cells.22 The elucidation of many of the genetic mutations which give rise to SCID, such as X-linked SCID (IL-2R gamma chain),23, 24 and 25 autosomal recessive SCID with B cells (JAK-3),26 and 27 classic SCID, Omenn's syndrome28, 29, 30 and 31 (recombinase defects (RAG-1, RAG-2), and CD8 deficiency with nonfunctional T-cells (ZAP-70),32, 33 and 34 has increased the proportion of infants who can be diagnosed by amniocentesis or chorionic villus sampling (CVS).35 and 36 Better prenatal diagnosis, earlier postnatal diagnosis, because of heightened awareness of immunodeficiency disorders resulting from the AIDS epidemic, in conjunction with advances in anti-microbial therapy, have reduced the number of children presenting to bone marrow transplant (BMT) with a life-threatening infection.Successful correction of SCID by BMT was first reported by Gatti et al using bone marrow derived from an HLA-matched sibling.37 Since that report, over 500 curative transplants for this disorder have been performed,38 the majority using T-cell–depleted haploidentical parental bone marrow. Within the last 5 years, advances in unrelated bone marrow39 and cord blood transplantation40 and successes with in utero stem cell transplants41 have expanded the options available to infants with SCID, particularly those lacking an HLA-matched sibling. In this article, the results and continued controversies of stem cell transplantation for SCID are reviewed.
    Immunology and Allergy Clinics of North America 02/2000; 20(1):207-220. DOI:10.1016/S0889-8561(05)70142-9 · 1.82 Impact Factor
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