Severe combined immunodeficiency: treatment by bone marrow transplantation in 15 infants using HLA-haploidentical donors

Summary:Reticular dysgenesis is a very rare congenital immunodeficiency classified within the severe combined immunodeficiencies (SCID) and characterized by impairment of both lymphoid and myeloid cell development. We report our experience in 10 patients with RD, treated between 1979 and 1999 with HLA-haploidentical hematopoietic stem cell transplantation (HSCT). All children but one were symptomatic within the first days of their lives. Five patients required two HSCT. Five patients received conditioning therapy with busulfan (16 mg/kg) and cyclophosphamide. Three of them are alive and well with myeloid and T and B cell lymphoid reconstitution, whereas two patients died (one chronic graftversus-host disease, one pneumonitis). Transplantation without or with other conditioning regimens in the other five cases led to absent or incomplete engraftment and none of these cases survived. These results demonstrate the mandatory need for intensive conditioning before haploidentical HSCT in RD to achieve full lymphoid and myeloid engraftment.

Section: Discussionmentioning

confidence: 99%

“…11 One patient has been previously reported. 4 Patient characteristics at HSCT are given in Table 1. Age at first HSCT ranged from 0.5 months to 4 months (median 2.5 months).…”

Section: Methodsmentioning

confidence: 99%

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Reticular dysgenesis: HLA non-identical bone marrow transplants in a series of 10 patients

Bertrand

Muller

Casanova

et al. 2002

“…Keywords: HLA non-identical transplantation; peripheral blood progenitor cells; grafted T cell number; GVHD HLA haplo-identical BMT with T cell depletion (TCD) has been used successfully to treat children with primary immunodeficiency disorders. [1][2][3] In patients with other diseases, this transplant approach has frequently failed because of graft rejection. [4][5][6] Graft failure may result from the profound T cell depletion required to prevent GVHD, with the ensuing loss of the graft-enhancing effect mediated by T cells.…”

Section: Discussionmentioning

confidence: 99%

Definition of a critical T cell threshold for prevention of GVHD after HLA non-identical PBPC transplantation in children

Muller

Schulz

Reiss

et al. 1999

Summary:The aim of this study was to reduce the rate of graft failure after HLA non-identical stem cell transplantation by using G-CSF mobilized CD34 ؉ peripheral blood progenitor cells (PBPC), either in combination with bone marrow or as single grafts. To prevent GVHD, PBPC were highly purified, resulting in a 5 to 6 log T cell depletion. In additon to T cell depletion no further GVHD prophylaxis was used. We transplanted 23 pediatric patients with life-threatening malignant or non-malignant hematological disorders, who had no available matched donor. Engraftment was obtained in 18 of 21 evaluable patients. Five patients developed acute GVHD of grade II and III, which became chronic in four cases and was fatal in four. The use of highly purified PBPC allowed the exact quantification of residual T cells in the grafts and a strict correlation between the residual T cell load and the development of GVHD was observed: patients with GVHD had received numbers of T cells between 8 and 20 ؋ 10 4 /kg, whereas patients without GVHD were grafted with T cell numbers ranging from 0.7 to 6.0 ؋ 10 4 /kg. We therefore clearly demonstrate that a residual T cell content of Ͻ5 ؋ 10 4 /kg is safe for prevention of GVHD after HLA non-identical PBPC transplantation in children. Keywords: HLA non-identical transplantation; peripheral blood progenitor cells; grafted T cell number; GVHD HLA haplo-identical BMT with T cell depletion (TCD) has been used successfully to treat children with primary immunodeficiency disorders. [1][2][3] In patients with other diseases, this transplant approach has frequently failed because of graft rejection. [4][5][6] Graft failure may result from the profound T cell depletion required to prevent GVHD, with the ensuing loss of the graft-enhancing effect mediated by T cells. 7,8 More intensive immunosuppressive conditioning to counterbalance this disadvantage has usually had limited success because of significant complications from toxicity. Less vigorously T cell-depleted grafts carry the risk of severe GVHD. From animal models it is clear that engraftment may also be improved by increasing the number of grafted cells, either using unmanipulated bone marrow, taking advantage of the effect of alloreactive T cells or, as shown in recent studies, by using high numbers of highly purified T cell-depleted stem cells. 9 The latter approach was used by Aversa et al to transplant patients with leukemia from HLA non-identical family donors using either a combination of purified peripheral blood progenitor cells (PBPC) and T cell-depleted marrow or, in more recent patients, PBPC alone. 10-12 A remarkably high engraftment rate of more than 90% was observed.Here we report results of a pilot study in pediatric patients, where we explored a comparable transplant approach. Like the findings of Aversa et al, we observed a high engraftment rate of 86%. In contrast, GVHD developed in the initial patients, but was completely preventable in patients receiving grafts containing fewer T cells than 5 ϫ 10 4 /kg. Patients and meth...

“…4,5 The time taken for engraftment of the marrow cells and immune reconstitution varies depending on multiple factors. These include: (a) the use of T cell depleted [6][7][8] vs unfractionated bone marrow cells; 9,10 (b) pre-transplant conditioning; (c) the presence or absence of graft-versushost disease (GVHD) and its treatment; 11 (d) concomitant infections; and (e) the general status of the patient. 12 During this early post-transplant period, the immune imbalance observed as the donor immune system emerges, modified by the host, results in well described symptom complexes such as GVHD.…”

mentioning

confidence: 99%

Acquired autoimmune thrombocytopenia post-bone marrow transplantation for severe combined immunodeficiency

Ting

Ziegler

Vowels

1998

Summary:Children with severe combined immunodeficiency (SCID) have profoundly diminished humoral and cellular immunity resulting in death during infancy unless immune reconstitution occurs by bone marrow transplantation (BMT). Thrombocytopenia post-bone marrow transplantation can be seen in relation to infection, graft-versus-host disease (GVHD) and rarely, as an autoimmune phenomenon due to immune dysregulation. We report two cases of severe AITP following BMT for SCID. Both cases developed large intracerebral hemorrhages from which one died. Autoimmune thrombocytopenia in this setting can be life-threatening and we recommend early and active intervention. Keywords: autoimmune thrombocytopenia; BMT; severe combined immunodeficiency Severe combined immunodeficiency (SCID) is a syndrome describing children with profound cellular and humoral immune dysfunction attributable to different causes such as enzyme deficiencies (ADA, PNP), 1,2 T cell defects, defective HLA expression, as well as the more common ␥c deficiency. 3 For these patients, with the exception of ADA deficiency, bone marrow transplantation (BMT) is the therapy of choice. 4,5 The time taken for engraftment of the marrow cells and immune reconstitution varies depending on multiple factors. These include: (a) the use of T cell depleted 6-8 vs unfractionated bone marrow cells; 9,10 (b) pre-transplant conditioning; (c) the presence or absence of graft-versushost disease (GVHD) and its treatment; 11 (d) concomitant infections; and (e) the general status of the patient. 12 During this early post-transplant period, the immune imbalance observed as the donor immune system emerges, modified by the host, results in well described symptom complexes such as GVHD. 11,[13][14][15][16] This underlying immune dysregulation may also result in autoimmune cytopenias. 12,17 We report two cases of severe AITP following a haploidentical, T cell-depleted allogeneic BMT for SCID. Case report Patient AA girl presented with recurrent respiratory infections and persistent diarrhea and was diagnosed with T − B + SCID with normal adenosine deaminase (ADA) and purine nucleophosphorylase (PNP) levels at 3 months of age. Her hematological and immunological profile at presentation were: hemoglobulin (Hb) 11.8 g/dl, white cell count (WCC) 4.6 × 10 9 /l, platelet count (plat) 225 × 10 9 /l, Ig G/A/M of 1.7, Ͻ 0.1, 0.3 g/l, respectively, CD3 Ͻ0.02 (normal 0.9-1.6), CD4 Ͻ0.02 (normal 0.7-1.2), CD8 Ͻ0.02 (0.3-9.7), CD19 1.74 (0.16-0.36) and NK cells 0.39 (0.13-0.35) × 10 9 /l. Response to mitogen was not performed due to the almost absent number of T cells. She underwent a T cell-depleted (soybean lectin sheep E-rosetting), haploidentical BMT without conditioning from her father at 4 months of age. Engraftment was documented on day +21 post-transplant by fluorescent in situ hybridization (FISH) studies for XY cells and the post-transplantation course was complicated by respiratory failure, acute renal failure and graft-versus-host disease (GVHD) involving skin and gastrointestinal tract...