Reduction of graft failure by a monoclonal antibody (anti-LFA-1 CD11a) after HLA nonidentical bone marrow transplantation in children with immunodeficiencies, osteopetrosis, and Fanconi's anemia: a European Group for Immunodeficiency/European Group for Bone Marrow Transplantation report

Abstract

Forty-six infants and children suffering from either inherited immunodeficiency disorders (Wiskott-Aldrich syndrome, functional T-cell immunodeficiency with or without HLA class II expression deficiency), malignant osteopetrosis, or Fanconi's anemia received HLA-nonidentical bone marrow transplantation (BMT) from related donors. Bone marrow was T-cell depleted to reduce the risk of graft-versus-host disease (GVHD). To prevent graft failure, a mouse monoclonal antibody specific for the CD11a-lymphocyte function-associated antigen 1 (LFA-1) molecule was infused into the patients. Eleven patients received five infusions of 0.1 mg/kg every other day from day -3 to +5. Thirty-five patients received 0.2 mg/kg daily from day -3 to +6. The overall sustained engraftment rate was 72% instead of 26.1% in a historical control group of 24 patients similarly treated except for the infusion of the anti- LFA-1 antibody. No late rejection occurred. The T-cell depletion method (E-rosetting or Campath IM plus complement) resulted in different rate of engraftment (83.3% v 57.9%, respectively, P = .05). Engraftment rate was slightly but not significantly influenced by the degree of HLA incompatibility between donor and recipient. Acute GVHD of grade II or more occurred in 35.5% of the patients and the rate of chronic GVHD was 12.9%. The overall actuarial survival rate with a functional graft is 47.3% with a mean follow-up of 28.0 months for patients with immunodeficiency and osteopetrosis, while none of the four patients with Fanconi's anemia survived. The development of full T-cell functions took on the average 6 months and of full B-cell functions 10 months. Significant infectious problems developed in the majority of the patients during the posttransplant course. Epstein-Barr virus- induced B-cell proliferative syndromes were observed in seven patients, six of whom had Wiskott-Aldrich syndrome. Correction of immunodeficiency was comparable in terms of kinetics and quality with that observed in patients with severe combined immunodeficiency undergoing HLA-nonidentical BMT. Correction of osteopetrosis appears not to be different from what has been observed after HLA-identical BMT. The in vivo use of an anti-CD11a-LFA-1 antibody as an additional immunosuppressive therapy in HLA-nonidentical BMT may thus promote engraftment and survival with correction of the primary disease in a significant number of patients with life-threatening immunodeficiency and osteopetrosis, but not with Fanconi's anemia.

HLA-Haploidentical T Cell–Depleted Allogeneic Hematopoietic Stem Cell Transplantation in Children with Fanconi Anemia

“…Median number and range of CD34 þ cells infused in patients who engrafted (24.5 Â 10 6 /kg; range, 12 to 35) and in the 2 patients who rejected the graft (7.25 Â 10 6 /kg; range, 5.6 to 8.9). Mann-Whitney P ¼ .026. patients when a HLA genotypically matched donor is not available [14,[17][18][19][20][21][22][23][24][25][26]. The first report of a successful haploidentical HSCT in FA was published in 2000 by Boulad et al [18], who used TCD stem cells from HLA-haploidentical relatives to treat 2 patients with FA, the first as a salvage therapy for graft rejection of a first unrelated cord blood allograft and the second in a patient lacking an HLA-matched donor.…”

“…Notwithstanding some encouraging results and potential benefits of allogeneic HSCT from an HLA partially matched related donor in FA patients, current evidence in the medical literature is limited to case reports and small retrospective case series [14,[17][18][19][20][21][22][23][24][25][26]. The present study describes the outcomes of 12 consecutive pediatric FA patients who underwent T celledepleted (TCD) HSCT from an HLA partially matched relative, after a Flu-based preparative regimen.…”

Immunological Aspects of Haploidentical Stem Cell Transplantation in Children

“…In the haploidentical group, we have therefore added in a first protocol the anti‐CD3 antibody OKT‐3 from day +1 to day +18 to the conditioning regimen including ATG and lately replaced the ATG completely by OKT‐3 from day ‐4 to day +13. A similar approach to prevent rejection using LFA‐1 antibody32 or LFA‐1 and anti‐CD2 antibody33 has been described. Other approaches to ensure engraftment could be the infusion of irradiated donor leukocytes34 or irradiated buffy coats35 or NK cells together with IL‐236 and large‐scale isolation of donor CD56 + NK cells, for such an approach has been described us 37.…”

Outcome in patients with Wiskott–Aldrich syndrome following stem cell transplantation: an analysis of 57 patients in Japan

“…Allogeneic SCT has been recognised as an effective method for curing WAS patients who have HLA‐matched siblings (Rimm and Rappeport, 1990; Bortin et al , 1994), but the number of WAS patients with such a sibling is only small. Although patients who do not have an HLA‐matched sibling can undergo SCT from an HLA‐mismatched related donor or an unrelated donor, the results to date have been extremely poor (Brochstein et al , 1991; Fischer et al , 1991). In particular, low survival rates are likely for patients receiving transplants from related donors other than HLA‐identical siblings, or from unrelated donors for boys older than 5 years, according to the National Marrow Donor Program (Filipovich et al , 2001).…”