BONE-MARROW TRANSPLANTATION FROM GENETICALLY HLA-NONIDENTICAL DONORS IN CHILDREN WITH FATAL INHERITED DISORDERS EXCLUDING SEVERE COMBINED IMMUNODEFICIENCIES - USE OF 2 MONOCLONAL-ANTIBODIES TO PREVENT GRAFT-REJECTION

Objective. For children with life-threatening inborn errors of metabol ism without a matched related bone marrow donor, transplantation from an HLA genetically nonidentical donor is the only therapeutic option. To reduce the high risk of graft rejection in this setting without inc reasing the conditioning regimen, a protocol based on the infusion of an antiadhesion antibody directed against the CD11a (leukocyte functio n-associated antigen 1 [LFA-1]) molecule was performed by the European Bone Marrow Transplantation-European Society for Immunodeficiency gro up with promising results. To optimize engraftment, and thereby surviv al, further, the additional blockade of a second important leukocyte a dhesion and signalization pathway mediated by the CD2 and LFA-3 intera ction was attempted in a multicenter protocol conducted by the Europea n Bone Marrow Transplantation-European Society for Immunodeficiency gr oup. Results of this study tie, engraftment and survival) were compare d with a historical control group that received the anti-LFA-1 antibod y alone. Factors that may have affected engraftment and survival were also considered in this study, Methods. Forty-four children with inbor n errors, including inherited immunodeficiencies (excluding severe com bined immunodeficiencies), Chediak-Higashi syndrome, familial hemophag ocytic lymphohistiocytosis, and malignant osteopetrosis, received bone marrow from HLA-nonidentical related donors or from HLA-identical unr elated donors at 13 European centers between August 1990 and June 1993 . Bone marrow was depleted of T cells by use of either erythrocyte (E) resetting: or monoclonal antibodies (MoAbs) to prevent graft-versus-h ost disease. The conditioning regimen consisted of busulfan and cyclop hosphamide for all patients plus etoposide for patients with osteopetr osis, familial hemophagocytic lymphohistiocytosis, and Chediak-Higashi syndrome. Infusions of MoAbs specific for the CD11a and the CD2 molec ules were started 4 and 3 days, respectively, before and continued thr ough the first 10 and 11 days, respectively, after bone marrow transpl antation (a total of 14 injections). Results. The overall sustained en graftment rate was 69.8%, with full chimerism in 80.6% of patients and no late graft rejection with the use of two MoAbs versus 65.7% and 58 .1%, respectively, in the control group, in which only one MoAb was in fused. The overall actuarial survival rate with a functional graft was 40.9%, with a mean follow-up of 39.3 months with two MoAbs versus 37. 8% with one. The engraftment rate was significantly influenced by the T-cell depletion method, with better results for recipients of E roset te-depleted marrow (78.6% vs 20% for Campath 1-M plus complement-deple ted marrows). Graft-versus-host disease and the kinetics of immune rec onstitution were similar in both groups. Conclusions. The overall engr aftment rate and overall survival rate with engraftment in patients tr eated with anti-LFA-1 and anti-CD2 were similar to those in patients t reated with anti-LFA-1 antibody alone. However, although the number of patients is too small to draw definitive conclusions, results from th e combined use of the two MoAbs indicates a trend toward better engraf tment and survival after infusion of E rosette-depleted marrow Further improvement in survival would demand additional strategies to hasten immunologic recovery.