Allogeneic Hematopoietic Stem-Cell Transplantation for Leukocyte Adhesion Deficiency

Abstract

OBJECTIVES Leukocyte Adhesion Deficiency (LAD) is a rare primary immune disorder caused by defects of the CD18 β-integrin molecule on immune cells. The condition usually presents in early infancy and is characterised by deep tissue infections, leukocytosis with impaired formation of pus and delayed wound healing. Allogeneic haematopoietic stem cell transplantation (HSCT) offers the possibility of curative therapy, and with patient numbers at any individual centre being limited, we surveyed the transplant experience at 14 centres worldwide. PATIENTS & METHODS The course of 36 children with a confirmed diagnosis of LAD who underwent HSCT between 1993 and 2007 was retrospectively analysed. Data was collected by the registries of the European Society for Immunodeficiencies (ESID)/European Group for Blood and Marrow Transplantation (EBMT), and the Center for International Blood and Marrow Transplant Research (CIBMTR) RESULTS At median followup of 62 months (extending to 14 years) overall survival was 75%. Myeloablative conditioning regimens were used in 28 patients, and reduced intensity conditioning (RIC) in 8 patients, with no deaths in this subgroup. Survival after matched family donor and unrelated donor transplants was similar, with 11/14 matched family donor and 12/14 unrelated donor recipients alive; mortality was greatest following haplo-identical transplants, where 4/8 children did not survive. Twenty seven transplant recipients are alive, with full donor engraftment in 17 cases, mixed multi-lineage chimerism in 7 patients, and mononuclear cell restricted chimerism in a further 3 cases. CONCLUSIONS HSCT offers long term benefit in LAD and should be considered as an early therapeutic option if a suitable HLA-matched stem cell donation is available. Reduced intensity conditioning was particularly safe, and mixed donor chimersim appears sufficient to prevent significant symptoms, although careful long term monitoring will be required for these patients.

Progress and prospects: gene therapy for inherited immunodeficiencies

“…The ability of low levels of circulating neutrophils to achieve disease control in leukocyte adhesion deficiency has been confirmed in the allogeneic transplant setting where patients with relatively low levels of donor engraftment remain symptom free. As haploidentical transplantation for leukocyte adhesion deficiency is a difficult and high-risk procedure, 19 gene therapy for this condition remains highly attractive for patients without suitable HLA-matched donors. Importantly, Foamy viruses are non-pathogenic in humans and vectors may have a favourable integration profile compared with gamma-retroviral vectors.…”

Paciente con deficiencia de adhesión leucocitaria tipo 1 y doble falla primaria de injerto

“…Se ha reportado una tasa de supervivencia de hasta 75% con donadores 100% compatibles. 2,6 Antes del trasplante de células progenitoras hematopoyéticas los tratamientos descritos son: utilización de antibióticos de amplio espectro en caso de infección; administración de antibióticos profilácticos: trimetoprim con sulfametoxazol e itraconazol, así como tener un buen estado nutricional. Se ha reportado también el uso de transfusiones de granulocitos en caso de infecciones graves como el ectima gangrenoso.…”

Reduced-intensity conditioning hematopoietic SCT for pediatric patients with LAD-1: clinical efficacy and importance of chimerism

“…This can be concluded from a small number of patients who underwent transplantation around the world and also different types of conditioning regimens used in different centers. [2][3][4][5][6][7][8][9][10] As pre-transplant infections in primary immunodeficiencies patients especially those affected by LAD-I lead to rise in mortality rate, [2][3][4][5][6][7][8][9][10] the use of less-toxic RIC as conditioning regimen seems to be highly effected in this regard. On the other hand, as LAD-I patients have hyperactive myeloid macrophage lineage, RIC regimen results in a high incidence of mixed chimerism and rejection in such affected patients.…”

“…Two distinct human disorders of LAD-I and LAD-II have been recognized. [2][3][4] LAD-I (the primary focus of our report) is the consequence of a heterogeneous mutation in the leukocyte b2-integrin (CD18) gene, which is located on chromosome 21. The b2-integrin a glycoprotein complex is required for adhesion dependant functions, such as aggregation, chemotaxis, phagocytosis, cell-mediated killing and adherence to vascular endothelium.…”

“…Later on patients develop nonpurulent, recurrent and necrotizing infections of the skin and mucous membranes, as well as persistent leukocytosis, gingivitis and periodontitis. [2][3][4][5][6] Hematopoietic SCT (HSCT) is the only known curative approach to LAD-I treatment. [6][7][8][9][10][11] Reduced intensity and myeloablative conditioning regimens are currently being used in the treatment of patients affected by LAD-I.…”