Hematopoietic Stem Cell Transplantation in 65 Patients with Leukocyte Adhesion Deficiency Type I and Type III — A Retrospective Multi-Center Study

Leukocyte adhesion deficiency (LAD) is an autosomal recessive, primary immunodeficiency disorder, characterized by lethal deep tissue infections, leukocytosis with impaired pus-formation, delayed wound healing and hyper-inflammation. Life expectancy of affected patients is severely shortened. LAD-I is caused by defective expression of beta-2 integrin on immune cells, resulting in impaired leukocyte adhesion and migration. LAD-II is a metabolic disease with syndromal features. LAD-III is caused by mutations in the FERMT3 gene resulting in activation defect of all beta-integrins. LAD-III is characterized by leukocyte adhesion/migration deficiency and an additional Glanzmann's thrombasthenia-like syndrome.

In this retrospective multi-center study, data were collected from the European Group for Blood and Marrow Transplantation (EBMT) registry. This study included 65 children from 14 European and Asian centers with either LAD-I (n=60) or LAD-III (n=5), all receiving an allogeneic hematopoietic stem-cell transplantation (alloHSCT) from 2008 to 2015.

Median age at diagnosis was 0.3 years (yrs); interval from diagnosis to alloHSCT was 8.1 months (median; range 0.6 to 134.5 months). An HLA-identical sibling or matched non-sibling family donor was available for 35 (54%) patients; 28 (43%) received the allograft from a matched unrelated donor and 2 (3%) patients were transplanted from an HLA-haplo-identical family donor. Stem cell source was bone marrow in 37 (58%) patients, peripheral blood in 17 (26%) and cord blood in 10 (16%) of the cohort. Reduced intensity conditioning (RIC) was used in 19 (29%) and myeloablative conditioning (MAC) in 46 (71%) patients. Half of the cohort (n=33) received a busulfan-based conditioning regimen; treosulfan was used in 18 (28%) patients. Serotherapy was applied to 71% of the cohort and consisted primarily of ATG (85%).

The overall survival of the cohort was 80% (95%CI: 70-91%) at 24 months, and 77% (95%CI: 65-89%) at 60 months post alloHSCT. In total 12 patients died. The cause of death was GVHD (n=6) and infections (n=6).

Primary or secondary graft failure occurred in 9 patients. The incidence of graft failure at 24 months was 11% (95% CI: 7-24%) in RIC and 14% (95% CI: 3-24%) in MAC group. A second alloHSCT was performed in 8 patients; it was successful in 7 cases.

At 100 days, 10% (95% CI: 2-17%) and 16% (95% CI: 7-25%) of patients developed grade I-II and grade III+IV aGVHD, respectively . Extensive chronic GVHD was reported in 2 cases.

AlloHSCT restored leukocyte function in LAD-I and both leukocyte and thrombocyte function in LAD-III leading to complete remission of symptoms with hematological and immunological reconstitution. Transplantation should be performed early in the course of the disease and prior to the occurrence of life-threatening infectious complications.