Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) Outcomes in Leukocyte Adhesion Deficiency Type -I

Background: Leukocyte adhesion deficiency type I (LAD-I) is a rare autosomal recessive inborn error of immunity caused by loss of function mutations in ITGB2, which encodes for the β2 common integrin subunit CD18, impairing leukocyte adhesion to inflamed endothelium and migration to sites of infection or injury. Allo-HSCT represents the only therapeutic option to enable survival beyond early childhood but is limited by donor availability, risk of infections, graft-versus-host disease (GvHD) and graft failure (GF).

Objective: To characterize outcomes of patients with LAD-I who underwent allo-HSCT over a very recent 10-year period in a large European cohort.

Methods: The European Society for Blood and Marrow Transplantation (EBMT) registry allo1 database was queried for patients with LAD-I who received an allo-HSCT using a single stem cell source between 2012 and 2021 and were under 12 years old at the time of transplant.

Patient, donor, and transplant characteristics were summarized using descriptive statistics. Ninety-five percent confidence intervals (CI) were calculated for overall survival (OS) and event-free survival (EFS). EFS was defined as survival without GF and/or grade II-IV acute GvHD (aGvHD). Percentages for categories with missing patient data were calculated based on the number of patients with available data.

Results: Among 56 patients with LAD-I who met the inclusion criteria, the median age at diagnosis was 2.0 months (IQR: 0.4-2.2) and median time from diagnosis to transplant was 6.8 months (IQR: 2.9-15.5). All patients received a conditioning regimen, with 80.4% receiving myeloablative conditioning. Most patients (80.4%) received serotherapy (mainly with ATG and alemtuzumab); and 98.2% received GvHD immunosuppressive prophylaxis. Among patients with available information, recipient/donor cytomegalovirus (CMV) status mismatch (−/+ and +/-) was present in 19.2% and 5.8%, respectively. Human Leukocyte Antigens (HLA) matched sibling donor (MSD) recipients comprised 39.3% of the cohort, matched unrelated family donors, 30.4%, matched unrelated donors, 12.5%, mismatched donors, 16.1% and unrelated donors, 1.8%. Transplant-related complications, including veno-occlusive disease, transplant-associated microangiopathy and renal insufficiency among others occurred in 31% of patients. Post-transplant infection-related hospitalizations occurred in 45.5% of patients. GF occurred in 16.4% of patients, while 27.3% developed aGvHD (Grade II-IV) and 7.7% developed chronic GvHD. Overall, the mortality rate was 14.3%.

OS at 1 and 3 years in the total patient population was 85% (95% CI: 75-95%). Recipient/donor CMV status was significantly associated with OS (p=0.003) with mismatched -/+ and +/- recipient 1 year and 3 year survival of 57% (range: 25-89%) and 67% (range: 13-100%) respectively; 1-3 year OS was 86% (range: 60-100%) and 100% for -/- and +/+ patients (no deaths occurred between year 1 and 3). The 1-year EFS in the total patient population was 58% (range: 45-71%). EFS at 1 year was highest in MSD recipients (86% [range: 71-100%]), whereas it was lowest among patients with HLA mismatched donors (33% [range: 3-64%]). EFS at 3 years was the same as EFS at 1 year in the total patient population and across HLA matched subgroups, as no additional events were recorded after the first year post-transplant in any group.

Conclusions: Allo-HSCT is the current standard-of-care for definitive treatment for LAD-I. However, despite a better OS in patients with LAD-I undergoing allo-HSCT, GvHD, GF, and other transplant-related complications remain significant sources of transplant-related morbidity, as shown in this recent cohort. These findings highlight the need for more effective and safer treatment approaches, including possibly lentiviral-based gene therapy.

Booth:Ensoma: Consultancy; Rocket Pharmaceuticals Inc.: Consultancy; Chiesi Farmaceutici S.p.A.: Honoraria. Toren:Minovia Therapeutics: Research Funding. Bader:Amgen, Novartis, Vertex: Speakers Bureau; Medac, Novartis, Vertex: Other: Travel grants . Güngör:Neovii: Other: Travel Grand; Novartis: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Forge: Membership on an entity's Board of Directors or advisory committees. Chitty-Lopez:Rocket Pharmaceuticals, Inc.: Current Employment. Matos:Rocket Pharmaceuticals, Inc.: Current Employment. Turner:Rocket Pharmaceuticals, Inc.: Current Employment. Rao:Rocket Pharmaceuticals, Inc.: Current Employment. Schwartz:Rocket Pharmaceuticals, Inc.: Current Employment. Albert:Medac: Membership on an entity's Board of Directors or advisory committees.