Leukocyte adhesion deficiency-I (LAD-I) is an ultra-rare inborn error of immunity (IEI), with severe cases characterized by recurrent, life-threatening infections, hyperinflammation, and high mortality rates. Treatment options are limited to allogeneic hematopoietic stem cell transplantation (allo-HSCT) and best supportive care (BSC). Without allo-HSCT, infection risk remains high despite antimicrobial prophylaxis. Even with allo-HSCT, patients are at risk of graft failure, graft-versus-host disease (GvHD), and transplant-related morbidity and mortality. Outcomes after allo-HSCT are strongly influenced by donor compatibility, with poorly matched grafts associated with higher complication rates. This study aimed to quantify the lifetime health economic burden associated with severe LAD-I and to compare outcomes across currently available treatment modalities.
A de novo Markov model estimated lifetime outcomes for patients with severe LAD-I receiving allo-HSCT (up to two rounds) or long-term BSC. Health states included initial/long-term BSC, engraftment success (with/without chronic GvHD), graft failure (primary [PGF] or secondary [SGF]), and death. Severe LAD-I complications and acute GvHD were modeled as one-off events. Allo-HSCT outcomes were explored by age (<13 months and ≥13 months at transplant) and donor type (matched sibling donor [MSD] and non-MSD). Clinical effectiveness and natural history inputs were sourced from real-world data via the European Society for Bone and Marrow Transplantation (EBMT) registry and observational studies. Due to limited utility data, health-state utility values were derived from published literature on proxy IEIs and supplemented by expert opinion. Costs were estimated for a U.S. healthcare payer perspective. Health state and one-off acute GvHD (aGvHD) event costs were obtained from an OPTUM claims analysis using clinically validated proxy IEIs and adjusted to 2024 prices. Model outcomes are reported as mean values using undiscounted costs and outcomes.
Patients receiving allo-HSCT were projected to live 44.2 years (35.9 quality-adjusted life years [QALYs]) at an estimated lifetime cost of $2.0 million. An “average” patient is based on 39% receiving an MSD, with 16% experiencing graft failure (3% PGF, 13% SGF), 10% chronic GvHD, and 23% aGvHD; outcomes may vary substantially if these rates change. Age at transplant also affects outcomes. Patients receiving long-term BSC had shorter survival (16.1 years), substantially impaired quality of life (7.1 QALYs), and higher lifetime costs ($9.0 million), driven by high annual healthcare costs and low health-state utility from frequent severe LAD-I-related complications. Lifetime burden was also assessed for an “average” severe LAD-I cohort, comprising both allo-HSCT and long-term BSC recipients, acknowledging ratios may vary by transplant center and region.
Long-term BSC is associated with substantial cumulative lifetime costs and poor clinical outcomes. Allo-HSCT offers the potential for cure and significantly reduces long-term management costs compared with BSC; however, it entails high upfront costs and carries risks of serious, potentially life-threatening complications, which contribute to both short- and long-term healthcare expenditures. Lifetime burden under allo-HSCT varies by rates of transplant-related complications, age at transplant, and donor type. Overall, these findings highlight that current treatment options for severe LAD-I remain suboptimal, underscoring a critical unmet need for alternative therapies.
