Allogeneic hematopoietic cell transplantation for infantile osteopetrosis: High rates of sinusoidal obstruction syndrome/veno-occlusive disease and transplant-related morbidity Free

Introduction Osteopetrosis is a group of heterogeneous inherited disorders characterized by osteoclast dysfunction-driven dysregulation in bone metabolism. Autosomal recessive infantile osteopetrosis is a severe lethal form with disease-related mortality largely caused by bone marrow failure. The insufficient bone marrow niche cannot support physiologic hematopoiesis leading to bone marrow failure, extramedullary hematopoiesis and subsequent organ dysfunction. Allogeneic hematopoietic cell transplantation (alloHCT) replenishes the hematopoietically derived osteoclast population to a functional phenotype and thus rescues the bone marrow niche. Early morbidity and mortality after alloHCT in patients with osteopetrosis are predominantly secondary to graft failure, infection, and complications of organ function including sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD). SOS/VOD is a potentially life-threatening complication of alloHCT in which endothelial cell injury leads to hepatic sinusoidal obstruction and multi-organ dysfunction. Busulfan-based conditioning is widely used in myeloablative regimens in osteopetrosis alloHCT, increasing SOS/VOD risk in an already at-risk population. We aimed to evaluate the characteristics of alloHCT in pediatric patients with infantile osteopetrosis at our institution with focus on SOS/VOD characteristics.

Methods Data regarding demographics, disease- and transplant-related characteristics and complications of pediatric patients transplanted for a diagnosis of osteopetrosis between the years 2005-2024 was collected from the University of Minnesota BMT Database. AlloHCT milestones including neutrophil engraftment, acute and chronic graft-versus host disease (GvHD), SOS/VOD incidence, and overall survival were prospectively recorded. Estimates of overall survival were calculated by Kaplan-Meier curves. For GVHD-free survival, the event date was the first date of acute GVHD, chronic GVHD, or death, with other follow-up times censored at the date of last contact. Cumulative incidence of GVHD was estimated using the cumulative incidence function, with death without GVHD defined as a competing risk. Other outcomes are reported as simple percentages.

Results The evaluated cohort consisted of 24 patients with a diagnosis of osteopetrosis who underwent HSCT between the years 2005-2024, with a median age at HSCT of 0.7 years (range 0.3 – 36.5 years) and median survivor follow-up of 7 years. Donor sources consisted of matched unrelated (MUD, N=8), mismatched unrelated (mMUD, N=4), haploidentical parent (N=6), and matched sibling donor (MSD, N=6). 20/24 (83%) patients were conditioned with a Busulfan containing regimen. Of the 24 evaluated patients, 6 (25%) were documented in the medical record to have SOS/VOD as a post-transplant complication. 17/24 (71%) patients were evaluated with abdominal ultrasound before 21 days post-transplant with a median time to imaging of 11 days (range 0-24 days). 4/24 (17%) patients received prophylactic defibrotide. Retrospective application of SOS/VOD diagnostic criteria, including the Modified Seattle Criteria and the Baltimore Criteria, showed 17/24 patients (71%) meeting criteria for SOS/VOD diagnosis per Modified Seattle and 10/24 (42%) fulfilling the Baltimore diagnostic criteria. Graft sources included bone marrow (N=14), umbilical cord blood (UCB, N=3) and peripheral blood stem cells (PBSC, N=7). Overall survival (OS) at 3 years was 36% (95% CI 17, 55) with 3-year GVHD-free survival of 27% (95% CI 11, 46, Fig. 2).

Conclusions Infantile osteopetrosis is a severe lethal form of osteopetrosis secondary to osteoclast dysfunction. AlloHCT rescues disease-related bone marrow failure by replenishing a functional osteoclast population, however it can exacerbate underlying predisposition to complications such as SOS/VOD. We evaluated a population of pediatric patients who were treated with alloHSCT for osteopetrosis between the years 2005-2024 with focus on SOS/VOD as a complication post-transplant. In this population, we demonstrated a high retrospective incidence of criteria fulfillment for diagnosis of VOD/SOS at 71% and 42% for Modified Seattle and Baltimore diagnostic criteria respectively, as well as a low 3-year overall survival of 36%. Our findings reinforce the need to optimize conditioning regimens as well as the approach to complications in the post-transplant setting.