Hematopoietic stem cell transplantation in 746 children with osteopetrosis: A study of the inborn errors working party of the EBMT

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Abstract Introduction Osteopetrosis (OP) is a group of rare inherited conditions characterized by dysfunctional osteoclasts, leading to hypocalcemia, cytopenia, bone fractures, compression of cranial nerves and vision loss. Hematopoietic stem cell transplantation (HSCT) is the only curative approach for most children with OP but was historically complicated by high incidence of graft failure (GF), veno-occlusive disease (VOD) and transplant-related mortality (TRM). To define prognostic risk factors in this setting, the IEWP of the EBMT performed a registry study on HSCT in OP. Patients and Methods We analyzed the outcomes of children with OP receiving HSCT in EBMT centers between 1990 and 2022. The main endpoints of the study were overall survival (OS) and event-free survival (EFS; events: death and graft failure) according to year of HSCT, donor type, stem cell source and conditioning regimen. Results We studied 746 children affected by OP, with a median age at transplant of 0.7 years (range 0-15). Genetic results were available for 321 patients: TCIRG1 66.4%, CLCN7 12.9%, SNX10 6.6%, RANK 5.9%, and others 8.2%. Pre-HSCT OP-related complications included: bone fractures (16.9%), hypocalcemia (76.6%), splenomegaly (70.5%), transfusion-dependent anemia (53.6%), severe visual impairment or blindness (57.5%), intracranial hypertension (16.9%), and seizures (11.7%). The median follow-up was 7 years (range 0-33.8 years). Conditioning regimens were Busulfan/Fludarabine (n=310; 43.5% of known values), Busulfan/Cyclophosphamide (n=236; 33.1%), Treosulfan/Fludarabine/Thiotepa (n=132; 18.5%), or other (n=34; 4.8%). Donors were human leukocyte antigen (HLA) matched sibling donor (MSD; n=208, 29.2%), matched related (MRD; n=78, 10.9%), matched unrelated (MUD, 10/10 or 6/6; n=174; 24.4%), mismatched related (MMRD; n= 168; 23.6%), mismatched unrelated (MMUD, n= 85; 11.9%). Stem cell source was bone marrow (BM, n=470; 64%), peripheral blood (PB, n=201; 27.4%) or umbilical cord blood (UCB, n=63; 8.6%). The 3-year Kaplan-Meier estimate of OS was 69% (95% CI, 66-73%). Survival improved over time: 3-year OS was 50% (41-59%), 67% (60-73%) and 77% (73-82%) for patients transplanted between 1990-2000, 2001-2011 and 2012-2022, respectively (p<0.001). Risk factor analysis was performed for patients transplanted between 2007-2022 (n=491, 66%), reflecting adoption of modern transplant procedures. In this group, the 3-year OS, EFS and CI of graft failure (GF) was 75% (71-79%), 61% (56-66%) and 21% (17-25%), respectively. Second HSCT was performed in 65/491 patients and resulted in a 3-year OS and EFS of 63% (51-75%) and 45% (32-59%), respectively. The 180-day CI of grade II-IV and grade III-IV acute GvHD was 26% (22-31%) and 11% (8-14%), respectively. The 2-year CI of chronic and extensive chronic GVHD was 9% (6-12%) and 3% (2-5%), respectively. In multi-variate analysis (MVA), OS was lower in patients with HLA-mismatched donors (HR, 1.53; p=0.045), poor performance status (HR 2.69; p<0.001), splenomegaly (HR 2.89; p<0.001), and those undergoing UCB transplant (HR 1.92; p=0.036). Large center size (≥20 transplants) was associated with better OS (p<0.001), motivating the inclusion of center in the MVA. In MVA, EFS was lower in patients with poor performance score (HR 2.11; p<0.001), splenomegaly (HR 2.92; p<0.001), use of HLA mismatched donors (HR 1.85; p=0.001) and PB as stem cell source (HR 1.67; p=0.01). The 30-day CI of VOD was 20% (16-24%); this was (very) severe in 36.6% patients. In MVA exposure to Busulfan/Fludarabine (HR 5.87; p<0.001) and age <6 months (HR 1.23; p=0.005) were independent risk factors. Arterial pulmonary hypertension and hypercalcemia were described in 51/375 (13.6%) and 76/371 (20.5%) evaluable patients, respectively. OP-related clinical phenotypes improved significantly post-HSCT, with evidence of improved anemia (p<0.001), leukocytosis (p<0.001), thrombocytopenia (p<0.001), height (p<0.001), and intracranial hypertension (p<0.001). In UVA, earlier HSCT (<6 months) contributed to improved vision preservation (p<0.001). Conclusion This is the largest study to date describing HSCT outcomes in children affected by OP. Although challenges remain in terms of risk of GF, VOD and TRM, survival has significantly improved over the last decade, especially when an HLA matched donor is unavailable. Due to the complexity of OP patients, it is recommended that HSCT is performed in large and experienced centers.

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