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

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.

Authors

Institutions

Publication Details

Journal
Blood
Published
2025-11-03
DOI
https://doi.org/10.1182/blood-2025-165
Primary Topic
Bone Metabolism and Diseases
Type
article
Field-Weighted Citation Impact
0.00
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

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

C. Rénard, Catherine Paillard, Krzysztof Kałwak, David Bueno et al.
Blood
Bone Metabolism and Diseases
article

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

C. Rénard, Catherine Paillard, Krzysztof Kałwak, David Bueno, Bénédicte Neven, Etai Adam, Matthias Felber, Manfred Hoenig, Barış Malbora, Mohammed Essa, Katarzyna Drabko, Srividhya Senthil, Alessandra Biffi, Ansgar Schulz, Rakefet Sidlik Muskatel, Bernd Gruhn, Mayada Abu Shanap, Tania Nicole Masmas, Despina Moshous, Mehtap Sirin, Michael H. Albert, Marta González‐Vicent, Melek Erdem, Serap Aksoylar, Hawazen Saleh Alsaedi, Melissa Gabriel, M. Akif Yeşilipek, Nuno Miranda, Marco Zecca, Barış Kuşkonmaz, Maura Faraci, Bénédicte Brichard, Jean‐Sébastien Diana, Martin Castelle, Amir Ali Hamidieh, Alphan Küpesiz, Cristina Díaz de Heredia, Beki James, Kerstin Felgentreff, Katharina Wustrau, Sophie Van Lancker, Musa Karakükçü, Amal Al-Seraihy, Robert Wynn, Samppa J. Ryhänen, Marleen Renard, Renata Formánková, Anna Villa, Jeroen Knippenberg, Carlos Pinho Vaz, Sarah Lawson, Natalia Maximova, Robert Chiesa, Jacek Winiarski, Irina Zaidman, Franco Locatelli, Patrick Gilbert, Bénedicte Bruno, Ingrid Furlan, Juliana Silva, Robbert Bredius, K. Suresh Rao, Т А Быкова, Persis Amrolia, Tariq Ghafoor, Zohreh Nademi
article en

Abstract

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.

BloodVol. 146(Supplement 1)
Medical University of Lublin (PL), Hôpital Necker-Enfants Malades (FR), Cliniques Universitaires Saint-Luc (BE), Izmir University (TR), Karolinska University Hospital (SE), University of Padua (IT), University of Trieste (IT), Vita-Salute San Raffaele University (IT), Inserm (FR), Iran University of Medical Sciences (IR), Rawalpindi Medical University (PK), Universität Ulm (DE), Akdeniz University (TR), Université Paris Cité (FR), Armed Forces Institute of Pathology (PK), Leeds Teaching Hospitals NHS Trust (GB), King Hussein Cancer Center (JO), First Pavlov State Medical University of St. Petersburg (RU), Sheba Medical Center (IL), Leiden University Medical Center (NL), Great Ormond Street Hospital (GB), Universitair Ziekenhuis Leuven (BE), Helsinki University Hospital (FI), Hospital Universitario La Paz (ES), King Faisal Specialist Hospital & Research Centre (SA), Ghent University Hospital (BE), Istituto Giannina Gaslini (IT), Children's Hospital at Westmead (AU), King Abdulaziz Medical City (SA), Copenhagen University Hospital (DK), LMU Klinikum (DE), Istanbul Yeni Yüzyıl University (TR), Jerusalem Multidisciplinary College (IL), Wroclaw Medical University (PL), Institut d’Hématologie et d’Oncologie Pédiatrique (FR), Institut de Cancérologie Strasbourg (FR), Helsinki Children's Hospital (FI), Lille’s Cardiology Hospital (FR), Manchester University NHS Foundation Trust (GB), Assistance Publique – Hôpitaux de Paris (FR), University Hospital in Motol (CZ), European Society for Blood and Marrow Transplantation (NL), Birmingham Children's Hospital (GB), Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia (IT), Sociedade Portuguesa de Cardiologia (PT), Ernst Abbe University of Applied Sciences Jena (DE), Schneider Children's Medical Center (IL), Antalya Eğitim ve Araştırma Hastanesi (TR), IPO Porto (PT), Hospital Infantil Universitario Niño Jesús (ES), Hacettepe University Hospital (TR), Institute of Genetic and Biomedical Research (IT), Jena Bioscience (Germany) (DE), Bambino Gesù Children's Hospital (IT), Kayseri Eğitim ve Araştırma Hastanesi (TR), Vall d'Hebron Hospital Universitari (ES), University Children's Hospital Zurich (CH), Willem-Alexander Kinderziekenhuis (NL), Jena University Hospital (DE), The San Raffaele Telethon Institute for Gene Therapy (IT), Policlinico San Matteo Fondazione (IT), University Hospital Ulm (DE), Technische Hochschule Ulm (DE), Antalya IVF (TR), Institut des Maladies Génétiques Imagine (FR), Altınbaş University (TR), University College London (GB), Tehran University of Medical Sciences (IR), Ludwig-Maximilians-Universität München (DE), Newcastle University (GB)
Openalex Percentile: Top 65%
Bone Metabolism and Diseases
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.