Hematopoietic stem cell transplantation in 746 children with osteopetrosis: A study of the inborn errors working party of the EBMT
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.
Article Details
Authors (67)
Robert Chiesa
Great Ormond Street Hospital for Children NHS Trust, London
Michael H. Albert
10Department of Pediatric Hematology and Oncology, Dr. von Hauner Children’s University Hospital, Ludwig Maximilian University, Munich, Germany
Patrick Gilbert
30European Society of Blood and Marrow Transplantation, Leiden Study Unit, Leiden, The Netherlands
Jeroen Knippenberg
3EBMT Office, Leiden, Netherlands
Irina Zaidman
21Department of Pediatric Hematology Oncology, Hadassah Medical Center, Jerusalem, Israel
Hawazen Alsaedi
5King Faisal specialities hospital and research centre, Riyadh, Saudi Arabia
Fulvio Porta
6Pediatric Oncohaematology and BMT Unit Children' s Hospital Spedali Civili, Brescia, Italy
R.F. Wynn
1Paediatric Haematology and BMT department, Royal Manchester Children's Hospital, Manchester, United Kingdom
Rakefet Sidlik Muskatel
8Rakefet Sidlik Muskatel, Schneider Children's Medical Center of Israel, Petach-Tikva, Israel
Serap Aksoylar
9Ege University Pediatric BMT Centre, Izmir, Türkiye
Barış Kuşkonmaz
10Hacettepe University Children's Hospital, Ankara, Turkey, Ankara, Türkiye
Zohreh Nademi
11Bone Marrow Transplant Department, Newcastle, United Kingdom, Newcastle, United Kingdom
Sarah Lawson
12Birmingham Children's Hospital Birmingham, Birmingham, United Kingdom
Akif Yeşilipek
4Pediatric Stem Cell Transplantation Unit, Antalya Medical Park Hospital, Antalya, Turkey
Kerstin Felgentreff
14Department of pediatrics, University Medical Center Ulm, Ulm, Germany, Ulm, Germany
Marta Gonzalez Vicent
15Nino Jesus Children's Hospital, Madrid, Spain, Madrid, Spain
Juliana Silva
1Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
Tatyana Bykova
16RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, St. Petersburg, Russia, St. Petersburg, Russian Federation
O. Alphan Kupesiz
36Akdeniz University School of Medicine, Pediatric Hematology and Oncology, Antalya, Türkiye
Marco Zecca
Maura Faraci
13Institute G. Gaslini, Genova, Italy
Amir Hamidieh
20Children's Medical Centre/Tehran University of Medical Sciences, Tehran, Iran, Tehran, Iran
Mayada Abu Shanap
1King Hussein Cancer Center, Amman, Jordan
Etai Adam
22Division of Pediatric Hematology and Oncology, Sheba Medical Center, Tel Hashomer, Israel, Tel Hashomer, Israel
Tariq Ghafoor
9Armed Forces Bone Marrow Transplant Centre (AFBMTC), Rawalpindi, Pakistan
Musa Karakükcü
24Erciyes University, Faculty of Medicine, Kayseri, Turkey, Kayseri, Türkiye
Natalia Maximova
25Institute for Maternal and Child Health, Trieste, Italy, Trieste, Italy
Sophie van Lancker
26Ghent University Hospital, Gent, Belgium, Gent, Belgium
Catherine Paillard
5CHU Strasbourg, Strasbourg, France
Marleen Renard
17University Hospital Leuven, Leuven, Belgium
Franco Locatelli
IRCCS Ospedale Pediatrico Bambino Gesù Rome, Rome
Martin Castelle
Persis Amrolia
5Great Ormond Street Hospital for Children, London, United Kingdom
Srividhya Senthil
7Department of Bone Marrow Transplantation, Manchester University NHS Foundation Trust, Manchester, United Kingdom
Cécile Renard
2IHOPE, Lyon, France
Mohammed Essa
Richard A. and Susan F. Smith Center for Outcomes Research, Boston, Massachusetts, United States
Benedicte Bruno
33Unite d'Hematologie Pediatrique, Lille, France, Lille, France
Cristina Diaz-de-Heredia
18Department of Pediatric Hematology and Oncology, Hospital Universitari Vall d’Hebron, Vall d’Hebron Institut de Recerca, Barcelona, Spain
Ingrid Furlan
14Department of pediatrics, University Medical Center Ulm, Ulm, Germany, Ulm, Germany
Renata Formankova
35University Hospital Motol, Prague, Czechia, Prague, Czech Republic
Matthias Felber
1Department of Stem Cell Transplantation, University Children's Hospital, Zurich, Switzerland
Nuno Miranda
1Instituto Português de Oncologia de Lisboa Francisco Gentil, Hematology, Lisbon, Portugal
Kanchan Rao
26Department of Blood and Bone Marrow Transplantation, Great Ormond Street Hospital, London, United Kingdom
Baris Malbora
38İstanbul Yeni Yüzyil University, Gaziosmanpasa Hospital, İstanbul,Turkey, İstanbul, Türkiye
Jacek Winiarski
39Astrid Lindgren Childrens Hospital, Karolinska University Hospital, Huddinge, Stockholm Sweden, Stockholm, Sweden
Robbert Bredius
40Department of Pediatrics, Willem-Alexander Children's Hospital, Leiden University Medical Center, Leiden, The Netherlands, Leiden, Netherlands
Beki James
41Leeds Children's Hospital, Leeds Teaching Hospitals, Leeds., Leeds, United Kingdom
Jean-Sebastien Diana
Melek Erdem
42Altinbas University, Faculty of Medicine, Bahcelievler Medicalpark Hospital, Pediatric BMT Unit, Istanbul, Turkey, Istanbul, Türkiye
Amal Alseraihy
43MD king Faisal specialities hospital and research centre, Riyadh, Saudi Arabia
Melissa Gabriel
16The Children's Hospital at Westmead, Sydney, Australia
Bernd Gruhn
45University of Jena, Jena, Germany, Jena, Germany
Tania Masmas
46Pediatric hematopoietic stem cell transplantation and immunodeficiency, The Child and Adolescent Clinic, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark, Copenhagen, Denmark
Alessandra Biffi
Katarzyna Drabko
48Department of Pediatric Hematology, Oncology and Transplantology Medical University of Lublin, Poland, Lublin, Poland
Krzysztof Kalwak
14Department of Pediatric Bone Marrow Transplantation, Oncology, and Hematology, Wroclaw Medical University, Wroclaw, Poland
David Bueno
50Pediatric Hemato-Oncology University Hospital La Paz, Madrid, Spain, Madrid, Spain
Manfred Hoenig
51Department of pediatrics, University Medical Center Ulm, Ulm, Germany, Ulm, United Kingdom
Carlos Vaz
Katharina Wustrau
14Department of pediatrics, University Medical Center Ulm, Ulm, Germany, Ulm, Germany
Benedicte Brichard
53Department of Paediatric Haematology and Oncology, Cliniques Universitaires saint Luc, UClouvain, Brussels, Belgium, Brussels, Belgium
Samppa Ryhänen
54HUS Helsinki University Hospital, Children's Hospital, Division of Hematology, Oncology, and Stem Cell Transplantation, Helsinki, Finland
Anna Villa
Bénédicte Neven
Mehtap Sirin
14Department of pediatrics, University Medical Center Ulm, Ulm, Germany, Ulm, Germany
Despina Moshous
8Université Paris Cité, Pediatric Hematology-Immunology and Rheumatology Department, Necker-Enfants Malades Hospital, Paris, France, Paris, France
Ansgar Schulz
14Department of pediatrics, University Medical Center Ulm, Ulm, Germany, Ulm, Germany