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Outcome of haematopoietic cell transplantation in children with lysosomal acid lipase deficiency: a study on behalf of the EBMT Inborn Errors Working Party

Bone Marrow Transplantation volume 58, pages 594–596 (2023)Cite this article

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Infantile onset lysosomal acid lipase deficiency (LALD), historically called Wolman disease, is a devastating lysosomal storage disease caused by a complete absence of functional LAL. It is a rare disorder with an estimated incidence of 1/300,000 newborns. The classical presentation is constellation of growth failure, diarrhoea, hepatosplenomegaly and adrenal calcification in first few weeks of life. A recent natural history study has described the rapidly progressive and fatal course of infantile LALD [1]. Without therapy, death typically occurs in the first 6 months of life, caused by growth failure and rapidly progressive hepatic disease. The pathology of the disease is lysosomal accumulation of cholesteryl esters and triglycerides throughout the body, predominantly in liver and macrophage-monocyte system, triggering an inflammatory cascade which is likely via inflammasome pathway leading to liver inflammation and activation of hepatic stellate cells [1, 2]. Haematopoietic cell transplantation (HCT) has demonstrated long-term clinical efficacy in infantile LALD by two mechanisms: (1) donor’s healthy macrophages repopulate recipient’s incompetent LAL deficient lipid laden, vacuolated macrophages; (2) cross-correction of metabolic defects with transferable enzymes from donor’s derived haematopoietic stem cells [3,4,5,6,7,8,9]. Exogenous enzyme replacement therapy (ERT) has been used for infants with LALD since 2012 [10]. The challenges of ERT are the development of antibodies that renders the therapy less effective, and the need for a life-long expensive therapy has a very significant health economic burden. The Inborn Errors Working Party of the European Society for Blood and Marrow Transplantation (EBMT) performed a retrospective registry study on the largest cohort of 24 children with LALD undergoing HCT between 1999 and 2019. Outcomes of interest were overall survival (OS), event-free survival (EFS; event was defined as death and graft failure), toxicity, graft-versus-host disease (GvHD) and long-term graft function and disease outcomes. Log-rank test was used to analyse predictors of OS. Variables included for predictor analysis were pre-transplant ERT, age at transplant, donor, stem cell source and conditioning (myeloablative (MAC) versus reduced toxicity conditioning (RCT)).

A detailed description of transplant characteristics is summarised in Tables S1 and S2. Median age at diagnosis was 1.6 months (range, 0–27.2 months) and median age at HCT was 3.5 months (1.0–48.0 months). Six (25%) had features of HLH prior to transplant, none in 16 patients (67%) and missing data in 2 patients. In 6 patients with known HLH features, 5 had cytopenia and splenomegaly, 2 had fever, 4 demonstrated haemaphagocytosis in marrow or spleen. Of 4 patients with available laboratory results, serum ferritin ranged 1080–6910 μg/L and triglycerides were mildly elevated in one patient and normal in three patients. Fibrinogen was normal in three patients with available result. Five (21%) received ERT. Donors were matched family donors (MFD) in 8 (33%), matched unrelated donor (MUD) in 6 (25%), mismatched unrelated donor in 4 (17%) and haploidentical donor in 4 (17%). Stem cell source was marrow (n = 8, 33%), PBSC (n = 2, 8%), ex vivo T-depleted PBSC (n = 4, 17%) and cord blood (CB, n = 9, 38%). Myeloablative conditioning was used in 11 (46%) and reduced toxicity/intensity was used in 13 (54%).

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Fig. 1: Transplant survival for infantile LALD.

Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Authors and Affiliations

  1. Children’s Hematopoietic Stem Cell Transplant Unit, Great North Children’s Hospital, Newcastle, UK

    Su Han Lum

  2. Translational and Clinical Research Institute, Newcastle University, Newcastle, UK

    Su Han Lum

  3. Sigmund Freud University, Vienna, Austria

    Milen Minkov

  4. Willink Unit, St Mary’s Hospital, Manchester, UK

    Simon A. Jones

  5. EBMT Leiden Study Unit, Leiden, the Netherlands

    Sheree Hazelaar & Tiarlan Sirait

  6. Royal Manchester Children’s Hospital, Manchester, UK

    Jane E. Potter & Robert Wynn

  7. Department of Bone Marrow Transplantation, Hadassah Hospital, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel

    Polina Stepensky

  8. CHU Grenoble Alpes, Université Grenoble Alpes, Grenoble, France

    Frederic Garban

  9. Department of Paediatrics, St. Anna Children’s Hospital, Medical University of Vienna, Vienna, Austria

    Herbert Pichler

  10. Schneider Children’s Medical Center of Israel, Petach-Tikva, Israel

    Jerry Stein

  11. Unit of Pediatric Hematology and Pediatric BMT, Gazi University School of Medicine, Ankara, Turkey

    Zuhre Kaya

  12. Department of Pediatrics, University Medical Center Ulm, Ulm, Germany

    Ansgar Schulz

  13. Department of Pediatric Oncology, Sahlgrenska University Hospital, Gothenburg i, Sweden

    Karin Mellgren

  14. Department of Pediatric Hematology and Oncology, Hospital Universitari Vall d’Hebron, Barcelona, Spain

    Cristina Diaz de Heredia

  15. Pediatric Onco-Hematology Department, Nancy University Hospital, Université de Lorraine, Vandoeuvre-les-Nancy, France

    Cecile Pochon

  16. Department of Pediatrics, Hospital Universitario de Salamanca, Salamanca, Spain

    Susana Riesco

  17. Niño Jesus Children’s Hospital, Madrid, Spain

    Miguel Angel Diaz

  18. La Timone Children’s Hospital and Aix-Marseille University, Marseille, France

    Gérard Michel

  19. Department of Pediatrics, University Medical Center, Utrecht, Utrecht, the Netherlands

    Caroline Lindemans

  20. Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands

    Caroline Lindemans

  21. Department of Pediatrics, Jena University Hospital, Jena, Germany

    Bernd Gruhn

  22. Dr. von Hauner University Children’s Hospital, Ludwig-Maximilians-Universität, Munich, Germany

    Michael H. Albert

  23. Willem-Alexander Children’s Hospital, Pediatric Stem Cell Transplantation program, Leiden University Medical Center, Leiden, the Netherlands

    Arjan C. Lankester

  24. Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Enfants Malades Hospital, Assistance Publique—Hôpitaux de Paris (APHP), Paris, France

    Bénédicte Neven

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  1. Su Han Lum
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Contributions

SHL developed the conceptualisation of the research, collected the data, performed the statistical analysis, interpreted the data, and prepared the paper. RW, MM, SAJ, ACL contributed to the conceptualisation of the research, paper writing and critical review at every level of the research stages. SH and TS collected the data and reviewed the paper. JEP, PS, FG, HP, JS, KZ, AS, KM, CDdeH, CP, SR, MAD, GM, CL, BG, MHA, BN contributed data and critically reviewed the paper.

Corresponding author

Correspondence to Robert Wynn.

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Competing interests

SAJ: investigator and consultant to Alexion; MHA: consulting fees from Orchard therapeutics. Other authors declare no competing interests.

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Lum, S.H., Minkov, M., Jones, S.A. et al. Outcome of haematopoietic cell transplantation in children with lysosomal acid lipase deficiency: a study on behalf of the EBMT Inborn Errors Working Party. Bone Marrow Transplant 58, 594–596 (2023). https://doi.org/10.1038/s41409-023-01918-4

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