Late effects after hematopoietic stem cell transplantation in patients with HLH: A Histiocyte Society, PDWP, IEWP, and TCWP EBMT Study - 25/10/25

Doi : 10.1016/j.jaci.2025.09.014

Kim Ramme, MD, PhD ^a,^{^{∗
These authors contributed equally to this work.}}, AnnaCarin Horne, MD, PhD ^b,^{^{∗
These authors contributed equally to this work.}}^⁎^⁎ , Karin Beutel, MD ^c, Jacques-Emmanuel Galimard, PhD ^d, Ali Abdallah Alahmari, MD ^e, Giorgio Ottaviano, MD ^f, Despina Moshous, MD, PhD ^g, Savas Kansoy, MD ^h, Zohreh Nademi, MD, PhD ⁱ, Maura Faraci, MD ^j, Mikael Sundin, MD, PhD ^k,^l, Franca Fagioli, MD ^m, Michael H. Albert, MD ⁿ, Petr Sedlacek, MD ^o, Yves Bertrand, MD, PhD ^p, Franco Locatelli, MD, PhD ^q, Catherine Paillard, MD ^r,^s, Karin Mellgren, MD, PhD ^t, Ingo Müller, MD ^u, Johann Greil, MD ^v, Adriana Balduzzi, MD ^w, Mary Slatter, MD, PhD ⁱ, Arnaud Dalissier, BSc ^x, Krzysztof Kalwak, MD, PhD ^y, Arjan Lankester, MD, PhD ^z, Benedicte Neven, MD, PhD ^g, K. Scott Baker, MD ^aa, Kanchan Rao, MD ^bb,^{^{∗
These authors contributed equally to this work.}}, Selim Corbacioglu, MD, PhD ^cc,^{^{∗
These authors contributed equally to this work.}}
^a Department of Pediatric Hematology and Oncology, Children’s Hospital, Uppsala University Hospital, Uppsala, Sweden
^b Department of Women’s and Children’s Health, Karolinska Institutet and Pediatric Rheumatology, Karolinska University Hospital, Stockholm, Sweden
^c Children’s Hospital München Schwabing, München Klinik and TUM University Hospital, Technical University of Munich, Munich, Germany
^d EBMT Statistical Unit, Sorbonne University, Saint-Antoine Hospital, AP-HP, INSERM UMRs 938, Paris, France
^e Department of Pediatric Hematology/Oncology, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
^f Blood and Bone Marrow Transplant Department, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
^g Unité d’Immunologie, Hématologie et Rhumatologie Pédiatriques (UIHR), Hôpital Necker-Enfants Malades, Paris, France
^h Ege University Pediatric BMT Centre, Izmir, Turkey
ⁱ Paediatric HSCT Unit, Great North Children’s Hospital, Newcastle upon Tyne, United Kingdom
^j HSCT Unit, Department of Hemato-Oncology, IRCCS Institute G. Gaslini, Genova, Italy
^k Section of Pediatric Hematology, Immunology and HCT, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden
^l Division of Pediatrics, CLINTEC, Karolinska Institutet, Stockholm, Sweden
^m Department of Pediatric Oncology and Hematology, Regina Margherita Children Hospital, University of Turin, Turin, Italy
ⁿ Department of Pediatrics, Dr von Hauner Children’s Hospital, University Hospital, LMU, Munich, Germany
^o Department of Paediatric Haematology and Oncology, University Hospital Motol, Prague, Czech Republic
^p Institut d`Hematologie et d`Oncologie Pediatrique, Unité de coordination interne et externe, Lyon, France
^q Department of Pediatric Hematology and Oncology IRRCS Ospedale Pediatrico Bambino Gesù, Rome, Italy
^r Department of Paediatric Haematology and Oncology, Strasbourg University Hospital, Strasbourg, France
^s Strasbourg University, INSERM, Strasbourg, France
^t Department of Pediatric Oncology, Queen Silvia Children Hospital/Sahlgrenska University Hospital, Goeteborg, Sweden
^u Division of Pediatric Stem Cell Transplantation and Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
^v University of Heidelberg, Heidelberg, Germany
^w Pediatric Department, Fondazione IRCCS San Gerardo dei Tintori and School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
^x EBMT Paris Study Unit, Sorbonne University, Saint-Antoine Hospital, AP-HP, INSERM UMRs 938, Paris, France
^y Clinical Department of Paediatric Bone Marrow Transplantation, Oncology and Haematology, Wroclaw Medical University, Wroclaw, Poland
^z Division of Pediatric Stem Cell Transplantation Willem-Alexander Children’s Hospital, Leiden University Medical Center, Leiden, The Netherlands
^aa Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, Wash
^bb Department of Bone Marrow Transplantation, Great Ormond Street Hospital NHS Foundation Trust, London, United Kingdom
^cc Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, University of Regensburg, Regensburg, Germany

^∗Corresponding author: AnnaCarin Horne, MD, PhD, Pediatric Rheumatology, C605, Karolinska University Hospital, Stockholm 171 76, Sweden.Pediatric RheumatologyC605Karolinska University HospitalStockholm171 76Sweden

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Abstract

Background

Hematopoietic stem cell transplantation (HCT) is the only curative treatment in primary hemophagocytic lymphohistiocytosis (pHLH). However, HCT is associated with a wide range of late effects (LEs).

Objective

We sought to characterize the long-term outcome and LEs following HCT in pHLH.

Methods

A total of 274 children with pHLH from the European Society for Blood and Marrow Transplantation registry who underwent allogeneic HCT between 2004 and 2015 were included. Multivariable logistic regression models were used to evaluate the adjusted impact of baseline variables on central nervous system and hormonal LEs, respectively.

Results

A broad spectrum of LEs was identified, with neurologic (31%) and hormonal (34.8%) complications being the most prevalent. Chemotherapy (HLH-1994/HLH-2004) before HCT was identified as a significant risk factor for endocrinological LEs (P = .03), highlighting a novel aspect not previously reported. The presence of neurologic abnormality at diagnosis was an independent risk factor for neurologic LEs (P < .001) as was incomplete remission status at the time of HCT (P = .04).

Conclusions

HCT has significantly improved survival in patients with pHLH. However, survivors still face significant risks of LEs.

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Key words : Primary hemophagocytic lymphohistiocytosis, familial hemophagocytic lymphohistiocytosis, hematopoietic stem cell transplantation, late effects

Abbreviations used : CNS, CR, CSF, EBMT, FHL, GvHD, HCT, HLH, LE, MAC, OR, OS, pHLH, sHLH, XLP1