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1. Rubella Virus Infected Macrophages and Neutrophils Define Patterns of Granulomatous Inflammation in Inborn and Acquired Errors of Immunity

Author

Ludmila Perelygina, Raeesa Faisthalab, Emily Abernathy, Min-hsin Chen, LiJuan Hao, Lionel Bercovitch, Diana K. Bayer, Lenora M. Noroski, Michael T. Lam, Maria Pia Cicalese, Waleed Al-Herz, Arti Nanda, Joud Hajjar, Koen Vanden Driessche, Shari Schroven, Julie Leysen, Misha Rosenbach, Philipp Peters, Johannes Raedler, Michael H. Albert, Roshini S. Abraham, Hemalatha G. Rangarjan, David Buchbinder, Lisa Kobrynski, Anne Pham-Huy, Julie Dhossche, Charlotte Cunningham Rundles, Anna K. Meyer, Amy Theos, T. Prescott Atkinson, Amy Musiek, Mehdi Adeli, Ute Derichs, Christoph Walz, Renate Krüger, Horst von Bernuth, Christoph Klein, Joseph Icenogle, Fabian Hauck, and Kathleen E. Sullivan

Subjects
inborn errors of immunity, primary immunodeficiency, vaccine-derived rubella viruses, granulomatous inflammation, skin lesion, neutrophils, Immunologic diseases. Allergy, RC581-607
Abstract

Rubella virus (RuV) has recently been found in association with granulomatous inflammation of the skin and several internal organs in patients with inborn errors of immunity (IEI). The cellular tropism and molecular mechanisms of RuV persistence and pathogenesis in select immunocompromised hosts are not clear. We provide clinical, immunological, virological, and histological data on a cohort of 28 patients with a broad spectrum of IEI and RuV-associated granulomas in skin and nine extracutaneous tissues to further delineate this relationship. Combined immunodeficiency was the most frequent diagnosis (67.8%) among patients. Patients with previously undocumented conditions, i.e., humoral immunodeficiencies, a secondary immunodeficiency, and a defect of innate immunity were identified as being susceptible to RuV-associated granulomas. Hematopoietic cell transplantation was the most successful treatment in this case series resulting in granuloma resolution; steroids, and TNF-α and IL-1R inhibitors were moderately effective. In addition to M2 macrophages, neutrophils were identified by immunohistochemical analysis as a novel cell type infected with RuV. Four patterns of RuV-associated granulomatous inflammation were classified based on the structural organization of granulomas and identity and location of cell types harboring RuV antigen. Identification of conditions that increase susceptibility to RuV-associated granulomas combined with structural characterization of the granulomas may lead to a better understanding of the pathogenesis of RuV-associated granulomas and discover new targets for therapeutic interventions.

Published
2021
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2. Wiskott-Aldrich Syndrome (WAS) and Dedicator of Cytokinesis 8- (DOCK8) Deficiency

Author

Michael H. Albert and Alexandra F. Freeman

Subjects
HSCT, Wiskott-Aldrich syndrome (WAS), DOCK8 deficiency, eczema, infection, Pediatrics, RJ1-570
Abstract

Both Wiskott-Aldrich syndrome (WAS) and dedicator of cytokinesis 8 (DOCK8) deficiency are primary immunodeficiency diseases caused by mutations in genes that result in defective organization of the cytoskeleton in hematopoietic tissues. They share some overlapping features such as a combined immunodeficiency, eczema and a predisposition to autoimmunity and malignancy, but also have some unique features that make them relatively easy to diagnose by clinical means. Both diseases can be cured by HSCT in a large proportion of patients. In WAS it is sometimes difficult to establish an indication for HSCT due to the large variability of disease severity, while HSCT is probably indicated in all patients affected by DOCK8 deficiency. There is considerably more published HSCT experience for WAS than for DOCK8 deficiency, but many open questions remain, which will be discussed in this review.

Published
2019
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4. Allogeneic HSCT in Adolescents and Young Adults With Primary Immunodeficiencies

Author

Emma C. Morris and Michael H. Albert

Subjects
primary immunodeficiencies, PID, allogeneic hematopoietic stem cell transplantation, Allo HSCT, adolescents and young adults (AYAs), Pediatrics, RJ1-570
Abstract

Significant advances in hematopoietic transplantation over the past 20 years, have facilitated the safe transplantation of older adults with higher co-morbidities. In pediatric practice these advances have simultaneously improved outcomes for sicker children with complex, rare diseases including the primary immunodeficiencies, PID. With more widespread adoption of genetic sequencing, older patients with disease-causing mutations restricted to the hematopoietic system can be identified who may benefit from allogeneic hematopoietic stem cell transplantation (Allo-HSCT). Here we discuss the evidence for Allo-HSCT in adolescent and younger adults (AYAs) with PID.

Published
2019
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5. Hematopoietic Stem Cell Transplantation for Primary Immunodeficiencies

Author

Andrew R. Gennery, Michael H. Albert, Mary A. Slatter, and Arjan Lankester

Subjects
primary immunodeficiency, severe combined immnunodeficiency, Wiskott Aldrich syndrome, chronic granulomatous disease, conditioning, Pediatrics, RJ1-570
Abstract

The field of primary immunodeficiencies has pioneered many of the advances in haematopoietic stem cell transplantation and cellular therapies over the last 50 years. The first patients to demonstrate sustained benefit and prolonged cure from the primary genetic defect following allogeneic haematopoietic stem cell transplantation were patients with primary immunodeficiencies. Although primary immunodeficiency patients began the modern era of haematopoietic stem cell transplantation, the history is nevertheless short-in answer to the question “what is the long term outcome of patients transplanted for primary immunodeficiencies?” we often have to say that we do not know. We believe that most patients who undergo haematopoietic stem cell transplantation for primary immunodeficiencies should live a normal lifespan with a fully corrected immune system. We are now beginning to understanding long term outcomes, the relationship to the underlying genetic defect, age, and pre-morbid condition of the patient at time of transplantation, stem cell source and donor, and effect of pre-transplant cytoreductive chemotherapy conditioning. The long term consequences of post-transplant complications such as graft vs. host disease, veno-occlusive disease, or immune dysregulation are also being recognized. Additionally, some genetic defects have a systemic distribution, and we are learning the natural history of these defects once the immunodeficiency has been removed.

Published
2019
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6. The German National Registry of Primary Immunodeficiencies (2012–2017)

Author

Sabine M. El-Helou, Anika-Kerstin Biegner, Sebastian Bode, Stephan R. Ehl, Maximilian Heeg, Maria E. Maccari, Henrike Ritterbusch, Carsten Speckmann, Stephan Rusch, Raphael Scheible, Klaus Warnatz, Faranaz Atschekzei, Renata Beider, Diana Ernst, Stev Gerschmann, Alexandra Jablonka, Gudrun Mielke, Reinhold E. Schmidt, Gesine Schürmann, Georgios Sogkas, Ulrich H. Baumann, Christian Klemann, Dorothee Viemann, Horst von Bernuth, Renate Krüger, Leif G. Hanitsch, Carmen M. Scheibenbogen, Kirsten Wittke, Michael H. Albert, Anna Eichinger, Fabian Hauck, Christoph Klein, Anita Rack-Hoch, Franz M. Sollinger, Anne Avila, Michael Borte, Stephan Borte, Maria Fasshauer, Anja Hauenherm, Nils Kellner, Anna H. Müller, Anett Ülzen, Peter Bader, Shahrzad Bakhtiar, Jae-Yun Lee, Ursula Heß, Ralf Schubert, Sandra Wölke, Stefan Zielen, Sujal Ghosh, Hans-Juergen Laws, Jennifer Neubert, Prasad T. Oommen, Manfred Hönig, Ansgar Schulz, Sandra Steinmann, Klaus Schwarz, Gregor Dückers, Beate Lamers, Vanessa Langemeyer, Tim Niehues, Sonu Shai, Dagmar Graf, Carmen Müglich, Marc T. Schmalzing, Eva C. Schwaneck, Hans-Peter Tony, Johannes Dirks, Gabriele Haase, Johannes G. Liese, Henner Morbach, Dirk Foell, Antje Hellige, Helmut Wittkowski, Katja Masjosthusmann, Michael Mohr, Linda Geberzahn, Christian M. Hedrich, Christiane Müller, Angela Rösen-Wolff, Joachim Roesler, Antje Zimmermann, Uta Behrends, Nikolaus Rieber, Uwe Schauer, Rupert Handgretinger, Ursula Holzer, Jörg Henes, Lothar Kanz, Christoph Boesecke, Jürgen K. Rockstroh, Carolynne Schwarze-Zander, Jan-Christian Wasmuth, Dagmar Dilloo, Brigitte Hülsmann, Stefan Schönberger, Stefan Schreiber, Rainald Zeuner, Tobias Ankermann, Philipp von Bismarck, Hans-Iko Huppertz, Petra Kaiser-Labusch, Johann Greil, Donate Jakoby, Andreas E. Kulozik, Markus Metzler, Nora Naumann-Bartsch, Bettina Sobik, Norbert Graf, Sabine Heine, Robin Kobbe, Kai Lehmberg, Ingo Müller, Friedrich Herrmann, Gerd Horneff, Ariane Klein, Joachim Peitz, Nadine Schmidt, Stefan Bielack, Ute Groß-Wieltsch, Carl F. Classen, Jessica Klasen, Peter Deutz, Dirk Kamitz, Lisa Lassay, Klaus Tenbrock, Norbert Wagner, Benedikt Bernbeck, Bastian Brummel, Eusebia Lara-Villacanas, Esther Münstermann, Dominik T. Schneider, Nadine Tietsch, Marco Westkemper, Michael Weiß, Christof Kramm, Ingrid Kühnle, Silke Kullmann, Hermann Girschick, Christof Specker, Elisabeth Vinnemeier-Laubenthal, Henriette Haenicke, Claudia Schulz, Lothar Schweigerer, Thomas G. Müller, Martina Stiefel, Bernd H. Belohradsky, Veronika Soetedjo, Gerhard Kindle, and Bodo Grimbacher

Subjects
registry for primary immunodeficiency, primary immunodeficiency (PID), German PID-NET registry, PID prevalence, European Society for Immunodeficiencies (ESID), IgG substitution therapy, Immunologic diseases. Allergy, RC581-607
Abstract

Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs.Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel.Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1–25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0–88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%—subcutaneous; 29%—intravenous; 1%—unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy.Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment.

Published
2019
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7. The Phenotype and Treatment of WIP Deficiency: Literature Synopsis and Review of a Patient With Pre-transplant Serial Donor Lymphocyte Infusions to Eliminate CMV

Author

Wolfgang Schwinger, Christian Urban, Raphael Ulreich, Daniela Sperl, Anna Karastaneva, Volker Strenger, Herwig Lackner, Kaan Boztug, Michael H. Albert, Martin Benesch, and Markus G. Seidel

Subjects
Wiskott-Aldrich syndrome protein-interacting protein (WIP), primary immunodeficiency (PID), Wiskott-Aldrich syndrome (WAS), hematopoietic stem cell transplantation (HSCT), donor lymphocyte infusions (DLI), combined immunodeficiency (CID) with syndromic features, Immunologic diseases. Allergy, RC581-607
Abstract

Early diagnosis of primary immunodeficiency disorders (PID) is vital and allows directed treatment, especially in syndromes with severe or profound combined immunodeficiency. In PID patients with perinatal CMV or other opportunistic, invasive infections (e.g., Pneumocystis or Aspergillus), multi-organ morbidity may already arise within the first months of life, before hematopoietic stem cell transplantation (HSCT) or gene therapy can be undertaken, compromising the definitive treatment and outcome. Deficiency of Wiskott-Aldrich syndrome (WAS) protein-interacting protein (WIP deficiency) causes an autosomal recessive, WAS-like syndrome with early-onset combined immunodeficiency that has been described in three pedigrees to date. While WAS typically includes combined immunodeficiency, microthrombocytopenia, and eczema, the clinical and laboratory phenotypes of WIP-deficient patients–including lymphocyte subsets, platelets, lymphocyte proliferation in vitro, and IgE—varied widely and did not entirely recapitulate WAS, impeding early diagnosis in the reported patients. To elucidate the phenotype of WIP deficiency, we provide a comprehensive synopsis of clinical and laboratory features of all hitherto-described patients (n = 6) and WIP negative mice. Furthermore, we summarize the treatment modalities and outcomes of these patients and review in detail the course of one of them who was successfully treated with serial, unconditioned, maternal, HLA-identical donor lymphocyte infusions (DLI) against life-threatening, invasive CMV infection, followed by a TCRαβ/CD19-depleted, treosulfan/melphalan-conditioned, peripheral blood HSCT and repetitive, secondary-prophylactic, CMV-specific DLI with 1-year post-HSCT follow-up. This strategy could be useful in other patients with substantial premorbidity, considered “too bad to transplant,” who have an HLA-identical family donor, to eliminate infections and bridge until definitive treatment.

Published
2018
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8. The Complexity of Pattern Matching for $321$-Avoiding and Skew-Merged Permutations

Author

Michael H. Albert, Marie-Louise Lackner, Martin Lackner, and Vincent Vatter

Subjects
mathematics - combinatorics, computer science - data structures and algorithms, 05a05, 68q25, Mathematics, QA1-939
Abstract

The Permutation Pattern Matching problem, asking whether a pattern permutation $\pi$ is contained in a permutation $\tau$, is known to be NP-complete. In this paper we present two polynomial time algorithms for special cases. The first algorithm is applicable if both $\pi$ and $\tau$ are $321$-avoiding; the second is applicable if $\pi$ and $\tau$ are skew-merged. Both algorithms have a runtime of $O(kn)$, where $k$ is the length of $\pi$ and $n$ the length of $\tau$.

Published
2016
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9. Risk assessment of relapse by lineage-specific monitoring of chimerism in children undergoing allogeneic stem cell transplantation for acute lymphoblastic leukemia

Author

Sandra Preuner, Christina Peters, Ulrike Pötschger, Helga Daxberger, Gerhard Fritsch, Rene Geyeregger, André Schrauder, Arend von Stackelberg, Martin Schrappe, Peter Bader, Wolfram Ebell, Cornelia Eckert, Peter Lang, Karl-Walter Sykora, Johanna Schrum, Bernhard Kremens, Karoline Ehlert, Michael H. Albert, Roland Meisel, Anita Lawitschka, Georg Mann, Renate Panzer-Grümayer, Tayfun Güngör, Wolfgang Holter, Brigitte Strahm, Bernd Gruhn, Ansgar Schulz, Wilhelm Woessmann, and Thomas Lion

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Allogeneic hematopoietic stem cell transplantation is required as rescue therapy in about 20% of pediatric patients with acute lymphoblastic leukemia. However, the relapse rates are considerable, and relapse confers a poor outcome. Early assessment of the risk of relapse is therefore of paramount importance for the development of appropriate measures. We used the EuroChimerism approach to investigate the potential impact of lineage-specific chimerism testing for relapse-risk analysis in 162 pediatric patients with acute lymphoblastic leukemia after allogeneic stem cell transplantation in a multicenter study based on standardized transplantation protocols. Within a median observation time of 4.5 years, relapses have occurred in 41/162 patients at a median of 0.6 years after transplantation (range, 0.13–5.7 years). Prospective screening at defined consecutive time points revealed that reappearance of recipient-derived cells within the CD34+ and CD8+ cell subsets display the most significant association with the occurrence of relapses with hazard ratios of 5.2 (P=0.003) and 2.8 (P=0.008), respectively. The appearance of recipient cells after a period of pure donor chimerism in the CD34+ and CD8+ leukocyte subsets revealed dynamics indicative of a significantly elevated risk of relapse or imminent disease recurrence. Assessment of chimerism within these lineages can therefore provide complementary information for further diagnostic and, potentially, therapeutic purposes aiming at the prevention of overt relapse. This study was registered at clinical.trials.gov with the number NC01423747.

Published
2016
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10. Treosulfan-based conditioning regimen for children and adolescents with hemophagocytic lymphohistiocytosis

Author

Kai Lehmberg, Michael H. Albert, Rita Beier, Karin Beutel, Bernd Gruhn, Nicolaus Kröger, Roland Meisel, Ansgar Schulz, Daniel Stachel, Wilhelm Woessmann, Gritta Janka, and Ingo Müller

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

In hematopoietic stem cell transplantation for hemophagocytic lymphohistiocytosis, high transplant-related mortality after busulfan-based myeloablative regimens has been observed. Conditioning regimens with reduced toxicity based on melphalan or treosulfan are promising alternatives. We retrospectively analyzed hematopoietic stem cell transplantations in 19 hemophagocytic lymphohistiocytosis patients after conditioning with fludarabine, treosulfan, alemtuzumab, with or without thiotepa. Overall and disease-free survivals were 100% (follow up 7–31 months). Two patients required second transplant (1 after haploidentical transplantation). In 6 patients, overall donor chimerism dropped below 75% and prompted donor lymphocyte infusions. Administration of donor lymphocytes or second transplantation were significantly more frequent after transplantation from a human leukocyte antigen mismatched (9/10) versus matched (10/10) donor (P=0.018). The toxicity profile was favorable, with one veno-occlusive disease, one grade 3 graft-versus-host disease after donor lymphocyte infusion, and 2 severe viral infections (1 influenza, 1 Epstein Barr virus). In conclusion, the treosulfan-based regimen in hemophagocytic lymphohistiocytosis is effective with low toxicity and gives excellent overall and disease-free survival rates. In the future, the incidence of mixed chimerism, particularly after human leukocyte antigen mismatched donor transplants, needs to be addressed.

Published
2014
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16. Hematopoietic stem cell transplantation for adolescents and adults with inborn errors of immunity: an EBMT IEWP study

Author

Michael H. Albert, Tiarlan Sirait, Dirk-Jan Eikema, Katerina Bakunina, Claudia Wehr, Felipe Suarez, Maria Laura Fox, Nizar Mahlaoui, Andrew R. Gennery, Arjan C. Lankester, Rita Beier, Maria Ester Bernardo, Venetia Bigley, Caroline A. Lindemans, Siobhan O. Burns, Ben Carpenter, Jaroslaw Dybko, Tayfun Güngör, Fabian Hauck, Su Han Lum, Dmitry Balashov, Roland Meisel, Despina Moshous, Ansgar Schulz, Carsten Speckmann, Mary A. Slatter, Brigitte Strahm, Duygu Uckan-Cetinkaya, Isabelle Meyts, Tanja C. Vallée, Robert Wynn, Bénédicte Neven, Emma C. Morris, Alessandro Aiuti, Alexei Maschan, Mahmoud Aljurf, Tobias Gedde-Dahl, Gunhan Gurman, Victoria Bordon, Gergely Kriván, Franco Locatelli, Fulvio Porta, David Valcárcel, Yves Beguin, Maura Faraci, Nicolaus Kröger, Aleksandr Kulagin, Peter J. Shaw, Joan Hendrik Veelken, Cristina Diaz de Heredia, Franca Fagioli, Matthias Felber, Bernd Gruhn, Wolfgang Holter, Claudia Rössig, Petr Sedlacek, Jane Apperley, Mouhab Ayas, Ivana Bodova, Goda Choi, J.J. Cornelissen, Anne Sirvent, Anjum Khan, Alphan Kupesiz, Stig Lenhoff, Hakan Ozdogu, Nicolas von der Weid, Montserrat Rovira, Rik Schots, Donald C. Vinh, Clinical sciences, and Hematology

Subjects
Adult, Adolescent, adolescenti, Trapianto, Immunology, Graft vs Host Disease, Biochemistry, Bronchiectasis/etiology, Humans, Transplantation, Homologous, Hematopoietic Stem Cell Transplantation/adverse effects, Child, Retrospective Studies, cellule staminali ematopoietiche, Hematopoietic Stem Cell Transplantation, Infant, Trapianto, cellule staminali ematopoietiche, adolescenti, Inborn errors of immunity, Cell Biology, Hematology, Middle Aged, Bronchiectasis, surgical procedures, operative, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, HSCT, young adult
Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) is the gold standard curative therapy for infants and children with many inborn errors of immunity (IEI), but adolescents and adults with IEI are rarely referred for transplant. Lack of published HSCT outcome data outside small, single-center studies and perceived high risk of transplant-related mortality have delayed the adoption of HSCT for IEI patients presenting or developing significant organ damage later in life. This large retrospective, multicenter HSCT outcome study reports on 329 IEI patients (age range, 15-62.5 years at HSCT). Patients underwent first HSCT between 2000 and 2019. Primary endpoints were overall survival (OS) and event-free survival (EFS). We also evaluated the influence of IEI-subgroup and IEI-specific risk factors at HSCT, including infections, bronchiectasis, colitis, malignancy, inflammatory lung disease, splenectomy, hepatic dysfunction, and systemic immunosuppression. At a median follow-up of 44.3 months, the estimated OS at 1 and 5 years post-HSCT for all patients was 78% and 71%, and EFS was 65% and 62%, respectively, with low rates of severe acute (8%) or extensive chronic (7%) graft-versus-host disease. On univariate analysis, OS and EFS were inferior in patients with primary antibody deficiency, bronchiectasis, prior splenectomy, hepatic comorbidity, and higher hematopoietic cell transplant comorbidity index scores. On multivariable analysis, EFS was inferior in those with a higher number of IEI-associated complications. Neither age nor donor had a significant effect on OS or EFS. We have identified age-independent risk factors for adverse outcome, providing much needed evidence to identify which patients are most likely to benefit from HSCT. ispartof: BLOOD vol:140 issue:14 pages:1635-1649 ispartof: location:United States status: published

Published
2022

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

Author

Su Han Lum, Milen Minkov, Simon A. Jones, Sheree Hazelaar, Tiarlan Sirait, Jane E. Potter, Polina Stepensky, Frederic Garban, Herbert Pichler, Jerry Stein, Zuhre Kaya, Ansgar Schulz, Karin Mellgren, Cristina Diaz de Heredia, Cecile Pochon, Susana Riesco, Miguel Angel Diaz, Gérard Michel, Caroline Lindemans, Bernd Gruhn, Michael H. Albert, Arjan C. Lankester, Bénédicte Neven, and Robert Wynn

Subjects
Transplantation, Hematology
Published
2023

21. Supplementary figure 2 from Hematopoietic Stem Cell Transplantation Positively Affects the Natural History of Cancer in Nijmegen Breakage Syndrome

Author

Wojciech Mlynarski, Krystyna Chrzanowska, Hanna Gregorek, Bendik Lund, Jochen Buechner, Johann Greil, Alexandra Kreins, Ewa Wiesik-Szewczyk, Agnieszka Tomaszewska, Sara S. Kilic, Markus G. Seidel, Peter Svec, Mary Eapen, Dmitry Balashov, Michael H. Albert, Sujal Ghosh, Karl-Walter Sykora, Andrew R. Gennery, Eva Hlavackova, Zdenka Krenova, Larysa Kostyuchenko, Elena Deripapa, Natalia Miakova, Alina Fedorova, Jan Styczynski, Jolanta Gozdzik, Sylwia Koltan, Monika Lejman, Katarzyna Drabko, Anna Pieczonka, Marek Ussowicz, Krzysztof Kałwak, Barbara Pietrucha, Barbara Piątosa, Edyta Heropolitanska-Pliszka, Bozena Dembowska-Baginska, Anna Wakulinska, Wojciech Fendler, Agata Pastorczak, and Beata Wolska-Kusnierz

Abstract

Overall survival of patients with Nijmegen breakage syndrome depending on the time when they were treated due to malignancies: before and after 2000 year.

Published
2023

22. Supplementary figure 1 from Hematopoietic Stem Cell Transplantation Positively Affects the Natural History of Cancer in Nijmegen Breakage Syndrome

Author

Wojciech Mlynarski, Krystyna Chrzanowska, Hanna Gregorek, Bendik Lund, Jochen Buechner, Johann Greil, Alexandra Kreins, Ewa Wiesik-Szewczyk, Agnieszka Tomaszewska, Sara S. Kilic, Markus G. Seidel, Peter Svec, Mary Eapen, Dmitry Balashov, Michael H. Albert, Sujal Ghosh, Karl-Walter Sykora, Andrew R. Gennery, Eva Hlavackova, Zdenka Krenova, Larysa Kostyuchenko, Elena Deripapa, Natalia Miakova, Alina Fedorova, Jan Styczynski, Jolanta Gozdzik, Sylwia Koltan, Monika Lejman, Katarzyna Drabko, Anna Pieczonka, Marek Ussowicz, Krzysztof Kałwak, Barbara Pietrucha, Barbara Piątosa, Edyta Heropolitanska-Pliszka, Bozena Dembowska-Baginska, Anna Wakulinska, Wojciech Fendler, Agata Pastorczak, and Beata Wolska-Kusnierz

Abstract

The dynamics of primary cancer incidence among patients with NBS described using the three-stage joint-point model.

Published
2023

23. Supplementary Figure 3 from Hematopoietic Stem Cell Transplantation Positively Affects the Natural History of Cancer in Nijmegen Breakage Syndrome

Author

Wojciech Mlynarski, Krystyna Chrzanowska, Hanna Gregorek, Bendik Lund, Jochen Buechner, Johann Greil, Alexandra Kreins, Ewa Wiesik-Szewczyk, Agnieszka Tomaszewska, Sara S. Kilic, Markus G. Seidel, Peter Svec, Mary Eapen, Dmitry Balashov, Michael H. Albert, Sujal Ghosh, Karl-Walter Sykora, Andrew R. Gennery, Eva Hlavackova, Zdenka Krenova, Larysa Kostyuchenko, Elena Deripapa, Natalia Miakova, Alina Fedorova, Jan Styczynski, Jolanta Gozdzik, Sylwia Koltan, Monika Lejman, Katarzyna Drabko, Anna Pieczonka, Marek Ussowicz, Krzysztof Kałwak, Barbara Pietrucha, Barbara Piątosa, Edyta Heropolitanska-Pliszka, Bozena Dembowska-Baginska, Anna Wakulinska, Wojciech Fendler, Agata Pastorczak, and Beata Wolska-Kusnierz

Abstract

Overall survival of patients with Nijmegen breakage syndrome after cancer diagnosis. Patients who underwent HSCT were marked with an asterix.

Published
2023

24. Supplementary Data legend from Hematopoietic Stem Cell Transplantation Positively Affects the Natural History of Cancer in Nijmegen Breakage Syndrome

Author

Wojciech Mlynarski, Krystyna Chrzanowska, Hanna Gregorek, Bendik Lund, Jochen Buechner, Johann Greil, Alexandra Kreins, Ewa Wiesik-Szewczyk, Agnieszka Tomaszewska, Sara S. Kilic, Markus G. Seidel, Peter Svec, Mary Eapen, Dmitry Balashov, Michael H. Albert, Sujal Ghosh, Karl-Walter Sykora, Andrew R. Gennery, Eva Hlavackova, Zdenka Krenova, Larysa Kostyuchenko, Elena Deripapa, Natalia Miakova, Alina Fedorova, Jan Styczynski, Jolanta Gozdzik, Sylwia Koltan, Monika Lejman, Katarzyna Drabko, Anna Pieczonka, Marek Ussowicz, Krzysztof Kałwak, Barbara Pietrucha, Barbara Piątosa, Edyta Heropolitanska-Pliszka, Bozena Dembowska-Baginska, Anna Wakulinska, Wojciech Fendler, Agata Pastorczak, and Beata Wolska-Kusnierz

Abstract

Supplementary Data legend

Published
2023

25. Supplementary Table 1 from Hematopoietic Stem Cell Transplantation Positively Affects the Natural History of Cancer in Nijmegen Breakage Syndrome

Author

Wojciech Mlynarski, Krystyna Chrzanowska, Hanna Gregorek, Bendik Lund, Jochen Buechner, Johann Greil, Alexandra Kreins, Ewa Wiesik-Szewczyk, Agnieszka Tomaszewska, Sara S. Kilic, Markus G. Seidel, Peter Svec, Mary Eapen, Dmitry Balashov, Michael H. Albert, Sujal Ghosh, Karl-Walter Sykora, Andrew R. Gennery, Eva Hlavackova, Zdenka Krenova, Larysa Kostyuchenko, Elena Deripapa, Natalia Miakova, Alina Fedorova, Jan Styczynski, Jolanta Gozdzik, Sylwia Koltan, Monika Lejman, Katarzyna Drabko, Anna Pieczonka, Marek Ussowicz, Krzysztof Kałwak, Barbara Pietrucha, Barbara Piątosa, Edyta Heropolitanska-Pliszka, Bozena Dembowska-Baginska, Anna Wakulinska, Wojciech Fendler, Agata Pastorczak, and Beata Wolska-Kusnierz

Abstract

Supplementary Table 1

Published
2023

26. Prospective Newborn Screening for SCID in Germany: A First Analysis by the Pediatric Immunology Working Group (API)

Author

Carsten Speckmann, Uta Nennstiel, Manfred Hönig, Michael H. Albert, Sujal Ghosh, Catharina Schuetz, Inken Brockow, Friederike Hörster, Tim Niehues, Stephan Ehl, Volker Wahn, Stephan Borte, Kai Lehmberg, Ulrich Baumann, Rita Beier, Renate Krüger, Shahrzad Bakhtiar, Joern-Sven Kuehl, Christian Klemann, Udo Kontny, Ursula Holzer, Andrea Meinhardt, Henner Morbach, Nora Naumann-Bartsch, Tobias Rothoeft, Alexandra Y. Kreins, E. Graham Davies, Dominik T. Schneider, Horst v. Bernuth, Thomas Klingebiel, Georg F. Hoffmann, Ansgar Schulz, and Fabian Hauck

Subjects
Immunology, Immunology and Allergy
Abstract

Backgr ound T-cell receptor excision circle (TREC)-based newborn screening (NBS) for severe combined immunodeficiencies (SCID) was introduced in Germany in August 2019. Methods Children with abnormal TREC-NBS were referred to a newly established network of Combined Immunodeficiency (CID) Clinics and Centers. The Working Group for Pediatric Immunology (API) and German Society for Newborn Screening (DGNS) performed 6-monthly surveys to assess the TREC-NBS process after 2.5 years. Results Among 1.9 million screened newborns, 88 patients with congenital T-cell lymphocytopenia were identified (25 SCID, 17 leaky SCID/Omenn syndrome (OS)/idiopathic T-cell lymphocytopenia, and 46 syndromic disorders). A genetic diagnosis was established in 88%. Twenty-six patients underwent hematopoietic stem cell transplantation (HSCT), 23/26 within 4 months of life. Of these, 25/26 (96%) were alive at last follow-up. Two patients presented with in utero onset OS and died after birth. Five patients with syndromic disorders underwent thymus transplantation. Eight syndromic patients deceased, all from non-immunological complications. TREC-NBS missed one patient, who later presented clinically, and one tracking failure occurred after an inconclusive screening result. Conclusion The German TREC-NBS represents the largest European SCID screening at this point. The incidence of SCID/leaky SCID/OS in Germany is approximately 1:54,000, very similar to previous observations from North American and European regions and countries where TREC-NBS was implemented. The newly founded API-CID network facilitates tracking and treatment of identified patients. Short-term HSCT outcome was excellent, but NBS and transplant registries will remain essential to evaluate the long-term outcome and to compare results across the rising numbers of TREC-NBS programs across Europe.

Published
2023

30. Allogeneic hematopoietic stem cell transplantation for adult HLH: a retrospective study by the chronic malignancies and inborn errors working parties of EBMT

Author

Rafal Machowicz, Felipe Suarez, Wieslaw Wiktor-Jedrzejczak, Diderik-Jan Eikema, Liesbeth C. de Wreede, Henric-Jan Blok, Cecilia Isaksson, Hermann Einsele, Xavier Poiré, Suzanne van Dorp, Emmanouil Nikolousis, Jan-Erik Johansson, Guido Kobbe, Marco Zecca, Renate Arnold, Armin Gerbitz, Jürgen Finke, Jose Luis Díez-Martín, Francesca Bonifazi, Grant McQuaker, Stig Lenhoff, Pierre-Simon Rohrlich, Matthias Theobald, Per Ljungman, Matthew Collin, Michael H. Albert, Gerhard Ehninger, Kristina Carlson, Kazimierz Halaburda, Kai Lehmberg, Stefan Schönland, Ibrahim Yakoub-Agha, Andrew R. Gennery, Arjan C. Lankester, Nicolaus Kröger, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre du cancer, and UCL - (SLuc) Service d'hématologie

Subjects
Adult, Cancer development and immune defence Radboud Institute for Health Sciences [Radboudumc 2], Transplantation, Transplantation Conditioning, Child, Preschool, Neoplasms, Hematopoietic Stem Cell Transplantation, Graft vs Host Disease, Humans, Hematology, Lymphohistiocytosis, Hemophagocytic, Retrospective Studies
Abstract

Contains fulltext : 251601.pdf (Publisher’s version ) (Closed access) Hemophagocytic lymphohistiocytosis (HLH; hemophagocytic syndrome) is a rare syndrome of potentially fatal, uncontrolled hyperinflammation. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is indicated in primary, recurrent or progressive HLH, but information about its outcomes in the adult population is limited. We obtained data about 87 adult (≥18 years of age) patients retrospectively reported to the EBMT. The median survival time was 13.9 months. The three and five-year overall survival (OS) was 44% (95% CI 33-54%). Among 39 patients with a follow-up longer than 15 months, only three died. Relapse rate was 21% (95% CI 13-30%), while NRM reached 36% (95% CI 25-46%). Younger patients (

Published
2022

32. Pulmonary alveolar proteinosis due to heterozygous mutation in OAS1 : Whole lung lavages for long‐term bridging to hematopoietic stem cell transplantation

Author

Dirk Schramm, Carola Schön, Michael H. Albert, Matthias Kappler, Matthias Griese, Simone Reu-Hofer, Elias Seidl, Fabian Hauck, Karl Reiter, and Ingo Pawlita

Subjects
Pulmonary and Respiratory Medicine, medicine.medical_specialty, medicine.medical_treatment, Hematopoietic stem cell transplantation, Pulmonary Alveolar Proteinosis, Bronchoalveolar Lavage, Gastroenterology, Hypogammaglobulinemia, Internal medicine, 2',5'-Oligoadenylate Synthetase, medicine, Humans, Lung, Heterozygous mutation, biology, business.industry, Hematopoietic Stem Cell Transplantation, Clinical course, Infant, medicine.disease, medicine.anatomical_structure, Child, Preschool, Mutation, Pediatrics, Perinatology and Child Health, biology.protein, Etiology, Female, Antibody, Pulmonary alveolar proteinosis, business
Abstract

Introduction Pulmonary alveolar proteinosis (PAP) is defined by increased accumulation of surfactant in the alveolar space. PAP has been reported to be associated with a large number of clinical conditions and diseases. Whole lung lavages can be helpful to stabilize the clinical course of PAP until the underlying condition is identified, which may enable more specific treatment. Recently, heterozygous OAS1 gain-of-function variants were described as cause in a patient with infantile-onset PAP combined with hypogammaglobulinemia. Case presentation At age 4 months, a female infant born to term was diagnosed with hypogammaglobulinemia and treated with monthly immunoglobulin injections. At age 15 months, the girl needed supplemental oxygen at night, and at age 18 months, also during the day. At age 2 years, pulmonary alveolar proteinosis of unknown etiology was diagnosed by computed tomography scan and open lung biopsy. Subsequently, monthly whole lung lavages (WLLs) were started, which stabilized the clinical course for over 2 years until a disease-causing OAS1 variant was diagnosed and the patient was successfully treated by hematopoietic stem cell transplantation. Conclusion Here, we describe the successful management of a female patient with severe PAP caused by a heterozygous OAS1 gain-of-function variant until a definitive diagnosis was made and cured by hematopoietic stem cell transplantation. This article is protected by copyright. All rights reserved.

Published
2021

33. Initial presenting manifestations in 16,486 patients with inborn errors of immunity include infections and noninfectious manifestations

Author

Tim Niehues, Catherine Waruiru, Conleth Feighery, Uwe Schauer, Virginie Courteille, Kai Lehmberg, Ingo Müller, I. Esteves, Henner Morbach, Michael Borte, Patrick Hundsdoerfer, Klaus Schwarz, Ewelina Gowin, Alessandro Aiuti, Andreas Holbro, Federica Barzaghi, João Farela Neves, Dagmar Graf, Hannah Tamary, Veneta Milenova, Benedikt Boetticher, Eleonora Gambineri, Vera Goda, Alia Eldash, Jan-Christian Wasmuth, Fabio Candotti, Svetlana O. Sharapova, Markus Metzler, Juergen Brunner, Anna Hilfanova, Brindusa Ruxandra Capilna, Pere Soler-Palacín, Arnau Antolí, Horst von Bernuth, Vassilios Lougaris, Maria Carrabba, Bernd H. Belohradsky, Julian Thalhammer, Nathalie de Vergnes, Peter Olbrich, Peter Kopač, Leif G. Hanitsch, Alexandra Nieters, Filomeen Haerynck, Juliana Gabzdilova, Sezin Aydemir, Rabab El Hawary, Patrick F.K. Yong, Maria Giovanna Danieli, Alberto Tommasini, Sandra Steinmann, Ulrich Baumann, Figen Dogu, Elisabeth Förster-Waldl, Carolina Marasco, Donato Amodio, Lorenzo Lodi, Xavier Solanich, Caterina Cancrini, Brigita Sitkauskiene, Torsten Witte, Clementina Vanessa, Nima Rezaei, Jean-Christophe Goffard, Kirsten Wittke, Emmanouil Liatsis, Helen Baxendale, Susana L. Silva, Bodo Grimbacher, Henrike Ritterbusch, Evangelia Farmaki, Safa Meshaal, Sujal Ghosh, Larysa Kostyuchenko, David Edgar, Simone Cesaro, R Zeuner, Nerea Salmón Rodríguez, Isabella Quinti, Stephan Ehl, Pauline Brosselin, Joerg C. Henes, Pilar Llobet Agulló, Rosa Maria Dellepiane, Andrea Meinhardt, Marina Kojić, Georgios Sogkas, Stephan Borte, Catharina Schuetz, Suheyla Ocak, Karin Marschall, Lukas M. Gasteiger, Stefan Raffac, Sofia Tantou, Sadia Noorani, Matthaios Speletas, Philippe Randrianomenjanahary, Ursula Holzer, Ayca Kiykim, Johannes G. Liese, Angelo Vacca, Gisela Fecker, Ekrem Unal, Koen J. van Aerde, Alba Parra-Martínez, Kaan Boztug, Sophie Stiehler, Sybille Landwehr-Kenzel, Claudio Pignata, Jennifer Neubert, Janine Reichenbach, Shahnaz Parvin, Sarah Goddard, Andrea Schroll, Dirk Holzinger, Asghar Aghamohammadi, Hassan Abolhassani, Johannes Trück, Estela Paz-Artal, Shereen M. Reda, Anna Shcherbina, Maria Raptaki, Jaroslava Orosova, Beata Wolska-Kuśnierz, Tessa Kerre, Gerrit Ahrenstorf, Ben Zion Garty, Dirk Foell, Benjamin Becker, Ulrike F. Demel, Androniki Kapousouzi, Abraham Rutgers, Klaus Warnatz, Gemma Rocamora Blanch, Stephan Rusch, Luis M. Allende, Dalia Abd Elaziz, Safa Baris, Jorisvan Montfrans, Dominik T. Schneider, Raphael Scheible, Juana Gil-Herrera, Gerhard Kindle, Annarosa Soresina, Giovanna Fabio, Uwe Wintergerst, Emilia Faria, Maria Fasshauer, Silvia Ricci, Aisha Elmarsafy, Barbara Pietrucha, Carsten Speckmann, Nizar Mahlaoui, Ulrich Heininger, Isabelle Meyts, Matthew Buckland, Efimia Papadopoulou-Alataki, Robin Kobbe, A Herwadkar, Sebastian F. N. Bode, Ali Sobh, László Maródi, Baldassarre Martire, Chiara Azzari, Maximilian Heeg, Katja Masjosthusmann, Michael H. Albert, Matteo Chinello, Juan Luis Santos-Pérez, Aarnoud Huissoon, Tanya I. Coulter, Hendrik Schulze-Koops, Norbert Graf, Radwa Alkady, Jolanta Bernatoniene, Seraina Prader, Alenka Gagro, Joachim Roesler, Taco W. Kuijpers, Ewa Więsik-Szewczyk, Maria Elena Maccari, Conrad Ferdinand Lippert, Miriam González-Amores, Johannes Dirks, Daniel E Pleguezuelo, Christof M. Kramm, Anders Fasth, Volker Schuster, Olov Ekwall, Nikolaus Rieber, Javier Carbone, Petra Kaiser-Labusch, Diana Ernst, Lucia Augusta Baselli, Luis Ignacio Gonzalez-Granado, Maria Kanariou, Stefanie S. V. Henriet, Sigune Goldacker, Kerstin Felgentreff, Oana Joean, Fine Roosens, Fabian Hauck, Eva C. Schwaneck, Milos Jesenak, Manfred Hoenig, Lenka Kapustova, Christoph Boesecke, Alain Fischer, Sara Pereira da Silva, Julia Körholz, Ansgar Schulz, Carolynne Schwarze-Zander, Mikko Seppänen, Nermeen Galal, Nora Naumann-Bartsch, Tomaz Garcez, Peter Ciznar, Klara M. Posfay-Barbe, Zelimir Pavle Eric, Reinhold E. Schmidt, Hermann J. Girschick, Sabine Heine, Anika-Kerstin Biegner, Annick A. J. M. van de Ven, Stefan Schreiber, J. Merlijn van den Berg, Nurit Assia Batzir, Alexandra Jablonka, Kim Stol, Gregor Dückers, Antonios G.A. Kolios, Ioannis Kakkas, Christian Klemann, Marina N. Guseva, Sofia Grigoriadou, Elif Karakoc-Aydiner, Antonio Marzollo, Peter D. Arkwright, Urs C. Steiner, Sara Sebnem Kilic, Romina Dieli-Crimi, Gergely Kriván, Monika Sparber-Sauer, Marco Cazzaniga, Fulvio Porta, Paraskevi Maggina, Tomas Milota, Robbert G. M. Bredius, Martine Pergent, Klaus Tenbrock, Jana Pachlopnik Schmid, Florentia Dimitriou, Cathal Laurence Steele, Helen Bourne, Anna Bobcakova, Gerd Horneff, Judith Potjewijd, Marc Schmalzing, Tobias Ankermann, Paul Ryan, Oksana Boyarchuk, Necil Kutukculer, Carl Friedrich Classen, Zita Chovancová, Moira Thomas, Cinzia Milito, Michaela Bitzenhofer-Grüber, Faranaz Atschekzei, Eva Hlaváčková, Viviana Moschese, Julie Smet, Hans-Hartmut Peter, Carla Teixeira, Sabine M El-Helou, Suzanne de Kruijf Bazen, Helmut Wittkowski, Donate Jakoby, Marina Garcia-Prat, Esther de Vries, Richard Herriot, Sven Kracker, Alessandro Plebani, Lisa Göschl, Laura Hora Marques, Anna Sediva, Jiri Litzman, Mark M. Gompels, Renate Krüger, Şefika İlknur Kökçü Karadağ, Nadine Binder, Anna Szaflarska, Peter Jandus, Lisa Ibberson, Johann Greil, Ulf Schulze-Sturm, Mehtap Sirin, Aydan Ikinciogullari, Edyta Heropolitańska-Pliszka, Michael E. Weiss, Alla Skapenko, Lukas Wisgrill, Hana Alachkar, Uta Behrends, Silvia Sánchez-Ramón, Maria N. Hatzistilianou, Otilia Petrovicova, Darko Richter, Zoreh Nademi, Jürgen K. Rockstroh, Sohilla Lotfy, Markus G. Seidel, Timothy Ronan Leahy, Audra Blažienė, Translational Immunology Groningen (TRIGR), Paediatric Infectious Diseases / Rheumatology / Immunology, AII - Inflammatory diseases, ARD - Amsterdam Reproduction and Development, University of Zurich, Ehl, Stephan, Thalhammer, J., Kindle, G., Nieters, A., Rusch, S., Seppanen, M. R. J., Fischer, A., Grimbacher, B., Edgar, D., Buckland, M., Mahlaoui, N., Ehl, S., Boztug, K., Brunner, J., Demel, U. F., Forster-Waldl, E., Gasteiger, L. M., Goschl, L., Kojic, M., Schroll, A., Seidel, M. G., Wintergerst, U., Wisgrill, L., Sharapova, S. O., Goffard, J. -C., Kerre, T., Meyts, I., Roosens, F., Smet, J., Haerynck, F., Eric, Z. P., Milenova, V., Gagro, A., Richter, D., Chovancova, Z., Hlavackova, E., Litzman, J., Milota, T., Sediva, A., Elaziz, D. A., Alkady, R. S., El Sayed El Hawary, R., Eldash, A. S., Galal, N., Lotfy, S., Meshaal, S. S., Reda, S. M., Sobh, A., Elmarsafy, A., Brosselin, P., Courteille, V., De Vergnes, N., Kracker, S., Pergent, M., Randrianomenjanahary, P., Ahrenstorf, G., Albert, M. H., Ankermann, T., Atschekzei, F., Baumann, U., Becker, B. C., Behrends, U., Belohradsky, B. H., Biegner, A. -K., Binder, N., Bode, S. F. N., Boesecke, C., Boetticher, B., Borte, M., Borte, S., Classen, C. F., Dirks, J., Duckers, G., El-Helou, S., Ernst, D., Fasshauer, M., Fecker, G., Felgentreff, K., Foell, D., Ghosh, S., Girschick, H. J., Goldacker, S., Graf, N., Graf, D., Greil, J., Hanitsch, L. G., Hauck, F., Heeg, M., Heine, S. I., Henes, J. C., Hoenig, M., Holzer, U., Holzinger, D., Horneff, G., Hundsdoerfer, P., Jablonka, A., Jakoby, D., Joean, O., Kaiser-Labusch, P., Klemann, C., Kobbe, R., Korholz, J., Kramm, C. M., Kruger, R., Landwehr-Kenzel, S., Lehmberg, K., Liese, J. G., Lippert, C. F., Maccari, M. E., Masjosthusmann, K., Meinhardt, A., Metzler, M., Morbach, H., Muller, I., Naumann-Bartsch, N., Neubert, J., Niehues, T., Peter, H. -H., Rieber, N., Ritterbusch, H., Rockstroh, J. K., Roesler, J., Schauer, U., Scheible, R., Schmalzing, M., Schmidt, R. E., Schneider, D. T., Schreiber, S., Schuetz, C., Schulz, A., Schulze-Koops, H., Schulze-Sturm, U., Schuster, V., Schwaneck, E. C., Schwarz, K., Schwarze-Zander, C., Sirin, M., Skapenko, A., Sogkas, G., Sparber-Sauer, M., Speckmann, C., Steinmann, S., Stiehler, S., Tenbrock, K., von Bernuth, H., Warnatz, K., Wasmuth, J. -C., Weiss, M., Witte, T., Wittke, K., Wittkowski, H., Zeuner, R. A., Farmaki, E., Hatzistilianou, M. N., Kakkas, I., Kanariou, M. G., Kapousouzi, A., Liatsis, E., Maggina, P., Papadopoulou-Alataki, E., Raptaki, M., Speletas, M., Tantou, S., Goda, V., Krivan, G., Marodi, L., Abolhassani, H., Aghamohammadi, A., Rezaei, N., Feighery, C., Leahy, T. R., Ryan, P., Batzir, N. A., Garty, B. Z., Tamary, H., Aiuti, A., Amodio, D., Azzari, C., Barzaghi, F., Baselli, L. A., Cancrini, C., Carrabba, M., Cazzaniga, M., Cesaro, S., Chinello, M., Danieli, M. G., Dellepiane, R. M., Fabio, G., Gambineri, E., Lodi, L., Lougaris, V., Marasco, C., Martire, B., Marzollo, A., Milito, C., Moschese, V., Pignata, C., Plebani, A., Porta, F., Quinti, I., Ricci, S., Soresina, A., Tommasini, A., Vacca, A., Vanessa, C., Blaziene, A., Sitkauskiene, B., Gowin, E., Heropolitanska-Pliszka, E., Pietrucha, B., Szaflarska, A., Wiesik-Szewczyk, E., Wolska-Kusnierz, B., Esteves, I., Faria, E., Marques, L. H., Neves, J. F., Silva, S. L., Teixeira, C., Pereira da Silva, S., Capilna, B. R., Guseva, M. N., Shcherbina, A., Bobcakova, A., Ciznar, P., Gabzdilova, J., Jesenak, M., Kapustova, L., Orosova, J., Petrovicova, O., Raffac, S., Kopac, P., Allende, L. M., Antoli, A., Blanch, G. R., Carbone, J., Dieli-Crimi, R., Garcia-Prat, M., Gil-Herrera, J., Gonzalez-Granado, L. I., Agullo, P. L., Olbrich, P., Parra-Martinez, A., Paz-Artal, E., Pleguezuelo, D. E., Rodriguez, N. S., Sanchez-Ramon, S., Santos-Perez, J. L., Solanich, X., Soler-Palacin, P., Gonzalez-Amores, M., Ekwall, O., Fasth, A., Bitzenhofer-Gruber, M., Candotti, F., Dimitriou, F., Heininger, U., Holbro, A., Jandus, P., Kolios, A. G. A., Marschall, K., Schmid, J. P., Posfay-Barbe, K. M., Prader, S., Reichenbach, J., Steiner, U. C., Truck, J., Bredius, R. G., de Kruijf- Bazen, S., de Vries, E., Henriet, S. S. V., Kuijpers, T. W., Potjewijd, J., Rutgers, A., Stol, K., van Aerde, K. J., Van den Berg, J. M., van de Ven, A. A. J. M., Montfrans, J., Aydemir, S., Baris, S., Dogu, F., Ikinciogullari, A., Karakoc-Aydiner, E., Kilic, S. S., Kiykim, A., Kokcu Karadag, S. I., Kutukculer, N., Ocak, S., Unal, E., Boyarchuk, O., Hilfanova, A., Kostyuchenko, L. V., Alachkar, H., Arkwright, P. D., Baxendale, H. E., Bernatoniene, J., Coulter, T. I., Garcez, T., Goddard, S., Gompels, M. M., Grigoriadou, S., Herriot, R., Herwadkar, A., Huissoon, A., Ibberson, L., Nademi, Z., Noorani, S., Parvin, S., Steele, C. L., Thomas, M., Waruiru, C., Yong, P. F. K., and Bourne, H.

Subjects
0301 basic medicine, Male, Pediatrics, syndromic, Sex Factor, Disease, registry, medicine.disease_cause, Cohort Studies, 0302 clinical medicine, Primary Immunodeficiency Disease, inborn error of immunity, Immunology and Allergy, warning signs, Age Factor, Registries, Family history, presenting symptom, Child, Primary immunodeficiency, Granuloma, autoimmune, immune dysregulation, inflammatory, Adult, Autoimmune Diseases, Female, Humans, Infections, Lymphoproliferative Disorders, Middle Aged, Primary Immunodeficiency Diseases, Sex Factors, Age Factors, 10177 Dermatology Clinic, Infections/epidemiology, 3. Good health, Settore MED/02, Warning signs, Lymphoproliferative Disorder, 2723 Immunology and Allergy, Infection, Human, medicine.medical_specialty, Immunology, 610 Medicine & health, Malignancy, primary immunodeficiency, Autoimmune Disease, 03 medical and health sciences, Immunity, Autoimmune Diseases/epidemiology, medicine, 2403 Immunology, business.industry, warning sign, Common variable immunodeficiency, Granuloma/epidemiology, Immune dysregulation, medicine.disease, Primary Immunodeficiency Diseases/epidemiology, 030104 developmental biology, Lymphoproliferative Disorders/epidemiology, Cohort Studie, business, 030215 immunology
Abstract

BACKGROUND: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations.OBJECTIVE: We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts.METHODS: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered.RESULTS: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years.CONCLUSIONS: An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations.

Published
2021

34. Prospective Newborn Screening for SCID in Germany: A first analysis by the Pediatric Immunology Working Group (API)

Author

Carsten Speckmann, Uta Nennstiel, Manfred Hönig, Michael H. Albert, Sujal Ghosh, Catharina Schütz, Inken Brockow, Friederike Hörster, Tim Niehues, Stephan Ehl, Volker Wahn, Stephan Borte, Kai Lehmberg, Ulrich Baumann, Rita Beier, Renate Krüger, Joern-Sven Kuehl, Christian Klemann, Udo Kontny, Ursula Holzer, Andrea Meinhardt, Henner Morbach, Nora Naumann, Tobias Rothoeft, Alexandra Y Kreins, Edward G Davies, Dominik Schneider, Horst von Bernuth, Thomas Klingebiel, Georg Hoffmann, Ansgar Schulz, and Fabian H Hauck

Abstract

Background T-cell receptor excision circle (TREC)-based newborn screening (NBS) for severe combined immunodeficiencies (SCID) was introduced in Germany in August 2019. Methods Children with abnormal TREC-NBS were referred to a newly established network of Combined Immunodeficiency (CID) Clinics and Centers. The Working Group for Pediatric Immunology (API) and German Society for Newborn Screening (DGNS) performed 6-monthly surveys to assess the TREC-NBS process after 2.5 years. Results Among 1.9 million screened newborns, 88 patients with congenital T-cell lymphocytopenia were identified (25 SCID, 17 leaky SCID/Omenn Syndrome (OS)/idiopathic T-cell lymphocytopenia and 46 syndromic disorders). A genetic diagnosis was established in 88%. Twenty-six patients underwent hematopoietic stem cell transplantation (HSCT), 23/26 within 4 months of life. Of these, 25/26 (96%) were alive at last follow-up. Two patients presented with in-utero onset OS and died shortly after birth. Five patients with syndromic disorders underwent thymus transplantation. Eight syndromic patients deceased, all from non-immunological complications. TREC-NBS missed one patient, who later presented clinically, and one tracking failure occurred after an inconclusive screening result. Conclusion TREC-NBS was successfully incorporated into German NBS and represents the largest prospective European TREC-NBS cohort at this point. The incidence of SCID/leaky SCID/OS in Germany is approximately 1:54.000. The overall incidence of severe congenital T-cell lymphocytopenia is 1:21.000. The newly founded API-CID network facilitates tracking and treatment of identified patients. Short-term HSCT outcome was excellent, but NBS and transplant registries will remain essential to evaluate the long-term outcome and to compare results across the rising numbers of TREC-NBS programs across Europe.

Published
2022

38. Reduced-Intensity/Reduced-Toxicity Conditioning Approaches Are Tolerated in XIAP Deficiency but Patients Fare Poorly with Acute GVHD

Author

Emma C. Morris, Ashok Kumar, Justin T. Wahlstrom, Danielle E. Arnold, Connor Wakefield, Tim Brettig, Michael B. Jordan, Stephan Ehl, Theresa Cole, Jennifer Heimall, Małgorzata Salamonowicz, Michael H. Albert, Carsten Speckmann, Austen Worth, Rofida Nofal, Claire Booth, Nancy Bunin, Rebecca A. Marsh, Sharon Choo, Kai Lehmberg, Kanchan Rao, and Katharina Wustrau

Subjects
Austen Worth and Rebecca A. Marsh contributed equally to this work, medicine.medical_specialty, Transplantation Conditioning, Immunology, Graft vs Host Disease, X-Linked Inhibitor of Apoptosis Protein, Hemophagocytic lymphohistiocytosis, Graft-versus-host disease, Inflammatory bowel disease, Gastroenterology, hemic and lymphatic diseases, Internal medicine, XIAP deficiency, Humans, Immunology and Allergy, Medicine, XIAP Deficiency, Retrospective Studies, Hematopoietic cell transplantation, business.industry, Hazard ratio, Hematopoietic Stem Cell Transplantation, Genetic Diseases, X-Linked, medicine.disease, Lymphoproliferative Disorders, XIAP, Reduced-intensity conditioning, Transplantation, surgical procedures, operative, Primary immunodeficiency, Original Article, business
Abstract

X-linked inhibitor of apoptosis (XIAP) deficiency is an inherited primary immunodeficiency characterized by chronic inflammasome overactivity and associated with hemophagocytic lymphohistiocytosis (HLH) and inflammatory bowel disease (IBD). Allogeneic hematopoietic cell transplantation (HCT) with fully myeloablative conditioning may be curative but has been associated with poor outcomes. Reports of reduced-intensity conditioning (RIC) and reduced-toxicity conditioning (RTC) regimens suggest these approaches are well tolerated, but outcomes are not well established. Retrospective data were collected from an international cohort of 40 patients with XIAP deficiency who underwent HCT with RIC or RTC. Thirty-three (83%) patients had a history of HLH, and thirteen (33%) patients had IBD. Median age at HCT was 6.5 years. Grafts were from HLA-matched (n = 30, 75%) and HLA-mismatched (n = 10, 25%) donors. There were no cases of primary graft failure. Two (5%) patients experienced secondary graft failure, and three (8%) patients ultimately received a second HCT. Nine (23%) patients developed grade II–IV acute GVHD, and 3 (8%) developed extensive chronic GVHD. The estimated 2-year overall and event-free survival rates were 74% (CI 55–86%) and 64% (CI 46–77%), respectively. Recipient and donor HLA mismatch and grade II–IV acute GVHD were negatively associated with survival on multivariate analysis with hazard ratios of 5.8 (CI 1.5–23.3, p = 0.01) and 8.2 (CI 2.1–32.7, p

Published
2021

40. Incidence of subsequent malignancies after total body irradiation-based allogeneic HSCT in children with ALL - long-term follow-up from the prospective ALL-SCT 2003 trial

Author

Anna Eichinger, Ulrike Poetschger, Evgenia Glogova, Peter Bader, Oliver Basu, Rita Beier, Birgit Burkhardt, Carl-Friedrich Classen, Alexander Claviez, Selim Corbacioglu, Hedwig E. Deubzer, Johann Greil, Bernd Gruhn, Tayfun Güngör, Kinan Kafa, Jörn-Sven Kühl, Peter Lang, Bjoern Soenke Lange, Roland Meisel, Ingo Müller, Martin G. Sauer, Paul-Gerhardt Schlegel, Ansgar Schulz, Daniel Stachel, Brigitte Strahm, Angela Wawer, Christina Peters, and Michael H. Albert

Subjects
Cancer Research, Transplantation Conditioning, Incidence, Medizin, Hematopoietic Stem Cell Transplantation, Graft vs Host Disease, Hematology, Oncology, Neoplasms, Humans, Transplantation, Homologous, Prospective Studies, Child, Busulfan, Cyclophosphamide, Whole-Body Irradiation, Follow-Up Studies, Etoposide
Abstract

Total body irradiation (TBI)-based conditioning is associated with superior leukemia-free survival in children with ALL undergoing HSCT. However, the risk for subsequent malignant neoplasms (SMN) remains a significant concern. We analyzed 705 pediatric patients enrolled in the prospective ALL-SCT-BFM-2003 trial and its subsequent registry. Patients >2 years received conditioning with TBI 12 Gy/etoposide (n = 558) and children ≤2 years of age or with contraindications for TBI received busulfan/cyclophosphamide/etoposide (n = 110). The 5- and 10-year cumulative incidence of SMN was 0.02 ± 0.01 and 0.13 ± 0.03, respectively. In total, 39 SMN (34 solid tumors, 5 MDS/AML) were diagnosed in 33 patients at a median of 5.8 years (1.7–13.4), exclusively in the TBI group. Of 33 affected patients, 21 (64%) are alive at a median follow-up of 5.1 years (0–9.9) after diagnosis of their first SMN. In univariate analysis, neither age at HSCT, donor type, acute GVHD, chronic GVHD, nor CMV constituted a significant risk factor for SMN. The only significant risk factor was TBI versus non-TBI based conditioning. This analysis confirms and quantifies the increased risk of SMN in children with ALL after conditioning with TBI. Future strategies to avoid TBI will need careful tailoring within prospective, controlled studies to prevent unfavorable outcomes.

Published
2022

43. Lineage-Specific Chimerism and Outcome After Hematopoietic Stem Cell Transplantation for DOCK8 Deficiency

Author

Fabian Hauck, Johannes Raedler, Thomas Magg, Michael H. Albert, Tanja Vallée, Christoph Klein, and Meino Rohlfs

Subjects
Male, medicine.medical_specialty, Adolescent, DOCK8 deficiency, medicine.medical_treatment, Immunology, Hematopoietic stem cell transplantation, Chimerism, Mixed chimerism, Hypogammaglobulinemia, Medical microbiology, Hypersensitivity, Guanine Nucleotide Exchange Factors, Humans, Immunology and Allergy, Medicine, Eosinophilia, Lymphocyte Count, Child, Immunodeficiency, Retrospective Studies, business.industry, Hematopoietic Stem Cell Transplantation, Immunologic Deficiency Syndromes, Infant, Immunoglobulin E, medicine.disease, Transplantation, Virus Diseases, HSCT, Female, Original Article, medicine.symptom, Dock8, business, DOCK8 Deficiency
Abstract

Bi-allelic variants in the dedicator of cytokinesis 8 (DOCK8) gene cause a combined immunodeficiency, characterized by recurrent sinopulmonary and skin infections, food allergies, eczema, eosinophilia, and elevated IgE. Long-term outcome is poor given susceptibility to infections, malignancy, and vascular complications. Allogeneic hematopoietic stem cell transplantation is currently the only curative treatment option and has shown promising outcome. The impact of mixed chimerism on long-term outcome is unclear. We reasoned that reversal of disease phenotype would depend on cell lineage-specific chimerism. DOCK8 variants were confirmed by Sanger and/or exome sequencing and immunoblot and/or intracellular flow cytometry. Donor chimerism was analyzed by XY-fluorescence in situ hybridization or quantitative short tandem repeat PCR. Outcome was assessed by laboratory tests, lymphocyte subsets, intracellular DOCK8 protein flow cytometry, T-cell proliferation analysis, and multiparameter immunoblot allergy screening. We report on nine patients, four of whom with mixed chimerism, with a median follow-up of 78 months after transplantation. Overall, we report successful transplantation with improvement of susceptibility to infections and allergies, and resolution of eczema in all patients. Immunological outcome in patients with mixed chimerism suggests a selective advantage for wild-type donor T-cells but lower donor B-cell chimerism possibly results in a tendency to hypogammaglobulinemia. No increased infectious and allergic complications were associated with mixed chimerism. Aware of the relatively small cohort size, we could not demonstrate a consistent detrimental effect of mixed chimerism on clinical outcomes. We nevertheless advocate aiming for complete donor chimerism in treating DOCK8 deficiency, but recommend reduced toxicity conditioning. Supplementary Information The online version contains supplementary material available at 10.1007/s10875-021-01069-5.

Published
2021

44. Upfront Enzyme Replacement via Erythrocyte Transfusions for PNP Deficiency

Author

Sebastian A. Schroeder, Giancarlo la Marca, Fabian Hauck, Anna Eichinger, Horst von Bernuth, Cinzia Dedieu, and Michael H. Albert

Subjects
chemistry.chemical_classification, medicine.medical_specialty, business.industry, Immunology, MEDLINE, Medical Microbiology, Internal Medicine, Infectious Diseases, PNP, SCID, Letter to Editor, Enzyme, Medical microbiology, chemistry, PNP Deficiency, Immunology and Allergy, Medicine, business
Published
2021

45. CLEC12A and CD33 coexpression as a preferential target for pediatric AML combinatorial immunotherapy

Author

Christoph Klein, Theresa Kaeuferle, Maximilian Hastreiter, Jonas Wilhelm, Meino Rohlfs, Marion Subklewe, Tobias Feuchtinger, Dana Stenger, Paula Rothämel, Franziska Blaeschke, Michael H. Albert, Vera Binder, Irene Schmid, and Semjon Willier

Subjects
Male, Myeloid, Adolescent, Sialic Acid Binding Ig-like Lectin 3, Immunology, CD33, CD34, Biology, Biochemistry, hemic and lymphatic diseases, medicine, Humans, Lectins, C-Type, Child, neoplasms, Gene Expression Regulation, Leukemic, Infant, Myeloid leukemia, Cell Biology, Hematology, medicine.disease, Up-Regulation, Leukemia, Myeloid, Acute, Leukemia, Haematopoiesis, medicine.anatomical_structure, Child, Preschool, Receptors, Mitogen, Cancer research, Female, Immunotherapy, Bone marrow, Stem cell, Transcriptome
Abstract

Emerging immunotherapies such as chimeric antigen receptor T cells have advanced the treatment of acute lymphoblastic leukemia. In contrast, long-term control of acute myeloid leukemia (AML) cannot be achieved by single lineage-specific targeting while sparing benign hematopoiesis. In addition, heterogeneity of AML warrants combinatorial targeting, and several suitable immunotargets (HAVCR2/CD33 and HAVCR2/CLEC12A) have been identified in adult AML. However, clinical and biologic characteristics of AML differ between children and the elderly. Here, we analyzed 36 bone marrow (BM) samples of pediatric AML patients and 13 age-matched healthy donors using whole RNA sequencing of sorted CD45dim and CD34+CD38−CD45dim BM populations and flow cytometry for surface expression of putative target antigens. Pediatric AML clusters apart from healthy myeloid BM precursors in principal-component analysis. Known immunotargets of adult AML, such as IL3RA, were not overexpressed in pediatric AML compared with healthy precursors by RNA sequencing. CD33 and CLEC12A were the most upregulated immunotargets on the RNA level and showed the highest surface expression on AML detected by flow cytometry. KMT2A-mutated infant AML clusters separately by RNA sequencing and overexpresses FLT3, and hence, CD33/FLT3 cotargeting is an additional specific option for this subgroup. CLEC12A and CD33/CLEC12Adouble-positive expression was absent in CD34+CD38−CD45RA−CD90+ hematopoietic stem cells (HSCs) and nonhematopoietic tissue, while CD33 and FLT3 are expressed on HSCs. In summary, we show that expression of immunotargets in pediatric AML differs from known expression profiles in adult AML. We identify CLEC12A and CD33 as preferential generic combinatorial immunotargets in pediatric AML and CD33 and FLT3 as immunotargets specific for KMT2A-mutated infant AML.

Published
2021

46. Towards homogenization of total body irradiation practices in pediatric patients across SIOPE affiliated centers. A survey by the SIOPE radiation oncology working group

Author

Mirjam E. Bosman, Christoph Losert, Bianca A.W. Hoeben, Stéphane Supiot, Soraya Mico Milla, Montserrat Pazos, Michael H. Albert, Marc Bierings, Geert O. Janssens, Jacob Engellau, Candan Demiröz Abakay, Inna Ospovat, Tom Boterberg, Farkhad Manapov, Gregor Kos, Enrica Seravalli, Institut Català de la Salut, [Hoeben BAW] Dept. of Radiation Oncology, University Medical Center Utrecht, The Netherlands. Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands. [Pazos M, Losert C] Dept. of Radiation Oncology, University Hospital, LMU Munich, Germany. [Albert MH] Dept. of Pediatrics, Dr. von Hauner Childrens Hospital, University Hospital, LMU Munich, Germany. [Seravalli E, Bosman ME] Dept. of Radiation Oncology, University Medical Center Utrecht, The Netherlands. [Milla SM] Servei d’Oncologia Radioteràpica, Vall d'Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
Pediatrics, medicine.medical_specialty, Transplantation Conditioning, medicine.medical_treatment, Otros calificadores::Otros calificadores::/radioterapia [Otros calificadores], Hematopoietic stem cell transplantation, Leucèmia mieloide aguda - Radioteràpia, 030218 nuclear medicine & medical imaging, neoplasias::neoplasias por tipo histológico::leucemia::leucemia mieloide::leucemia mieloide aguda [ENFERMEDADES], 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, Internal medicine, Radiation oncology, Investigative Techniques::Whole-Body Irradiation [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], medicine, Humans, Radiology, Nuclear Medicine and imaging, Child, Acute leukemia, Hematology, Cèl·lules mare hematopoètiques - Trasplantació, Other subheadings::Other subheadings::/radiotherapy [Other subheadings], business.industry, Hematopoietic Stem Cell Transplantation, Neoplasms::Neoplasms by Histologic Type::Leukemia::Leukemia, Myeloid::Leukemia, Myeloid, Acute [DISEASES], Myeloid leukemia, Total body irradiation, técnicas de investigación::irradiación corporal total [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], medicine.disease, Radiation therapy, Leukemia, Myeloid, Acute, Leukemia, Oncology, 030220 oncology & carcinogenesis, Radiation Oncology, Therapeutics::Biological Therapy::Cell- and Tissue-Based Therapy::Cell Transplantation::Stem Cell Transplantation::Hematopoietic Stem Cell Transplantation [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], business, terapéutica::terapia biológica::tratamientos basados en células y tejidos::trasplante de células::trasplante de células madre::trasplante de células madre hematopoyéticas [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Whole-Body Irradiation
Abstract

Pediatric; Radiotherapy; Stem cell transplantation Pediatria; Radioteràpia; Trasplantament de cèl·lules mare Pediatría; Radioterapia; Trasplante de células madre Background and purpose To reduce relapse risk, Total Body Irradiation (TBI) is part of conditioning regimens for hematopoietic stem cell transplantation (HSCT) in pediatric acute leukemia. The study purpose was to evaluate clinical practices regarding TBI, such as fractionation, organ shielding and delivery techniques, among SIOPE affiliated radiotherapy centers. Methods An electronic survey was sent out to 233 SIOPE affiliated centers, containing 57 questions about clinical practice of TBI. Surveys could be answered anonymously. Results From over 25 countries, 82 responses were collected. For TBI-performing centers, 40/48 irradiated ≤10 pediatric patients annually (range: 1–2 to >25). Most indications concerned acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). Four different fractionation schedules were used, of which 12 Gy in 6 fractions was applied in 91% for ALL and 86% for AML. Dose reduction to the lungs, mostly to a mean dose of 8–10 Gy, was applied by 28/33 centers for ALL and 19/21 centers for AML, in contrast to much less applied dose reduction to the kidneys (7/33 ALL and 7/21 AML), thyroid (2/33 ALL and 2/21 AML), liver (4/33 ALL and 3/21 AML) and lenses (4/33 ALL and 4/21 AML). Conventional TBI techniques were used by 24/29 responding centers, while 5/29 used advanced optimized planning techniques. Conclusion Across SIOPE, there is a high level of uniformity in fractionation and use of lung shielding. Practices vary regarding other organs-at-risk shielding and implementation of advanced techniques. A SIOPE radiotherapy working group will be established to define international guidelines for pediatric TBI.

Published
2021

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