The minimum required level of donor chimerism in hereditary hemophagocytic lymphohistiocytosis.
Reduced-intensity conditioning has improved survival after hematopoietic stem cell transplantation (HSCT) for hemophagocytic lymphohistiocytosis (HLH) at the cost of more frequent mixed chimerism. The minimum level of donor chimerism (DC) required to prevent HLH reactivation in humans remains to be determined. In a multicenter retrospective study, 103 patients transplanted for hereditary HLH (2000-2013) and DC permanently or transiently <75% (overall, CD3(+), CD56(+)) were analyzed regarding DC, specific immunologic function, occurrence of systemic reactivations (≥5/8 HLH criteria), partial systemic flares (<5 criteria and HLH-directed treatment), isolated central nervous system reactivations, and management. Recurrence was reported in 18 patients (systemic reactivation n = 11, partial flare n = 3, isolated central nervous system reactivation n = 4). Ten events occurred during profound immune suppression before day 180 (median DC, 10%; range, 1-100%; CD3(+) if available, otherwise overall DC), which renders a differentiation between secondary post-HSCT HLH and HLH related to the genetic defect difficult. Eight events occurred between 0.5 and 6.7 years post-HSCT (median DC, 13%; range, 0-30%). In 5 patients, overall and lineage-specific DC were ≤10% for >6 months (median, 5.1; range, 1.1-10 years) without reactivation. A second HSCT was performed in 18 patients (median, DC 4%; range, 0-19%). Death from reactivation occurred in 4 patients (22% of recurrences). Six patients died of transplant complications following a second HSCT (33% of second HSCT). We conclude that a DC >20%-30% is protective against late reactivation. Lower levels do not, however, inescapably result in recurrences. The decision for or against second HSCT must be based on a thorough risk assessment.
Department of Pediatric Hematology and Oncology, University Medical Center Hamburg Eppendorf, Hamburg, Germany;
Bernd
0000-0002-3043-3048
B
Hartz
Cincinnati Children's Hospital, Cincinnati, OH;
Rebecca
R
Marsh
Great Ormond Street Hospital, London, United Kingdom;
Kanchan
K
Rao
Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden;
Jan-Inge
JI
Henter
Cincinnati Children's Hospital, Cincinnati, OH;
Michael
M
Jordan
Cincinnati Children's Hospital, Cincinnati, OH;
Lisa
L
Filipovich
Division for Stem Cell Transplantation and Immunology, University Children's Hospital, Frankfurt am Main, Germany;
Peter
P
Bader
Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany; Department of Pediatric Hematology and Oncology, University Medical Center Essen, Germany;
Rita
R
Beier
Department of Pediatric Hematology and Oncology, University Medical Center Münster, Münster, Germany;
Birgit
B
Burkhardt
Department of Pediatric Hematology, Oncology and Immunology, University Children's Hospital Düsseldorf, Düsseldorf, Germany;
Roland
R
Meisel
Department of Pediatric and Adolescent Medicine, University Hospital Ulm, Ulm, Germany;
Ansgar
A
Schulz
Department of Pediatric Hematology and Oncology, University Medical Center Hamburg Eppendorf, Hamburg, Germany; Department of Pediatric Hematology/Oncology and Stem Cell Transplantation, University Children's Hospital, Würzburg, Germany;
Beate
B
Winkler
Dr. von Hauner University Children's Hospital, Ludwig-Maximilian University Munich, Munich, Germany.
Michael H
MH
Albert
Department of Pediatric Hematology and Oncology, University Children's Hospital Heidelberg, Heidelberg, Germany;
Johann
J
Greil
Pediatric Stem Cell Transplantation Unit, Goztepe Medicalpark Hospital, Bahcesehir University, Istanbul, Turkey;
Gülsün
G
Karasu
Department of Pediatric Hematology and Oncology, University Children's Hospital, Giessen, Germany;
Wilhelm
W
Woessmann
Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, University Children's Hospital, Regensburg, Germany;
Selim
S
Corbacioglu
Department of Pediatrics, Jena University Hospital, Jena, Germany;
Bernd
B
Gruhn
St. Anna Children's Hospital, Medical University Vienna, Vienna, Austria; Department of Pediatric Hematology and Oncology, University Medical Center Erlangen, Erlangen, Germany;
Wolfgang
W
Holter
Department of Pediatric Oncology, Hematology, and Stem Cell Transplantation, Charité, Berlin, Germany;
Jörn-Sven
JS
Kühl
Department of Hematology and Oncology, University Children's Hospital Tübingen, Tübingen, Germany;
Peter
P
Lang
St. Anna Children's Hospital, Medical University Vienna, Vienna, Austria; Division of Pediatric Hematology-Oncology, Department of Pediatrics and Adolescent Medicine, Medical University Graz, Graz, Austria;
Markus G
MG
Seidel
Great Ormond Street Hospital, London, United Kingdom;
Paul
P
Veys
Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Clinical Science, Intervention and Technology, Karolinska Institutet, and Hematology/Immunology Section, Astrid Lindgren Children's Hospital, Karolinska University Hospital Huddinge, Stockholm, Sweden; and.
Alexandra
A
Löfstedt
Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.
Sandra
S
Ammann
Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.
Stephan
S
Ehl
Department of Pediatric Hematology and Oncology, University Medical Center Hamburg Eppendorf, Hamburg, Germany;
Gritta
G
Janka
Department of Pediatric Hematology and Oncology, University Medical Center Hamburg Eppendorf, Hamburg, Germany;
Ingo
I
Müller
Department of Pediatric Hematology and Oncology, University Medical Center Hamburg Eppendorf, Hamburg, Germany;
Kai
0000-0003-2365-4341
K
Lehmberg
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D046528:Chimerism; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D051359:Lymphohistiocytosis, Hemophagocytic / Q000276:immunology* / Q000628:therapy*; D008297:Male; D012008:Recurrence; D012189:Retrospective Studies; D014019:Tissue Donors; D019172:Transplantation Conditioning / Q000379:methods; D014181:Transplantation Immunology; D014184:Transplantation, Homologous / Q000009:adverse effects; D016896:Treatment Outcome; D055815:Young Adult