title: Eculizumab therapy in children with severe hematopoietic stem cell transplantation-associated thrombotic microangiopathy.
abstract: We recently observed that dysregulation of the complement system may be involved in the pathogenesis of hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA). These findings suggest that the complement inhibitor eculizumab could be a therapeutic option for this severe HSCT complication with high mortality. However, the efficacy of eculizumab in children with HSCT-TMA and its dosing requirements are not known. We treated 6 children with severe HSCT-TMA using eculizumab and adjusted the dose to achieve a therapeutic level >99 μg/mL. HSCT-TMA resolved over time in 4 of 6 children after achieving therapeutic eculizumab levels and complete complement blockade, as measured by low total hemolytic complement activity (CH50). To achieve therapeutic drug levels and a clinical response, children with HSCT-TMA required higher doses or more frequent eculizumab infusions than currently recommended for children with atypical hemolytic uremic syndrome. Two critically ill patients failed to reach therapeutic eculizumab levels, even after dose escalation, and subsequently died. Our data indicate that eculizumab may be a therapeutic option for HSCT-TMA, but HSCT patients appear to require higher medication dosing than recommended for other conditions. We also observed that a CH50 level ≤ 4 complement activity enzyme units correlated with therapeutic eculizumab levels and clinical response, and therefore CH50 may be useful to guide eculizumab dosing in HSCT patients as drug level monitoring is not readily available.
authors.affiliation: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. Electronic address: sonata.jodele@cchmc.org.
authors.forename: Sonata
authors.initials: S
authors.lastname: Jodele
authors.affiliation: Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Fukuda
authors.affiliation: Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Alexander
authors.initials: A
authors.lastname: Vinks
authors.affiliation: Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Kana
authors.initials: K
authors.lastname: Mizuno
authors.affiliation: Division of Nephrology, The Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Laskin
authors.affiliation: Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Jens
authors.initials: J
authors.lastname: Goebel
authors.affiliation: Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Bradley P
authors.initials: BP
authors.lastname: Dixon
authors.affiliation: Department of Pharmacy, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Ashley
authors.initials: A
authors.lastname: Teusink
authors.affiliation: Division of Nephrology, The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada.
authors.forename: Fred G
authors.initials: FG
authors.lastname: Pluthero
authors.affiliation: Division of Nephrology, The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada.
authors.forename: Lily
authors.initials: L
authors.lastname: Lu
authors.affiliation: Division of Nephrology, The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada.
authors.forename: Christoph
authors.initials: C
authors.lastname: Licht
authors.affiliation: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Stella M
authors.initials: SM
authors.lastname: Davies
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D015941:Complement Hemolytic Activity Assay; D051056:Complement Inactivating Agents / Q000627:therapeutic use*; D015938:Complement Membrane Attack Complex / Q000037:antagonists & inhibitors*; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D016903:Drug Monitoring; D019337:Hematologic Neoplasms / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D012720:Severity of Illness Index; D016019:Survival Analysis; D057049:Thrombotic Microangiopathies / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology / Q000401:mortality; D014182:Transplantation, Autologous; D014184:Transplantation, Homologous
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D051056:Complement Inactivating Agents; D015938:Complement Membrane Attack Complex; C481642:eculizumab
keywords: CH50; Eculizumab; Eculizumab pharmacokinetics; Hematopoietic stem cell transplant; Thrombotic microangiopathy