title: An intermediate alemtuzumab schedule reduces the incidence of mixed chimerism following reduced-intensity conditioning hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis.
abstract: Reduced-intensity conditioning (RIC) improves the outcomes of hematopoietic cell transplantation (HCT) in patients with hemophagocytic lymphohistiocytosis (HLH). Proximal (ie, close to graft infusion) dosing of alemtuzumab is associated with a high incidence of mixed chimerism, whereas distal (ie, distant from graft infusion) dosing is associated with less mixed chimerism but more acute graft-versus-host disease (GVHD). The alemtuzumab dose per kilogram of body weight also influences these outcomes. We hypothesized that an intermediate alemtuzumab dosing schedule would reduce mixed chimerism and maintain a low incidence of acute GVHD. In this study, 24 consecutive HCTs were performed in patients with HLH or a related disorder using a novel intermediate alemtuzumab schedule of 1 mg/kg starting on day -14. The cumulative incidences (CIs) of mixed chimerism, upfront acute GVHD grades II-IV, and receipt of additional hematopoietic cell products after HCT were compared in patients treated with a distal alemtuzumab schedule (n = 15) and those treated with a proximal alemtuzumab schedule (n = 33). All patients received fludarabine and melphalan. The CI of mixed chimerism was 31% in the intermediate group, 72% in the proximal group (P < .01), and 75% in the distal group patients who received ≥2 mg/kg alemtuzumab (P = .03). The CI of acute GVHD grades II-IV before the development of mixed chimerism was 4% in the intermediate group, 0% in the proximal group, and 13% in the distal group (P = .04, proximal versus distal). The 1-year CI of administration of additional hematopoietic cell products for mixed chimerism (donor lymphocyte infusion ± hematopoietic stem cell boost ± repeat HCT) was 14% in the intermediate group, 53% in the proximal group (P = .01), and 38% in the distal ≥2 mg/kg alemtuzumab group (P = .02). Our findings indicate that intermediate RIC reduces the incidence of mixed chimerism, is associated with a low incidence of upfront acute GVHD, and decreases the need for additional hematopoietic cell products after HCT.
authors.affiliation: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. Electronic address: Rebecca.Marsh@cchmc.org.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Marsh
authors.forename: Mi-Ok
authors.initials: MO
authors.lastname: Kim
authors.forename: Chunyan
authors.initials: C
authors.lastname: Liu
authors.forename: Denise
authors.initials: D
authors.lastname: Bellman
authors.forename: Laura
authors.initials: L
authors.lastname: Hart
authors.forename: Michael
authors.initials: M
authors.lastname: Grimley
authors.forename: Ashish
authors.initials: A
authors.lastname: Kumar
authors.forename: Sonata
authors.initials: S
authors.lastname: Jodele
authors.forename: Kasiani C
authors.initials: KC
authors.lastname: Myers
authors.forename: Sharat
authors.initials: S
authors.lastname: Chandra
authors.forename: Tom
authors.initials: T
authors.lastname: Leemhuis
authors.forename: Parinda A
authors.initials: PA
authors.lastname: Mehta
authors.forename: Jack J
authors.initials: JJ
authors.lastname: Bleesing
authors.forename: Stella M
authors.initials: SM
authors.lastname: Davies
authors.forename: Michael B
authors.initials: MB
authors.lastname: Jordan
authors.forename: Alexandra H
authors.initials: AH
authors.lastname: Filipovich
mesh_terms: D000293:Adolescent; D000328:Adult; D000074323:Alemtuzumab; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002648:Child; D002675:Child, Preschool; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D006801:Humans; D015994:Incidence; D007223:Infant; D007231:Infant, Newborn; D051359:Lymphohistiocytosis, Hemophagocytic / Q000188:drug therapy / Q000601:surgery / Q000628:therapy*; D008297:Male; D018183:Transplantation Chimera; D019172:Transplantation Conditioning / Q000009:adverse effects / Q000379:methods*; D014184:Transplantation, Homologous; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000074323:Alemtuzumab
keywords: Alemtuzumab; Bone marrow transplantation; Familial hemophagocytic lymphohistiocytosis; Hematopoietic cell transplantation; Hemophagocytic lymphohistiocytosis; Reduced-intensity conditioning; SAP deficiency; X-linked lymphoproliferative disease; XIAP deficiency
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