A Prospective Study of Alemtuzumab as a Second-Line Agent for Steroid-Refractory Acute Graft-versus-Host Disease in Pediatric and Young Adult Allogeneic Hematopoietic Stem Cell Transplantation.
We describe a single-center prospective study of alemtuzumab as a second-line agent for steroid-refractory (SR) acute graft-versus-host disease (aGVHD) in pediatric and young adult allogeneic hematopoietic stem cell transplant recipients. Alemtuzumab was administered for grades II to IV aGVHD if patients did not improve within 5 days or worsened within 48 hours after corticosteroids. Interim analyses of alemtuzumab levels and response were performed after every 5 patients enrolled, resulting in 3 dosing cohorts, as follows: (1) .2 mg/kg alemtuzumab subcutaneously on days 1 to 5 (maximum of 31 mg over 5 days) and .2 mg/kg/dose (not exceeding 10 mg/dose) on days 15, 22, and 29; (2) .2 mg/kg alemtuzumab subcutaneously on days 1 to 5 (maximum of 43 mg over 5 days) and .2 mg/kg/dose on day 7, 10, 15, 22, and 29; and (3) .2 mg/kg subcutaneously on days 1 to 5 and .2 mg/kg/dose on day 7, 10, 15, and 22. Alemtuzumab levels were assessed before starting alemtuzumab and at days 1, 3, 6, 10, and 14 and weekly until day 99, where day 1 was the day of first alemtuzumab dose. Fifteen patients (median age, 10 years; range, 1.4 to 27) received alemtuzumab for grades II (6%), III (74%), and IV (20%) SR-aGVHD. The overall response rate was 67%, with complete response (CR) in 40%, partial response (PR) in 27%, and no response in 33%. The median day 6 alemtuzumab level was 2.79 µg/mL (interquartile range, 1.34 to 4.89) in patients with CR compared with .62 µg/mL (interquartile range, .25 to 1.45) in patients with PR + no response (P < .05). Ninety percent (n = 9) of patients with a CR or PR reduced corticosteroid doses within 8 weeks from first alemtuzumab dose. Side effects included fever (26%) and transient thrombocytopenia (53%). Asymptomatic viremias occurred in all patients but invasive viral disease occurred in 2 patients. One patient developed Epstein-Barr virus-post-transplantation lymphoproliferative disorder. Eighty percent (n = 12) of patients were alive at 6 months, of whom 53% (n = 8) were free of GVHD whereas 13% (n = 2) developed chronic GVHD. Alemtuzumab is an effective second-line agent for children and young adults with SR-aGVHD. Higher alemtuzumab levels are associated with CR. A real-time dose adjusted alemtuzumab study is needed to further optimize the dose of alemtuzumab in aGVHD.
Division of Bone Marrow Transplantation and Immune Deficiency, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio. Electronic address: Pooja.khandelwal@cchmc.org.
Pooja
P
Khandelwal
Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Chie
C
Emoto
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Tsuyoshi
T
Fukuda
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Alexander A
AA
Vinks
Division of Bone Marrow Transplantation and Immune Deficiency, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Lisa
L
Neumeier
Division of Bone Marrow Transplantation and Immune Deficiency, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
Christopher E
CE
Dandoy
Division of Bone Marrow Transplantation and Immune Deficiency, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
Javier
J
El-Bietar
Division of Bone Marrow Transplantation and Immune Deficiency, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
Sharat
S
Chandra
Division of Bone Marrow Transplantation and Immune Deficiency, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
Stella M
SM
Davies
Division of Bone Marrow Transplantation and Immune Deficiency, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
Jacob J
JJ
Bleesing
Division of Bone Marrow Transplantation and Immune Deficiency, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Michael B
MB
Jordan
Division of Bone Marrow Transplantation and Immune Deficiency, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
Parinda A
PA
Mehta
Division of Bone Marrow Transplantation and Immune Deficiency, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
Sonata
S
Jodele
Division of Bone Marrow Transplantation and Immune Deficiency, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
Michael S
MS
Grimley
Division of Bone Marrow Transplantation and Immune Deficiency, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Experimental Hematology, Cincinnati Children's Hospital, Cincinnati, Ohio.
Ashish
A
Kumar
Division of Bone Marrow Transplantation and Immune Deficiency, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
Kasiani C
KC
Myers
Division of Bone Marrow Transplantation and Immune Deficiency, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
Rebecca A
RA
Marsh
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000074323:Alemtuzumab / Q000008:administration & dosage*; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D005260:Female; D005334:Fever / Q000209:etiology; D006086:Graft vs Host Disease / Q000188:drug therapy*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D006801:Humans; D007223:Infant; D008297:Male; D011446:Prospective Studies; D012074:Remission Induction; D016879:Salvage Therapy / Q000379:methods*; D013256:Steroids / Q000494:pharmacology / Q000627:therapeutic use; D013921:Thrombocytopenia / Q000209:etiology; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D014777:Virus Diseases / Q000209:etiology; D055815:Young Adult
D013256:Steroids; D000074323:Alemtuzumab
Alemtuzumab; Alemtuzumab for GVHD; Alemtuzumab in children; Graft-versus-host disease (GVHD); Steroid-refractory acute graft-versus-host disease (SR-aGVHD)
Bone Marrow Transplant. 2009 Mar;43(5):423-7
18850021
Biol Blood Marrow Transplant. 2005 Sep;11(9):680-7
16125638
Biol Blood Marrow Transplant. 2005 Sep;11(9):734-6
16125645
Bone Marrow Transplant. 2004 Aug;34(3):285-7
15170160
Biol Blood Marrow Transplant. 2015 Aug;21(8):1460-70
25865646
Best Pract Res Clin Haematol. 2008 Jun;21(2):193-204
18503986
Bone Marrow Transplant. 2007 Sep;40(5):473-80
17618323
Biol Blood Marrow Transplant. 2009 May;15(5):639-42
19361757
Biol Blood Marrow Transplant. 2008 Jan;14(1):10-5
18158956
Pediatr Transplant. 2014 Feb;18(1):94-102
24384050
Bone Marrow Transplant. 2004 Jan;33(1):131-2
14566330
Bone Marrow Transplant. 2011 Jan;46(1):143-7
20348971
Biol Blood Marrow Transplant. 2013 May;19(5):804-11
23416855
Bone Marrow Transplant. 2002 Dec;30(12 ):899-903
12476283
Ann Oncol. 2011 Jul;22(7):1595-600
21212158
Am J Hematol. 1996 Jul;52(3):236-7
8756101
Bone Marrow Transplant. 1995 Jun;15(6):825-8
7581076
Bone Marrow Transplant. 2016 Aug;51(8):1153-5
27042838
Blood. 2004 Aug 15;104(4):1224-6
15113758
Blood. 2000 Oct 1;96(7):2419-25
11001893
Biol Blood Marrow Transplant. 2009 Aug;15(8):910-8
19589480
Blood. 2004 Aug 1;104(3):649-54
15069017
Biol Blood Marrow Transplant. 2014 Sep;20(9):1451-4
24910381
J Immunol Methods. 2002 Feb 1;260(1-2):285-302
11792397
Blood. 2016 Jan 28;127(4):503-12
26644451
Bone Marrow Transplant. 2006 May;37(10 ):961-5
16565744
J Clin Immunol. 2011 Aug;31(4):615-22
21541793
Cochrane Database Syst Rev. 2012 Feb 15;(2):CD008078
22336834
Blood. 2007 May 15;109(10):4119-26
17234737
Nature. 1988 Mar 24;332(6162):323-7
3127726