TRANSPLANTATION A randomized, placebo-controlled trial of oral beclomethasone dipropionate as a prednisone-sparing therapy for gastrointestinal graft-versus-host disease David M. Hockenbery,1 Scott Cruickshank,2 Timothy C. Rodell,2 Ted Gooley,1 Friedrich Schuening,3 Scott Rowley,4 Donald David,5 Mark Brunvand,6 Brian Berryman,7 Sunil Abhyankar,8 Michelle Bouvier,1 and George B. McDonald,1 for the orBec GVHD Study Group 1Fred Hutchinson Cancer Research Center and University of Washington School of Medicine, Seattle; 2DOR BioPharma Inc, Miami, FL; 3Vanderbilt University School of Medicine, Nashville, TN; 4Hackensack University Medical Center, NJ; 5City of Hope National Medical Center, Duarte, CA; 6Rocky Mountain Blood & Marrow Transplant Program, Denver, CO; 7Baylor University School of Medicine, Dallas, TX; 8Oncology & Hematology Associates, Kansas City, MO We tested the hypothesis that oral be- confidence interval [CI] 0.35-1.13) and at tation day 200 was reduced by 91% in the clomethasone dipropionate (BDP) would 30 days follow-up (HR 0.55, 95% CI 0.32- BDP group compared with placebo (HR The survival benefit was .(02. ؍ control gastrointestinal graft-versus-host 0.93). Among patients eligible for pred- 0.09, P disease (GVHD) in patients with anorexia, nisone taper at study day 10, the risk of durable to 1 year after randomization. vomiting, and diarrhea. Patients were ran- GVHD-treatment failure was significantly Oral BDP prevents relapses of gastroin- domized to prednisone for 10 days and reduced at both study days 50 and 80 (HR testinal GVHD following tapering of pred- -or pla- 0.39 and 0.38, respectively). By day 200 nisone; survival is statistically signifi (62 ؍ either oral BDP 8 mg/d (n tablets for 50 days. At study after transplantation, 5 patients random- cantly better among patients receiving (67 ؍ cebo (n day 10, prednisone was rapidly tapered ized to BDP had died compared with 16 BDP. (Blood. 2007;109:4557-4563) while continuing study drug. On an intent- deaths on placebo, a 67% reduction in the In .(03. ؍ to-treat basis, the risk of GVHD-treatment hazard of mortality (HR 0.33, P failure was reduced for the BDP group at 47 recipients of unrelated and HLA-mis- study day 50 (hazard ratio [HR] 0.63, 95% matched stem cells, mortality at transplan- © 2007 by The American Society of Hematology Introduction Gastrointestinal graft-versus-host disease (GVHD) affects up to tion compared with placebo. Because of this survival benefit, we 60% of patients after allogeneic hematopoietic cell transplanta- also examined outcomes from a previous randomized trial of a tion.1 Intestinal GVHD involves release of cytokines within the shorter 30-day course of oral BDP.11 mucosa, infiltration of donor T lymphocytes, and crypt-cell apopto- sis.2,3 Clinical manifestations include anorexia, nausea, vomiting, diarrhea, and, in patients with severe involvement, fever, cholesta- sis, protein-losing enteropathy, and sloughing of mucosa.4-8 In Patients, materials, and methods animal studies, the extent of intestinal involvement and T-cell Patient selection activation in Peyer patches are determinants of survival.2,9 Initial treatment is with prednisone 1 to 2 mg/kg/d, followed by a Patients with symptoms of GVHD were evaluated with endoscopy and prednisone tapering schedule to prevent GVHD relapses and allow mucosal biopsy. If biopsy specimens demonstrated histologic findings of 12,13 recovery of the hypothalamic-pituitary-adrenal axis.4 Another GVHD and stool and mucosal biopsy cultures were negative for pathogens,14,15 patients were invited to participate. Patients were excluded approach to GVHD treatment involves a 5-day course of pred- if diarrhea exceeded 1 L/d or if skin or liver GVHD were present. All nisolone at 2 mg/kg/d; the response after 5 days is prognosis patients received medications for GVHD prophylaxis; patients receiving determining.10 Prednisone-related side effects are common, particu- corticosteroids within 30 days of study entry were excluded. Patients signed larly fatal infections, weakness, hyperglycemia, hypertension, informed consent documents, in accordance with the Declaration of osteopenia, and psychiatric symptoms. Helsinki, approved by the institutional review boards of all participating We tested the hypothesis that a topically active corticosteroid institutions. (beclomethasone dipropionate [BDP, or Bec]), taken orally, allows rapid tapering of prednisone while maintaining control of intestinal Formulation of BDP GVHD. The results show that a 50-day course of treatment with Both immediate-release tablets and enteric-coated tablets contained 1 mg of oral BDP reduces the frequency of relapses of GVHD following BDP (DOR BioPharma, Miami, FL). The dosing regimen was 1 immediate- accelerated withdrawal of prednisone therapy and results in better release and 1 enteric-coated tablet taken orally, 4 times daily (total daily survival at transplantation day 200 and at 1 year after randomiza- dose, 8 mg BDP). Submitted May 9, 2006; accepted January 12, 2007. Prepublished online as Blood The publication costs of this article were defrayed in part by page charge First Edition Paper, January 23, 2007; DOI 10.1182/blood-2006-05-021139. payment. Therefore, and solely to indicate this fact, this article is hereby marked ‘‘advertisement’’ in accordance with 18 USC section 1734. An Inside Blood analysis of this article appears at the front of this issue. The online version of this article contains a data supplement. © 2007 by The American Society of Hematology BLOOD, 15 MAY 2007 ⅐ VOLUME 109, NUMBER 10 4557 4558 HOCKENBERY et al BLOOD, 15 MAY 2007 ⅐ VOLUME 109, NUMBER 10 Stratification and randomization 113 patients received an initial prednisone dose of 1 mg/kg/d after hypothalamic-pituitary-adrenal axis suppression was observed at the higher A blocked stratified allocation scheme was used to balance the treatment dose at the time of study day–50 testing. In patients with control of GVHD groups within study centers (Table 1). Additional stratifying variables were symptoms at study day 10, prednisone was tapered over 7 days (0.25 mg/kg HLA-matched sibling and use of cutaneous corticosteroids at baseline. twice daily on study days 11 and 12; 0.125 mg/kg twice daily on study days Patients were randomized to receive either BDP or identical placebo tablets 13 and 14; 0.0625 mg/kg twice daily on study days 15 and 16), after which in a 1:1 allocation. patients were maintained on physiologic replacement doses of prednisone (0.0625 mg/kg daily). Patients who did not demonstrate adequate control of Treatment plan GVHD by study day 10 were considered treatment failures. Patients Therapy consisted of study drugs plus 10 days of prednisone. The initial 16 received study drug for 50 days, until they met the treatment-failure end patients were administered prednisone 2 mg/kg/d for 10 days; the remaining point, or until they were withdrawn from the study. Patients who were Table 1. Characteristics of patients according to randomization assignment Characteristic Placebo BDP Overall No. of patients 67 62 129 Age at randomization, y Mean Ϯ SD 44.5 Ϯ 13.4 45.9 Ϯ 13.6 45.2 Ϯ 13.5 Median 47.0 47.0 47.0 Range 17-66 6-70 6-70 Sex, no. of patients (%) Male 41 (61) 36 (58) 77 (60) Female 26 (39) 26 (42) 52 (40) Race, no. of patients (%) White 56 (84) 54 (87) 110 (85) American Hispanic 7 (10) 4 (6) 11 (9) Asian 1 (1) 3 (5) 4 (3) Black 3 (4) 1 (2) 4 (3) Time from transplantation to randomization, d Mean Ϯ SD 45.7 Ϯ 31.80 48.3 Ϯ 32.56 47.0 Ϯ 32.07 Median 35.0 37.0 36.0 Range 18-171 18-190 18-190 Primary diagnosis, no. of patients (%) Acute myelogenous leukemia 22 (33) 19 (31) 41 (32) Acute lymphocytic leukemia 7 (10) 9 (14) 16 (12) Chronic myelogenous leukemia 8 (12) 8 (13) 16 (12) Non-Hodgkin lymphoma 7 (10) 6 (10) 13 (10) Myelodysplastic syndrome 6 (9) 2 (3) 8 (6) Multiple myeloma 1 (1) 6 (10) 7 (5) Chronic lymphocytic leukemia 4 (6) 2 (3) 6 (5) Chronic myelomonocytic leukemia 3 (5) 2 (3) 5 (4) Aplastic anemia 2 (3) 1 (2) 3 (2) Hodgkin disease 2 (3) 1 (2) 3 (2) Myelofibrosis 2 (3) 1 (2) 3 (2) Acute promyelocytic leukemia 0 (0) 2 (3) 2 (2) Other* 3 (5) 3 (5) 6 (5) Risk of relapse after transplantation,† no. of patients (%) High risk 29 (43) 40 (65) 69 (53) Low risk 38 (57) 22 (35) 60 (47) Source of donor cells, no. of patients (%) Peripheral-blood stem cells 62 (93) 54 (87) 116 (90) Bone marrow 5 (7) 8 (13) 13 (10) Conditioning regimen, no. of patients (%) Myeloablative 52 (78) 36 (58) 88 (68) Nonmyeloablative 15 (22) 26 (42) 41 (32) Patient/donor relationship, no. of patients (%) Unrelated 22 (33) 19 (31) 41 (32) Related 45 (67) 43 (69) 88 (68) Biologic parent 2 (3) 0 (0) 2 (2) Sibling 43 (64) 40 (65) 83 (64) Other relation 0 (0) 3 (4) 3 (2) HLA allele match status in siblings, no. of patients (%) Matched 43 (64) 39 (63) 82 (64) Mismatched for 1 or more alleles 0 (0) 1 (2) 1 (Ͻ 1) *Other primary diagnoses included (1 each) biphenotypic acute leukemia, extramedullary leukemia tumor, metastatic renal cell carcinoma, myeloproliferative syndrome, plasmacytic leukemia, and polycythemia vera. †Patients were considered to be at low risk of relapse following transplantation if the indication for transplantation was 1 of these diagnoses: aplastic anemia, chronic lymphocytic leukemia, chronic myelogenous leukemia in chronic phase, chronic myelomonocytic leukemia, acute myelogenous leukemia in first remission, myelodysplastic syndrome, myelofibrosis, myeloproliferative syndrome, or polycythemia vera. Patients with other diagnoses were considered to be at high risk for relapse after transplantation.