Antilymphocyte Globulin for Prevention of Chronic Graft-versus-Host Disease.

BACKGROUND Chronic graft-versus-host disease (GVHD) is the leading cause of later illness and death after allogeneic hematopoietic stem-cell transplantation. We hypothesized that the inclusion of antihuman T-lymphocyte immune globulin (ATG) in a myeloablative conditioning regimen for patients with acute leukemia would result in a significant reduction in chronic GVHD 2 years after allogeneic peripheral-blood stem-cell transplantation from an HLA-identical sibling. METHODS We conducted a prospective, multicenter, open-label, randomized phase 3 study of ATG as part of a conditioning regimen. A total of 168 patients were enrolled at 27 centers. Patients were randomly assigned in a 1:1 ratio to receive ATG or not receive ATG, with stratification according to center and risk of disease. RESULTS After a median follow-up of 24 months, the cumulative incidence of chronic GVHD was 32.2% (95% confidence interval [CI], 22.1 to 46.7) in the ATG group and 68.7% (95% CI, 58.4 to 80.7) in the non-ATG group (P<0.001). The rate of 2-year relapse-free survival was similar in the ATG group and the non-ATG group (59.4% [95% CI, 47.8 to 69.2] and 64.6% [95% CI, 50.9 to 75.3], respectively; P=0.21), as was the rate of overall survival (74.1% [95% CI, 62.7 to 82.5] and 77.9% [95% CI, 66.1 to 86.1], respectively; P=0.46). There were no significant between-group differences in the rates of relapse, infectious complications, acute GVHD, or adverse events. The rate of a composite end point of chronic GVHD-free and relapse-free survival at 2 years was significantly higher in the ATG group than in the non-ATG group (36.6% vs. 16.8%, P=0.005). CONCLUSIONS The inclusion of ATG resulted in a significantly lower rate of chronic GVHD after allogeneic transplantation than the rate without ATG. The survival rate was similar in the two groups, but the rate of a composite end point of chronic GVHD-free survival and relapse-free survival was higher with ATG. (Funded by the Neovii Biotech and the European Society for Blood and Marrow Transplantation; ClinicalTrials.gov number, NCT00678275.).

[1]  A. Nagler,et al.  Anti-T Lymphocyte Globulin (ATG) Induces Generation of Regulatory T Cells, at Least Part of Them Express Activated CD44 , 2011, Journal of Clinical Immunology.

[2]  Tao Wang,et al.  Increasing incidence of chronic graft-versus-host disease in allogeneic transplantation: a report from the Center for International Blood and Marrow Transplant Research. , 2015, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[3]  G. Rosner,et al.  Single-agent GVHD prophylaxis with posttransplantation cyclophosphamide after myeloablative, HLA-matched BMT for AML, ALL, and MDS. , 2014, Blood.

[4]  A. Gennery,et al.  Hematopoietic SCT in Europe: data and trends in 2012 with special consideration of pediatric transplantation , 2014, Bone Marrow Transplantation.

[5]  Daniel Wolff,et al.  National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. , 2005, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[6]  N. Kröger,et al.  Antithymocyte globulin induces ex vivo and in vivo depletion of myeloid and plasmacytoid dendritic cells. , 2005, Transplantation.

[7]  J. Ritz,et al.  Reduced frequency of FOXP3+ CD4+CD25+ regulatory T cells in patients with chronic graft-versus-host disease. , 2005, Blood.

[8]  Lluís Armadans,et al.  Hospital de la Santa Creu i Sant Pau , 2011 .

[9]  M. Mohty,et al.  NCI First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation: report from the Committee on the Epidemiology and Natural History of Relapse following Allogeneic Cell Transplantation. , 2010, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[10]  Robert Gray,et al.  A Proportional Hazards Model for the Subdistribution of a Competing Risk , 1999 .

[11]  R. Storb,et al.  Life expectancy in patients surviving more than 5 years after hematopoietic cell transplantation. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  M. Turner,et al.  National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. , 2005, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[13]  H. Deeg,et al.  Methotrexate and cyclosporine versus cyclosporine alone for prophylaxis of graft-versus-host disease in patients given HLA-identical marrow grafts for leukemia: long-term follow-up of a controlled trial. , 1989, Blood.

[14]  P. Neiman,et al.  CLINICAL MANIFESTATIONS OF GRAFT‐VERSUS-HOST DISEASE IN HUMAN RECIPIENTS OF MARROW FROM HL‐A-MATCHED SIBLING DONOR,S , 1974, Transplantation.

[15]  M. Sorror,et al.  Long-term survival and late deaths after allogeneic hematopoietic cell transplantation. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[16]  H. Einsele,et al.  Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial. , 2009, The Lancet. Oncology.

[17]  M. Baccarani,et al.  Intensification of GVHD prophylaxis with low-dose ATG-F before allogeneic PBSC transplantation from HLA-identical siblings in adult patients with hematological malignancies: results from a retrospective analysis , 2012, Bone Marrow Transplantation.

[18]  F. Appelbaum,et al.  Regimen-related toxicity in patients undergoing bone marrow transplantation. , 1988, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  H. Deeg,et al.  A controlled trial of long-term administration of intravenous immunoglobulin to prevent late infection and chronic graft-vs.-host disease after marrow transplantation: clinical outcome and effect on subsequent immune recovery. , 1996, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[20]  F. Appelbaum,et al.  Comparative outcomes of donor graft CD34+ selection and immune suppressive therapy as graft-versus-host disease prophylaxis for patients with acute myeloid leukemia in complete remission undergoing HLA-matched sibling allogeneic hematopoietic cell transplantation. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[21]  H. Greinix,et al.  Diverse T-cell responses characterize the different manifestations of cutaneous graft-versus-host disease. , 2013, Blood.

[22]  A. Pettitt,et al.  Impact of in vivo alemtuzumab dose before reduced intensity conditioning and HLA-identical sibling stem cell transplantation: pharmacokinetics, GVHD, and immune reconstitution. , 2010, Blood.

[23]  H. Greinix,et al.  National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease , 2015 .

[24]  P. Westervelt,et al.  Peripheral-blood stem cells versus bone marrow from unrelated donors. , 2012, The New England journal of medicine.

[25]  M. Horowitz,et al.  Validation and refinement of the Disease Risk Index for allogeneic stem cell transplantation. , 2014, Blood.

[26]  J. Ritz,et al.  High Levels of B-Cell Activating Factor in Patients with Active Chronic Graft-Versus-Host Disease , 2007, Clinical Cancer Research.

[27]  H. Lee,et al.  Allogeneic Peripheral Blood Stem-Cell Compared With Bone Marrow Transplantation in the Management of Hematologic Malignancies: An Individual Patient Data Meta-Analysis of Nine Randomized Trials , 2005 .

[28]  F. Aversa,et al.  Competing risk analysis using R: an easy guide for clinicians , 2007, Bone Marrow Transplantation.

[29]  P. Bruzzi,et al.  Antithymocyte globulin for graft-versus-host disease prophylaxis in transplants from unrelated donors: 2 randomized studies from Gruppo Italiano Trapianti Midollo Osseo (GITMO). , 2001, Blood.

[30]  N. Kröger,et al.  Antithymocyte globulin induces complement-dependent cell lysis and caspase-dependent apoptosis in myeloma cells. , 2005, Experimental hematology.

[31]  R. Storb,et al.  Lack of B cells precursors in marrow transplant recipients with chronic graft-versus-host disease. , 1996, American journal of hematology.

[32]  R. Newcombe,et al.  Interval estimation for the difference between independent proportions: comparison of eleven methods. , 1998, Statistics in medicine.

[33]  R. Gray.  A Class of $K$-Sample Tests for Comparing the Cumulative Incidence of a Competing Risk , 1988 .

[34]  D. Porter,et al.  Impact of immune modulation with anti-T-cell antibodies on the outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation for hematologic malignancies. , 2011, Blood.

[35]  M. Flowers,et al.  Chronic graft-versus-host disease. , 2003, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[36]  H. Deeg,et al.  Cyclosporine or cyclosporine plus methylprednisolone for prophylaxis of graft-versus-host disease: a prospective, randomized trial. , 1997, Blood.

[37]  R. Storb,et al.  Lack of B cell precursors in marrow transplant recipients with chronic graft‐versus‐host disease , 1996 .

[38]  N. Kröger,et al.  Effective prevention of GVHD using in vivo T-cell depletion with anti-lymphocyte globulin in HLA-identical or -mismatched sibling peripheral blood stem cell transplantation , 2014, Bone Marrow Transplantation.

[39]  H. Deeg,et al.  Administration of cyclosporine for 24 months compared with 6 months for prevention of chronic graft-versus-host disease: a prospective randomized clinical trial. , 2001, Blood.

[40]  F. Frassoni,et al.  Increased risk of leukemia relapse with high-dose cyclosporine A after allogeneic marrow transplantation for acute leukemia. , 1991, Blood.

[41]  J. Klein,et al.  Chronic GVHD risk score: a Center for International Blood and Marrow Transplant Research analysis. , 2011, Blood.