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

Quyen Bach, Mercer University College of Pharmacy

Background

Chronic graft-versus-host disease (GVHD) is stated to be a major complication of allogenic stem-cell transplantation may result in later illness, death, or a reduction in quality of life. [1,2] Randomized studies aiming at reducing the incidence of chronic GVHD have not shown success in achieving their goal, while only antihuman T-lymphocyte immune globulin (ATG) has been shown to lower the incidence of chronic GVHD after stem-cell transplantation from an unrelated donor and, in smaller, retrospective studies, after HLA-identical transplantation. [3,4]

Table 1

Antilymphocyte Globulin for Prevention of Chronic Graft-versus-Host Disease [5]
Design Prospective, multicenter, open-label, phase 3 study; N = 155
Objective To study whether including ATG in the myeloablative conditioning regimen would reduce the risk of chronic GVHD among patients in complete remission from acute leukemia who received peripheral blood stem cells from an HLA-identical sibling
Study Groups ATG (n = 83); non-ATG (n = 72)
Methods Patients were randomized 1:1 to receive ATG or not receive ATG as part of a myeloablative conditioning regimen. For the ATG group, the regimen consisted of cyclophosphamide (120 mg/kg) and total body irradiation (12Gy) or busulfan (16 mg/kg orally or 12.8 mg/kg IV), with or without etoposide (30 to 60 mg/kg), as well as ATG at a dose of 10 mg/kg.
Duration December 2006 to February 2012
Primary Outcome Measure The cumulative incidence of chronic GVHD at 2 years as determined according to the revised Seattle criteria and the National Institutes of Health (NIH) criteria.
Baseline Characteristics Characteristic ATG Group (n = 83) Non-ATG Group (n = 72) p-value
Mean age (yr) 39 43.5 0.04
Mean time between diagnosis and stem-cell transplantation (mo.) 5.2 5.3  
Acute myeloid leukemia (no.) 55 55 0.17
Acute lymphoid leukemia (no.) 28 17  
Mean number of courses of chemotherapy before transplantation (no.) 2 2 0.89
First complete remission (no.) 73 66  
Second complete remission (no.) 10 6  
Total-body irradiation plus cyclophosphamide 23 18  
Busulfan plus cyclophosphamide 56 51  
Total-body irradiation plus etoposide 4 3  
Mean donor’s age (yr) 39.1 42.7 0.71
Female donor-make recipient pairs (no.) 20 16 0.75
Cytomegalovirus IgG-positive recipients (no.) 50 42 0.90
Mean infused CD34+ cells x 10-6/kg 5.4 5.0  
Results   ATG Group Non-ATG Group p-value
Cumulative incidence of chronic GVHD at 2 years as determined according to the revised Seattle criteria – no. (%) < 0.001
Limited severity 17 (20.5) 22 (30.6)  
Extensive severity 5 (6.0) 24 (33.3)  
Cumulative incidence of chronic GVHD at 2 years as determined according to NIH criteria – no. (%) < 0.001
Mild severity 13 (15.7) 12 (16.7)  
Moderate severity 7 (8.4) 18 (25.0)  
Severe severity 2 (2.4) 16 (22.2)  
Adverse Events Common Adverse Events: infectious complications (57.8%), gastrointestinal toxic effects (28.9%)
Serious Adverse Events: nonrelapse-related death at 2 years (14%)
Percentage that Discontinued due to Adverse Events: N/A
Study Author Conclusions Our study shows that incorporation of ATG in the myeloablative conditioning regimen before transplantation of peripheral blood stem cells from HLA-identical siblings resulted in a significantly lower rate of chronic GVHD than the rate without ATG. The rate of relapse-free and overall survival were similar in the two groups, but the rate of a composite end point of survival free from chronic GVHD and survival free from relapse was significantly higher with ATG.

 

Chronic GVHD is the second leading cause of late illness and death after allogeneic hematopoietic stem-cell transplantation. [1,2] This study showed that there were a significantly fewer incidence of chronic GVHD if ATG was added to the conditioning regimen than when it was not added. It could be beneficial to add such regimen to prevent the detrimental consequences of stem-cell transplantation. However, this study was terminated at 2 years; extending follow-up would confirm its effect on long-term survival.

 

References:

  1. Wingard JR, Majhail NS, Brazauskas R, et al. Long-term survival and late deaths after allogeneic hematopoietic cell transplantation. J Clin Oncol. 2011;29(16):2230-9.
  2. Martin PJ, Counts GW, Appelbaum FR, et al. Life expectancy in patients surviving more than 5 years after hematopoietic cell transplantation. J Clin Oncol. 2010;28(6):1011-6.
  3. Wolschke C, Zabelina T, Ayuk F, 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. Bone Marrow Transplant. 2014;49(1):126-30.
  4. Bonifazi F, Bandini G, Arpinati M, 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. Bone Marrow Transplant. 2012;47(8):1105-11.
  5. Kröger N, Solano C, Wolschke C, et al. Antilymphocyte Globulin for Prevention of Chronic Graft-versus-Host Disease. N Engl J Med. 2016;374(1):43-53.
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