Chronic graft-versus-host disease (GVHD) is a major cause of late morbidity and mortality post-allogeneic haematopoietic stemcell transplantation. Compared with acute GVHD, for which progress in preventative measures have been made, chronic GVHD describes a more diverse syndrome, and may adversely affect almost all organs in the body. A new prospective, multicentre, open-label, randomised phase III study (n=168) showed that the use of anti-human T-lymphocyte immune globulin (ATLG) in a myeloablative conditioning regimen for patients with acute leukaemia led to a significantly lower rate of chronic GVHD post-allogeneic transplantation compared with those receiving the same regimen without ATLG. Importantly, no increased rate of relapses in the patients who received ATLG was seen compared with those who did not. Thus, there was no apparent impairment in the graft-versus-leukaemia effect in ATLG-treated patients. The study was terminated at 2 years and more evidence about the long-term effect of ATLG on survival and GVHD relapses beyond this time-point are needed. Nonetheless, the findings represent a significant advance in the prevention of chronic GVHD.
Chronic graft-versus-host disease (GVHD) is one of the major complications of allogeneic haematopoietic stem cell transplantation (HSCT) resulting from a complex interaction between the donor-derived immune system and recipient organ.1 While acute GVHD is a distinctive syndrome consisting of the development of mainly dermatitis, hepatitis and enteritis, chronic GVHD describes a more diverse syndrome, potentially affecting almost all organs and tissues in the body. The National Institutes of Health (NIH) Consensus Development Project has proposed two subcategories for chronic GVHD: classic and overlap syndrome (Figure 1). These syndromes, which have been shown to have clinical validity,2 are based on clinical features rather than time of onset. This is due to recognition that both classical features of chronic GVHD can occur within 100 days post-HSCT and that features of acute and chronic GVHD could occur together.3 Therapies such as steroids that are effective in treating acute GVHD might be much less effective for chronic GVHD and this together with the differences in clinical presentation, suggest that unique physiologic mechanisms may be involved in chronic GVHD.4 Unlike acute GVHD, which is mediated almost entirely by donor T cells, chronic GVHD immune pathology is more complicated and donor B cells have also been found to play an important role.5
In the literature the incidence of chronic GVHD following allo-HSCT ranges from 6–80%, according to presence of risk factors and diagnostic criteria used.3,6–8 Several potential risk factors have been described, including transplant from donors other than a matched sibling,9,10 older recipients11,12 and the use of peripheral blood graft.13–15
Chronic GVHD can lead to later illness, including immune dysfunction and infection risk, a reduction in quality of life and a decline in life expectancy.6,17 In a records review of 10,632 patients who were alive and disease free 2 years after receiving myeloablative allogeneic HCT before 2004, 3,788 patients were studied for 10 or more years.16 The probability of being alive 10 years post-HCT was 85%. Older age and chronic GVHD were the main risk factors for late death. In a cohort of 2,574 patients who survived without recurrence for 5 years or more post- HCT, the estimated survival of the cohort was 80.4% (95% confidence interval [CI] 78.1–82.6%). The leading causes of additional deaths, in descending order, were second malignancies and recurrent disease, GVHD, respiratory diseases and cardiovascular diseases.
A US report in 2011 from the Chronic GVHD Consortium revealed that patients with moderate and severe chronic GVHD had physical component scores comparable with scores reported for systemic sclerosis, systemic lupus erythematosus, and multiple sclerosis. They also had greater impairment compared with common chronic conditions including diabetes, hypertension, and chronic lung disease.18 A comparison of the mean Short Form-36 scores between chronic GVHD patients and the normal US population showed significant impairment
for chronic GVHD patients across multiple domains, including physical functioning, bodily pain, general health, vitality, social functioning and physical component scores.18
The purpose of this article is to provide a succinct overview of the unique role of anti-human T-lymphocyte immune globulin (ATLG) in the prevention of chronic GVHD.
Prevention of GVHD
None of the current calcineurin-based pharmacological approaches (such as cyclosporine or tacrolimus) that have been successful in acute GVHD prophylaxis have shown a major impact on chronic GVHD in randomised trials.19–23 However, ex vivo T-cell depletion can reduce chronic GVHD, but the approach is limited by a higher rate of malignancy relapse and infections, which are associated with a lack of survival advantage or even with reduced survival.24,25 In a prospective study, post-transplantation cyclophosphamide reduced the risk of both acute and chronic GVHD, although data from randomised studies are lacking. There exists the concern that some strategies aimed at addressing the GVHD effect might impair the beneficial graft-versus-leukaemia (GVL) effect, increasing the risk for relapse.26 Animal and human studies of allogeneic stem-cell transplantation have demonstrated that immunological non-identity between donor and recipient is responsible for a GVL effect.27,28 The recognition of the GVL effect is now driving the evolution of allogeneic stem cell transplantation towards an immunotherapeutic approach.
Anti-human T-lymphocyte immune globulin
The use of ATLG and anti-thymocyte globulin (ATG) has been shown to lead to a reduced incidence of chronic GVHD after stem cell transplantation from an unrelated donor.29–31 In a prospective, randomised, multicentre, open-label, phase III trial (n=202), the addition of Grafalon®(ATLG, formerly known as ATG-Fresenius-S [Neovii Pharmaceuticals AG, Rapperswil, Switzerland]) to GVHD prophylaxis with ciclosporin and methotrexate resulted in decreased incidence of acute and chronic GVHD.29 This was achieved without
an increase in relapse or non-relapse mortality, and without compromising overall survival. Small, retrospective studies have also suggested the benefits of this approach after human leukocyte antigen (HLA)-identical transplantation.32,33
Anti-human T-lymphocyte immune globulin in a myeloablative conditioning regimen
A recent prospective, multicentre, open-label, randomised phase III study (n=168) showed that ATLG inclusion in a myeloablative conditioning regimen for patients in complete remission from acute leukaemia who received peripheral blood stem cells from an HLA-identical sibling, resulted in a significantly lower rate of chronic GVHD post-allogeneic transplantation compared with those receiving the same regimen without ATLG.34 Patients in the ATLG group received a dose of 10 mg/kg, on 3, 2 and 1 days prior to transplantation of allogeneic peripheral blood stem cells from an HLA-identical donor. The cumulative incidence of chronic GVHD at 2 years was 32.2% in the patients (n=83) who received ATLG (95% CI 22.1–46.7) and 68.7% in those patients (n=72) who did not receive ATLG (95% CI 58.4–80.7; p<0.001) (Figure 2). In addition, on the composite endpoint of chronic-free and relapse-free survival at 2 years, the rate was significantly improved for the ATLG group versus the non-ATLG group (36.6% versus 16.8%; p=0.005) (Figure 3). The rate of 2-year relapse free survival was similar between the two groups (59.4% in the ATLG group [95% CI, 47.8–69.2] and 64.6% in the non-ATLG group [95% CI, 50.9–75.3], respectively; p=0.21). The rate of overall survival was likewise similar between the ATLG and non-ATLG groups (74.1% [95% CI, 62.7–82.5] and 77.9% [95% CI, 66.1–86.1], respectively). The median times to leukocyte engraftment (absolute neutrophil count, ≥0.5 × 109 per litre) and platelet engraftment (platelet count, ≥20 × 109 per litre) were statistically significantly longer in the ATLG group compared with the non-ATLG group: 18 days (range, 10–31) versus 15 days (range, 11–34; p<0.001).
According to NIH scores, there was less chronic GVHD involvement of grade 2 or higher in the ATLG group than in the non-ATLG group in all organs except genital organs (Table 1).34 In addition, there was significantly less chronic GVHD involvement of the skin, the mouth and the eyes. There were no significant differences between the two groups in the rates of relapse, infectious complications, acute GVHD or adverse events.
This is an open study and this, as well as the subjective nature of GVHD grading, represents important limitations of this study. Possible selection bias is another limitation. The patients in the ATG group were aware of group assignment which means that the potential of bias in grading the chronic GVHD cannot be ruled out. In addition, the rate of the composite end-point of 2-year survival free from chronic GVHD and freedom from relapse was significantly higher among those who received ATG than among those who did not (37% versus 17%). The study ended at 2 years and longer-term follow-up data are unfortunately not available.
ATLG, as part of a myeloablative conditioning regimen, administered before transplantation of peripheral-blood stem cells from HLA-identical siblings led to a significantly lower rate of chronic GVHD.34 There was no increased rate of relapse in the patients who received ATLG compared with those who did not, hence no evidence of a reduced GVL effect in ATLG-treated patients. The pathophysiology and immunobiology involved in GVHD and GVL requires further investigation. More data are required on reduced intensity regimens in the same setting and on the long-term effect of ATLG on survival and GVHD relapses beyond 2 years. In addition, improved understanding of the pathophysiology of chronic GVHD will facilitate the design of more prevention studies.
Nicolaus Kröger received research grant from Neovii Pharmaceuticals AG.
Nicolaus Kröger, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. E: email@example.com
The publication of this article was supported by Neovii Pharmaceuticals AG, who were given the opportunity to review the article for scientific accuracy before submission. Any resulting changes were made at the author’s discretion.
This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.
Medical writing assistance was provided by Catherine Amey for Touch Medical Media funded by Neovii Pharmaceuticals AG. This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors.
1. Socie G, Blazar BR, Acute graft-versus-host disease: from the bench to the bedside, Blood, 2009;114:4327–36.
2. Jagasia MH, Savani BN, Stricklin G, et al., Classic and overlap chronic graft-versus-host disease (cGVHD) is associated with superior outcome after extracorporeal photopheresis (ECP), Biol Blood Marrow Transplant, 2009;15:1288–95.
3. Filipovich AH, Weisdorf D, Pavletic S, 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,Biol Blood Marrow Transplant, 2005;11:945–56.
4. Paczesny S, Hakim FT, Pidala J, et al., National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: III. The 2014 Biomarker Working Group Report, Biol Blood Marrow Transplant, 2015;21:780–92.
5. Sarantopoulos S, Blazar BR, Cutler C, Ritz J, B cells in chronic graft-versus-host disease, Biol Blood Marrow Transplant, 2015;21:16–23.
6. Carlens S, Ringden O, Remberger M, et al., Risk factors for chronic graft-versus-host disease after bone marrow transplantation: a retrospective single centre analysis, Bone Marrow Ttransplantation, 1998;22:755–61.
7. Atkinson K, Horowitz MM, Gale RP, et al., Risk factors for chronic graft-versus-host disease after HLA-identical sibling bone marrow transplantation, Blood, 1990;75:2459–64.
8. Ochs LA, Miller WJ, Filipovich AH, et al., Predictive factors for chronic graft-versus-host disease after histocompatible sibling donor bone marrow transplantation, Bone Marrow Transplantation, 1994;13:455–60.
9. Kollman C, Howe CW, Anasetti C, et al., Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age, Blood, 2001;98:2043–51.
10. Arora M, Klein JP, Weisdorf DJ, et al., Chronic GVHD risk score: a Center for International Blood and Marrow Transplant Research analysis, Blood, 2011;117:6714–20.
11. Ringden O, Paulin T, Lonnqvist B, Nilsson B, An analysis of factors predisposing to chronic graft-versus-host disease, Exp Haematol, 1985;13:1062–7.
12. Stewart BL, Storer B, Storek J, et al., Duration of immunosuppressive treatment for chronic graft-versus-host disease, Blood, 2004;104:3501–6.
13. Remberger M, Beelen DW, Fauser A, et al., Increased risk of extensive chronic graft-versus-host disease after allogeneic peripheral blood stem cell transplantation using unrelated donors, Blood, 2005;105:548–51.
14. Ringden O, Labopin M, Bacigalupo A, et al., Transplantation of peripheral blood stem cells as compared with bone marrow from HLA-identical siblings in adult patients with acute myeloid leukemia and acute lymphoblastic leukemia, J Clin Oncol, 2002;20:4655–64.
15. Anasetti C, Logan BR, Lee SJ, et al., Peripheral-blood stem cells versus bone marrow from unrelated donors, N Engl J Med, 2012;367:1487–96.
16. Wingard JR, Majhail NS, Brazauskas R, et al., Long-term survival and late deaths after allogeneic hematopoietic cell transplantation, J Clin Oncol, 2011;29:2230–9.
17. Martin PJ, Counts GW, Jr., Appelbaum FR, et al., Life expectancy in patients surviving more than 5 years after hematopoietic cell transplantation, J Clin Oncol, 2010;28:1011–6.
18. Pidala J, Kurland B, Chai X, et al., Patient-reported quality of life is associated with severity of chronic graft-versus-host disease as measured by NIH criteria: report on baseline data from the Chronic GVHD Consortium, Blood, 2011;117:4651–7.
19. Deeg HJ, Lin D, Leisenring W, et al., Cyclosporine or cyclosporine plus methylprednisolone for prophylaxis of graft-versus-host disease: a prospective, randomized trial, Blood, 1997;89:3880–7.
20. Storb R, Deeg HJ, Pepe M, et al., Graft-versus-host disease prevention by methotrexate combined with cyclosporin compared to methotrexate alone in patients given marrow grafts for severe aplastic anaemia: long-term follow-up of a controlled trial, Br J Haematol, 1989;72:567–72.
21. Kansu E, Gooley T, Flowers ME, 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, Blood, 2001;98:3868–70.
22. Bacigalupo A, Van Lint MT, Occhini D, et al., Increased risk of leukemia relapse with high-dose cyclosporine A after allogeneic marrow transplantation for acute leukemia, Blood, 1991;77:1423–8.
23. Sullivan KM, Storek J, Kopecky KJ, 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, Biol Blood Marrow Transplant, 1996;2:44–53.
24. Antin JH, T-cell depletion in GVHD: less is more?, Blood, 2011;117:6061–2.
25. Soiffer RJ, Lerademacher J, Ho V, 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, Blood, 2011;117:6963–70.
26. Kolb HJ, Graft-versus-leukemia effects of transplantation and donor lymphocytes, Blood, 2008;112:4371–83.
27. Barnes DW, Corp MJ, Loutit JF, Neal FE, Treatment of murine leukaemia with X rays and homologous bone marrow; preliminary communication, Br Med J, 1956;2:626–7.
28. Weiden PL, Flournoy N, Thomas ED, et al., Antileukemic effect of graft-versus-host disease in human recipients of allogeneicmarrow grafts, N Engl J Med, 1979;300:1068–73.
29. Finke J, Bethge WA, Schmoor C, et al., Standard graft-versushost 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, Lancet Oncol, 2009;10:855–64.
30. Bacigalupo A, Lamparelli T, Bruzzi P, 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), Blood, 2001;98:2942–7.
31. Bacigalupo A, Lamparelli T, Barisione G, et al., Thymoglobulin prevents chronic graft-versus-host disease, chronic lung dysfunction, and late transplant-related mortality: long-term follow-up of a randomized trial in patients undergoing unrelated donor transplantation, Biol Blood Marrow Transplant, 2006;12:560–5.
32. 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 Transplantation, 2014;49:126–30.
33. 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 Transplantation, 2012;47:1105–11.
34. Kroger N, Solano C, Wolschke C, et al., Antilymphocyte Globulin for Prevention of Chronic Graft-versus-Host Disease, N Engl J Med, 2016;374:43–53.