Graft-versus-host disease (GvHD) remains a major complication of allogeneic bone marrow transplants (BMT) and will predict morbidity and mortality.1,2 GvHD is classified as acute GvHD or chronic GvHD, according to whether it occurs before or after day +100 after an allogeneic BMT: this rigid time point may not be always valid, and changing transplant procedures may also change the timing of GvHD. However, whatever the time point one wishes to take, increasing severity of acute and chronic GvHD will have both short-term and long-term effects. Transplant-related mortality (TRM) for patients with acute GvHD grades 0, I, II, III, IV is, respectively, 28, 27, 43, 68, 92%.1 For chronic GvHD, the 3-year risk of TRM is 28% if limited and 48% if extensive.2 Treatment of chronic GvHD has made little progress over the past three decades, with average mortality remaining stable at 24%,3 and intensified immunosuppression does not seem to improve survival.4,5
Several programs have been developed to prevent GvHD: depletion of donor T cells from the stem cell harvest,6 the so-called 'ex vivo T-cell depletion', the use of T-cell antibodies in vivo referred to as 'in vivo T-cell depletion'7 and combined immunosuppressive therapy post-transplant.8 As to the latter, the preferred associations are cyclosporin (CsA)+methotrexate (MTX) or FK506 and MTX,8 and these are now considered standard.
GvHD is increased in patients receiving alternative donor grafts, both unrelated donor (UD) and family mismatched, when compared to transplants from HLA-identical siblings,9,10 when using standard CsA+MTX or FK506+MTX. Antithymocyte globulin (ATG) has been added to conventional CsA+MTX prophylaxis in many centers for patients undergoing an UD transplant.7 This practice has not become uniform and, although GvHD seems to be reduced when using ATG, the increased risk of infections has discouraged other centers from using ATG pre-transplant. In this report, we review the available data on the use of ATG in allogeneic BMT, as determined by retrospective comparative studies, or prospective trials.
In this review, we will use two abbreviations: ALG (antilymphocyte globulin) and ATG (antithymocyte globulin). Currently there are three commercial preparations: from France, Germany and the USA. The French-based preparation (Merieux, now Genzyme – Sangstat; Lyon, France) includes horse ALG (Lymphoglobulin) and rabbit ATG (Thymoglobulin). The German product (Fresenius) includes only rabbit antibodies (ATG-F, or ATG Fresenius, Grafelfing, Germany); it is produced against a Jurkatt cell line, which resembles activated T cells. The USA product, ATG Pharmacia (ATGAM, Pharmacia Upjohn, Kalamazoo, Michigan, USA), is derived from horses immunized with human thymocytes. There used to be (1970–1980) a horse ALG produced in Switzerland (Berna), which was intensively used in aplastic anemia trials, and there used to be (1970–1980) a rabbit ALG produced in the Netherlands. When talking about doses, it is important that we quote the specific commercial product, because the immunosuppressive activity varies significantly from one preparation to the other, and, as a consequence, the dosage is quite different. The conventional dose of ATG as part of the conditioning regimen would be 7.5 mg/kg for Thymoglobulin; 40–60 mg/kg for ATG Fresenius, 60 mg/kg for Lymphoglobulin; 60 mg/kg for ATGAM. It is also clear that, when deriving these regimens from the publications, one should be very cautious.
Current use of ALG/ATG in Europe
Antilymphocyte globulin (ALG) was first used in Europe by George Mathe and then Bruno Speck11,12 in the setting of BMT, but the fact is that ALG/ATG is still very popular among European transplant Centres. This is shown by the number of abstracts on ALG/ATG at the last annual meeting of the European Group for Blood and Marrow Transplantation (EBMT) in Barcelona (March 2004):13 there were 31 abstracts dealing with the use of ALG/ATG, and these abstracts involved some 2130 patients undergoing an allogeneic transplant. The reports came mainly from Germany (n=9), Italy (n=5), France (n=4), Belgium (n=2), Poland (n=2), UK (n=2), and one each from Turkey, Sweden, Israel, Iran, Check Republic, and Denmark. One exception among the large countries is Spain, apparently because transplanters use other forms of GvHD prophylaxis, such as positive CD34 selection.
Most reports at the EBMT meeting dealt with GvHD prophylaxis in the context of UD transplants, and reduced intensity conditioning (RIC) regimens: in all studies, the use of ALG/ATG produced a reduction of both acute and especially chronic GvHD. There were studies on immune reconstitution in patients receiving different doses of ALG/ATG, or different commercial preparations, and on serum levels of the agents after transplant. Others compared the outcome of patients receiving ALG/ATG or alentuzumab (CAMPATH). Infections were the primary aim of some abstracts, which associated such complications, including Epstein–Barr virus (EBV)-related lymphoproliferative diseases (LPDs) with the use of ALG/ATG. There was only one prospective randomized trial from the Italian cooperative transplant group (GITMO), and this was also the only report on the use of ATG for treatment of acute GvHD, which proved negative.14
Currently, ATG is used in Europe for GvHD prophylaxis in patients at high risk of GvHD: this includes UD transplants, and reduced intensity (RIC) transplants. ATG is also used in the haploidentical setting, with the aim of reducing rejection and GvHD.
ALG/ATG acute GVHD prophylaxis trials
Randomized trials
There have been three randomized trials testing the hypothesis that ALG/ATG would prevent acute GvHD.15,16,17 The first trial tested early treatment rather than prophylaxis.15 The second was published in 1982 by Ramsay et al16: in this study, HLA-identical sibling transplant recipients were given methotrexate (MTX) as initial GvHD prophylaxis, and were then randomized to receive (n=32) or not to receive (n=35) seven doses of ALG starting on day +8. Acute GvHD was diagnosed in 21% of patients randomized to receive ALG compared to 48% for patients not receiving ALG (P<0.01). Severe (grade III–IV) was seen, respectively, in 20 and 6% (P=0.07) (Table 1). In a more recent report, 109 patients with hematologic malignancies, undergoing UD-BMT, were randomized to receive or not ATG in the conditioning regimen.17 The first 54 patients were randomized to non-ATG (n=25) or 7.5 mg/kg rabbit ATG (Thymoglobulin) (n=29) and grade III–IV GvHD was comparable in the two arms (36 vs 41%, respectively, P=0.8). The next 55 patients were randomized to the non-ATG arm (n=28) or to receive ATG 15 mg/kg (n=27), and acute GvHD grade III–IV was significantly reduced in patients receiving ATG (50 vs 11%, P=0.001) (Table 1). The highly significant difference was not solely due to the increased dose of ATG: in fact, the first group received 3.75 mg/kg on days -4, -3, whereas the second group received 3.75 mg/kg on days -5, -4, -3, and -2. As a consequence, the second group was given more ATG and closer to transplant. This raises the issue of timing of ATG and will be discussed in more detail.
Table 1 - Acute GvHD in patients receiving or not receiving ATG in the conditioning regimen.
Full table Comparative nonrandomized studies
There are numerous retrospective studies showing that acute GvHD is less frequent and less severe in patients receiving ALG/ATG in the conditioning regimen.18,19,20,21,22,23,24,25,26,27,28,29,30 One of these23 was the result of a joint effort between the transplant units in Huddinge and in Seattle: all patients received marrow from UDs, in Huddinge with the addition of ATG in the conditioning regimen (N=52), in Seattle with no ATG (N=104). Patients were matched for clinical characteristics and relevant predictors of outcome. Patients receiving ATG had less grade II acute GvHD (12 vs 55%, P<0.00001), less grade III–IV acute GvHD (0 vs 30%, P<0.00001).23
Recently, the German cooperative group studied 155 patients with acute myeloid leukemia (AML) undergoing an allogeneic UD transplant: 87 received ATG as part of the conditioning regimen, whereas 68 did not. Grade III–IV acute GvHD was seen in 12% of the ATG patients vs 22% of the non-ATG patients (P=0.04)24 (Table 1).
In transplants from HLA-identical siblings, ATG is not frequently used: however, the Hamburg group has compared the outcome of good-risk myeloid leukemia patients who received a conditioning regimen with (n=45) or without ATG (n=57).25 Acute GvHD II–IV was seen in 20% of ATG patients vs 47% of non-ATG patients (0.004), and grade III–IV was seen in 7 vs 32% (P=0.002). The Alberta group in Canada has gone further still, and has completed a matched pair analysis of MUD transplants receiving ATG in the conditioning regimen, with HLA-identical sibling transplants not receiving ATG.26 In this study, all patients received the FLUBUP regimen (fludarabine, intravenous busulfan, peripheral blood allogeneic stem cells). Acute GvHD grade II was 19 vs 36% for patients receiving or not ATG, grade III–IV was 10 vs 18%. This study suggests that patients receiving UD PB transplants with ATG have less acute GvHD when compared to patients receiving HLA-identical sibling PB transplants without ATG (Table 1).
Both prospective randomized and retrospective studies indicate that acute GvHD is significantly reduced in patients receiving ATG as part of the conditioning regimen (Figure 1).
Figure 1.
Percentage of patients with acute GvHD (grade II+) (first pair of bars on the left), chronic GvHD (second pair of bars) and percentage of patients surviving (at 2 years) (third pair of bars on the right). The upper graph represents results from prospective randomized trials with 88 patients in each arm (no-ATG or ATG). The lower graph represents results from retrospective studies, with 588 patients in the no-ATG and 511 patients in the ATG arm. Both graphs show a significant reduction of acute GvHD and chronic GvHD. As to survival, there is a modest increment in the prospective trials (upper graph).
Full figure and legend (118K)ALG/ATG prevents chronic GvHD
Randomized trials
There are no randomized studies designed to address this question specifically. However, in the GITMO randomized study,17 extensive chronic GvHD developed overall more frequently in patients not receiving ATG as compared to patients receiving ATG (62 vs 39%, P=0.04) (Table 2). An update of that study with an additional follow-up of 4 years (unpublished) shows that chronic GvHD (limited+extensive) is seen in 68 vs 31% of non-ATG vs ATG patients (P=0.002).
Table 2 - Chronic GvHD in patients receiving or not receiving ATG in the conditioning regimen.
Full table Phase II nonrandomized retrospective studies
In one retrospective analysis, alternative donor transplants were stratified according to whether they had received (n=102) or not (n=58) ATG in the conditioning regimen.28 The two groups were matched for disease phase, diagnosis, donor age, interval diagnosis transplant, and number of cells infused at the time of transplant. In the ATG group, there were significantly less patients with chronic GvHD (35 vs 63%) (Table 2). Although survival was comparable in the two groups, there were more ATG patients with a Karnowski score greater than 90 (P=0.01) and more patients off cyclosporin 2-year post-transplant (P=0.003). In the study from the Hamburg group25 in HLA-identical siblings, there was a similar significant reduction of chronic GvHD: in the ATG group, the risk of developing cGvHD was 36 vs 67% for non-ATG patients (P=0.005).25 Extensive chronic GvHD in the same study was 17 vs 33% (P=0.08) (Table 2). It is interesting that both the Genova and Hamburg studies show a 30% reduction of chronic GvHD in patients receiving ATG. Other retrospective studies confirm that ATG pre-transplant reduces the risk of chronic GvHD26,27,28,29,30,31 (Russell JA, personal communication) (Table 2).
These studies show that ATG given pre-transplant reduces significantly the incidence and severity of chronic GvHD: although survival seems unaffected, quality of life may be improved and time to come off cyclosporin may be shortened in the ATG group (Figure 1).
Dose and timing of ATG
If one wishes to use ATG in the conditioning regimen, two important questions arise: what is the optimal dose, what is the optimal timing. As already outlined in the Introduction, one should first be aware that different commercial ATG preparations have different potencies and therefore should be used in different dosages.
The total dose (in mg/kg) does make a difference, as suggested by two randomized studies comparing ATG (Thymoglobulin) 15 mg/kg vs controls and 7.5 mg/kg vs controls.17 Also, timing however may be quite relevant: in a retrospective study on 257 patients allografted from alternative donors,31 we could show a reduction of acute GvHD depending on ATG timing: the lowest risk was in patients given ATG on day +1 or +7 post transplant. The same effect was seen on chronic GvHD. In multivariate analysis, both timing of ATG (P=0.002) and ATG dose (P=0.003) were significant predictors of acute GvHD grade II–IV.31 The French report by Mohty et al32 confirms the impact of ATG dose on the occurrence of acute GvHD. In a dose-finding study, Meijer et al33 recommend 6–8 mg/kg of ATG Sangstat-Genzyme. The Canadian protocol FLU-BUP, comprising fludarabine, intravenous busulfan, and peripheral blood allogeneic transplants, uses a small dose of Thymoglobulin (4.5 mg/kg), but the infusion of ATG ends on the day of transplant, and results seem excellent.26 For ATG Fresenius, the total recommended dose is 60 mg/kg.34
Therefore, when using ATG in the conditioning regimen, one needs to consider (a) the ATG brand, (b) the dose, which will depend on the ATG brand, and (c) the timing. If one gives ATG 3–4 days before HSCT, the dose will need to be high; if one gives ATG on the day of transplant, then the dose can be significantly lower.
Adverse effects of ATG: delayed immune reconstitution and infections
The administration of ATG during the conditioning regimen produces in vivo T-cell depletion: indeed, serum levels of ATG on the day of transplant may be quite significant, depending on the interval between the last day of ATG infusion and the transplant, and serum levels may be high for several weeks post transplant.35 As a consequence, there is downregulation of mature T cells infused on day zero, and of newly generated lymphocytes post-graft. There have been several recent studies looking at immune recovery after HSCT with or without ATG.36,37,38,39,40,41 All of these reports agree that T-cell recovery is delayed when patients receive ATG, and as a consequence there is an increased risk of infections, depending on the dose of ATG administered. Not all studies report an increased risk of infections, and the Japanese group of Nakai et al37 shows equally distributed infections in patients receiving a RIC transplant with or without ATG. One of the reports at the EBMT meeting 2004 suggests that there may be differences between ATG Sangstat-Genzyme and ATG Fresenius: the former would produce more pronounced and prolonged in vivo T-cell depletion.42 Hematologic reconstitution may also be delayed with high-dose ATG.16
ATG given in the conditioning regimen will delay immune reconstitution and hematologic reconstitution, especially when using high-dose ATG. This should be carefully considered and appropriate monitoring of viral infections should be in place (Table 3).
EBV infections
EBV is one important complication of prolonged immune deficiency: risk factors for EBV are alternative donor transplants, ex vivo T-cell depletion, the use of ATG, acute GvHD, and its treatment.43 In other words, all patients who have few circulating T cells and still have B cells are at risk of developing EBV reactivation. Quantitative PCR can now be used to monitor EBV viremia, and assess whether the viral load exceeds 1000 DNA copies/105 cells. In the latter case, early treatment with an antiCD20 antibody (Mabthera) is recommended and does prevent the occurrence of an EBV (often lethal) lymphoma.43,44 In patients undergoing an alternative donor transplant, EBV reactivation is high (over 50%) and occurs at a median interval of 45 days from HSCT.44 The risk of developing a post-transplant LPD is high in patients with over 1000 DNA copies/105 cells (33%) as compared to patients with <1000 copies (2%).44 Mabthera given to patients with >1000 DNA EBV copies (pre-emptive therapy), before there are clinical signs of LPD, is very effective (90% in our experience).44
EBV reactivation is a very frequent event in patients undergoing alternative donor HSCT with ATG in the conditioning regimen, and patients should be monitored weekly with quantitative PCR; the viral load is a significant predictor of LPD; early treatment with mabthera is highly successful and is indicated for patients reactivating with a high EBV load (more than 1000 copies) (Table 3). Prophylactic mabthera may be considered in a prospective trial.
Does ATG reduce TRM
In two randomized studies,16,17 although GvHD was significantly reduced, TRM and survival were comparable in patients receiving or not receiving ATG: this is due to a higher risk of infections in patients receiving ATG.17 In the retrospective Seattle/Huddinge study, patients receiving ATG had a lower TRM (6 vs 21%) with borderline statistical significance (P=0.05),23 Also, the German study (again retrospective) reports improved survival in patients receiving ATG.22 Although we should be cautious about improved survival with ATG, we should note that none of the numerous retrospective studies7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30 reports decreased survival in patients receiving ATG.
It is reasonable to say that ATG given in the conditioning regimen does not seem to reduce TRM in the short term (first years). Whether a reduction will be seen in the long term (
10 years) as a consequence of less chronic GvHD is at present unknown (Figure 1).
RIC regimens
RIC transplants have been designed for elderly or unfit patients and can be performed with relatively low toxicity.45 The preferred stem cell source is peripheral blood and the preferred GvHD prophylaxis is cyclosporin+methotrexate (CsA+MTX) or CsA+mycofenolate (MMF). The agents used in the conditioning include low-dose total body irradiation (TBI) 200 cGy,46 Busulfan (BU) 8 mg/kg,47 Thiotepa (THIO) 10 mg/kg48 or melphalan (MEL) 140 mg/m2,49 most of them in combination with fludarabine. Extensive chronic GvHD is seen in a considerable proportion of patients, unless ATG47 or alentuzumab49 is given in the conditioning regimen. We can therefore divide RIC regimens into two categories: the ones that do not use in vivo T-cell depletion, such as the Seattle protocol with TBI 200 cGy, and programs with ATG or alentuzumab, such as the original Slavin busulfan protocol47 and the program at University College in London.49 Some centres have used ATG extensively in RIC programs, also addressing the issue of ATG dose.32 A recent report from Kroger et al50 shows very encouraging results in a difficult disease such as multiple myeloma.
ATG is used in several RIC programs. Reduction of chronic GvHD in this elderly group of patients seems desirable and can be achieved with ATG. Prospective studies are needed to assess the optimal ATG dose and timing.
Are different brands of ATG any different?
There have been no prospective comparisons of different ATG preparations, possibly because most groups are active in assessing the optimal dose and timing of one ATG brand, available in that country.
There have been two retrospective comparisons of ATG Sangstat-Genzyme and ATG Fresenius.24,27 The first study looked at patients with acute myeloid leukemia grafted from UDs in Germany: 49 received ATG Sangstat-Genzyme and 46 received ATG Fresenius. Chronic GvHD was more frequent in the ATG Sangstat patients (40 vs 20%) and there was a trend for improved survival in the ATG Sangstat group, due to reduced leukemia relapse.24 The second study, in patients with chronic myeloid leukemia, showed again more chronic GvHD in patients receiving ATG Sangstat (24%, n=46 vs 0%, n=14), but the trend for improved survival was in the ATG Fresenius patients.27
Different ATG brands are different. The biologic effect is different, the impact on GvHD is different, and possibily also the infectious complications may differ. A prospective comparison in homogeneous patients is needed to test whether the difference in chronic GvHD can be confirmed, and whether this will impact leukemia relapse.
Future perspectives
The trend in allogeneic HSCT shows increased use of alternative donors and of peripheral blood as a stem cell source.51 Alternative donor transplants are associated with more acute and chronic GvHD, despite the fact that bone marrow is still used in a large number of cases.52 Peripheral blood transplants have been shown to increase the risk of chronic GvHD,53 despite the use of cyclosporin methotrexate as post-transplant immunosuppression. The use of peripheral blood grafts from UDs is now increasing, and thus combines two significant predictors of chronic GvHD: stem cell source and donor type. In the present report, we have reviewed the studies suggesting that ATG reduces significantly both acute and chronic GvHD.
One could of course argue: but why use and old drug such as ATG, when we have monoclonal antibodies like alentuzumab, which abrogate both acute and chronic GvHD.40 The answer is simple: we should test both agents, and we could also envisage comparing one of the commercially available ATG with alentuzumab. The final outcome of an allogeneic transplant depends on control of GvHD, control of relapse, and control of long-term sequelae, and we still have a long way to go to have more patients free of leukemia, free of GvHD with good quality of life. At least we know that outcome can be modified, depending on the way we prepare our patients for transplant: in vivo T cell depletion is one component of the conditioning regimen and needs to be looked at carefully and prospectively.
References
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