Acute Leukemias

Antithymocyte globulins and chronic graft-vs-host disease after myeloablative allogeneic stem cell transplantation from HLA-matched unrelated donors: a report from the Sociéte Française de Greffe de Moelle et de Thérapie Cellulaire

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Abstract

This retrospective report assessed the impact of rabbit antithymocyte globulins (ATG), incorporated within a standard myeloablative conditioning regimen prior to allogeneic stem cell transplantation (allo-SCT) using human leukocyte antigen-matched unrelated donors (HLA-MUD), on the incidence of acute and chronic graft-vs-host disease (GVHD). In this series of leukemia patients, 120 patients (70%) did not receive ATG (‘no-ATG’ group), whereas 51 patients received ATG (‘ATG’ group). With a median follow-up of 30.3 months, the cumulative incidence of grade 3–4 acute GVHD was 36% in the no-ATG group and 20% in the ATG group (P=0.11). The cumulative incidence of extensive chronic GVHD was significantly lower in the ATG group as compared to the no-ATG group (4 vs 32%, respectively; P=0.0017). In multivariate analysis, the absence of use of ATG was the strongest parameter associated with an increased risk of extensive chronic GVHD (relative risk)=7.14, 95% CI: 1.7–33.3, P=0.008). At 2 years, the probability of nonrelapse mortality, relapse, overall and leukemia-free survivals was not significantly different between the no-ATG and ATG groups. We conclude that the addition of ATG to GVHD prophylaxis resulted in decreased incidence of extensive chronic GVHD without an increase in relapse or nonrelapse mortality, and without compromising survival after myeloablative allo-SCT from HLA-MUD.

Introduction

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is an effective treatment modality for a number of hematological malignancies that are resistant to standard chemotherapy.1 Allo-SCT is presently considered the only treatment modality with curative potential for different disease categories. Unfortunately, more than 65% of the patients who could benefit from allo-SCT do not have a human leukocyte antigen (HLA)-matched sibling. The lack of suitable HLA-matched related donors has led to the use of alternative donors, such as HLA-matched unrelated donors (HLA-MUD).2, 3, 4 However, despite significant improvements in HLA matching techniques,5, 6 allo-SCT from MUD is still limited by the immunological recognition and destruction of host tissues, termed graft-vs-host disease (GVHD). Both in its acute and chronic forms, GVHD continues to be the major source of morbidity and mortality following allo-SCT, and the risk of severe GVHD is well admitted to increase with the level of HLA mismatches between recipient and donor.7, 8 In one study, the rate of clinically significant acute GVHD increased from 29% for recipients of HLA genotypically identical sibling grafts to 63% for recipients of one antigen incompatible unrelated donor grafts.9 In the standard myeloablative conditioning (MAC) allo-SCT setting using HLA-matched related or unrelated donors, the classical prophylaxis of GVHD consists of administration of a calcineurin inhibitor (cyclosporine A or tacrolimus) combined with low-dose methotrexate. This regimen results in approximately 35 and 45% incidence of grade 2–4 acute and chronic GVHD after allo-SCT using matched-related donors,10, 11 whereas these incidences are 60 and 70% in the MUD transplant setting.12 Attempts are therefore needed to improve GVHD prophylaxis in the MUD allo-SCT setting.13 The aim of this multicenter retrospective report was to assess the impact of rabbit antithymocyte globulins (ATG), incorporated within a standard MAC regimen prior to allo-SCT using HLA-MUD, on the incidence and severity of both acute and chronic GVHD.

Materials and methods

Study design, inclusion criteria, clinical evaluation and data collection

This was a multicenter, retrospective, registry-based study that included patients with acute leukemia and myelodysplastic syndromes (MDS) who received allo-SCT from HLA-MUD and reported to the registry of the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC). The study was approved by the scientific board of the SFGM-TC. The SFGM-TC registry is a national working group of all stem cell transplant centers in France, participants of which are required to report all consecutive stem cell transplantations and follow-up. Participating centers were requested to report on patients (1) aged 15 years, (2) who received allo-SCT from an HLA-MUD, (3) who had acute leukemia (AML or ALL) or MDS, (4) who received a standard MAC regimen including or not ATG prior to allo-SCT, (5) whose detailed HLA typing was available and (6) whose clinical data on outcomes were adequate. Only patients receiving the ATG brand Thymoglobuline (Genzyme Corporation, Cambridge, MA, USA) were included because this is the only ATG brand approved in France for use in allo-SCT. Patients receiving previous allo-SCT and/or autologous transplantation were not excluded from this analysis. Using these criteria, we identified 171 consecutive patients, of whom 120 patients (70%) did not receive ATG (‘no-ATG’ group) during conditioning, whereas 51 patients received ATG (‘ATG’ group; Thymoglobuline in all cases) as part of their standard MAC regimen. Each local clinical investigator was requested to report detailed demographic and clinical data including disease type, age, gender, pretransplant disease status, time between diagnosis and transplant, stem cell source, conditioning regimen, GVHD prophylaxis regimen, engraftment, frequency and grade of acute or chronic GVHD, post-transplant disease progression, severe infectious complications, cause of death and patient status at last follow-up.

HLA typing

Detailed HLA data were obtained from the ‘Agence de Biomédecine’ (Paris, France), which is the national French agency centralizing the search for alternative donors for allo-SCT. All donor–recipient pairs were typed at the allelic level. They were first typed at the two-digit level for HLA class I (HLA-A, HLA-B and HLA-Cw) and class II (HLA-DRB1 and HLA-DQB1) using published HLA class I polymerase chain reaction sequence-specific oligonucleotide (PCR-SSO) and/or PCR sequence-specific primers (PCR-SSP) typing protocols. HLA-A, HLA-B, HLA-Cw, HLA-DRB1, HLA-B3, HLA-B4, HLA-B5 and HLA-DQB1 subtyping was performed using different PCR-SSP kits. HLA typing was performed according to the current use of the European Federation for Immunogenetics Histocompatibility Laboratory standards. Additional assays using sequence-specific amplification and direct DNA sequencing of amplified DNA were used as needed in specific cases to aid in allelic identification without ambiguities. Interpretation of typing results was based on alleles described in the WHO HLA nomenclature (four digits).14 Samples from donors and recipients with only a single allele identified by specific PCR or sequence analysis were assumed to be homozygous after review of transplantation center typing.

Patients and transplant procedures

The characteristics of patients, diseases and transplants are given in Table 1. The majority of patients (84%) received a total body irradiation (TBI; 12 Gy)-based MAC regimen (cyclophosphamide and TBI), whereas the remaining patients received high-dose chemotherapy (mainly cyclophosphamide and busulfan) without TBI for conditioning. In the ‘ATG group’, various total doses of ATG were used at the discretion of the attending physician (total ATG dose: 5 mg/kg, n=13; >5 and <10 mg/kg, n=17; 10 mg/kg, n=21) as part of the MAC regimen. Per study, patients from the no-ATG group did not receive ATG during conditioning. Because the use of ATG in the setting of standard MAC allo-SCT is still controversial,15 the decision to incorporate or not ATG as part of the MAC regimen depended on each center's policy. The majority of patients from both groups (85%) received cyclosporine A and short-course methotrexate (15 mg/m2 at day +1, 10 mg/m2 at day +3 and 10 mg/m2 at day +6) for GVHD prophylaxis.16 The day of cell infusion was designated as day 0. According to current practice in France, prophylactic G-CSF after transplantation was not routinely used. Patient management was performed according to the standard procedures of each center and was expected to be the same in the two groups for a given center.

Table 1 Comparison of patients, donors and transplant characteristics between the no-ATG and ATG groups

Study end points and statistical analysis

The aim of this analysis was to estimate the effect of ATG used as part of the MAC regimen in the HLA-MUD setting on post-transplantation outcome, adjusting for other risk factors. Primary end points were acute GVHD grade 3 or 4 and extensive chronic GVHD. Secondary end points were neutrophils and platelets recovery, overall (OS) and leukemia-free survival (LFS), relapse and nonrelapse mortality (NRM). Acute GVHD was evaluated according to standard criteria.17 Chronic GVHD was defined as any GVHD present after day 100. Limited or extensive chronic GVHD was defined according to standard criteria.18 LFS was defined as survival without evidence of relapse or progression. Patient-, disease- and transplant-related variables of the two groups (receiving or not ATG) were compared, using the χ2-statistic for categorical and the Mann–Whitney test for continuous variables. Variables considered were recipient age, sex and cytomegalovirus serology; ABO group, disease characteristics, donor characteristics (age, gender, cytomegalovirus serology, HLA typing), history of prior stem cell transplantation, disease characteristics; allo-SCT characteristics (MAC regimen, GVHD prophylaxis and stem cell source). Cumulative incidence curves were used in a competing risks setting, death being treated as a competing event to calculate probabilities of acute and chronic GVHD, neutrophil and platelet recovery, NRM and relapse.19 Probabilities of survival and LFS were calculated using the Kaplan–Meier estimate. For univariate analysis, the Gray test and the log-rank test were used to compare cumulative incidence curves and Kaplan–Meier curves, respectively. Factors differing in distribution between the two groups with a P-value <0.10 and factors associated with a nonrestrictive P-value of 0.15 in univariate analyses were included in the multivariate analyses, using proportional subdistribution hazard regression model of Fine and Gray20 for other outcomes. All P-values are two sided with type I error rate fixed at 0.05. Statistical analyses were performed with SPSS (SPSS Inc., Chicago, IL, USA) and R 2.9.0 software packages (R Development Core Team, Vienna, Austria).

Results

Patients and donors characteristics

A total of 171 patients were included in this retrospective analysis. The median age was 33 (range, 15–62) years. The cohort included 57% male recipients, 35% female donors, 44% AML, 43% ALL, 11% MDS and 2% unclassified leukemias. The stem cell source was bone marrow in 72.5% of patients, whereas G-CSF-mobilized peripheral blood stem cells were used in 27.5% of cases. In total, 81% of patients were transplanted from 10/10 allelic HLA-MUD and 19% from an MUD with at least one allelic difference. In this series, 120 patients (70%) did not receive ATG (no-ATG group), whereas 51 patients received ATG (ATG group) as part of the MAC regimen. There was a significantly higher number of allelic differences between the recipient and the donor between the ATG group and the no-ATG group (33 vs 13%, P=0.002), suggesting that centers were more inclined to use ATG in case of HLA alleles mismatches as previously reported.21 Except for this difference, the no-ATG and ATG groups were comparable relative to patient, disease and transplant characteristics (Table 1).

Engraftment and GVHD

Transplant-related events and outcome data for the whole study population and according to the use of ATG or not are summarized in Table 2. The cumulative incidence of ANC>500 per μl at day 30 was 95% in the overall population. It was 93% in the no-ATG group and 98% in the ATG group (P=0.20). The cumulative incidence of grade 2–4 acute GVHD was 54% (53% in the no-ATG group and 57% in the ATG group, P=0.33). The cumulative incidence of grade 3–4 acute GVHD was 31% (36% in the no-ATG group and 20% in the ATG group, P=0.11; Figure 1a). The cumulative incidence of chronic GVHD (both limited and extensive forms) was 41% (44% in the no-ATG group vs 32% in the ATG group, P=0.26). However, the cumulative incidence of extensive chronic GVHD was significantly lower in the ATG group as compared to the no-ATG group (4 vs 32%, respectively, P=0.0017; Figure 1b). In the subgroup of 138 patients who received allo-SCT from 10/10 HLA-MUD (10 out of 10 alleles), the cumulative incidence of grade 3–4 acute GVHD was 35±6% in the no-ATG group vs 9±5% in the ATG group (P=0.017). Also, in this same subgroup, the cumulative incidence of extensive chronic GVHD at 2 years was 32±5% in the no-ATG group vs 3±3% in the ATG group (P=0.005). Univariate analyses of risk factors for grade 3–4 acute GVHD and for extensive chronic GVHD are shown in Tables 3 and 4, respectively. In multivariate analysis including all relevant risk factors tested in the univariate analysis, we found that male recipient, HLA allelic mismatch and the absence of use of ATG were associated with an increased risk of severe grade 3–4 acute GVHD (relative risk (RR)=1.89, 95% CI: 1.02–3.57, P=0.05; RR=2.86, 95% CI: 1.64–5, P=0.0002 and RR=2.08, 95% CI: 1.04–4.17, P=0.04, respectively). Multivariate analysis showed that the absence of use of ATG as part of the conditioning regimen was the unique and strongest parameter associated with an increased risk of extensive chronic GVHD (RR=7.14, 95% CI 1.7–33.3, P=0.008).

Table 2 Transplant-related events
Figure 1
figure1

(a) Cumulative incidence of grade 3–4 acute GVHD (solid line: no-ATG group; dotted line: ATG group; P=0.11); (b) cumulative incidence of extensive chronic GVHD (solid line: no-ATG group; dotted line: ATG group; P=0.0017).

Table 3 Univariate analysis of risk factors for grade 3–4 acute GVHD
Table 4 Univariate analysis of risk factors for extensive chronic GVHD (2 years cumulative incidence)

Outcome

The median follow-up after allo-SCT was 30.3 (range, 2.6–68.1) months. In the total population at 2 years, the probability of OS was 54±4% (53% in the no-ATG group vs 54% in the ATG group, P=0.71; Figure 2a). The probability of LFS at 2 years was 47±4% (49% in the no-ATG group vs 45% in the ATG group, P=0.5; Figure 2b). Also, when considering the advanced disease subgroup of patients (n=46), there was no statistically significant difference for OS between the no-ATG and ATG groups (P=0.14). Overall, 79 patients have died. The different causes of death were comparable between the no-ATG and ATG groups. Of note, infection-related mortality was comparable between the two groups (27% in the ATG group vs 23% in the no-ATG group; Table 2). The NRM rates at 2 years were 31±4% (31 and 29% in the no-ATG and ATG groups, respectively, P=0.95; Figure 2c).

Figure 2
figure2

(a) Overall survival (solid line: no-ATG group; dotted line: ATG group; P=0.71); (b) leukemia-free survival (solid line: no-ATG group; dotted line: ATG group; P=0.5); (c) cumulative incidence of nonrelapse mortality (solid line: no-ATG group; dotted line: ATG group; P=0.95).

Discussion

The use of ATG in the setting of standard MAC allo-SCT is still controversial.15 The current analysis suggested a protective effect of ATG against severe acute and chronic GVHD, when used as part of an MAC regimen and allo-SCT from HLA-MUD without an increased risk of graft failure, infections, or compromising disease response or occurrence of B-cell lymphoproliferative disorders that are usually observed after T-cell depletion for allo-SCT.22, 23 Although previous studies have shown that removal of T cells from the graft by ex vivo T-cell depletion resulted in a dramatic decrease in acute GVHD, this has been shown to be associated with a significant increase in graft failure and the risk of relapse,24, 25, 26 even in studies in which T-cell add-back has been investigated.27, 28 An alternative strategy is to provide for in vivo T-cell depletion by using ATG.

Recently, Finke et al.29 conducted a prospective, randomized, multicenter, phase III trial comparing standard GVHD prophylaxis with cyclosporine and short-course methotrexate with or without ATG. Results from this prospective study showed that the addition of ATG-Fresenius to GVHD prophylaxis resulted in decreased incidence of acute and chronic GVHD without an increase in relapse or NRM, and without compromising OS. Though this prospective trial tested a different ATG brand, used peripheral blood-derived grafts and required donors and recipients to be HLA compatible only at HLA-A, HLA-B, HLA-DRB1 and HLA-DQB1 (eight out of eight alleles), these results are very superimposable to the findings from the current retrospective study where the majority of donors and recipients (81%) were HLA compatible at the level of 10 out of 10 alleles and transplanted with unmanipulated bone marrow grafts. Of note, in this series, the beneficial effect of ATG on GVHD incidence and severity could be observed specifically in the subgroup of patients who received a 10 out of 10 HLA-MUD, further supporting the overall beneficial effect of ATG in the MUD allo-SCT setting.

Similarly, data from Bacigalupo et al.30 showed in the early 2000s that pretransplant ATG administration (Thymoglobuline) decreased the risk of acute and chronic GVHD. The long-term update (>5 years) from this group confirmed that the addition of ATG to cyclosporine/methotrexate provides significant protection against extensive chronic GVHD and chronic lung dysfunction, reduces late transplant mortality and improves long-term quality of life in patients undergoing unrelated donor transplantation.31 The latter suggests that extended follow-up is needed to see a meaningful long-term impact (especially quality of life and performance status) associated with the use of ATG. Unfortunately, given the retrospective nature of the current study, quality of life data was not available for assessment. However, patients in the ATG group experiencing less extensive chronic GVHD are likely to have a better quality of life than those in the non-ATG group.

One major issue associated with the use of ATG is the potential risk of a high incidence of opportunistic infections. This is likely true when using the highest ATG doses (>10 mg/kg in the case of Thymoglobuline),32 and one has to question the issue of the optimal ATG dosing. Also, one should bear in mind that this study only assessed the fatal infectious complications. Also, this study did not have sufficient statistical power to assess the impact of the total ATG dose on patients’ outcome. Also, this study did not capture the schedule of ATG application that, in addition to the total dose, might have a role in the overall outcome. However, based on our experience and different other reports,33, 34, 35, 36, 37, 38, 39 it is likely that the use of low (4.5 mg/kg) to moderate (7.5 mg/kg) doses of ATG prior to allo-SCT can decrease the risk of GVHD without increasing the risk of relapse.

From the pathophysiological standpoint, the use of antibodies in vivo to modulate GVHD reactions is appealing. Alemtuzumab is being tested with some promising results,40, 41 although the long half-life of alemtuzumab may result in delayed post-transplant immune reconstitution.42, 43 However, polyclonal antibodies such as ATG have a wider immunomodulatory activity.44 Interestingly, in the current series, ATG did not completely abrogate the risk of chronic GVHD. Patients in the ATG group had a higher incidence of limited chronic GVHD compared to the no-ATG group (33 vs 18%). Thus, patients were protected from deleterious extensive chronic GVHD, but still had some form of limited chronic GVHD that would allow for the graft-vs-leukemia effect. However, one may question why does such a beneficial effect of ATG in reducing severe acute and chronic GVHD not have an effect on survival? Indeed, measuring the outcome of allo-SCT therapy is difficult because the net outcome is affected by several complex variables that all might have a role in determining the final outcome. However, better GVHD prevention, even if it does not significantly improve survival, may still a reasonable approach.

In all, despite its retrospective nature, combined with the already available prospective data, our results indicate a global beneficial effect of ATG when used as part of the MAC regimen prior to allo-SCT from HLA-MUD. Although prospective studies are still needed to assess the optimal ATG dosing and administration schedule and whether ATG affects immune reconstitution, such protective effect of ATG against severe GVHD can be likely achieved without an increased risk of infections or leukemia recurrence. These results provide a framework for the refinement and further development of the use of ATG in allo-SCT (including quality of life and resource utilization measurements in a prospective manner), as this may have a significant effect on the probability of a favorable outcome.

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Acknowledgements

M Mohty thank the ‘Région Pays de Loire’, the ‘Association pour la Recherche sur le Cancer (ARC)’, the ‘Fondation de France’, the ‘Fondation contre la Leucémie’, the ‘Agence de Biomédecine’, the ‘Association Cent pour Sang la Vie’, and the ‘Association Laurette Fuguain’, for their generous and continuous support for his clinical and basic research work.

Authorship and DisclosuresAll authors listed in the article have contributed substantially to this work. Conception and design: M Mohty, H Espérou, and I Yakoub-Agha. Statistical analysis: M Mohty and M Labopin. Patient recruitment and clinical care: M Mohty, G Socié, N Milpied, N Ifrah, Y Hicheri, R Tabrizi, N Dhedin, M Michallet, A Buzyn, J-Y Cahn, J-H Bourhis, D Blaise, H Espérou and I Yakoub Agha. Collection and assembly of data: M Mohty, M L Balère, A Buzyn, H Espérou and I Yakoub-Agha. Manuscript writing and revisions: M Mohty. Final approval of manuscript: M Mohty, ML Balère, G Socié, N Milpied, R Tabrizzi, N Ifrah, Y Hicheri, N Dhedin, M Michallet, A Buzyn, J-Y Cahn, J-H Bourhis, D Blaise, C Raffoux, H Espérou and I Yakoub-Agha.

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Correspondence to M Mohty.

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Competing interests

Dr Mohty, Dr Milpied, Dr Blaise, Dr Michallet and Dr Buzyn have acted as a consultant to Genzyme whose product is discussed in this article.

Appendix

Appendix

We thank all other SFGM-TC participating centers who contributed to this study: CHU Hotel-Dieu, Paris (B Rio), CHU de Besancon (E Deconinck), CHU de Saint-Etienne (D Guyotat), CHU de Nice (A Sirvent), CHU de Toulouse (M Attal, A Hyun), CHU de Strasbourg (K Bilger, B Lioure), CHU de Poitiers (F Guilhot), CHU de Rennes (T Lamy), CHU de Rouen (N Contentin) and CHU de Brest (C Berthou).

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Keywords

  • ATG
  • GVHD
  • unrelated donors
  • allogeneic stem cell transplantation

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