Elsevier

The Lancet Haematology

Volume 7, Issue 2, February 2020, Pages e100-e111
The Lancet Haematology

Articles
Addition of anti-thymocyte globulin to standard graft-versus-host disease prophylaxis versus standard treatment alone in patients with haematological malignancies undergoing transplantation from unrelated donors: final analysis of a randomised, open-label, multicentre, phase 3 trial

https://doi.org/10.1016/S2352-3026(19)30220-0Get rights and content

Summary

Background

Previous trials testing prevention strategies for chronic graft versus host disease (GVHD) have measured its cumulative incidence. In this trial of anti-thymocyte globulin, we measured treatment-independence at a long-term timepoint as the primary endpoint.

Methods

This was a randomised, open-label, multicentre, phase 3 trial done at ten centres in Canada and one in Australia. Eligible patients had a haematological malignancy (leukaemia, myelodysplastic syndrome, or lymphoma), were between 16 and 70 years of age, eligible for transplantation with a Karnofsky score of at least 60, and received an unrelated donor (fully matched or one-locus mismatched at HLA-A, HLA-B, HLA-C, or DRB1 loci) graft following myeloablative or non-myeloablative–reduced intensity conditioning. Patients were randomly assigned to receive anti-thymocyte globulin 4·5 mg/kg plus standard GVHD prophylaxis (cyclosporine or tacrolimus plus methotrexate or mycophenolate) or standard GVHD prophylaxis alone. The primary endpoint, freedom from immunosuppressive therapy without resumption at 12 months, was previously reported. Here we report on the prespecified 24-month analysis. Analyses were per-protocol, excluding those patients who did not proceed to transplantation. This trial is registered as ISRCTN 29899028 and NCT01217723, status completed.

Findings

Between June 9, 2010, and July 8, 2013, we recruited and randomly assigned 203 eligible patients to receive anti-thymocyte globulin (n=101) or no additional treatment (n=102) along with standard GVHD prophylaxis. 7 (3%) patients did not receive a transplant and were excluded from the analysis. 38 (38%) of 99 evaluable patients in the anti-thymocyte globulin plus GVHD prophylaxis group were free from immunosuppressive therapy at 24 months compared with 18 (19%) of 97 patients in the standard GVHD prophylaxis group (adjusted odds ratio [OR] 3·49 [95% CI 1·60–7·60]; p=0·0016). At 24 months, the cumulative incidence of relapse was 16·3% (95% CI 8·9–23·7) in the anti-thymocyte globulin plus GVHD prophylaxis group compared with 17·5 (9·9–25·1) in the standard GVHD prophylaxis group (p=0·73) and non-relapse mortality was 21·2% (95% CI 13·2–29·2) versus 31·3% (21·9–40·7; p=0·15). The cumulative incidence of chronic GVHD at 24 months was 26·3% (95% CI 17·5–35·1) in the anti-thymocyte globulin group and 41·3% (31·3–51·3) in the standard GVHD prophylaxis group (p=0·032). Overall survival at 24 months was 70·6% (95% CI 60·6–78·6) in the anti-thymocyte globulin plus GVHD prophylaxis group compared with 53·3% (42·8–62·8) in the standard GVHD prophylaxis group (adjusted hazard ratio [HR] 0·56, 95% CI [0·35–0·90]; p=0·017). Symptoms of chronic GVHD by the Lee Scale were more prevalent in the standard GVHD prophylaxis group, with scores of 13·27 (SD 10·94) in the anti-thymocyte globulin plus GVHD prophylaxis group and 20·38 (SD 14·68) in the standard GVHD prophylaxis group (p=0·040). Depressive symptoms were more prominent in the standard GVHD prophylaxis group, the mean Center for Epidemiological Studies Depression scale (CES-D) scores were 10·40 (SD 9·88) in the anti-thymocyte globulin group and 14·62 (SD 12·26) in the standard GVHD prophylaxis group (p=0·034). Serious adverse events (CTCAE grade 4 or 5) occurred in 38 (38%) patients in the anti-thymocyte globulin group and in 49 (51%) in the standard GVHD prophylaxis group, the most common being infection and GVHD. One patient in the anti-thymocyte globulin plus GVHD prophylaxis group died of Epstein-Barr virus hepatitis, but no deaths were attributable to anti-thymocyte globulin.

Interpretation

The results of this prespecified 24-month analysis suggest that pretreatment with anti-thymocyte globulin provides clinically meaningful benefits when added to standard GVHD prophylaxis in patients undergoing unrelated donor transplantation, including decreases in use of immunosuppressive therapy, chronic GVHD and its symptoms, and depressive symptoms, and improved overall survival. Anti-thymocyte globulin should be included in the preparative regimens of patients with haematological malignancies selected for unrelated donor transplantation.

Funding

Canadian Institutes of Health Research and Sanofi.

Introduction

Chronic graft versus host disease (GVHD) is the most important long-term complication of bone marrow transplantation. It affects 40–60% of recipients, causes severe morbidity and decreases in quality of life, and increases the risk of mortality. The morbidity of chronic GVHD is long lasting; one-third of patients still take immunosuppressive therapy a median of 5·6 years after the onset of chronic GVHD.1 Unfortunately, the prevalence of chronic GVHD is increasing.2

Only anti-thymocyte globulin and anti-T lymphocyte globulin Grafalon have been shown to decrease the incidence of chronic GVHD after unrelated donor transplantation. In five published randomised trials,3, 4, 5, 6, 7 the incidence of chronic GVHD in patients who received anti-thymocyte globulin was substantially reduced. In four trials,4, 5, 6, 7 with follow-up periods ranging from 24 to 67 months, there was no difference between treatment groups in frequency of infection, incidence of relapse, or overall survival. whereas in the fifth trial,3 with a median follow-up for survivors of 24 months, patients receiving anti-T lymphocyte globulin Grafalon had a significant decrease in 2-year overall survival, 95 (74%) of 128 patients receiving placebo surviving compared with 74 (59%) of 126 receiving anti-T -lymphocyte globulin Grafalon (p=0·034). Relapses were increased in patients receiving anti-T lymphocyte globulin grafalon, 32% compared to 21%; this was not statistically significant (p=0·1), but relapse was the leading cause of death in both groups. The fifth trial of anti-thymocyte globulin has highlighted leukaemic relapse as a potential ill effect of anti-lymphocyte serums and a need for individual dosing protocols has been proposed.8 Validation of newer methods of GVHD prevention, T-lymphocyte depletion, and post-transplantation cyclophosphamide in particular, await testing in ongoing randomised trials.

Research in context

Evidence before this study

We searched PubMed on Sept 1, 2019 for randomised trials comparing anti-thymocyte globulin to controls for the prevention of chronic graft-versus-host disease (GVHD) published from Jan 1 2006 until Sept 1, 2019. We used search terms “peripheral blood stem cell transplantation”; “bone marrow cell transplantation”; “antithymocyte globulin)”; “anti-t lymphocyte globulin grafalon”; “ATLG”; “clinical trial, phase iii OR “randomized controlled trial” separately and in various combinations. We found five randomised trials, four in patients receiving unrelated donor transplants and one in patients receiving sibling donor transplants. These five trials reported consistent results showing reductions in the incidence of chronic GVHD, and to a lesser extent, in acute GVHD.

Added value of this study

The present trial confirms the previously observed decrease in the incidence of chronic GVHD, but also shows improvements in patient-centred endpoints, such as a decrease in the need for immunosuppressive therapy, in symptoms associated with chronic GVHD, and depressive symptoms. These endpoints are in keeping with the 2006 and 2015 National Institute of Health (NIH) Consensus recommendations that primary and secondary endpoints of chronic GVHD treatment studies should focus on the clinical benefits of central importance to patients. Research groups continue to debate about appropriate primary endpoints for these trials; the need for immunosuppressive therapy at 2 years that we measured, parallels current chronic GVHD-free relapse-free survival and refractory chronic GVHD-free relapse-free survival in pinpointing benefits at longer timepoints of follow-up.

Implications for all the available evidence

The present trial showed an improvement in overall survival for patients receiving anti-thymocyte globulin, confirming a previous case control study that used the same brand and dose of antibody. These results contrast with those of the previous randomised studies, as mentioned. Available evidence suggests that both the dose and schedule of anti-thymocyte globulin administration are crucial. Improvements in anti-thymocyte globulin therapy will probably hinge on both dose finding studies, such as a paediatric study showing meaningful benefit from a lower dose, and the results of s that determine dose by recipient lymphocyte count, the major biological target of anti-thymocyte globulin.

We previously reported on this trial. At 12 months of follow-up6 there was an absolute 21% (SE 6%) decrease in the need for immunosuppressive therapy and a decrease in patient-reported chronic GVHD symptoms as measured by the Lee scale.9 We present here the prespecified 24-month analysis of this trial, in which we expected an absolute 20% decrease in the use of immunosuppressive therapy in patients receiving anti-thymocyte globulin compared with those not receiving it.

Section snippets

Study design and participants

We did a randomised, controlled, multicentre, parallel group, open-label, phase 3 trial comparing pretransplantation anti-thymocyte globulin plus standard GVHD prophylaxis with standard GVHD prophylaxis alone (cyclosporine or tacrolimus plus methotrexate or mycophenolate), in recipients receiving either myeloablative or non-myeloablative conditioning before haemopoietic stem cell transplantation from unrelated donors. We completed the study in ten transplantation centres in Canada and one in

Results

Between June 9, 2010, and July 8, 2013, we recruited and randomly assigned 203 patients to receive pretreatment anti-thymocyte globulin plus GVHD prophylaxis (n=101) or standard GVHD prophylaxis alone (n=102). Three patients relapsed before transplantation (two in the anti-thymocyte globulin plus GVHD prophylaxis group and one in the standard GVHD prophylaxis alone group) and four withdrew from the study (all in the standard GVHD prophylaxis alone group; figure 1). One patient from the

Discussion

In this prespecified 24-month follow-up analysis we have shown that patients benefitted from anti-thymocyte globulin by a decrease in the need for immunosuppressive therapy and symptoms of chronic GVHD and depression, and improved overall survival. Patients needed immunosuppressive therapy for long periods, 81% of patients in the standard GVHD prophylaxis group and 75% in the anti-thymocyte globulin group on immunosuppressive therapy at 12 months maintained their immunosuppressive therapy

Data sharing

No clinical trial data has been shared outside the authors and coordinating centre. The trial protocol, individual de-identified participant data and a data dictionary defining each field in the set, will be made available to others.

References (31)

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    Here the addition of ATG was associated with a reduced risk of aGVHD in BM recipients (see supplementary Table 3), and this observation was compatible with previous reports [41,42]. Administration of ATG with PBSCs can reduce both aGVHD and cGVHD [43–46], but at the same time, it can also induce severe infections and post-transplant lymphoproliferative disorders and increase the incidence of relapse by reducing GVL effects [43,44,47]. As a result, overall, ATG does not always improve NRM or survival [43,45,48,49] and can even reduce OS [50].

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