ArticlesGVHD prophylaxis plus ATLG after myeloablative allogeneic haemopoietic peripheral blood stem-cell transplantation from HLA-identical siblings in patients with acute leukaemia in remission: final results of quality of life and long-term outcome analysis of a phase 3 randomised study
Introduction
Chronic graft-versus-host disease (cGVHD) is one of the major complications after allogeneic haemopoietic stem-cell transplantation, especially when peripheral blood stem cells are used.1, 2 Previous acute GVHD (aGVHD), age, sex mismatch, and the use of peripheral blood stem cells as stem-cell source are well recognised risk factors of cGVHD occurrence. Peripheral blood stem cells have become the most frequently used stem-cell source for allogeneic transplants,3, 4 even though this source has been associated with a higher incidence of cGVHD in transplants with both unrelated and sibling donors.1, 2, 4 cGVHD, in particular the extensive type, has a significant effect on non-relapse mortality, morbidity, and quality of life (QoL).5, 6 A new composite endpoint (cGVHD-free and relapse-free survival [cGRFS]) has been increasingly used to measure the outcome of the transplant procedure by assessing cGVHD-free and relapse-free survival.7, 8 For these reasons, several attempts to improve the efficacy of GVHD prophylaxis are being made, in particular with the aim of reducing incidence and severity of cGVHD. Different preparations of rabbit anti-T-cell globulins are available and have been tested as in-vivo T-cell depletion. Human anti-T-lymphocyte globulin (ATLG) was prepared by immunisation of rabbits with a Jurkat cell line, and anti-thymocyte globulin (ATG) was obtained in rabbits against human thymocytes.
Several randomised studies have already shown that the addition of ATLG or ATG to the standard GVHD prophylaxis with a calcineurin inhibitor and methotrexate given to patients having myeloablative transplants from unrelated donors reduces both aGVHD and cGVHD incidence without increasing the relapse risk,9, 10, 11 with the exception of one study,12 and improves cGRFS. However, in the case of sibling transplantation the only available randomised study13 showed that ATLG, given at 10 mg/kg once daily 3 days to 1 day before myeloablative sibling transplants for patients with acute leukaemia in remission, reduced the cumulative incidence of cGVHD from 68·7% to 32·2% at 2 years, without increasing relapse incidence or infectious complications. Overall survival and relapse-free survival in this study were not affected by the addition of ATLG, whereas cGRFS significantly improved from 16·8% to 36·6% at 2 years.
Here, we report unpublished data on QoL from the original study and the results of a follow-up extension, with the aim of assessing the main outcomes (cGVHD incidence, relapse risk, non-relapse mortality, overall survival, disease-free survival, and cGRFS), recording new cases of cGVHD, and assessing immunosuppression discontinuation, secondary malignancies, and occupational status after transplantation.
Section snippets
Study design and participants
The multicentre, open-label, phase 3 ATGFamilyStudy,13 was run in Italy (16 haemopoietic stem-cell transplant programmes), Spain (six), Germany (three), and Israel (one; appendix). Patients with acute leukaemia in complete remission were randomly allocated (1:1) to receive ATLG plus the standard regimen of ciclosporin and methotrexate after a myeloablative conditioning regimen or the standard regimen alone. The myeloablative conditioning regimen consisted of cyclophosphamide (120 mg/kg) and
Results
Between Dec 14, 2006, and Feb 2, 2012, 161 patients were enrolled, and six patients were excluded because of donor refusal or disease progression. 155 patients were randomly assigned to each group (n=83 in the ATLG group; n=72 in the non-ATLG group) and were included in the full analysis set. The final analysis was performed after the last patient achieved at least a 2-year observation (June 8, 2014). 119 (77%) of 155 patients were alive at the end of the study. The extension study started on
Discussion
cGVHD is a major cause of late morbidity and mortality after allogeneic stem-cell transplantation.17 Additionally, cGVHD, especially in the more severe forms, is known to be associated with lower QoL.5, 6, 10 For these reasons, in the last years, much more attention has been given to QoL, and QoL measures are increasingly used as an indirect measure of efficacy in studies exploring new platforms for GVHD prophylaxis. Although mortality from cGVHD is decreasing nowadays because of better
Data sharing
The study did not foresee a data sharing plan. Individual participant data that underlie the results reported in this Article, after deidentification and a dictionary defining each field in the set, will be made available only after approval of the proposal from the Study Committee (FB, CSo, and NK) for meta-analyses. The signature of data access agreement will be requested after the approval. The application should be addressed to [email protected] beginning 3 months and ending 5 years after
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