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H.T. Greinix et al.
Interestingly, the use of BM as stem cell source was associated with an increased risk for aGvHD grades II-IV and grades III-IV but also with a significantly higher DFS and overall survival. In a phase III, multicenter, random- ized study of transplantation of PBSC versus BM from URD, the rates of aGvHD were similar in the two groups.35 However, these incidences were around 50% and, thus, markedly higher than in our cohorts where, in the most recent patient group, incidence was 28%. Further, Anasetti et al., did not observe survival differences between their study cohorts. In a retrospective analysis including 2463 recipients of PBSC and 1713 of BM from URD, no significant differences in the three-year probabil- ities of TRM, relapse, leukemia-free survival, and OS between the groups were observed in patients with leukemia and MDS.36 In a long-term follow-up report of the randomized study, recipients of URD BM had better psychological well-being, less burdensome cGvHD symp- toms, and were more likely to return to work than recipi- ents of PBSC at five years after HSCT.37
In our study, three-year relapse incidence after aGvHD grades II-IV significantly increased from 19% to 25% over time and was associated with a lack of CR at HSCT. It is important to acknowledge that more patients with MDS have been given HSCT in recent years and, of these, it is probable that patients were either not in CR or were untreated due to the fact that it still controversial as to whether pretreatment of MDS patients prior to HSCT is of clinical benefit and thus, should be recom- mended.38 Furthermore, in recent years, AML patients referred to HSCT in first CR have intermediate and adverse risk disease, as defined by the European Leukemia Net criteria39 and, especially, the later patient category is known to have a higher relapse risk after HSCT.39 Three-year relapse incidence in our cohort was also significantly increased after the use of RIC in patients with AML and MM. In line with our findings, substantially higher relapse rates after RIC compared to myeloablative conditioning have been reported in patients with AML and MDS.40,41
The strength of our study is the large sample size and long time period for comparison of HSCT outcome, as well as the participation of many transplant centers reporting consecutive patients to the EBMT registry and thus, providing real world data for detailed analysis over time. We would like to acknowledge the following limita- tions to this analysis. First, we cannot distinguish between mismatched and matched unrelated donors (10/10).
Second, limitations in data on antimicrobial agents and other supportive care measures do not allow an analysis of changes in these practices over time as a potential factor for improved outcome. Thirdly, insufficient data on steroid dose, and type/duration of salvage immunosup- pressive therapy do not allow detailed analyses of treat- ment intensity on outcome. In addition, detailed aGvHD treatment response data are not available, therefore we cannot characterize the burden of steroid-refractory aGvHD across cohorts.
In conclusion, our findings demonstrate that the advances and changes in allogeneic HSCT practices over the past 2.5 decades have led to significantly improved outcomes in patients experiencing severe aGvHD. Although incidences of aGvHD have significantly declined and the OS of patients experiencing aGvHD has improved, there is still a need for further progress. Increasing use of posttransplant cyclophosphamide for GvHD prophylaxis, not only after haploidentical but also related and URD transplants, could have an impact on incidences of both acute as well as chronic GvHD, as pre- viously reported.42,43 The administration of BM rather than PBSC as stem cell source reportedly reduces the incidence of cGvHD and the use of myeloablative conditioning reg- imens in patients with aggressive malignant disease is another option for improvement of HSCT outcome. More efficient and less toxic front-line immunosuppressive ther- apies for treatment of aGvHD, including treatments with- out the administration of corticosteroids, would have the potential to further reduce NRM and improve survival of patients following allogeneic HSCT.
Disclosures
No conflicts of interest to disclose.
Contributions
HTG designed the study and wrote the manuscript; LK pre- pared the dataset and DJE LK performed statistical analyses; OP, IYA, SM, CC, JS, AN, MR, SR, YC, MM, SS, ZP, AR, FL, MM, GWB, and NK interpreted the data. All authors criti- cally reviewed the manuscript and approved the final version for submission.
Acknowledgments
The authors would like to thank all patients and their families. They would also like to thank all data managers and transplant centers for contributing and collecting their data for the EBMT registry.
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