Page 215 - 2019_05-HaematologicaMondo-web

HLA discrepancy and outcome of second HSCT
of relapse versus the 0 MM group (RR, 0.75; 95%CI: 0.58- 0.95; P=0.018), but this was offset by a higher rate of TRM (RR, 1.44; 95%CI: 1.03-2.00; P=0.033). Our data suggested that use of an HLA-MM donor may induce a more potent GvL effect, but also increases the allogeneic responses of the second HSCT and provokes an increase in TRM events. These effects tended to cancel each other out in respect to OS.
This is the first study to focus on patients after initial HLA-MM transplantation and identify risk factors for a poor second HSCT outcome. However, several limitations of the study should be mentioned. First, although this was a relatively large-scale study on second transplant, the sample size was still modest, and therefore further studies with larger sample sizes are required. Second, it used a ret- rospective design and included a heterogeneous patient group. Moreover, the strategies of the different treatment centers with respect to donor change are unknown, and any heterogeneity in transplantation procedure, year of transplant, and patients' characteristics may have biased the results, although we attempted to reduce bias by adjusting for these factors in multivariate analyses. Third, we did not adjust for multiple comparisons and therefore caution is required when interpreting the results, in partic-
ular those of the stratified analyses. In addition, HLA-C typing and high-resolution DNA typing were either rarely, or not routinely, performed on the donors. Finally, donor chimerism was not systematically analyzed and cell sub- set chimerism data were not available for most patients.
In conclusion, HLA-MM donor is an option after initial HLA-MM transplantation. However, TRM remains a chal- lenge, particularly with a ≥2 MM donor regarding graft-versus-host. In this study, the biological effects of HLA discrepancy between the graft and the first donor on the outcome appeared negligible, and our findings shed light on the role of non-hematopoietic APCs on trans- plant-related immunological responses.
Funding
This work was supported in part by the Practical Research Project for Allergic Diseases and Immunology (Research Technology of Medical Transplantation) from Japan Agency for Medical Research and Development, AMED under Grant Number 18ek0510023h0002. The authors are grateful to all physicians and data managers at the centers who contributed valuable data on transplantation to the JMDP and TRUMP. The authors also thank the members of the data management commit- tees of JDMP and TRUMP for their assistance.
References
1. Bosi A, Laszlo D, Labopin M, et al. Second allogeneic bone marrow transplantation in acute leukemia: results of a survey by the European Cooperative Group for Blood and Marrow Transplantation. J Clin Oncol. 2001;19(16):3675-3684.
2. Shaw BE, Mufti GJ, Mackinnon S, et al. Outcome of second allogeneic transplants using reduced-intensity conditioning follow- ing relapse of haematological malignancy after an initial allogeneic transplant. Bone Marrow Transplant. 2008;42(12):783-789.
3. Eapen M, Giralt SA, Horowitz MM, et al. Second transplant for acute and chronic leukemia relapsing after first HLA-identical sibling transplant. Bone Marrow Transplant. 2004;34(8):721-727.
4. Christopeit M, Kuss O, Finke J, et al. Second allograft for hematologic relapse of acute leukemia after first allogeneic stem-cell trans- plantation from related and unrelated donors: the role of donor change. J Clin Oncol. 2013; 31(26):3259-3271.
5. Ruutu T, de Wreede LC, van Biezen A, et al. Second allogeneic transplantation for relapse of malignant disease: retrospective analysis of outcome and predictive factors by the EBMT. Bone Marrow Transplant. 2015; 50(12):1542-1550.
6. VrhovacR,LabopinM,CiceriF,etal.Second reduced intensity conditioning allogeneic transplant as a rescue strategy for acute leukaemia patients who relapse after an ini- tial RIC allogeneic transplantation: analysis of risk factors and treatment outcomes. Bone Marrow Transplant. 2016;51(2):186-193.
7. OrtiG,SanzJ,BermudezA,etal.Outcomeof Second Allogeneic hematopoietic cell trans- plantation after relapse of myeloid malignan- cies following allogeneic hematopoietic cell transplantation: a Retrospective Cohort on Behalf of the Grupo Espanol de Trasplante Hematopoyetico. Biol Blood Marrow
Transplant. 2016;22(3):584-588.
8. Andreola G, Labopin M, Beelen D, et al.
Long-term outcome and prognostic factors of second allogeneic hematopoietic stem cell transplant for acute leukemia in patients with a median follow-up of 10 years. Bone Marrow Transplant. 2015;50(12):1508-1512.
9. Horstmann K, Boumendil A, Finke J, et al. Second allo-SCT in patients with lymphoma relapse after a first allogeneic transplantation. A retrospective study of the EBMT Lymphoma Working Party. Bone Marrow Transplant. 2015;50(6):790-794.
10. Jones SC, Murphy GF, Friedman TM, Korngold R. Importance of minor histocom- patibility antigen expression by non- hematopoietic tissues in a CD4+ T cell-medi- ated graft-versus-host disease model. J Clin Invest. 2003;112(12):1880-1886.
Med. 2005;11(11):1244-1249.
17. Atsuta Y, Suzuki R, Yoshimi A, et al.
Unification of hematopoietic stem cell trans- plantation registries in Japan and establish- ment of the TRUMP System. Int J Hematol. 2007;86(3):269-274.
18. Atsuta Y. Introduction of Transplant Registry Unified Management Program 2 (TRUMP2): scripts for TRUMP data analyses, part I (vari- ables other than HLA-related data). Int J Hematol. 2016;103(1):3-10.
19. Kanda J. Scripts for TRUMP data analyses. Part II (HLA-related data): statistical analyses specific for hematopoietic stem cell trans- plantation. Int J Hematol. 2016;103(1):11-19.
20. Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995;15(6):825-828.
11. Koyama M, Kuns RD, Olver SD, et al.
Recipient nonhematopoietic antigen-present-
ing cells are sufficient to induce lethal acute graft-versus-host disease. Nat Med. 2011; 18(1):135-142. 259.
12. Shlomchik WD, Couzens MS, Tang CB, et al. Prevention of graft versus host disease by inactivation of host antigen-presenting cells. Science. 1999;285(5426):412-415.
13. Teshima T, Ordemann R, Reddy P, et al. Acute graft-versus-host disease does not require alloantigen expression on host epithelium. Nat Med. 2002;8(6):575-581.
14. Duffner UA, Maeda Y, Cooke KR, et al. Host dendritic cells alone are sufficient to initiate acute graft-versus-host disease. J Immunol. 2004;172(12):7393-7398.
15. Zhang Y, Louboutin JP, Zhu J, Rivera AJ, Emerson SG. Preterminal host dendritic cells in irradiated mice prime CD8+ T cell-mediat- ed acute graft-versus-host disease. J Clin Invest. 2002;109(10):1335-1344.
16. Reddy P, Maeda Y, Liu C, Krijanovski OI, Korngold R, Ferrara JL. A crucial role for anti- gen-presenting cells and alloantigen expres- sion in graft-versus-leukemia responses. Nat
22. Gooley TA, Leisenring W, Crowley J, Storer BE. Estimation of failure probabilities in the presence of competing risks: new representa- tions of old estimators. Stat Med. 1999; 18(6):695-706.
23. Kanda Y. Investigation of the freely available easy-to-use software 'EZR' for medical statis- tics. Bone Marrow Transplant. 2013; 48(3):452-458.
24. Duncan CN, Majhail NS, Brazauskas R, et al. Long-term survival and late effects among one-year survivors of second allogeneic hematopoietic cell transplantation for relapsed acute leukemia and myelodysplastic syndromes. Biol Blood Marrow Transplant. 2015;21(1):151-158.
25. Bacigalupo A, Sormani MP, Lamparelli T, et al. Reducing transplant-related mortality after allogeneic hematopoietic stem cell transplan- tation. Haematologica. 2004; 89(10):1238- 1247.
21. Sullivan KM, Agura E, Anasetti C, et al. Chronic graft-versus-host disease and other late complications of bone marrow trans- plantation. Semin Hematol. 1991;28(3):250-
haematologica | 2019; 104(5)
1061