Donor-Specific Anti-Human Leukocyte Antigen Antibodies Predict Prolonged Isolated Thrombocytopenia and Inferior Outcomes of Haploidentical Hematopoietic Stem Cell Transplantation

Xiaosu Zhao, Xiangyu Zhao, Mingrui Huo, Qiaozhen Fan, Xuying Pei, Yu Wang, Xiaohui Zhang, Lanping Xu, Xiaojun Huang, Kaiyan Liu, Yingjun Chang, Xiaosu Zhao, Xiangyu Zhao, Mingrui Huo, Qiaozhen Fan, Xuying Pei, Yu Wang, Xiaohui Zhang, Lanping Xu, Xiaojun Huang, Kaiyan Liu, Yingjun Chang

Abstract

Prolonged isolated thrombocytopenia (PT) after allogeneic stem cell transplantation (allo-SCT) has a great impact on transplant outcome. In this study, we performed a retrospective analysis to investigate the association of donor-specific anti-human leukocyte antigen (HLA) antibodies (DSAs) with PT in 394 patients who underwent unmanipulated haploidentical blood and marrow transplantation (HBMT). For HLA antibody positive samples with a median fluorescent intensity (MFI) > 500, DSAs were further examined. A total of 390 patients (99.0%) achieved sustained myeloid engraftment. Of the 394 cases tested, 45 (11.4%) were DSA positive. The cumulative incidence of PT in this cohort of patients was 9.9 ± 1.5%. The incidence of PT was higher in patients with a MFI ≥ 1000 compared with those with a MFI < 1000 (16.8 ± 6.4% versus 7.4 ± 1.4%, P = 0.05). Multivariate analysis showed that the presence of DSAs (MFI ≥ 1000) was correlated to PT (hazard ratio (HR) 3.262; 95% confidence interval (CI), 1.339-7.946; P = 0.009) and transplant-related mortality (HR 2.320; 95% CI, 1.169-4.426; P = 0.044). Our results, for the first time, suggest an association of DSAs with PT after unmanipulated HBMT. It would help screen out the suitable donor and guide intervention. This indicated that DSAs should be incorporated in the algorithm for unmanipulated HBMT.

Figures

Figure 1
Figure 1
PT and transplant outcomes after haploidentical transplantation. (a) Cumulative incidence of relapse (CIR) and (b) TRM. (c) Disease-free survival. (d) Overall survival.

References

    1. Aversa F., Terenzi A., Tabilio A., et al. Full haplotype-mismatched hematopoietic stem-cell transplantation: a phase II study in patients with acute leukemia at high risk of relapse. Journal of Clinical Oncology. 2005;23(15):3447–3454. doi: 10.1200/JCO.2005.09.117.
    1. Chang Y. J., Huang X. J. Haploidentical hematopoietic stem cell transplantation with unmanipulated granulocyte colony stimulating factor mobilized marrow and blood grafts. Current Opinion in Hematology. 2012;19(6):454–461. doi: 10.1097/MOH.0b013e3283582322.
    1. Reisner Y., Hagin D., Martelli M. F. Haploidentical hematopoietic transplantation: current status and future perspectives. Blood. 2011;118(23):6006–6017. doi: 10.1182/blood-2011-07-338822.
    1. Zhang X. H., Zhou S. Y., Feng R., et al. Increased prostacyclin levels inhibit the aggregation and activation of platelets via the PI3K-AKT pathway in prolonged isolated thrombocytopenia after allogeneic hematopoietic stem cell transplantation. Thrombosis Research. 2016;139:1–9. doi: 10.1016/j.thromres.2016.01.003.
    1. Zhang X. H., Wang Q. M., Zhang J. M., et al. Desialylation is associated with apoptosis and phagocytosis of platelets in patients with prolonged isolated thrombocytopenia after allo-HSCT. Journal of Hematology & Oncology. 2015;8(1):p. 116. doi: 10.1186/s13045-015-0216-3.
    1. Yamazaki R., Kuwana M., Mori T., et al. Prolonged thrombocytopenia after allogeneic hematopoietic stem cell transplantation: associations with impaired platelet production and increased platelet turnover. Bone Marrow Transplantation. 2006;38(5):377–384. doi: 10.1038/sj.bmt.1705444.
    1. Mehta R. S., Saliba R. M., Chen J., et al. Post-transplantation cyclophosphamide versus conventional graft-versus-host disease prophylaxis in mismatched unrelated donor haematopoietic cell transplantation. British Journal of Haematology. 2016;173(3):444–455. doi: 10.1111/bjh.13977.
    1. Kong Y., Hu Y., Zhang X. H., et al. Association between an impaired bone marrow vascular microenvironment and prolonged isolated thrombocytopenia after allogeneic hematopoietic stem cell transplantation. Biology of Blood and Marrow Transplantation. 2014;20(8):1190–1197. doi: 10.1016/j.bbmt.2014.04.015.
    1. Nash R. A., Gooley T., Davis C., Appelbaum F. R. The problem of thrombocytopenia after hematopoietic stem cell transplantation. The Oncologist. 1996;1(6):371–380.
    1. Ciurea S. O., Thall P. F., Wang X., et al. Donor-specific anti-HLA Abs and graft failure in matched unrelated donor hematopoietic stem cell transplantation. Blood. 2011;118(22):5957–5964. doi: 10.1182/blood-2011-06-362111.
    1. Cutler C., Kim H. T., Sun L., et al. Donor-specific anti-HLA antibodies predict outcome in double umbilical cord blood transplantation. Blood. 2011;118(25):6691–6697. doi: 10.1182/blood-2011-05-355263.
    1. Ruggeri A., Rocha V., Masson E., et al. Impact of donor-specific anti-HLA antibodies on graft failure and survival after reduced intensity conditioning-unrelated cord blood transplantation: a Eurocord, Societe Francophone d’Histocompatibilite et d'Immunogenetique (SFHI) and Societe Francaise de Greffe de Moelle et de Therapie Cellulaire (SFGM-TC) analysis. Haematologica. 2013;98(7):1154–1160. doi: 10.3324/haematol.2012.077685.
    1. Yoshihara S., Maruya E., Taniguchi K., et al. Risk and prevention of graft failure in patients with preexisting donor-specific HLA antibodies undergoing unmanipulated haploidentical SCT. Bone Marrow Transplantation. 2012;47(4):508–515. doi: 10.1038/bmt.2011.131.
    1. Ciurea S. O., de Lima M., Cano P., et al. High risk of graft failure in patients with anti-HLA antibodies undergoing haploidentical stem-cell transplantation. Transplantation. 2009;88(8):1019–1024. doi: 10.1097/TP.0b013e3181b9d710.
    1. Chang Y. J., Zhao X. Y., Xu L. P., et al. Donor-specific anti-human leukocyte antigen antibodies were associated with primary graft failure after unmanipulated haploidentical blood and marrow transplantation: a prospective study with randomly assigned training and validation sets. Journal of Hematology & Oncology. 2015;8(1):p. 84. doi: 10.1186/s13045-015-0182-9.
    1. Wang Y., Fu H. X., Liu D. H., et al. Influence of two different doses of antithymocyte globulin in patients with standard-risk disease following haploidentical transplantation: a randomized trial. Bone Marrow Transplantation. 2014;49(3):426–433. doi: 10.1038/bmt.2013.191.
    1. Wang Y., Liu D. H., Liu K. Y., et al. Long-term follow-up of haploidentical hematopoietic stem cell transplantation without in vitro T cell depletion for the treatment of leukemia: nine years of experience at a single center. Cancer. 2013;119(5):978–985. doi: 10.1002/cncr.27761.
    1. Qin X. Y., Li G. X., Qin Y. Z., et al. Quantitative chimerism: an independent acute leukemia prognosis indicator following allogeneic hematopoietic SCT. Bone Marrow Transplantation. 2014;49(10):1269–1277. doi: 10.1038/bmt.2014.158.
    1. Morin-Zorman S., Loiseau P., Taupin J. L., Caillat-Zucman S. Donor-specific anti-HLA antibodies in allogeneic hematopoietic stem cell transplantation. Frontiers in Immunology. 2016;7:p. 307. doi: 10.3389/fimmu.2016.00307.
    1. Chang Y. J., Luznik L., Fuchs E. J., Huang X. J. How do we choose the best donor for T-cell-replete, HLA-haploidentical transplantation? Journal of Hematology & Oncology. 2016;9(1):p. 35. doi: 10.1186/s13045-016-0265-2.
    1. Wang Y., Chang Y. J., Xu L. P., et al. Who is the best donor for a related HLA haplotype-mismatched transplant? Blood. 2014;124(6):843–850. doi: 10.1182/blood-2014-03-563130.
    1. Spellman S., Bray R., Rosen-Bronson S., et al. The detection of donor-directed, HLA-specific alloantibodies in recipients of unrelated hematopoietic cell transplantation is predictive of graft failure. Blood. 2010;115(13):2704–2708. doi: 10.1182/blood-2009-09-244525.
    1. Barge A. J., Johnson G., Witherspoon R., Torok-Storb B. Antibody-mediated marrow failure after allogeneic bone marrow transplantation. Blood. 1989;74(5):1477–1480.
    1. Kong Y., Hu Y., Zhang X. H., et al. Association between an impaired bone marrow vascular microenvironment and prolonged isolated thrombocytopenia after allogeneic hematopoietic stem cell transplantation. Biology of Blood and Marrow Transplantation: Journal of the American Society for Blood and Marrow Transplantation. 2014;20(8):1190–1197. doi: 10.1016/j.bbmt.2014.04.015.
    1. Zhang X. H., Wang G. X., Zhu H. H., et al. Recruitment of CD8(+) T cells into bone marrow might explain the suppression of megakaryocyte apoptosis through high expression of CX3CR1(+) in prolonged isolated thrombocytopenia after allogeneic hematopoietic stem cell transplantation. Annals of Hematology. 2015;94(10):1689–1698. doi: 10.1007/s00277-015-2436-6.
    1. Kanakry C. G., Fuchs E. J., Luznik L. Modern approaches to HLA-haploidentical blood or marrow transplantation. Nature Reviews. Clinical Oncology. 2016;13(1):10–24. doi: 10.1038/nrclinonc.2015.128.

Source: PubMed

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