Risk factors and prognosis of Epstein-Barr virus DNAemia in children with aplastic anemia after allogeneic hematopoietic stem cell transplantation

doi:10.3877/cma.j.issn.2095-1221.2020.02.004

Abstract

Abstract:

Objective

To investigate risk factors of Epstein-Barr virus (EBV) DNAemia, treatment effects of rituximab, and clinical outcomes of Epstein-Barr virus (EBV) diseasesin children with aplastic anemia (AA) after allogeneic hematopoietic stem cell transplantation (allo- HSCT) .

Method

A retrospective analysis was conducted on children with aplastic anemia (AA) who underwent allo-HSCT from April 2010 to March 2018 in Shanghai Children's Medical Center. According to the occurrence of EBV DNAemia, they were divided into: EBV DNAemia group (141cases, including simple EBV DNAemia 125 cases and EBV-relateddiseases group 16 cases) and non-EBV DNAemia group (116 cases) . Cox regression was used to analyze the risk factors, Kaplan-Meier method was used to analyze the cumulative survival rate, and chi-square test was used to compare the qualitative data between groups.

Result

(1) After allo-HSCT in 257 children, 141 cases developed EBV, the incidence was 54.86﹪ (141/257) , the primary infection was 5.67﹪ (8/257) , the reactivation was 94.33﹪ (133/141) . The median time of EBV was 44 days (13 ~ 568 days) after transplantation. The mortality of simple EBV DNAemia and EBV-related diseases were 6.40﹪ (8/125) and 56.25﹪ (9/16) respectively. (2) Approximately 88.73﹪ (63/71) of patients with EBV were successfully treated preemptively with rituximab. (3) Compared with the EBVemia group, the survival rate of children with EBV-related disease group decreased, and the difference was statistically significant (Log-rank P <0.001) . (4) The results of multivariate analysis showed that children with TBI pretreatment had a 1.717-fold higher probability of EBV infection than those without TBI pretreatment (95﹪ CI 1.160-2.542) . The CD34-positive cells in the grafts of patients were≥3×10⁶ cells/kg, which was 1.775 times than children with <3×10⁶ cells/kg (95﹪ CI 1.089-2.894) .

Conclusion

The occurrence of EBVemia after transplantation is related to the whole body irradiation treatment and the number of CD34-positive cells infused greater than 3×10⁶ cells/kg. EBV DNAemia progression to EBV disease increases transplant-related mortality. The usage of rituximab as preemptive prophylaxis may reduce the incidence and mortality.

Key words: Allogeneic hematopoietic stem cell transplantation, Children, Epstein-Barr virus, Rituximab

Manpin Zhang, Xia Qin, Chengjuan Luo, Jianmin Wang, Changying Luo, Jing Chen. Risk factors and prognosis of Epstein-Barr virus DNAemia in children with aplastic anemia after allogeneic hematopoietic stem cell transplantation[J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2020, 10(02): 90-96.

/ / Recommend

Add to citation manager EndNote|Ris|BibTeX

URL: https://zhxbygxbzz.cma-cmc.com.cn/EN/10.3877/cma.j.issn.2095-1221.2020.02.004

https://zhxbygxbzz.cma-cmc.com.cn/EN/Y2020/V10/I02/90

Figures/Tables 5

References 18

[1]	Styczynski J, Van Der Velden W, Fox CP, et al. Management of Epstein- Barr virus infections and post-transplant lymphoproliferative disorders in patients after allogeneic hematopoietic stem cell transplantation: sixth European conference on infections in leukemia (ECIL-6) guidelines[J]. Haematologica, 2016, 101(7):803-811.
[2]	Styczynski J, Gil L, Tridello G, et al. Response to Rituximab- Based therapy and risk factor analysis in epstein Barr Virus-Related lymphoproliferative disorder after hematopoietic stem cell transplant in children and adults: a study from the infectious diseases working party of the European Gro[J]. Clin Infect Dis, 2013, 57(6):794-802.
[3]	Kinch A, Hallböök H, Arvidson J, et al. Long-term outcome of Epstein- Barr virus DNAemia and PTLD with the use of preemptive rituximab following allogeneic HSCT[J]. Leuk Lymphoma, 2018, 59(5):1172-1179.
[4]	Wareham NE, Mocroft A, Sengeløv H, et al. The value of EBV DNA in early detection of post-transplant lymphoproliferative disorders among solid organ and hematopoietic stem cell transplant recipients[J]. J Cancer Res Clin Oncol, 2018, 144(8):1569-1580.
[5]	Uhlin M, Wikell H, Sundin M, et al. Risk factors for Epstein- Barr virus- related post-transplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation[J]. Haematologica, 2014, 99(2):346-352.
[6]	Storek J. Anti-thymocyte globulin dosing-per kg or per lymphocyte?[J]. Lancet Haematol, 2017, 4(4):e154-e155.
[7]	Dubey S, Srivastava A, Nityanand S. Induction of apoptosis of peripheral blood mononuclear cells by antithymocyte globulin (ATG) in aplastic anemia: an in vivo and in vitro study[J]. Ann Hematol, 2002, 81(5):249-253.
[8]	Gagelmann N, Ayuk F, Wolschke C, et al. Comparison of different rabbit anti-thymocyte globulin formulations in allogeneic stem cell transplantation:Systematic literature review and network meta- analysis[J]. Biol Blood Marrow Transplant, 2017, 23(12):2184-2191.
[9]	Baron F, Mohty M, Blaise D, et al. Anti-thymocyte globulin as graft- versus-host disease prevention in the setting of allogeneic peripheral blood stem cell transplantation:A review from the acute leukemia working party of the European society for blood and marrow transplantation[J]. Haematologica, 2017, 102(2):224-234.
[10]	Patriarca F, Medeot M, Isola M, et al. Prognostic factors and outcome of Epstein-Barr virus DNAemia in high-risk recipients of allogeneic stem cell transplantation treated with preemptive rituximab[J]. Transpl Infect Dis, 2013, 15(3):259-267.
[11]	Styczynski J. Managing post-transplant lymphoproliferative disorder[J]. Expert Opinion On Orphan Drugs, 2017, 5(1):19-35.
[12]	Czerw T, Labopin M, Schmid C, et al. High CD3⁺ and CD34⁺ peripheral blood stem cell grafts content is associated with increased risk of graft- versus-host disease without beneficial effect on disease control after reduced-intensity conditioning allogeneic transplantation from matched unrelated donors for acute myeloid leukemia-an analysis from the acute leukemia working party of the European society for blood and marrow transplantation[J]. Oncotarget, 2016, 7(19):27255-27266.
[13]	Van Esser JW, Van Der Holt B, Meijer E, et al. Epstein-Barr virus (EBV) reactivation is a frequent event after allogeneic stem cell transplantation (SCT) and quantitatively predicts EBV-lymphoproliferative disease following T-cell-depleted SCT[J]. Blood, 2001, 98(4):972-978.
[14]	Burns DM, Rana S, Martin E, et al. Greatly reduced risk of EBV reactivation in rituximab-experienced recipients of alemtuzumab- conditioned allogeneic HSCT[J]. Bone Marrow Transplant, 2016, 51(6):825-832.
[15]	Garcia-Cadenas I, Castillo N, Martino R, et al. Impact of Epstein Barr virus-related complications after high-risk allo-SCT in the era of pre- emptive rituximab[J]. Bone Marrow Transplant, 2015, 50(4):579-584.
[16]	Solano C, Mateo EM, Pérez A, et al. Epstein-barr virus DNA load kinetics analysis in allogeneic hematopoietic stem cell transplant recipients: Is it of any clinical usefulness?[J]. J Clin Virol, 2017, 97:26-32.
[17]	Chiereghin A, Piccirilli G, Belotti T, et al. Clinical utility of measuring epstein-barr virus-specific cell-mediated immunity after hsct in addition to virological monitoring:Results from a prospective study[J]. Med Microbiol Immunol, 2019, 208(6):825-834.
[18]	Sanz J, Andreu R. Epstein-Barr virus-associated posttransplant lymphoproliferative disorder after allogeneic stem cell transplantation[J]. Curr Opin Oncol, 2014, 26(6):677-683.

因素		例数	EBV感染发生率（﹪）	单因素分析			多因素分析
因素		?	EBV感染发生率（﹪）	HR值	95﹪CI	P值	HR值	95﹪CI	P值
性别		?	?	0.935	0.670 ~ 1.304	0.692	0.900	0.633 ~ 1.278	0.555
?	女	116	52.59	?	?	?	?	?	?
?	男	141	56.74	?	?	?	?	?	?
年龄		?	?	1.150	0.790 ~ 1.674	0.465	1.271	0.855 ~ 1.891	0.236
?	>5岁	182	57.14	?	?	?	?	?	?
?	≤5岁	75	49.33	?	?	?	?	?	?
移植前EBV血清学		?	?	1.491	0.730 ~ 3.044	0.273	1.716	0.827 ~ 3.562	0.147
?	EBV IgG阴性	18	44.44	?	?	?	?	?	?
?	EBV IgG阳性*	238	55.88	?	?	?	?	?	?
HLA配型		?	?	1.128	0.809 ~ 1.574	0.478	1.004	0.697 ~ 1.447	0.983
?	HLA不全相合	140	56.43	?	?	?	?	?	?
?	HLA全相合	117	52.99	?	?	?	?	?	?
移植类型		?	?	1.154	0.968 ~ 1.376	0.111	1.014	0.820 ~ 1.254	0.897
?	非血缘	160	59.38	?	?	?	?	?	?
?	血缘	97	47.42	?	?	?	?	?	?
是否使用TBI		?	?	1.865	1.305 ~ 2.665	0.001	1.717	1.160 ~ 2.542	0.007
?	是	156	62.18	?	?	?	?	?	?
?	否	101	43.56	?	?	?	?	?	?
急性GVHD		?	?	1.299	0.922 ~ 1.830	0.134	1.288	0.904 ~ 1.837	0.162
?	0 ~ I度	171	52.05	?	?	?	?	?	?
?	II ~ IV度	86	60.47	?	?	?	?	?	?
移植物中单个核细胞数		?	?	1.310	0.908 ~ 1.891	0.149	1.218	0.820 ~ 1.808	0.329
?	≤15×10⁸个/kg	171	47.95	?	?	?	?	?	?
?	>15×10⁸个/kg	85	36.47	?	?	?	?	?	?
移植物中CD34阳性细胞数		?	?	1.821	1.155 ~ 2.872	0.010	1.775	1.089 ~ 2.894	0.021
?	>3×10⁶个/kg	200	59.00	?	?	?	?	?	?
?	≤3×10⁶个/kg	55	40.00	?	?	?	?	?	?
移植物中CD3阳性细胞数		?	?	1.207	0.862 ~ 1.690	0.273	1.102	0.760 ~ 1.596	0.609
?	≤3×10⁸个/kg	140	58.58	?	?	?	?	?	?
?	>3×10⁸个/kg	115	50.43	?	?	?	?	?	?
移植物中CD19阳性细胞数		?	?	1.249	0.845 ~ 1.846	0.265	1.441	0.950 ~ 2.184	0.085
?	≤10×10⁷个/kg	55	53.82	?	?	?	?	?	?
?	>10×10⁷个/kg	199	60.00	?	?	?	?	?	?

因素		例数	EBV感染发生率（﹪）	单因素分析			多因素分析
因素		?	EBV感染发生率（﹪）	HR值	95﹪CI	P值	HR值	95﹪CI	P值
性别		?	?	0.935	0.670 ~ 1.304	0.692	0.900	0.633 ~ 1.278	0.555
?	女	116	52.59	?	?	?	?	?	?
?	男	141	56.74	?	?	?	?	?	?
年龄		?	?	1.150	0.790 ~ 1.674	0.465	1.271	0.855 ~ 1.891	0.236
?	>5岁	182	57.14	?	?	?	?	?	?
?	≤5岁	75	49.33	?	?	?	?	?	?
移植前EBV血清学		?	?	1.491	0.730 ~ 3.044	0.273	1.716	0.827 ~ 3.562	0.147
?	EBV IgG阴性	18	44.44	?	?	?	?	?	?
?	EBV IgG阳性*	238	55.88	?	?	?	?	?	?
HLA配型		?	?	1.128	0.809 ~ 1.574	0.478	1.004	0.697 ~ 1.447	0.983
?	HLA不全相合	140	56.43	?	?	?	?	?	?
?	HLA全相合	117	52.99	?	?	?	?	?	?
移植类型		?	?	1.154	0.968 ~ 1.376	0.111	1.014	0.820 ~ 1.254	0.897
?	非血缘	160	59.38	?	?	?	?	?	?
?	血缘	97	47.42	?	?	?	?	?	?
是否使用TBI		?	?	1.865	1.305 ~ 2.665	0.001	1.717	1.160 ~ 2.542	0.007
?	是	156	62.18	?	?	?	?	?	?
?	否	101	43.56	?	?	?	?	?	?
急性GVHD		?	?	1.299	0.922 ~ 1.830	0.134	1.288	0.904 ~ 1.837	0.162
?	0 ~ I度	171	52.05	?	?	?	?	?	?
?	II ~ IV度	86	60.47	?	?	?	?	?	?
移植物中单个核细胞数		?	?	1.310	0.908 ~ 1.891	0.149	1.218	0.820 ~ 1.808	0.329
?	≤15×10⁸个/kg	171	47.95	?	?	?	?	?	?
?	>15×10⁸个/kg	85	36.47	?	?	?	?	?	?
移植物中CD34阳性细胞数		?	?	1.821	1.155 ~ 2.872	0.010	1.775	1.089 ~ 2.894	0.021
?	>3×10⁶个/kg	200	59.00	?	?	?	?	?	?
?	≤3×10⁶个/kg	55	40.00	?	?	?	?	?	?
移植物中CD3阳性细胞数		?	?	1.207	0.862 ~ 1.690	0.273	1.102	0.760 ~ 1.596	0.609
?	≤3×10⁸个/kg	140	58.58	?	?	?	?	?	?
?	>3×10⁸个/kg	115	50.43	?	?	?	?	?	?
移植物中CD19阳性细胞数		?	?	1.249	0.845 ~ 1.846	0.265	1.441	0.950 ~ 2.184	0.085
?	≤10×10⁷个/kg	55	53.82	?	?	?	?	?	?
?	>10×10⁷个/kg	199	60.00	?	?	?	?	?	?

Please choose a citation manager

Content to export