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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2019, Vol. 13 Issue (6) : 667-679    https://doi.org/10.1007/s11684-019-0702-z
RESEARCH ARTICLE
Risk factors for chronic graft-versus-host disease after anti-thymocyte globulin-based haploidentical hematopoietic stem cell transplantation in acute myeloid leukemia
Meng Lv1, Xiaohui Zhang1, Lanping Xu1, Yu Wang1, Chenhua Yan1, Huan Chen1, Yuhong Chen1, Wei Han1, Fengrong Wang1, Jingzhi Wang1, Kaiyan Liu1, Xiaojun Huang1,2, Xiaodong Mo1()
1. Peking University People’s Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, China
2. Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100044, China
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Abstract

Chronic graft-versus-host disease (cGVHD) is a major complication following unmanipulated haploidentical hematopoietic stem cell transplantation (haplo-HSCT). We aimed to identify the risk factors for cGVHD in patients who underwent anti-thymocyte globulin-based haplo-HSCT for acute myeloid leukemia (n=280). The diagnosis of cGVHD was in accordance with the National Institutes of Health consensus criteria. A total of 169 patients suffered from cGVHD. The patients who had 3 loci mismatched had a higher 8-year incidence of cGVHD (total, 66.0% vs. 53.7%, P=0.031; moderate to severe, 42.4% vs. 30.1%, P=0.036) than the patients who had 1 to 2 loci mismatched. The patients who had maternal donors had a higher 8-year incidence of moderate to severe cGVHD (49.2% vs. 32.9%, P=0.024) compared with the patients who had other donors. The patients who had grades III to IV acute GVHD (aGVHD) had higher 8-year incidence of cGVHD (total, 88.0% vs. 50.4%, P<0.001; moderate to severe, 68.0% vs. 27.0%, P<0.001) compared with the patients without aGVHD. In multivariate analysis, grades III to IV aGVHD was the only independent risk factor for cGVHD. Thus, further interventions should be considered in patients with severe aGVHD to prevent cGVHD.

Keywords acute graft-versus-host disease      chronic graft-versus-host disease      National Institutes of Health consensus criteria      acute myeloid leukemia      anti-thymocyte globulin     
Corresponding Authors: Xiaodong Mo   
Just Accepted Date: 24 July 2019   Online First Date: 23 September 2019    Issue Date: 16 December 2019
 Cite this article:   
Meng Lv,Xiaohui Zhang,Lanping Xu, et al. Risk factors for chronic graft-versus-host disease after anti-thymocyte globulin-based haploidentical hematopoietic stem cell transplantation in acute myeloid leukemia[J]. Front. Med., 2019, 13(6): 667-679.
 URL:  
http://academic.hep.com.cn/fmd/EN/10.1007/s11684-019-0702-z
http://academic.hep.com.cn/fmd/EN/Y2019/V13/I6/667
Characteristics Non-cGVHD
(n = 111)
cGVHD
(n = 169)
P*
Median age at HSCT, year (range) 25 (3–55) 26 (2–54) 0.298
Time in months from diagnosis to HSCT, median (range) 6 (2–94) 6 (2–60) 0.303
Gender, n (%)
Male 69 (62.2) 96 (56.8) 0.373
Female 42 (37.8) 73 (43.2)
Disease status at transplantation, n (%)
CR1 99 (89.2) 153 (90.5) 0.714
CR2 12 (10.8) 16 (9.5)
Cytogenetic risk, n (%)
Good 17 (15.3) 21 (12.4) 0.634
Intermediate 91 (82.0) 140 (82.8)
Poor 3 (2.7) 8 (4.7)
Donor–recipient gender match, n (%)
Female–male 23 (20.7) 38 (22.5) 0.726
Others 88 (79.3) 131 (77.5)
Donor–recipient relation, n (%)
Father–child 35 (31.5) 46 (27.2) 0.558
Mother–child 19 (17.1) 42 (24.9)
Sibling–sibling 40 (36.0) 62 (36.7)
Child–parent 11 (9.9) 14 (8.3)
Other 6 (5.5) 5 (2.9)
Number of HLA-A, -B, -DR mismatches, n (%)
1 19 (17.2) 13 (7.7) 0.019
2 44 (39.6) 60 (35.5)
3 48 (43.2) 96 (56.8)
ABO match, n (%)
Matched 63 (56.8) 94 (55.6) 0.851
Mismatched 48 (43.2) 75 (44.4)
HCT-CI scores
0 56 (50.5) 84 (49.7) 0.100
1–2 35 (31.5) 68 (40.2)
≥3 20 (18.0) 17 (10.1)
aGVHD, n (%)
None 57 (51.4) 58 (34.3) <0.001
Grades I–II 52 (46.8) 88 (52.1)
Grades III–IV 2 (1.8) 23 (13.6)
Viral infection
Cytomegaloviremia 55 (49.5) 96 (56.8) 0.234
Cytomegalovirus disease 2 (1.8) 8 (4.7) 0.324
Epstein–Barr viremia 5 (4.5) 7 (4.1) 1.000
PTLD 3 (2.7) 3 (1.8) 0.684
Median mononuclear cells, × 108/kg (range) 8.2 (4.0–16.3) 7.8 (2.7–18.8) 0.141
Median CD3+ counts, × 108/kg (range) 1.5 (0.2–6.3) 1.5 (0.2–8.3) 0.249
Median CD34+ counts, × 106/kg (range) 2.2 (0.4–55.3) 2.2 (0.3–12.1) 0.424
Tab.1  Characteristics of patients
Characteristics of cGVHD N = 169
Time from cGVHD to haplo-HSCT, day (range) 100 (172–1023)
Severity of cGVHD, n (%)
Mild 66 (39.1)
Moderate 67 (39.6)
Severe 36 (21.3)
Type of cGVHD, n (%)
Classical cGVHD 155 (91.7)
Overlap syndrome 14 (8.3)
Site of cGVHD, n (%)
Skin 145 (85.8)
Mouth 41 (24.3)
Eye 32 (18.9)
Liver 48 (28.4)
Gut 27 (16.0)
Lung 5 (3.0)
Joint 3 (1.8)
Number of sites, n (%)
1 83 (49.1)
2 48 (28.4)
≥3 38 (22.5)
Treatment of cGVHD
Corticosteroid 123 (72.8)
Cyclosporine A 118 (69.8)
Methotrexate 52 (30.8)
Mycophenolate mofetil 35 (20.7)
Penicillamine 22 (13.0)
Tacrolimus 17 (10.1)
Azathioprine 9 (5.3)
Number of drugs
0 8 (4.8)
1 20 (11.8)
2 83 (49.1)
≥3 58 (34.3)
Tab.2  Characteristics of cGVHD after haplo-HSCT
Variables Total cGVHD Moderate to severe cGVHD
Univariable analysis Multivariate analysis Univariable analysis Multivariate analysis
HR (95% CI) P value HR (95% CI) P value HR (95% CI) P value HR (95% CI) P value
Patient characteristics
Gender
Male 1 1
Female 1.08 (0.79–1.46) 0.644 1.02 (0.69–1.52) 0.912
Age
<median 1 1
≥median 1.02 (0.75–1.38) 0.897 1.02 (0.69–1.50) 0.934
HCT-CI scores
0−2 1 1
≥3 0.69 (0.42–1.14) 0.148 0.71 (0.37–1.37) 0.308
Disease characteristics
Disease status before haplo-HSCT
CR1 1 1
CR2 0.86 (0.51–1.44) 0.562 0.94 (0.49–1.81) 0.859
Adverse cytogenetics
No 1 1
Yes 1.10 (0.54–2.25) 0.785 0.84 (0.31–2.28) 0.728
Time from diagnosis to HSCT
<6 months 1 1
≥6 months 0.89 (0. 64–1.22) 0.463 0.87 (0.58–1.32) 0.517
Donor characteristics
HLA disparity
1 locus 1 1
2 loci 1.60 (0.88–2.92) 0.124 2.01 (0.85–4.79) 0.113
3 loci 2.03 (1.14–3.63) 0.017 2.67 (1.16–6.18) 0.022
Donor type
Others 1 1
Maternal donors 1.22 (0.86–1.73) 0.267 1.64 (1.07–2.52) 0.022
Donor–recipient sex matched
Others 1 1
Female donor/male recipient 1.06 (0.74–1.52) 0.745 1.21 (0.77–1.90) 0.409
ABO matched
Matched/minor mismatched 1 1
Major/major-minor mismatched 1.03 (0.76–1.40) 0.829 0.77 (0.52–1.15) 0.201
aGVHD after haplo-HSCT
None 1 1 1 1
Grades I to II 1.38 (0.99–1.92) 0.058 1.36 (0.98–1.90) 0.070 1.56 (1.00–2.43) 0.048 1.52 (0.98–2.37) 0.063
Grades III to IV 2.49 (1.52–4.09) <0.001 2.40 (1.46–3.93) 0.001 3.55 (1.96–6.42) <0.001 3.09 (1.69–5.66) < 0.001
Infection after haplo-HSCT
Cytomegalovirus infection
None 1 1
Cytomegaloviremia 1.10 (0.81–1.49) 0.537 1.17 (0.79–1.73) 0.433
Cytomegalovirus disease 1.59 (0.78–3.24) 0.199 1.48 (0.60–3.63) 0.394
Epstein-Barr virus infection
None 1 1
Epstein-Barr viremia 1.19 (0.56–2.54) 0.652 1.41 (0.57–3.46) 0.456
PTLD 1.46 (0.46–4.58) 0.519 1.56 (0.38–6.35) 0.533
Tab.3  Risk factors for cGVHD after haplo-HSCT
Fig.1  cGVHD according to HLA disparity and donor–recipient relation. (A) HLA disparity and total cGVHD; (B) HLA disparity and moderate to severe cGVHD; (C) Donor–recipient relationship and moderate to severe cGVHD. cGVHD, chronic graft-versus-host disease.
Fig.2  cGVHD according to aGVHD severity. (A) aGVHD and total cGVHD; (B) aGVHD and moderate to severe cGVHD. aGVHD, acute graft-versus-host disease; cGVHD, chronic graft-versus-host disease.
Fig.3  Clinical outcomes according to cGVHD grading. (A) relapse; (B) non-relapse mortality; (C) disease-free survival; (D) overall survival. cGVHD, chronic graft-versus-host disease; DFS, disease-free survival; NRM, non-relapse mortality; OS, overall survival.
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[1] FMD-19011-OF-MXD_suppl_1 Download
[2] FMD-19011-OF-MXD_suppl_2 Download
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