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Y. Maeda et al.
Table 3. Effect of HLA allele mismatch on Grades III to IV acute graft-versus-host disease (GvHD) by affected organ. HLA mismatch for graft-versus-host
Skin GvHD SHR1 (95%CI) Gut GvHD SHR1 (95%CI) Liver GvHD
SHR1 (95%CI)
Match (N=85)
1 (ref)
1 (ref)
1 (ref)
1 allele mismatch (N=160)
2.49 (0.87-7.13, P=0.088)
3.33 (0.90-12.3, P=0.072)
2.16 (0.53-8.85, P=0.283)
≥2 allele mismatch (N=401) 2.94 (0.94-9.19, P=0.063)
3.14 (0.82-12.0, P=0.094) 3.24 (0.73-14.4, P=0.122)
1Adjusted for recipient age at transplant (continuous),recipient gender,gender mismatch (match,male to female,female to male,unknown),diagnosis (acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, malignant lymphoma or others), disease risk at transplant (standard or high), stem cell source (bone marrow, peripheral blood, cord blood), conditioning regimen (myeloablative or reduced intensity), graft-versus-host disease (GvHD) prophylaxis (cyclosporine based, tacrolimus based, others), in vivo T-cell depletion (Yes, No), year of transplant (1994-2010, 2011-2016), interval between first and second stem cell transplantation (SCT) (<12 months, ≥12-23 months, ≥24 months, missing) and interval between first SCT and relapse (<2 months, ≥2-12 months, ≥12 months, missing). SHR: subdistribution hazard ratios.
Table 4. Effect of HLA allele mismatch on transplant-related mortality, relapse and overall survival in multivariate analyses.
Transplant-related mortality SHR1 (95%CI)
Relapse
SHR1 (95%CI)
Overall survival HR1 (95%CI)
Match (N=85)
1 (ref)
1 (ref)
1 (ref)
1 allele mismatch (N=160)
1.67 (0.94-2.98, P=0.081)
0.73
(0.50-1.07, P=0.110) 1.00
(0.72-1.41, P=0.952)
≥2 allele mismatch (N=401)
1.90
(1.04-3.50, P=0.038) 0.68
(0.44-1.06, P=0.086) 1.21
(0.84-1.73, P=0.313)
Match (N=72)
1 (ref)
1 (ref)
1 (ref)
1 allele mismatch N=100)
0.89 (0.52-1.52, P=0.665)
1.18
(0.72-1.95, P=0.516) 0.84
(0.57-1.21, P=0.347)
≥2 allele mismatch (N=474)
0.67 (0.42-1.07, P=0.095)
1.41
(0.89-2.22, P=0.143) 0.85
(0.61-1.17, P=0.313)
HLA mismatch for graft-versus-host
HLA mismatch for graft-versus-first donor
*Bold denotes statistical significance. 1Adjusted for recipient age at transplant (continuous), recipient gender, gender mismatch (match, male to female, female to male, unknown), diagnosis (acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, malignant lymphoma or others), disease risk at transplant (standard or high),stem cell source (bone marrow,peripheral blood,cord blood),conditioning regimen (myeloablative or reduced intensity),graft-versus-host disease (GvHD) prophylaxis (cyclosporine based, tacrolimus based, others), in vivo T-cell depletion (Yes, No), year of transplant (1994-2010, 2011-2016), interval between first and second stem cell transplantation (SCT) (<12 months, ≥12-23 months, ≥24 months, missing) and interval between first SCT and relapse (<2 months, ≥2-12 months, ≥12 months, missing). SHR: subdistribution hazard ratios; HR: hazard ratios.
APCs originating from the first donor. The antigen-pre- senting function of the first-donor hematopoietic cells may be insufficiently strong to induce GvHD. An alterna- tive explanation is that recipient hematopoietic APCs have a limited capacity to induce acute GvHD, possibly owing to their predisposition to induce donor T-cell death.11 In contrast, HLA discrepancy between the graft and host may impact the risk of acute GvHD during the second transplant. In this study, HLA-MM between the graft and host showed increased risk of grade III-IV acute GvHD, although the results were not significant. In addi- tion, B allele MM was significantly associated with an increased risk of grade III-IV acute GvHD in the analysis of each HLA allele mismatch [relative risk (RR) 2.87, 95%CI: 1.42-5.79; P=0.003]. Several experimental studies showed that non-hematopoietic gastrointestinal cells are able to express MHC class II and induce CD4+ T-cell-dependent acute GvHD.10,11 As the antigen-present- ing function of epithelial cells is enhanced in the presence of an inflammatory environment, epithelial cells after the first HSCT could play a major role in inducing GvHD fol- lowing second HSCT, although further studies are needed to validate this.
The length of remission after first HSCT and the disease
status at second HSCT, are two main independent prog- nostic factors for predicting the outcome of a second HSCT.2,3,5 Despite a significant increase in the proportion of patients of advanced age, having an advanced disease stage, and receiving alternative donor transplants, there has been a continual decrease in TRM, reflecting the impact of advances in supportive care and more wide- spread use of reduced-intensity conditioning regimens. However, the reduction in rate of TRM has been less obvi- ous in patients following a second remission or refractory disease.25 Due to more advanced disease and accumulating toxicity, second transplants are more problematic than first transplants, and often result in an increase in TRM and overall mortality rates. Attempted enhancement of the GvT effect by switching donor may be affected by the toxicity of the second HSCT. Reducing TRM remains one of the most significant challenges in second HSCT. Our analysis showed that HLA-MM between the graft and first donor had no influence on GvHD, relapse, TRM, or OS. In contrast, with regard to graft-versus-host, the risk of TRM was significantly higher in the ≥2 MM group versus the 0 MM group (RR, 1.90; 95%CI: 1.04-3.50; P=0.038). Analysis of each HLA allele MM revealed that the DR allele MM was significantly associated with a lower rate
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