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Y. Maeda et al.
Table 2. Effect of HLA allele mismatch on acute graft-versus-host disease (GvHD), chronic GvHD and engraftment in multivariate analyses.
Grades III to IV acute GvHD SHR1 (95%CI)
Chronic GvHD
SHR1 (95%CI)
Neutrophil engraftment SHR1 (95%CI)
Match (N=85)
1 (ref)
1 (ref)
1 (ref)
1 allele mismatch (N=160)
1.88 (0.79-4.45, P=0.163)
1.45
(0.84-2.50, P=0.181) 0.81
(0.62-1.06, P=0.126)
≥2 allele mismatch (N=401)
1.84 (0.75-4.51, P=0.182)
1.20
(0.60-2.38, P=0.605) 0.77
(0.56-1.05, P=0.097)
Match (N=72)
1 (ref)
1 (ref)
1 (ref)
1 allele mismatch (N=100)
0.84 (0.35-2.02, P=0.669)
0.98
(0.55-1.76, P=0.956) 1.06
(0.75-1.48, P=0.753)
≥2 allele mismatch (N=474)
0.91 (0.43-1.93, P=0.800)
0.91
(0.54-1.51, P=0.702) 1.23
(0.92-1.66, P=0.167)
HLA mismatch for graft-versus-host
HLA mismatch for graft-versus-first donor
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.
months: 0 MM, 34.1%; 1 MM, 44.4%; ≥ 2 MM, 50.2%, P=0.008). With regard to graft-versus-first donor compari- son, the ≥2 MM group showed a similar trend to that for the graft-versus-host group comparison. The ≥2 MM group required more cord blood (P=0.001), used a reduced-inten- sity conditioning regimen (P=0.004), and had greater in vivo T-cell depletion (P<0.001) and a shorter interval between the first and second HSCT (P=0.029).
Acute graft-versus-host disease, chronic
graft-versus-host disease, and engraftment
With regard to the graft-versus-host results, the unadjust- ed cumulative incidence rates of grade III-IV acute GvHD at 100 days post transplantation were 9.5% (95%CI: 4.4- 17.0%) in the 0 MM group, 13.8% (95%CI: 9.0-19.7%) in the 1 MM group, and 11.0% (95%CI: 8.2-14.3%) in the ≥2 MM group (Figure 1). In multivariate analysis, the 1 MM group (SHR, 1.88; 95%CI: 0.79-4.45; P=0.163) and ≥2 MM group (SHR, 1.84; 95%CI: 0.75-4.51; P=0.182) tended to have higher risk of grade III-IV acute GvHD compared to the 0 MM group, although the results were not statistical- ly significant (Table 2). With regard to affected organ, the risk of skin, gut and liver acute GvHD increased among the 1 MM group and ≥2MM group compared to the 0 MM group (Table 3). There was no statistically significant dif- ference in risk of chronic GvHD among the groups in multivariate analysis. The cumulative incidence rate of neutrophil engraftment at day 50 was 94.0% (95%CI: 85.6-97.6%) in the 0 MM group, 96.9% (95%CI: 92.3- 98.7%) in the 1 MM group, and 91.0% (95%CI: 87.7- 93.4%) in the ≥2 MM group. In multivariate analysis, the ≥2 MM group tended to show delayed engraftment com- pared to the 0 MM group (SHR, 0.77; 95%CI: 0.56-1.05;
P=0.097).
With regard to the graft-versus-first donor results, there
were no significant differences in the risk of grade III-IV acute GvHD, chronic GvHD, or neutrophil engraftment among the groups in multivariate analysis (Table 2).
Next, the association of each HLA allele MM with
GvHD was evaluated (Online Supplementary Table S1). With regard to graft-versus-host, B allele MM was associ- ated with an increased risk of grade III-IV acute GvHD in multivariate analysis (SHR, 2.87; 95%CI: 1.42-5.79; P=0.003), and DR allele MM was associated with delayed neutrophil engraftment (SHR, 0.80; 95%CI: 0.67-0.95, P=0.011); no such associations were found for the other MM types. With regard to the graft-versus-first donor results, no HLA allele MM showed an association with grade III-IV acute GvHD, chronic GvHD, or neutrophil engraftment in multivariate analysis.
Transplant-related mortality, relapse, and overall
survival
With regard to the graft-versus-host results, the unadjust- ed cumulative incidence rates of TRM and relapse at 5 years post transplantation were 19.8% (95%CI: 11.8- 29.2%) and 55.6% (95%CI: 43.9-65.7%) in the 0 MM group, 32.5% (95%CI:25.2-39.9%) and 45.2% (95%CI: 37.3-52.8%) in the 1 MM group, and 34.7% (95%CI: 30.0- 39.4%) and 46.8% (95%CI: 41.8-51.7%) in the ≥2 MM group, respectively (Figures 2 and 3). Multivariate analysis indicated that the risk of TRM was marginally higher in the 1 MM group (SHR, 1.67; 95%CI: 0.94-2.98; P=0.081), and significantly higher in the ≥2 MM group (SHR, 1.90; 95%CI: 1.04-3.50; P=0.038), versus the 0 MM group. In contrast, the risk of relapse was slightly lower in both the 1 MM group (SHR, 073; 95%CI: 0.50-1.07; P=0.110) and the ≥2 MM group (SHR, 068; 95%CI: 0.44-1.06; P=0.086). Consequently, no significant differences in OS were found among the three groups in multivariate analyses (Table 4). Analysis of each HLA allele MM revealed that only HLA DR allele MM was significantly associated with a lower risk of relapse (SHR, 0.75; 95%CI: 0.58-0.95; P=0.018) and a higher risk of TRM (SHR, 1.44; 95%CI: 1.03-2.00; P=0.033) (Online Supplementary Table S2). The main causes of TRM differed among the three groups. The rates of interstitial pneumonia, TMA, and especially acute GvHD
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