Page 210 - 2019_05-HaematologicaMondo-web

Y. Maeda et al.
Introduction
For patients with malignant hematologic diseases who relapse after allogeneic hematopoietic stem cell transplan- tation (HSCT), a second HSCT is thought to be a curative option. It is believed that use of a second donor may con- fer increased therapeutic potency by inducing a more potent graft-versus-leukemia (GvL) effect; however, there are no data to support this assumption.1-9 In early studies, a second HSCT after a first HLA-matched transplantation was associated with similar risks of relapse and acute graft-versus-host disease (GvHD) using a different HLA- matched donor.3 There was no significant difference in survival between the transplantations from the original donor and another donor.
Over the years, the use of HLA-mismatched (MM) transplantation for hematologic diseases has increased, including haploidentical HSCT and cord blood transplan- tation (CBT). Following HLA-MM transplantation, a sec- ond donor is selected due to HLA discrepancy between the graft and the host. Physicians pay little attention to HLA discrepancy between the graft and the first donor, although the impact of this discrepancy on the outcome of second HSCT is unclear. Recipient non-hematopoietic gastrointestinal cells can express MHC class II, which is critical for inducing experimental acute GvHD in cases of minor histocompatibility antigen (mHAg) MM.10,11 In con- trast, hematopoietic antigen presenting cells (APCs), espe- cially dendritic cells, induce MHC class I-dependent acute GvHD in mHAg MM cases.12 Furthermore, in the MHC MM setting, hematopoietic APCs play an important role in the induction of both MHC class I- and II-dependent acute GvHD.13-16 As hematopoietic APCs are of first donor origin, HLA discrepancy between the graft and the first donor may be related to transplant-related immunological responses of the second HSCT.
To elucidate the biological effects of HLA discrepancy between the graft and the first donor that impact the out- come of the second HSCT, we compared the effects of HLA-MM between the graft and the first donor to those between the graft and the host in 646 patients receiving a second HSCT after an initial HLA-MM transplantation.
Methods
Study population
Patients who were at least 16 years of age with acute myeloge- nous leukemia (AML), acute lymphoblastic leukemia (ALL), myelodysplastic syndrome (MDS), chronic myelogenous leukemia (CML), malignant lymphoma (ML), or other malignant hematologic disease, and who received a second HSCT after an initial HLA-MM transplantation, were included in this study. Furthermore, patients must have received first and second allo- geneic HSCTs between 1994 and 2016, with full HLA-A, -B, and -DRB1 allele data. Hematopoietic stem cell transplantation recipi- ent clinical data were collected by the Japan Society for Hematopoietic Cell Transplantation (JSHCT) and the Japanese Data Center for Hematopoietic Cell Transplantation (JDCHCT) using the Transplant Registry Unified Management Program (TRUMP).17-19 We excluded individuals who: 1) first received HLA-matched HSCT; 2) received a second HSCT within 30 days after the first HSCT, in a planned manner or due to rejection/engraftment failure; 3) died within 30 days and lacked data on survival status and survival date; 4) lacked accurate allele
data; or 5) received more than two HSCTs. The final study popu- lation consisted of 646 patients. The study was approved by the Data Management Committee of TRUMP and the Institutional Review Board of Okayama University.
Study end points
The outcomes assessed included acute GvHD, chronic GvHD, neutrophil engraftment, transplant-related mortality (TRM), relapse, and overall survival (OS). Acute and chronic GvHD were diagnosed and graded using the standard criteria.20,21 Neutrophil engraftment was considered to have occurred when the absolute neutrophil count was ≥ 0.5x109 cells/L for 3 consecutive days. Death from any cause was the event of interest in determining OS. TRM was defined as death during remission.
Statistical analysis
Descriptive statistics were generated for patients' characteris- tics. Differences in characteristics between groups were evaluated by the c2 test and analysis of variance. The probability of OS was estimated according to the Kaplan-Meier method, and groups were compared using the log rank test. Subsequently, the proba- bilities of relapse, TRM, and acute and chronic GvHD were esti- mated on the basis of cumulative incidence curves.22 Competing events were death without relapse for relapse, relapse for TRM, death without engraftment for engraftment, and death without GvHD for acute or chronic GvHD. The groups were compared using Gray’s test.
To evaluate the impact of HLA discrepancy on transplant out- comes, we estimated the hazard ratios (HRs) or subhazard ratios (SHRs) and 95% confidence intervals (CIs) adjusted for potential confounders. The Cox proportional hazards model was used to evaluate the impact on OS, whereas multivariable competing- risks regression was used to evaluate the impact on the other end points. Several potential confounders considered in the multivari- able analyses were provided in the Online Supplementary Appendix.
In all analyses, P<0.05 was considered statistically significant. All statistical analyses are performed with Stata (v.15,0; Stata Corp., College Station, TX, USA) and EZR software (Saitama Medical Center, Jichi Medical University, Japan).23
Results
Patients' and transplantation characteristics
A total of 646 patients who received a second HSCT after an initial HLA-MM transplantation were analyzed. Patients' and transplantation characteristics are presented in Table 1. With respect to the HLA discrepancy in the graft-versus-host direction (graft vs. host), HLA matching was categorized as follows: HLA -A, -B, -DRB1 match (0 MM, n=85), MM at one allele (1 MM, n=160), or mis- match at more than one allele (≥2 MM, n=401). With regard to HLA discrepancy in the graft-versus-first donor direction (graft vs. first donor), the second HSCT was cat- egorized as follows: HLA -A, -B, -DRB1 match (0 MM, n=72), mismatch at one allele (1 MM, n=100), or mis- match at more than one allele (≥2 MM, n=474). In the graft-versus-host comparison, the ≥2 MM group received cord blood more frequently (0 MM, 20.0%; 1 MM, 21.3%; ≥2 MM, 60.2%, P<0.001), were more likely to use a reduced-intensity conditioning regimen (0 MM, 56.5%; 1 MM, 66.3%; ≥2 MM, 70.7%, P=0.012), and had a higher rate of in vivo T-cell depletion (0 MM, 10.6%; 1 MM, 18.1%; ≥2 MM, 25.4%, P=0.003). The interval between the first and second HSCT was shorter in this group (<12
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haematologica | 2019; 104(5)