Scholarly article on topic 'Impact of HLA Mismatch Direction on the Outcome of Unrelated Bone Marrow Transplantation: A Retrospective Analysis from the Japan Society for Hematopoietic Cell Transplantation'

Impact of HLA Mismatch Direction on the Outcome of Unrelated Bone Marrow Transplantation: A Retrospective Analysis from the Japan Society for Hematopoietic Cell Transplantation Academic research paper on "Clinical medicine"

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{"Donor selection" / "HLA mismatch" / GVHD / "Overall survival" / "Graft-versus-host direction" / "Host-versus-graft direction"}

Abstract of research paper on Clinical medicine, author of scientific article — Junya Kanda, Tatsuo Ichinohe, Shigeo Fuji, Yoshinobu Maeda, Kazuteru Ohashi, et al.

Abstract The relative desirability of an unrelated donor with a bidirectional 1-locus mismatch (1MM-Bi), a 1-locus mismatch only in the graft-versus-host direction (1MM-GVH), or a 1-locus mismatch only in the host-versus-graft direction (1MM-HVG) is not yet clear. We analyzed adult patients with leukemia or myelodysplastic syndrome who received a first allogeneic stem cell transplant from an HLA-A, -B, -C, and -DRB1 matched or 1-allele mismatched unrelated donor in Japan. The effects of 1MM-Bi (n = 1020), 1MM-GVH (n = 83), and 1MM-HVG (n = 83) compared with a zero mismatch (0MM) (n = 2570) were analyzed after adjusting for other significant variables. The risk of grades III to IV acute graft-versus-host disease (GVHD) was higher with marginal significance in the 1MM-GVH group than in the 0MM group (hazard ratio, 1.85; P = .014). However, there was no significant difference in overall or nonrelapse mortality between the 1MM-GVH and 0MM groups. There was no significant difference in acute GVHD or overall or nonrelapse mortality between the 1MM-HVG and 0MM groups. The risks of acute GVHD and overall mortality were significantly higher in the 1MM-Bi group than in the 0MM group. These findings indicate that unrelated donors with 1MM-GVH and 1MM-HVG are both good candidates for patients without an HLA-matched unrelated donor in a Japanese cohort.

Academic research paper on topic "Impact of HLA Mismatch Direction on the Outcome of Unrelated Bone Marrow Transplantation: A Retrospective Analysis from the Japan Society for Hematopoietic Cell Transplantation"

AS BMI

American Society for Blood and Marrow Transplantation

Biology of Blood and Marrow Transplantation

journal homepage: www.bbmt.org

Impact of HLA Mismatch Direction on the Outcome of Unrelated Bone Marrow Transplantation: A Retrospective Analysis from the Japan Society for Hematopoietic Cell Transplantation

Junya Kanda1, Tatsuo Ichinohe 2, Shigeo Fuji3, Yoshinobu Maeda 4, Kazuteru Ohashi5, Takahiro Fukuda3, Koichi Miyamura6, Koji Iwato7, Tetsuya Eto8, Hirohisa Nakamae9, Naoki Kobayashi10, Takehiko Mori11, Shin-ichiro Mori12, Yasuo Morishima13, Yoshiko Atsuta14, Yoshinobu Kanda1,*, on behalf of the HLA Working Group of the Japan Society for Hematopoietic Cell Transplantation

1 Division of Hematology, Saitama Medical Center, Jichi Medical University, Saitama, Japan

2 Department of Hematology and Oncology Research Institute for Radiation Biology and Medicine Hiroshima University Hiroshima Japan

3 Stem Cell Transplantation Division, National Cancer Center Hospital, Tokyo, Japan

4 Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

5 Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan

6 Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan

7 Department of Blood Transfusion, Hiroshima Red Cross and Atomic Bomb Survivors Hospital, Hiroshima, Japan

8 Department of Hematology, Hamanomachi Hospital, Fukuoka, Japan

9 Department of Hematology, Graduate School of Medicine, Osaka City University, Osaka, Japan

10 Department of Hematology, Sapporo Hokuyu Hospital, Sapporo, Japan

11 Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan

12 Hematology-Oncology Department, St. Luke's International Hospital, Tokyo, Japan

13 Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan

14 Japanese Data Center for Hematopoietic Cell Transplantation and Nagoya University Graduate School of Medicine, Nagoya, Japan

^Jjj^l CrossMark

Article history:

Received 12 September 2014 Accepted 13 October 2014

Key Words: Donor selection HLA mismatch GVHD

Overall survival Graft-versus-host direction Host-versus-graft direction

ABSTRACT

The relative desirability of an unrelated donor with a bidirectional 1-locus mismatch (1MM-Bi), a 1-locus mismatch only in the graft-versus-host direction (1MM-GVH), or a 1-locus mismatch only in the host-versus-graft direction (1MM-HVG) is not yet clear. We analyzed adult patients with leukemia or myelodys-plastic syndrome who received a first allogeneic stem cell transplant from an HLA-A, -B, -C, and -DRB1 matched or 1-allele mismatched unrelated donor in Japan. The effects of 1MM-Bi (n = 1020), 1MM-GVH (n = 83), and 1MM-HVG (n = 83) compared with a zero mismatch (0MM) (n = 2570) were analyzed after adjusting for other significant variables. The risk of grades III to IV acute graft-versus-host disease (GVHD) was higher with marginal significance in the 1MM-GVH group than in the 0MM group (hazard ratio, 1.85; P = .014). However, there was no significant difference in overall or nonrelapse mortality between the 1MM-GVH and 0MM groups. There was no significant difference in acute GVHD or overall or nonrelapse mortality between the 1MM-HVG and 0MM groups. The risks of acute GVHD and overall mortality were significantly higher in the 1MM-Bi group than in the 0MM group. These findings indicate that unrelated donors with 1MM-GVH and 1MM-HVG are both good candidates for patients without an HLA-matched unrelated donor in a Japanese cohort.

© 2015 American Society for Blood and Marrow Transplantation.

Financial disclosure: See Acknowledgments on page 310.

* Correspondence and reprint requests: Yoshinobu Kanda, MD, Division of Hematology, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma-cho, Omiya-ku, Saitama City, Saitama, Japan 330-8503. E-mail address: ycanda-tky@umin.ac.jp (Y. Kanda).

INTRODUCTION

An HLA-identical sibling is the best donor for allogeneic stem cell transplantation because of the low risk of immune complications such as acute graft-versus-host disease (GVHD) and graft rejection. However, for patients without an HLA-identical sibling, an HLA-A, -B, -C, and -DRB1 allele-matched

http://dx.doi.org/10.1016/j.bbmt.2014.10.015

1083-8791/® 2015 American Society for Blood and Marrow Transplantation.

unrelated donor is considered the best alternative when an immediate transplant is not necessary [1,2]. Finally, when an HLA-matched unrelated donor is not available, an HLA 1-allele mismatched unrelated donor is an attractive donor source, although the overall survival rate after HLA 1-allele mismatched unrelated transplantation is 5% to 10% lower than that after HLA-matched unrelated transplantation [3-5].

Among 1-allele mismatched unrelated donors, the mismatch is only in the graft-versus-host direction (1MM-GVH) when a mismatched allele of the donor is homozygous. On the other hand, the mismatch is only in the host-versus-graft direction (1MM-HVG) when a mismatched allele of the recipient is homozygous. The effect of the immune reaction caused by an HLA mismatch differs according to whether the mismatch is in the GVH or HVG direction, because a mismatched antigen in the GVH direction can be a major target for donor T cells and can cause GVHD, whereas a mismatched antigen in the HVG direction can be a major target for the remaining recipient T cells and can lead to graft rejection. In related transplantation, the presence of HLA mismatches in the GVH direction is associated with a higher incidence of GVHD, whereas the presence of HLA mismatches in the HVG direction is associated with a higher incidence of rejection [6-8]. Therefore, from a biological perspective, the impact of 1MM-GVH, 1MM-HVG, or bidirectional 1-locus mismatch (1MM-Bi) on the clinical outcome should differ, and questions regarding donor selection priority should arise when several donor candidates with 1MM-Bi, 1MM-GVH, or 1MM-HVG are available for patients without an HLA-matched unrelated donor.

In a recent study by the Center for International Blood and Marrow Transplant Research (CIBMTR), transplantation from an unrelated donor with 1MM-Bi or a donor with 1MM-GVH was significantly associated with higher risks of severe acute GVHD and overall mortality than transplantation from an unrelated donor without a mismatch at the HLA-A, -B, -C, or -DRB1 locus (0MM) [9]. However, transplantation from a donor with 1MM-HVG was not associated with these risks. Therefore, selection of an unrelated donor with 1MM-HVG is recommended when an unrelated donor with 0MM is not available. However, hazard ratios (HRs) of overall and disease-free survival in the 1MM-HVG group as compared with the 0MM group were also high (1MM-HVG HR, 1.37 [P = .03] and 0MM HR, 1.38 [P = .013]). Although these values were not statistically significant as defined in that study (P < .01), these HRs in the 1MM-HVG group were comparable with those in the 1MM-Bi group (1.29 and 1.35, respectively), suggesting the study may have had insufficient power to detect a significant difference between the 1MM-HVG and 0MM groups. Therefore, the effect of the HLA mismatch direction in unrelated bone marrow transplantation (UBMT) needs to be validated in other populations. In the present study, we conducted a retrospective analysis using Japanese national registry data on 3756 patients who underwent HLA-matched or 1-allele mismatched UBMT.

METHODS Data Collection

Patients who were at least 16 years of age with acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), myelodysplastic syndrome (MDS), or chronic myelogenous leukemia (CML), who received a first BMT from a serologically HLA-A, -B, and -DR matched unrelated donor between 2000 and 2011, and who had full HLA-A, -B, -C, and -DRB1 allele data were included in this study. Data were obtained from the Transplant Registry Unified Management Program (TRUMP) [10], where all UBMTs are registered through the Japan Marrow Donor Program (JMDP). We excluded

those who had more than 1-allele mismatch at the HLA-A, -B, -C, or -DRB1 locus; those who lacked data on survival status, survival date, and sex; and those in whom ex vivo or in vivo T cell depletion was used. As a result, 3756 patients were included in this study. The study was approved by the data management committee of TRUMP and by the Institutional Review Board of Saitama Medical Center, Jichi Medical University, where this study was organized.

Histocompatibility

Histocompatibility data for serological and genetic typing for the HLA-A, -B, -C, and -DR loci were obtained from the TRUMP database, which includes HLA allele data determined retrospectively by the JMDP using frozen samples [11,12]. The extent of HLA testing was exons 2 and 3 for HLA class I and exon 2 for HLA class II. Exon 4 and exon 3 were additionally analyzed for classes I and II, respectively, if required. An HLA mismatch in the GVH direction was defined as when the recipient's antigens or alleles were not shared by the donor, and a mismatch in the HVG direction was defined as when the donor's antigens or alleles were not shared by the recipient.

Endpoints

The primary endpoint of the study was overall survival. Other endpoints assessed were relapse, nonrelapse mortality, neutrophil engraftment, acute GVHD, and chronic GVHD. Neutrophil recovery was considered to have occurred when the absolute neutrophil count exceeded 0.5 x 109 cells/L for 3 consecutive days after transplantation. The physicians who performed transplantation at each center diagnosed and graded acute and chronic GVHD according to the traditional criteria [13,14]. The incidence of chronic GVHD was evaluated in patients who survived without relapse for more than 100 days.

Statistical Analysis

The probability of overall survival was estimated according to the Kaplan-Meier method, and groups were compared using the log-rank test. The probabilities of relapse, nonrelapse mortality, neutrophil engraftment, and acute and chronic GVHD were estimated on the basis of cumulative incidence curves [15]. Competing events were death without relapse for relapse, relapse for nonrelapse mortality, death without engraftment for neutrophil engraftment, and death or relapse without GVHD for acute and chronic GVHD. The groups were compared using Gray's test [16]. The Cox proportional hazards model was used to evaluate the effect of confounding variables on overall survival, whereas Fine and Gray's proportional hazards model was used for the other endpoints [17]. Based on the report by the CIBMTR, we classified the conditioning regimens as myeloablative if total body irradiation > 8 Gy, oral busulfan > 9 mg/kg, intravenous busulfan > 7.2 mg/kg, or melphalan > 140 mg/m2 was used in the conditioning regimen; otherwise, we classified the conditioning regimen as reduced intensity [18]. For patients with insufficient data regarding the doses of the agents used in the conditioning regimen, we used the information on conditioning intensity (myeloablative or reduced intensity) reported by the treating clinicians. We defined AML and ALL in the first or second remission, CML in the first or second chronic phase or accelerated phase, and MDS with refractory anemia or refractory anemia with ringed sideroblasts as standard-risk diseases and other conditions as high risk.

The following possible confounding variables were considered: the recipient's age group (16 to 49 years or >50 years), the recipient's sex, sex mismatch between the recipient and donor (match, male [donor]/female [recipient] or female [donor]/male [recipient]), disease (AML, ALL, CML, or MDS), disease status before transplantation (standard or high risk), type of GVHD prophylaxis (cyclosporine based, tacrolimus based, or other/missing), type of conditioning regimen (myeloablative, reduced intensity, or missing), and year of transplantation (2000-2005 or 2006-2011). Factors other than HLA matching were selected in a stepwise manner from the model with a variable retention criterion of P < .05. We then added HLA matching to the final model. For multiple comparisons, a value of P < .01 was used to determine statistical significance.

All statistical analyses were performed with Stata version 13 (Stata Corp., College Station, TX) and EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan) [19]. EZR is a graphical user interface for R (The R Foundation for Statistical Computing, version 2.13.0, Vienna, Austria). More precisely, it is a modified version of R commander (version 2.0-1) designed to add statistical functions that are frequently used in biostatistics.

RESULTS

Patient Characteristics

Table 1 shows patient and transplant characteristics. The median age of recipients at transplantation was 43 years (range, 16 to 77). The diagnosis for transplant was

Table 1

Patient Characteristics

Characteristics 0MM (n = 2570) 1MM-Bi (n = 1020) 1MM-GVH (n = 83) 1MM-HVG (n = 83) P

Median recipient age at transplant, yr (range) 43 (16-77) 41(16-74) 43 (16-65) 43 (18-71) .037

Recipient age at transplant

16-39 yr 1061 457 32 31 .175

40 + yr 1509 563 51 52

HLA mismatch

A locus 0 119 11 21

B locus 0 27 0 3

C locus 0 521 47 38

DR locus 0 353 25 21

Recipient sex

Female 1018 423 34 29 .573

Male 1552 597 49 54

Sex mismatch between donor and recipient

Match 1591 617 43 52 .017

Male donor—female recipient 580 207 17 16

Female donor—male recipient 399 196 23 15

Diagnosis

AML 1329 513 33 49 .137

ALL 647 240 24 17

CML 236 122 11 6

MDS 358 145 15 11

Disease risk at transplant

Standard risk 1659 616 55 46 .188

High risk 832 373 26 33

Missing 79 31 2 4

GVHD prophylaxis

Cyclosporine based 811 299 22 31 .177

Tacrolimus based 1701 704 59 48

Others/missing 58 17 2 4

Conditioning regimen

Meyeloablative 2001 806 64 58 .444

Reduced intensity 486 176 15 22

Missing 83 38 4 3

Transplant year

2000-2005 1147 548 40 47 <.001

2006-2011 1423 472 43 36

Values are total number of cases, unless otherwise noted.

AML in 1924, ALL in 928, CML in 375, and MDS in 529. Two-thirds of the patients had standard-risk diseases. Tacrolimus-based GVHD prophylaxis was used in 67%. Transplantation was performed between 2006 and 2011 in 1974 cases (53%).

HLA matching was categorized as follows: HLA match in both the GVH and HVG directions (0MM, n = 2570, 68%), bidirectional 1-allele mismatch in the GVH and HVG directions (1MM-Bi, n = 1020, 27%), 1-allele mismatch in the GVH direction but 0 mismatches in the HVG direction (1MM-GVH, n = 83, 2%), and 1-allele mismatch in the HVG direction but 0 mismatches in the GVH direction (1MM-HVG, n = 83, 2%). More transplants using a matched unrelated donor with 0MM were performed between 2006 and 2011.

Overall Survival

The median follow-up period in survivors was 3.4 years (range, .7 to 12.6). The unadjusted 3-year overall survival rate was 55% (95% confidence interval [CI], 52% to 57%) in the 0MM group, 46% (95% CI, 43% to 49%) in the 1MM-Bi group, 62% (95% CI, 50% to 72%) in the 1MM-GVH group, and 52% (95% CI, 41% to 63%) in the 1MM-HVG group (P < .001, Figure 1). The risk of overall mortality was significantly higher in the 1MM-Bi group than in the 0MM group (hazard ratio [HR], 1.31; 95% CI, 1.19 to 1.46; P < .001), whereas there was no difference between the 0MM group and the 1MM-GVH group (HR, .97; 95% CI, .70 to 1.34; P = .850) or the 1MM-HVG group (HR, 1.13; 95% CI, .85 to 1.55; P = .439) (Table 2).

Nonrelapse Mortality and Relapse

The cumulative incidence of unadjusted 3-year nonrelapse mortality was 24% (95% CI, 22% to 25%) in the 0MM group, 30% (95% CI, 27% to 33%) in the 1MM-Bi group, 26% (95% CI, 17% to 36%) in the 1MM-GVH group, and 25% (95% CI, 16% to 35%) in the 1MM-HVG group (P < .001, Figure 2). The risk of nonrelapse mortality was significantly higher in the

Years after transplantation

Number at risk

0ММ 2570 1565 1099 834 655 533

1MM-Bi 1020 558 405 320 250 192

1MM-GVH 83 49 42 34 22 20

1MM-HVG 83 46 36 33 26 23

Figure 1. Overall survival. The unadjusted probability of overall survival is shown.

Table 2

Overall Mortality, Nonrelapse Mortality, and Relapse

HR 95% CI P

Overall mortality*

0MM 1.00 Reference

1MM-Bi 1.31 1.19-1.45 <.001

1MM-GVH .97 .70-1.34 .850

1MM-HVG 1.13 .83-1.52 .439

Nonrelapse mortality*

0MM 1.00 Reference

1MM-Bi 1.38 1.21-1.59 <.001

1MM-GVH 1.22 .81-1.84 .334

1MM-HVG 1.12 .75-1.69 .575

Relapse*

0MM 1.00 Reference

1MM-Bi .98 .85-1.14 .810

1MM-GVH .78 .48-1.29 .338

1MM-HVG .88 .55-1.43 .614

* Other significant variables were the recipient's age group, sex of the recipient, diagnosis, and disease risk.

y Other significant variables were the recipient's age group, sex of the recipient, diagnosis, disease risk, and transplant year. z Other significant variables were diagnosis and disease risk.

1MM-Bi group than in the 0MM group (HR, 1.38; P < .001), whereas no difference was found between the 0MM group and the 1MM-GVH group (HR, 1.22; P = .334) or the 1MM-HVG group (HR, 1.12; P = .575) (Table 2). The cumulative incidence of unadjusted 3-year relapse was 26% (95% CI, 24% to 27%) in the 0MM group, 27% (95% CI, 24% to 29%) in the 1MM-Bi group, 21% (95% CI, 12% to 31%) in the 1MM-GVH group, and 24% (95% CI, 15% to 34%) in the 1MM-HVG group (P = .635, Figure 2). There was no significant difference between the 0MM group and the other groups in the multi-variate analysis (Table 2).

Neutrophil Engraftment

The cumulative incidence of neutrophil engraftment at day 50 was 96% (95% CI, 95% to 96%) in the 0MM group, 94% (95% CI, 92% to 95%) in the 1MM-Bi group, 100% in the 1MM-GVH group, and 92% (95% CI, 83% to 96%) in the 1MM-HVG group (P = .224, Figure 3). There was no significant difference between the 0MM group and the other groups in the multivariate analysis (Table 3).

Acute and Chronic GVHD

The unadjusted cumulative incidence of grades III to IV acute GVHD was 12% (95% CI, 10% to 13%) in the 0MM group, 18% (95% CI, 16% to 20%) in the 1MM-Bi group, 18% (95% CI, 11% to 27%) in the 1MM-GVH group, and 15% (95% CI, 8% to 23%) in the 1MM-HVG group (P < .001, Figure 4). The risk of grades III to IV acute GVHD was significantly higher in the 1MM-Bi group (HR, 1.57; P < .001) and higher in the 1MM-GVH group with marginal significance (HR, 1.85; P = .014) than in the 0MM group (Table 3). There was no difference between the 0MM group and the 1MM-HVG group (HR, 1.25; P = .468). The unadjusted cumulative incidence of chronic GVHD was 37% (95% CI, 35% to 39%) in the 0MM group, 35% (95% CI, 32% to 38%) in the 1MM-Bi group, 41% (95% CI, 30% to 52%) in the 1MM-GVH group, and 30% (95% CI, 20% to 41%) in the 1MM-HVG group (P = .584, Figure 4). No significant difference was found between the 0MM group and the other groups in the multivariate analysis (Table 3).

DISCUSSION

Using Japanese registry data, we analyzed patients who received UBMT with either 1MM-GVH or 1MM-HVG and

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0MM ÍMM-BÍ 1MM-GVH 1MM-HVG

--ÍMM-Bi

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Number at risk

1 2 3 4 5

Years after transplantation

2519 1392 996 767 598 486

987 502 370 296 236 183

83 41 36 28 19 17

81 42 34 31 26 23

o <u u c <u -o

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--IMM-Bi

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Number at risk Years after transplantation

0MM 2519 1392 996 767 598 486

IMM-Bi 987 502 370 296 236 183

1MM-GVH 83 41 36 28 19 17

1MM-HVG 81 42 34 31 26 23

Figure 2. Nonrelapse mortality and relapse. The unadjusted incidences of nonrelapse mortality (A) and relapse (B) are shown.

evaluated the impact of 1MM-GVH and 1MM-HVG on the clinical outcome. The risk of severe acute GVHD in the 1MM-GVH group tended to be higher than that in the 0MM group. However, there was no significant difference in overall survival or nonrelapse mortality between the 2 groups. The overall survival and nonrelapse mortality rates in the 1MM-HVG group were also comparable with those in the 0MM group. Unlike the conclusion of the CIBMTR study, there is no evidence in this study that an unrelated donor with 1MM-HVG should be prioritized over 1 with 1MM-GVH in aJapa-nese cohort.

Although the incidence of grades III to IV acute GVHD tended to be higher in the 1MM-GVH group than in the 0MM group, this did not translate into worse overall survival in this Japanese cohort. In interpreting this finding, several differences in patient background between the CIBMTR study [9] and the present study should be clarified. First, the CIBMTR study included transplants performed from 1988 to 2009, whereas our study included transplants performed from 2000 to 2011. Because treatment and supportive care for transplant-related complications such as GVHD and fungal or viral infections improved over this decade, the incidence of nonrelapse mortality was shown to be significantly decreased

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--IMM-Bi

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10 20 30 40 50 Days after transplantation

-ОММ

--1MM-Bi

- - - 1MM-GVH ---1MM-HVG

Number at risk 2559 2521

Number at risk

20 40 60 80 100 Days after transplantation

IMM-Bi 1018 1010 285 40 21 16 0ММ 2500 2285 2119 2002 1902 1820

1MM-GVH 83 83 26 2 1 0 IMM-Bi 991 868 769 716 682 647

1MM-HVG 83 83 22 6 6 4 1MM-GVH 83 79 68 63 60 57

1MM-HVG 82 73 69 61 57 55

Figure 3. Neutrophil engraftment The unadjusted incidence of neutrophil engraftment is shown.

in a recent cohort [20,21]; the 1-year survival in patients who developed grades III to IV acute GVHD after HLA 1-allele mismatched UBMT improved from 32.1% in the period from 1993 to 2001 to 44.4% in the period from 2002 to 2011 [21]. Including only a recent cohort in our study may have reduced the impact of acute GVHD on the nonrelapse mortality rate.

The second difference is the definition of allele mismatch. We included only patients who received UBMT from HLA-A, -B, or -DR antigen matched pairs, following the standard donor selection process of the JMDP, because such a donor can be found for more than 90% of patients in Japan. In this process, we start to search for an HLA-A, -B, -C, and -DRB1 matched unrelated donor; if one is not available, we then search for a 1-allele mismatched donor among HLA-A, -B, and -DR antigen matched unrelated donor pools. We generally do not extend the donor search to an HLA-A and -B antigen mismatched unrelated donor (an HLA-DR antigen mismatched donor is an exception [22]). Regarding HLA-C mismatch, 89% of the HLA-C allele mismatches were at the antigen level in this study. Another CIBMTR study showed no significant differences in overall survival or acute GVHD rates

Table 3

Neutrophil Engraftment, Acute GVHD, and Chronic GVHD

HR 95% CI P

Neutrophil engraftment *

0MM 1.00 Reference

1MM-Bi .94 .88-1.01 .108

1MM-GVH 1.01 .84-1.21 .956

1MM-HVG .97 .78-1.21 .781

Grades III to IV acute GVHDy

0MM 1.00 Reference

1MM-Bi 1.57 1.30-1.90 <.001

1MM-GVH 1.85 1.13-3.01 .014

1MM-HVG 1.25 .69-2.27 .468

Chronic GVHDz

0MM 1.00 Reference

1MM-Bi .97 .85-1.11 .681

1MM-GVH 1.10 .76-1.59 .618

1MM-HVG .88 .57-1.35 .558

* Other significant variables were the recipient's age group, sex of the recipient, sex mismatch, GVHD prophylaxis, and disease risk.

y Other significant variables were the recipient's age group, sex of the recipient, sex mismatch, disease risk, and transplant year. z Another significant variable was transplant year.

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Number at risk

1 2 3 4 5

Years after transplantation

0ММ 2432 809 525 379 283 220

IMM-Bi 932 282 194 150 120 97

1MM-GVH 79 22 18 12 8 7

1MM-HVG 77 25 18 16 14 13

Figure 4. Acute and chronic GVHD. The unadjusted incidences of grades III to IV acute GVHD (A) and chronic GVHD (B) are shown.

between HLA-A, -B, or -DR 1-antigen and 1-allele mismatched transplants [4]. However, the possibility remains that acute GVHD may have less impact on nonrelapse mortality in 1-allele mismatch transplantation than in 1-antigen mismatched transplantation in a specific HLA mismatch status, such as 1 mismatch only in the GVH direction.

The third difference is in ethnicity. The incidence of severe acute GVHD is higher in White populations than in Japanese populations in HLA-matched related or unrelated BMT [23,24], although there was no difference in pediatric UCBT [25]. Ethnic differences may affect the treatment response for severe acute GVHD.

The fourth difference is the stem cell source. Both peripheral blood stem cells (PBSCs) and bone marrow were included in the CIBMTR study, whereas bone marrow was exclusively included in our study. Although there is no difference in the incidence of severe acute GVHD between unrelated PBSC transplantation and BMT [26], the use of PBSCs might be associated with a lower treatment response for acute GVHD, leading to a relatively higher incidence of nonrelapse mortality and overall mortality in a White cohort.

The impact of the HLA mismatch direction has also been evaluated in UCBT. In the New York Blood Center study, UCBT with a mismatch only in the GVH direction was associated

with a higher probability of overall survival compared with UCBT with 1MM-Bi [27], whereas a Japanese study showed the direction of the HLA mismatch does not significantly affect overall survival [28]. The different findings in the UCBT studies as compared with UBMT studies may be partly attributable to the difference in graft components, that is, a cord blood unit contains significantly fewer T cells and total nucleated cells than bone marrow or PBSCs and lower frequency of severe GVHD in the UCBT. The counting method of HLA mismatches was also different. Matching in HLA-A and HLA-B was counted as antigen level and HLA-C was not considered. In addition, 2 unidirectional mismatches were included in the UCBT studies.

We did not find any association between neutrophil engraftment and HLA mismatch in the HVG direction. One explanation for this observation is that our cohort included only HLA-A, -B, and -DR antigen-matched pairs, in which graft failure associated with HLA antibodies against donor-specific HLA antigens is less likely to occur [29-31]. However, even in the CIBMTR cohorts that included antigen-mismatched pairs, no association between graft failure and HLA mismatch direction was observed.

Each locus mismatch may have a different effect on the transplant outcome. For example, an HLA-C mismatch in the GVH direction can be a killer immunoglobulin-like receptor 2DL (K1R2DL) ligand mismatch in the HVG direction in some patients, and vice versa. In a Japanese population, a K1R2DL ligand mismatch in the GVH direction, but not that in the HVG direction, has been shown to be associated with a high risk of acute GVHD and overall mortality [32]. Therefore, the adverse impact of an HLA-C mismatch in the HVG direction may be increased by the presence of a K1R2DL ligand mismatch in the GVH direction in some patients. However, it is difficult to test any hypothesis regarding the impact of each locus mismatch and a K1R2DL ligand mismatch because of the small sample size in this study.

This study has several limitations inherent to a retrospective analysis. First, the heterogeneous backgrounds may have resulted in a statistical bias, although we tried to reduce this bias by adjusting the impact in multivariate analyses. Second, the number of subjects in the 1MM-GVH and 1MM-HVG groups was limited. Therefore, the results should be interpreted with caution. Finally, we did not find any differences in any of the outcomes among the 1MM-GVH, 1MM-HVG, and 1MM-Bi groups (data not shown), partly because of the small sample size in the 1MM-GVH and 1MM-HVG groups. Therefore, we could not make any conclusion regarding the comparison between the 1MM-GVH or 1MM-HVG and 1MM-Bi groups.

In conclusion, the risk of severe acute GVHD in the 1MM-GVH group tended to be higher than that in the 0MM group. However, there were no significant differences in overall survival or nonrelapse mortality between the 0MM and 1MM-GVH or 1MM-HVG groups. Our results suggest that for patients without a matched sibling or matched unrelated donor, we can choose either an unrelated donor with 1MM-GVH or 1 with 1MM-HVG when available.

ACKNOWLEDGMENTS

The authors are indebted to all physicians and data managers at the centers who contributed valuable data on transplantation to the JMDP and TRUMP. The authors also thank the members of the data management committees of JDMP and TRUMP for their assistance.

Financial disclosure: This work was supported in part by the Japan Leukemia Research Fund (to J.K.).

Conflict of interest statement: There are no conflicts of interest to report.

Authorship statement: J. K. and Y. K. designed the research, organized the project, performed the statistical analysis, and analyzed the data. T. 1., S. F., Y. Maeda, Y. Morishima, and Y. A. analyzed the data. K. O., T. F., K. M., K. 1., T. E., H. N., N. K., T. M., S. M., Y. Morishima, and Y. A. gathered the data. J. K. wrote the first draft, and all other authors contributed to the final version.

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