Key Points
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The effects of older donor age and HLA mismatch on OS significantly differed based on the donor CMV serostatus in unrelated allo-HCT.
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In unrelated allo-HCT from a CMV-seronegative donor, an HLA-mismatched older donor may be able to be selected without affecting OS.
Visual Abstract
Abstract
In unrelated allogeneic hematopoietic cell transplantation (allo-HCT), older and/or HLA-mismatched donors are known risk factors for survival outcomes. In healthy individuals, cytomegalovirus (CMV) seropositivity is associated with impaired adaptive immune systems. We assessed whether the adverse effects of donor risk factors are influenced by the donor CMV serostatus. We analyzed 5836 patients with CMV seropositivity who received unrelated allo-HCT. We divided the entire cohort into 2 cohorts according to the donor CMV serostatus: CMV positive (DP) and negative (DN). We also stratified each cohort into 4 groups based on donor age (aged ≥40 or <40 years) and HLA parity (8/8 or 7/8): Young88 and Old88, and Young78 and Old78, respectively. In the CMV-DP cohort, the Old88 (hazard ratio [HR], 1.20; P = .012), Young78 (HR, 1.35; P < .001), and Old78 (HR, 1.60; P < .001) groups were associated with inferior overall survival (OS) than the Young88 group. In contrast, in the CMV-DN cohort, neither donor age nor HLA disparity was associated with inferior OS. The adverse impact of donor age was different between the cohorts (CMV-DP: HR, 1.19; P = .001; CMV-DN: HR, 1.04; P = .53; P for interaction, .070), as was the impact of HLA (CMV-DP: HR, 1.34; P < .001; CMV-DN: HR, 1.08; P = .23; P for interaction, .012). The impacts of donor age and HLA mismatch on OS might differ according to the donor CMV serostatus. In unrelated allo-HCT from a CMV-seronegative donor, an HLA-mismatched older donor may be able to be selected without affecting OS.
Introduction
Allogeneic hematopoietic cell transplantation (allo-HCT) from an unrelated donor still plays a crucial role in clinical practice throughout the world, although various donor sources have been developed.1, 2, 3, 4, 5 In unrelated allo-HCT other than cord blood transplantation, older donor age and HLA mismatch are well-established risk factors for survival outcomes.6, 7, 8 Therefore, a younger and HLA-matched donor is recommended for optimal donor selection.9,10
As another essential donor factor in unrelated allo-HCT, donor cytomegalovirus (CMV) seropositivity was previously reported to be favorable for overall survival (OS), when a recipient was CMV seropositive, and received myeloablative conditioning (MAC).11 In healthy individuals, CMV seropositivity is known to be associated with increased senescent immune cells such as effector memory T cells12 and also accelerated immunosenescence with aging compared with CMV-seronegative individuals.13,14 Therefore, in the allo-HCT setting, more senescent cells might be included in a graft from a CMV-seropositive older donor compared with a graft from a CMV-seronegative donor or CMV-seropositive younger donor.
Based on these facts, we hypothesized that the adverse effect of older donor age might be reduced when a CMV-seronegative donor was selected. In addition, HLA mismatch can also be associated with posttransplant immune reactions. Focusing on these 2 important risk factors, we assessed whether the adverse effects of donor age and HLA mismatch on survival outcomes would differ according to the donor CMV serostatus. This analysis might also clarify the importance of donor CMV serostatus when we had to consider the risk of donor age and HLA disparity, and might allow for optimal donor selection.
Patients and methods
Patient selection
Clinical data on allo-HCT recipients were collected by the Japanese Society for Transplantation and Cellular Therapy and the Japanese Data Center for Hematopoietic Cell Transplantation with the Transplant Registry Unified Management Program.15
We retrospectively analyzed adult patients aged between 16 and 70 years with hematologic malignancies. They underwent their first allo-HCT from 8/8 or 7/8 HLA-matched unrelated donors between 2012 and 2021, and we focused on only CMV-seropositive recipients. Donors were aged between 20 and 55 years, because this age range was required for donor eligibility by the Japan Marrow Donor Program. We excluded patients for whom data on recipient/donor CMV serostatus, donor age, and graft-versus-host disease (GVHD) prophylaxis were not available to avoid missing values in multivariate analysis. Those who had received cord blood transplantation were also excluded because their donor’s age was 0 years.
This retrospective study was approved by the data management committee of Japanese Society for Transplantation and Cellular Therapy and the institutional review board of Jichi Medical University Saitama Medical Center.
Definitions and end points
A donor with 8/8 allelic matches at HLA-A, -B, -C, and -DR loci was defined as an HLA-matched unrelated donor. MAC was defined as total body irradiation of >8 Gy, melphalan of >140 mg/m2, or IV busulfan of ≥7.2 mg/kg, and other regimens were classified as reduced-intensity conditioning.16 Standard-risk diseases were defined as acute leukemia in first or second complete remission; myelodysplastic syndrome; chronic myeloid leukemia in first or second chronic phase, or accelerated phase; and malignant lymphoma in first or second complete remission, or first or second partial remission. All adult T-cell leukemia/lymphoma cases were classified as high risk. Acute GVHD was graded according to standard criteria.17 T-cell depletion included a pretransplant administration of antithymocyte globulin (ATG) or antilymphocyte globulin. Clinically significant CMV reactivation (CMVR) was defined as the administration of antiviral drugs as preemptive therapy.
We divided the entire cohort into 2 cohorts based on the donor CMV serostatus: CMV-seropositive donor (CMV-DP) and CMV-seronegative donor (CMV-DN). In addition, we stratified these cohorts into 4 groups according to donor age (≥40 and <40 years) and HLA parity (8/8 or 7/8 matched): Young88 and Old88, and Young78 and Old78 groups, respectively. Because the median donor age was 40 and 38 years in the CMV-DP and CMV-DN cohorts, we used a cutoff age of 40 years to distinguish between older and younger donors.
We compared transplant outcomes among these 4 groups in each cohort and evaluated whether they differed according to the donor CMV serostatus. The primary outcome assessment was OS; we also evaluated the cumulative incidences of nonrelapse mortality (NRM), relapse, acute GVHD, CMVR, and the cause of death (COD) as secondary outcome assessments. This study adopted the primary COD reported by the physicians.
Statistical analysis
OS from allo-HCT was calculated by the Kaplan-Meier method with a 95% confidence interval (CI) and compared by the log-rank test. The cumulative incidences of NRM and relapse were estimated by the Gray method considering the other as a competing risk. The cumulative incidences of CMVR and acute GVHD were estimated and compared by the Gray method treating death and relapse as competing risks. A Cox proportional hazard model was used for multivariate analyses, and the hazard ratios (HRs) of the donor groups are shown after being adjusted for recipient age at allo-HCT (≥50 vs <50 years), the underlying disease (acute myeloid leukemia vs acute lymphoblastic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, or malignant lymphoma), disease risk (standard vs high), European Cooperative Oncology Group performance status (0-1 vs ≥2), HCT comorbidity index (≥3 vs <3), sex mismatch (female to male vs others), stem cell source (bone marrow vs peripheral blood stem cells [PBSCs]), GVHD prophylaxis (cyclosporine based vs tacrolimus based), conditioning intensity (reduced-intensity conditioning vs MAC), use of T-cell depletion, use of letermovir (LTV) prophylaxis, use of total body irradiation, and year of allo-HCT (2012-2016 vs 2017-2021). We considered that there was statistical significance when a 2-tailed P value of <.025 was obtained according to Bonferroni adjustment for multiple comparisons.
All statistical analyses were performed with EZR version 1.62 (Jichi Medical University Saitama Medical Center), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria).18
Results
Patient characteristics
We identified 5836 patients who met the eligibility criteria: CMV-DP (n = 3275; Young88, n = 930; Old88, n = 991; Young78, n = 638; and Old78, n = 716) and CMV-DN (n = 2561; Young88, n = 921; Old88, n = 628; Young78, n = 572; and Old78, n = 440). The median recipient age was 55 years for patients with CMV-DP and 54 years for patients with CMV-DN.
The patients in the CMV-DP cohort tended to be older, and the CMV-DP cohort included more recipients who had received PBSCs, undergone T-cell depletion, received female-to-male allo-HCT, and had undergone allo-HCT between 2017 and 2021 (Table 1).
Table 1.
Patient characteristics
| Variables | Donor CMV serostatus |
P value | ||
|---|---|---|---|---|
| Positive |
Negative |
|||
| n = 3275 | n = 2561 | |||
| Donor group (HLA × age) (%) | Young88 | 930 (28.4) | 921 (36.0) | <.001 |
| Old88 | 991 (30.3) | 628 (24.5) | ||
| Young78 | 638 (19.5) | 572 (22.3) | ||
| Old78 | 716 (21.9) | 440 (17.2) | ||
| Recipient age, y (%) | <50 | 1187 (36.2) | 964 (37.6) | .27 |
| ≥50 | 2088 (63.8) | 1597 (62.4) | ||
| Disease (%) | AML | 1399 (42.7) | 1109 (43.3) | .14 |
| ALL | 609 (18.6) | 502 (19.6) | ||
| CML | 109 (3.3) | 59 (2.3) | ||
| MDS | 682 (20.8) | 510 (19.9) | ||
| ML | 476 (14.5) | 381 (14.9) | ||
| Disease risk (%) | Standard | 2421 (73.9) | 1851 (72.3) | .16 |
| High | 854 (26.1) | 710 (27.7) | ||
| HCT-CI score | <3 | 2705 (83.0) | 2165 (84.8) | .067 |
| ≥3 | 553 (17.0) | 387 (15.2) | ||
| ECOG PS (%) | 0-1 | 3091 (94.4) | 2388 (93.4) | .086 |
| ≥2 | 182 (5.6) | 170 (6.6) | ||
| Recipient sex (%) | Female | 1303 (39.8) | 980 (38.3) | .25 |
| Male | 1971 (60.2) | 1579 (61.7) | ||
| Donor sex (%) | Female | 1079 (33.0) | 687 (26.8) | <.001 |
| Male | 2191 (67.0) | 1874 (73.2) | ||
| Female to male (%) | No | 2699 (82.6) | 2190 (85.6) | .002 |
| Yes | 570 (17.4) | 369 (14.4) | ||
| Donor stem cell source | BM | 2799 (85.5) | 2273 (88.8) | <.001 |
| PBSCs | 476 (14.5) | 288 (11.2) | ||
| GVHD prophylaxis (%) | CsA based | 273 (8.3) | 217 (8.5) | .85 |
| TAC based | 3002 (91.7) | 2344 (91.5) | ||
| LTV prophylaxis (%)∗ | No | 658 (45.3) | 361 (43.7) | .46 |
| Yes | 795 (54.7) | 466 (56.3) | ||
| Conditioning regimen (%) | MAC | 2112 (64.5) | 1659 (64.8) | .83 |
| RIC | 1163 (35.5) | 902 (35.2) | ||
| Use of TBI (%) | No | 1219 (37.2) | 881 (34.4) | .026 |
| Yes | 2056 (62.8) | 1680 (65.6) | ||
| In vivo T-cell depletion (%) | No | 2798 (85.4) | 2238 (87.4) | .032 |
| Yes | 477 (14.6) | 323 (12.6) | ||
| Year of transplantation (%) | 2012-2016 | 1455 (44.4) | 1525 (59.5) | <.001 |
| 2017-2021 | 1820 (55.6) | 1036 (40.5) | ||
AML, acute myeloid leukemia; ALL, acute lymphoblastic leukemia; BM, bone marrow; CML, chronic myeloid leukemia; CsA, cyclosporine A; HCT-CI, hematopoietic cell transplantation comorbidity index; MDS, myelodysplastic syndrome; ML, malignant lymphoma; RIC, reduced-intensity conditioning; Tac, tacrolimus; TBI, total-body irradiation.
Includes only patients who received allo-HCT after the year 2018.
Both the CMV-DP and CMV-DN cohorts showed a trend in which HLA-mismatched donor groups (Young78 and Old78) had more patients receiving total body irradiation, T-cell depletion, and PBSCs than those in HLA-matched groups (Young88 and Old88). In addition, in the CMV-DP cohort, the Young78 and Old78 groups included more recipients aged ≥50 years and those who received tacrolimus-based GVHD prophylaxis compared with the Young88 and Old88 groups. There were more recipients with acute lymphoblastic leukemia in the Old78 group (supplemental Table 1A-B).
In addition, the patient characteristics of the CMV-DP and CMV-DN cohorts according to the transplant years are further shown in supplemental Table 2.
The median duration of follow-up for survivors was 1412 days.
OS, NRM, and relapse in each donor group in the CMV-DP and CMV-DN cohorts
We assessed survival outcomes of the 4 donor groups in the CMV-DP and CMV-DN cohorts, individually. In the CMV-DP cohort, 5-year OS was significantly inferior in allo-HCT from older and/or HLA-mismatched donors (57.3% [95% CI, 53.5-60.9] in the Young88 group, 49.7% [95% CI, 46.1-53.2] in the Old88 group, 50.7% [95% CI, 46.2-55.0] in the Young78 group, and 47.3% [95% CI, 43.1-51.4] in the Old78 group; P < .001; Figure 1A). In contrast, there was no significant difference in 5-year OS among the 4 groups in the CMV-DN cohort (50.5% [95% CI, 46.9-54.0] in the Young88 group, 52.2% [95% CI, 48.0-56.3] in the Old88 group, 52.5% [95% CI, 48.0-56.9] in the Young78 group, and 53.2% [95% CI, 47.9-58.1] in the Old78 group; P = .93; Figure 1B).
Figure 1.
Survival outcomes in each donor group. OS (A-B) and cumulative incidences of NRM (C-D) and relapse (E-F) among 4 donor groups in the CMV-DP and CMV-DN cohorts.
In the CMV-DP cohort, the 5-year NRM was significantly worse in the 3 groups with older donors and/or the presence of HLA mismatch (19.3% [95% CI, 16.5-22.2] in the Young88 group, 27.5% [95% CI, 24.4-30.7] in the Old88 group, 25.4% [95% CI, 21.6-29.2] in the Young78 group, and 30.6% [95% CI, 26.9-34.4] in the Old78 group; P < .001; Figure 1C). In contrast, the 5-year NRM was not significantly different among the 4 groups in the CMV-DN cohort (22.6% [95% CI, 19.6-25.6] in the Young88 group, 26.0% [95% CI, 22.4-29.7] in the Old88 group, 26.8% [95% CI, 22.9-30.7] in the Young78 group, and 26.8% [95% CI, 22.4-31.4] in the Old78 group; P = .27; Figure 1D).
There was no significant difference in the 5-year incidence of relapse among the 4 groups in each of the CMV-DP (P = .93) and CMV-DN (P = .23) cohorts (Figure 1E-F).
Additionally, we compared all 8 donor groups to visualize the difference beyond the donor CMV serostatus. There were statistically significant differences in OS (P = .003) and NRM (P < .001) among the 8 groups. The CMV-DP Young88 group demonstrated the most favorable OS and NRM, whereas the CMV-DP Old78 groups showed the worst OS and NRM (supplemental Figure 1).
Impact of donor risk factors on survival outcomes in the CMV-DP and CMV-DN cohorts, and the interaction between donor factors and donor CMV serostatus
The multivariate analysis confirmed that the Old88 (HR, 1.20; [95% CI, 1.04-1.39]; P = .012), Young78 (HR, 1.35; [95% CI, 1.15-1.59]; P < .001), and Old78 (HR, 1.60; [95% CI, 1.37-1.87]; P < .001) groups were associated with inferior OS compared with the Young88 group in the CMV-DP cohort. In contrast, donor age and HLA disparity were not associated with inferior OS in the CMV-DN cohort (HR of Old88, 1.07; [95% CI, 0.92-1.24]; P = .41; HR of Young78, 1.11; [95% CI, 0.95-1.30]; P = .20; and HR of Old78, 1.11; [95% CI, 0.93-1.32]; P = .25; Figure 2A; supplemental Table 3A-B). We found significant interactions between the Old78 group (vs the Young88 group) and donor CMV serostatus (P = .002), suggesting that the adverse impacts of older age and HLA mismatch significantly differed according to the donor CMV serostatus (Figure 2A).
Figure 2.
Impact of donor risk factors on survival outcomes. Impacts of the 3 donor groups with older age and/or HLA mismatch on OS (A), NRM (B), and relapse (C) compared with the Young88 group when stratified according to the donor CMV serostatus. Ref, reference.
In addition, when we focused on each donor factor (donor age or HLA mismatch) and donor CMV serostatus, a significant interaction between HLA parity and donor CMV serostatus (P = .012), and a borderline interaction between donor age and donor CMV serostatus (P = .070) were detected (supplemental Figure 2A-B). When 30 years were set as the cutoff similar to a median of donor age in US or European countries,19,20 the adverse effect of older donor age on OS was still observed only in the CMV-DP cohort with a significant interaction (P = .014, supplemental Figure 3A). Furthermore, we divided donor age by 10 years and confirmed that there was a trend of increased HRs as donor age became older in the CMV-DP cohort but not in the CMV-DN cohort (supplemental Figure 3B). Eventually, we treated donor age as a continuous variable, which revealed that donor age was significantly associated with inferior OS only in the CMV-DP cohort (HR, 1.013; [95% CI, 1.007-1.020]; P < .001) but not in the CMV-DN cohort (HR, 1.002; [95% CI, 0.995-1.009]; P = .51), and a significant interaction was also confirmed (P = .015).
Multivariate analyses demonstrated that the Old88, Young78, and Old78 groups were associated with an increased risk of NRM in the CMV-DP cohort (HR of Old88, 1.39; [95% CI, 1.14-1.71]; P = .001; HR of Young78, 1.58; [95% CI, 1.25-1.99]; P < .001; and HR of Old78, 2.10; [95% CI, 1.70-2.60]; P < .001), whereas the Young78 and Old78 groups were identified as risk factors for NRM in the CMV-DN cohort (HR of Young78, 1.38; [95% CI, 1.11-1.73]; P = .005; and HR of Old78, 1.45; [95% CI, 1.14-1.85]; P = .003). The adverse impacts of donor age and HLA disparity seemed smaller in the CMV-DN cohort than in the CMV-DP cohort (Figure 2B; supplemental Table 3A-B), and a significant interaction was observed between the Old78 group and donor CMV serostatus (P = .023; Figure 2B).
In both the CMV-DP and CMV-DN cohorts, neither older donor age nor HLA disparity was associated with the incidence of relapse, and no interaction was observed (Figure 2C; supplemental Table 3A-B).
OS in the subgroup according to the year of allo-HCT
We separately analyzed OS according to the transplant year (before 2017 or after 2017). OS among the 4 donor groups was significantly different in the CMV-DP cohort (P = .016, and P = .010, respectively) but not in the CMV-DN cohort (P = .39, and P = .41, respectively) both in the early and late study periods (supplemental Figure 4). We still observed that impacts of donor age and HLA mismatch on OS tended to differ according to the donor CMV serostatus (supplemental Figure 5A-B).
Impact of donor risk factors on CMVR and acute GVHD in each cohort
Next, we assessed the impact of donor risk factors in each cohort on CMVR, and grade 2 to 4 acute GVHD. Because the use of LTV would strongly affect CMVR, we separately analyzed the cases with and without LTV. Among cases without LTV prophylaxis, the cumulative incidences of CMVR 6 months after allo-HCT were significantly increased in the Young78 and Old78 groups in the CMV-DP (P < .001 in each) and CMV-DN cohorts (P < .001 in each). When we considered patients with LTV, there was no significant difference among the 4 groups in the CMV-DP cohort (P = .23). Meanwhile, in the CMV-DN cohort, patients in the young78 and Old78 groups experienced CMVR significantly more frequently (P = .008; supplemental Figure 6A-D). Multivariate analysis in cases without LTV prophylaxis revealed that the Young78 and Old78 groups were associated with an increased risk of CMVR compared with the Young88 group, both in the CMV-DP and CMV-DN cohorts, and no interaction was observed (supplemental Figure 7A-B). Considering patients with LTV prophylaxis, any donor types were not significantly associated with an increased risk of CMVR in the CMV-DP or -DN cohorts, and no interaction was observed (supplemental Figure 7A-B; supplemental Table 3C-D).
Grade 2 to 4 acute GVHD frequently occurred in older and/or HLA-mismatched donors in both the CMV-DP and CMV-DN cohorts (P < .001 in each; supplemental Figure 6E-F). Compared with the Young88 group, the Young78 and Old78 groups in the CMV-DP cohort were significantly associated with an increased risk of grade 2 to 4 acute GVHD (Young78, P < .001, and Old78, P < .001). In contrast, the adverse impacts of the Old88 and Old78 groups were observed in the CMV-DN cohort (Old88, P = .002, and Old78, P < .001; supplemental Figure 7C; supplemental Table 3C-D). No significant interactions between the donor groups and donor CMV serostatus were observed in grade 2 to 4 acute GVHD (supplemental Figure 7C).
COD
COD significantly differed among the 4 groups in the CMV-DP cohort (P < .001). Fatal GVHD (2.5%, 2.8%, 3.9%, and 5.7% in the Young88, Old88, Young78, and Old78 groups, respectively) and fatal infection (5.9%, 9.7%, 7.8%, and 10.8%, respectively) were more frequently observed in the group with older and/or HLA-mismatched donors (Figure 3).
Figure 3.
COD among the 4 donor groups in the CMV-DP and CMV-DN cohorts. NA, not assessed; TMA, thrombotic microangiopathy.
In contrast, when we focused on the CMV-DN cohort, we did not observe a significant difference in the COD distribution (P = .075). However, fatal infection seemed to be more prevalent in the older and/or HLA-mismatched donor groups (7.3%, 7.6%, 9.3%, and 12.0%, respectively; Figure 3). In detail, bacterial infection and noninfectious pulmonary complications were the 2 leading causes of nonrelapse death in all 8 groups (supplemental Figure 8).
Discussion
This study demonstrated that the adverse impacts of donor age and HLA disparity differed according to the donor CMV serostatus. In general, younger and/or HLA-matched donors are considered to be preferable candidates in unrelated transplantation.9,10 If donor candidates were limited, older and/or HLA-mismatched donors could be selected without strongly affecting overall mortality as long as the candidates tested negative for CMV. However, stringent attention should be given to the adverse complications such as CMVR, acute GVHD, and subsequent NRM. Conversely, in allo-HCT from a CMV-seropositive donor, we should avoid selecting an older and/or HLA-mismatched donor.
Donor CMV seronegativity was previously found to be a risk factor for OS in patients who are CMV seropositive who received MAC.11 Meanwhile, data from this study suggest that the impact of donor CMV serostatus on OS was influenced by the donor age and HLA parity based on our interaction analysis in OS (Figure 2) and the survival analysis among the 8 groups (supplemental Figure 1). When only older/HLA-mismatched donors are available, a CMV-seronegative donor would be preferable. In contrast, the CMV-seropositive donor might be the better option when the donor candidates are younger/HLA-matched.
To the best of our knowledge, this is the first study to address the combined impacts of donor age and HLA disparity on clinical outcomes in individual cohorts divided based on the donor CMV serostatus. Several large registry-based studies have suggested that older age and HLA disparity in unrelated allo-HCT adversely affect OS, NRM, and acute GVHD.6, 7, 8 However, no previous report has evaluated the combined impacts of donor age and donor CMV serostatus. In contrast, 2 studies previously evaluated OS based on the combination of recipient/donor CMV matching (match vs mismatch) and HLA compatibility in unrelated allo-HCT.21,22 Ayuk et al focused only on patients who were CMV seropositive, similar to this study. Ayuk et al divided their cohort into 4 groups according to the donor CMV serostatus and the presence of HLA mismatch, and demonstrated that both HLA-mismatched CMV-DP and HLA-mismatched CMV-DN groups were associated with inferior OS compared with the HLA-matched CMV-seropositive group.21 In contrast, in this study, the adverse impact of HLA mismatch on OS was only confirmed in the CMV-DP cohort, and a significant interaction was observed between the donor CMV serostatus and HLA disparity (supplemental Figure 2B). The difference between these results might be because of the preference for T-cell depletion strategies in allo-HCT. In the aforementioned study by Ayuk et al, ∼70% of patients received ATG, and 20% received alemtuzumab for T-cell depletion.21 In our study, <15% of patients received ATG. Subgroup analyses stratified by the use of T-cell depletion could not be performed because of insufficient statistical power in this analysis. Further studies are required to explore the association between donor factors and T-cell depletion.
The adverse impacts of donor age and HLA disparity on CMVR and grade 2 to 4 acute GVHD were not different according to the donor CMV serostatus, based on the absence of an interaction. Regarding acute GVHD, Seo et al showed that unrelated allo-HCT from both older and HLA-mismatched donors (equivalent to the Old78 group in this study) was the most adverse risk group for acute GVHD using the Japanese registry database.8 Similar results were observed when we divided the entire cohort into 2 cohorts according to the donor CMV serostatus. In addition, in terms of CMVR without LTV prophylaxis, older donors, in addition to HLA-mismatched donors, might be associated with an increased risk of CMVR. Furthermore, the frequency of CMVR in the CMV-DN cohort seemed to be higher than that in the CMV-DP cohort, which is similar to previous reports.23, 24, 25 These outcomes might provide important information when considering LTV prophylaxis.26
When we consider the causes of nonrelapse death, there was no significant difference among the 4 groups in the CMV-DN cohort. However, the incidences of fatal infection and fatal GVHD were increased in the older and/or HLA-mismatched donor groups only in the CMV-DP cohort. Interestingly, the development of acute GVHD among the 4 groups did not differ according to the donor CMV serostatus, based on the absence of an interaction. These outcomes suggest that the increased incidences of acute GVHD in the older and/or HLA-mismatched donor groups might have contributed to treatment-refractory GVHD, leading to higher incidences of subsequent fatal infections in the CMV-DP cohort. In contrast, GVHD might be more controllable in the CMV-DN cohort. Although the true reasons are still unclear, CMV seropositivity has recently been reported to affect the adaptive immune system.12,27 Thus, recipients in the CMV-DP cohort might be vulnerable to infection during posttransplant immune reconstitution, and these recipients could easily develop infection after acute GVHD.
In healthy people, immune cell senescence in the adaptive immune system tends to occur easily in those who are CMV seropositive. In particular, the number of effector memory (EM) and terminally differentiated EM CD4+ T cells increased with aging in individuals who are CMV seropositive.13 In the allo-HCT setting, some previous studies showed that not only CMVR but also recipient/donor CMV seropositivity significantly affected posttransplant immune reconstitution.28,29 In this study, we postulated that, in allo-HCT from CMV-seropositive donors, EM and/or terminally differentiated EM CD4+ T cells would be more likely to be included in a graft from an older donor, and the number of these cells might be increased after HLA-mismatched allo-HCT in response to major histocompatibility antigens. Subsequently, the increased number of these cells might adversely influence posttransplant outcomes such as acute GVHD and infection. Future basic studies are warranted to confirm these hypotheses and evaluate how these cells can affect posttransplant complications.
This study had several limitations. First, patients who are CMV seronegative were excluded because the prevalence of recipient CMV was ∼80% in Japan,30,31 and there was not enough statistical power for assessing the CMV-seronegative cohort. Second, the CMV seroprevalence rate in healthy individuals has been fluctuating over time and differs according to geography, race, and socioeconomic state.32, 33, 34, 35, 36, 37, 38 Third, the method used to assess donor CMV immunoglobulin G in the Japan Marrow Donor Program transitioned from complement fixation to enzyme immunoassay in 2020, and subsequently to the chemiluminescent immunoassay in 2021. These 2 new technologies showed high sensitivity,39,40 but there was a strong correlation between CMV immunoglobulin G by complement fixation and enzyme-linked immunosorbent assay,41 and also by enzyme-linked immunosorbent assay and chemiluminescent immunoassay.39 We also treated the study period as a covariate in all multivariate analyses. In addition, in the period of this study, posttransplant cyclophosphamide (PTCy) had not yet been approved for GVHD prophylaxis in unrelated allo-HCT in Japan, and this study addressed data in the pre-PTCy era. A recent study from the European Society for Blood and Marrow Transplantation revealed that donor age affected survival outcomes even in the PTCy era, whereas the adverse effect of an HLA mismatch appeared to have diminished.19,20 Finally, this study included fewer patients who had received PBSCs than the US and European cohorts.19,20 Although the use of PBSCs has recently been increasing in Japan, PBSCs were used only in 22% of allo-HCT recipients between 2017 and 2021. Thus, the sample sizes were not large enough to perform subgroup analyses. Further research focusing on allo-HCT with PBSCs or with PTCy will be required to evaluate the difference in impact of donor age or HLA disparity according to the donor CMV serostatus.
In conclusion, this study revealed that the adverse effects of donor age and HLA on outcomes were significantly influenced by the donor CMV serostatus. Unrelated allo-HCT is still an important option for the treatment of hematologic malignancies. Therefore, our results may represent crucial information for donor selection in unrelated allo-HCT. Further clinical research including various settings would be warranted.
Conflict-of-interest disclosure: N.D. has consulted for Janssen Pharmaceutical K.K., and has received honoraria from Nippon Shinyaku Co Ltd, Janssen Pharmaceutical K.K., Novartis Pharma K.K., Kyowa Kirin Co, Ltd, Daiichi-Sankyo Co Ltd, AbbVie GK, AstraZeneca K.K., Astellas Pharma Inc, Otsuka Pharmaceutical Co Ltd, Chugai Pharmaceutical Co Ltd, Asahi Kasei Pharma K.K., Shionogi and Co Ltd, Sanofi K.K., Merck and Co, Inc, Pfizer Inc, and Takeda Pharmaceutical Company Limited. J.K. has consulted for AbbVie Inc, Megakaryon Co, SymBio Pharmaceuticals Ltd, Daiichi Sankyo Co Ltd, Novartis Pharma K.K., Janssen Pharmaceutical K.K., and Astellas Pharma Inc; has received grants from Eisai; and has received honoraria from CSL Behring K.K., MSD K.K., Astellas Pharma Inc, AbbVie Inc, Amgen Pharma Inc, Otsuka Pharmaceutical Co Ltd, Ono Pharma Inc, Janssen Pharmaceutical K.K., Sanofi K.K., Kyowa Kirin Co Ltd, Nippon Shinyaku Co Ltd, Daiichi Sankyo Co Ltd, Sumitomo Dainippon Pharma Co Ltd, Takeda Pharmaceutical Company Limited, Chugai Pharmaceutical Co Ltd, Novartis Pharma K.K., Bristol Myers Squibb Co, Asahi Kasei Pharma Corporation, Asclepia, Otsuka Pharmaceutical Co Ltd, and Nippon Kayaku Co, Ltd. K.S. has received honoraria from Sanofi K.K., Takeda Pharmaceutical Company Limited, and Janssen Pharmaceutical K.K. The remaining authors declare no competing financial interests.
Acknowledgments
The authors are grateful for the contributions of all of the participating patients and donors, and for the work of all of the physicians and data managers at the centers that contributed valuable data on transplantation to the Japanese Society for Transplantation and Cellular Therapy (JSTCT). The authors thank all of the members of the Transplant Registry Unified Management committees at JSTCT for their dedicated data management.
Authorship
Contribution: S.K. designed the study, analyzed data, and wrote the manuscript; D.N. and T. Nagayama designed the study or advised on methods and wrote the manuscript; Y. Katayama, N.D., W.T., T. Nishida, K-i.M., T.I., H.O., M.S., K.F., J.K., K.S., and Y. Kanda collected data and revised the manuscript; M.O. and T.F. collected data, revised the manuscript, and were responsible for data management at JSTCT; Y.A. managed the unified registry database and revised the manuscript; and H.N. designed the study, advised on the methods, revised the manuscript, and was responsible for the project of the JSTCT Donor/Source Working Group.
Footnotes
The data from this study are not publicly available because of ethical restrictions regarding the scope of the recipient/donor consent for research use in the registry.
The full-text version of this article contains a data supplement.
Supplementary Material
References
- 1.The Japanese Data Center for Hematopoietic Cell Transplantation. The Japanese Society for Transplantation and Cellular Therapy Hematopoietic cell transplantation in Japan a report from a nationwide survey in 2023. Jpn J Transplant. 2024;59(3):271–281. [Google Scholar]
- 2.Auletta JJ, Kou J, Chen M, et al. Real-world data showing trends and outcomes by race and ethnicity in allogeneic hematopoietic cell transplantation: a report from the Center for International Blood and Marrow Transplant Research. Transplant Cell Ther. 2023;29(6):346.e1–346.e10. doi: 10.1016/j.jtct.2023.03.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Passweg JR, Baldomero H, Chabannon C, et al. Hematopoietic cell transplantation and cellular therapy survey of the EBMT: monitoring of activities and trends over 30 years. Bone Marrow Transplant. 2021;56(7):1651–1664. doi: 10.1038/s41409-021-01227-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Xu LP, Lu PH, Wu DP, et al. Hematopoietic stem cell transplantation activity in China 2019: a report from the Chinese Blood and Marrow Transplantation Registry Group. Bone Marrow Transplant. 2021;56(12):2940–2947. doi: 10.1038/s41409-021-01431-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Gragert L, Eapen M, Williams E, et al. HLA match likelihoods for hematopoietic stem-cell grafts in the U.S. registry. N Engl J Med. 2014;371(4):339–348. doi: 10.1056/NEJMsa1311707. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Kollman C, Spellman SR, Zhang MJ, et al. The effect of donor characteristics on survival after unrelated donor transplantation for hematologic malignancy. Blood. 2016;127(2):260–267. doi: 10.1182/blood-2015-08-663823. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Kollman C, Howe CW, Anasetti C, et al. Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age. Blood. 2001;98(7):2043–2051. doi: 10.1182/blood.v98.7.2043. [DOI] [PubMed] [Google Scholar]
- 8.Seo S, Usui Y, Matsuo K, et al. Impact of the combination of donor age and HLA disparity on the outcomes of unrelated bone marrow transplantation. Bone Marrow Transplant. 2021;56(10):2410–2422. doi: 10.1038/s41409-021-01289-8. [DOI] [PubMed] [Google Scholar]
- 9.Ayuk F, Balduzzi A. In: The EBMT Handbook: Hematopoietic Stem Cell Transplantation and Cellular Therapies. Carreras E, Dufour C, Mohty M, Kroger N, editors. Springer; 2019. Donor selection for adults and pediatrics; pp. 87–97. [PubMed] [Google Scholar]
- 10.Dehn J, Spellman S, Hurley CK, et al. Selection of unrelated donors and cord blood units for hematopoietic cell transplantation: guidelines from the NMDP/CIBMTR. Blood. 2019;134(12):924–934. doi: 10.1182/blood.2019001212. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Ljungman P, Brand R, Hoek J, et al. Donor cytomegalovirus status influences the outcome of allogeneic stem cell transplant: a study by the European group for blood and marrow transplantation. Clin Infect Dis. 2014;59(4):473–481. doi: 10.1093/cid/ciu364. [DOI] [PubMed] [Google Scholar]
- 12.Patin E, Hasan M, Bergstedt J, et al. Natural variation in the parameters of innate immune cells is preferentially driven by genetic factors. Nat Immunol. 2018;19(3):302–314. doi: 10.1038/s41590-018-0049-7. [DOI] [PubMed] [Google Scholar]
- 13.Weltevrede M, Eilers R, de Melker HE, van Baarle D. Cytomegalovirus persistence and T-cell immunosenescence in people aged fifty and older: a systematic review. Exp Gerontol. 2016;77:87–95. doi: 10.1016/j.exger.2016.02.005. [DOI] [PubMed] [Google Scholar]
- 14.Fulop T, Larbi A, Pawelec G. Human T cell aging and the impact of persistent viral infections. Front Immunol. 2013;4:271. doi: 10.3389/fimmu.2013.00271. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Atsuta Y, Suzuki R, Yoshimi A, et al. Unification of hematopoietic stem cell transplantation registries in Japan and establishment of the TRUMP system. Int J Hematol. 2007;86(3):269–274. doi: 10.1532/IJH97.06239. [DOI] [PubMed] [Google Scholar]
- 16.Giralt S, Ballen K, Rizzo D, et al. Reduced-intensity conditioning regimen workshop: defining the dose spectrum. Report of a workshop convened by the Center for International Blood and Marrow Transplant Research. Biol Blood Marrow Transplant. 2009;15(3):367–369. doi: 10.1016/j.bbmt.2008.12.497. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Przepiorka D, Weisdorf D, Martin P, et al. 1994 consensus conference on acute GVHD grading. Bone Marrow Transplant. 1995;15(6):825–828. [PubMed] [Google Scholar]
- 18.Kanda Y. Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant. 2013;48(3):452–458. doi: 10.1038/bmt.2012.244. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Sanz J, Labopin M, Choi G, et al. Younger unrelated donors may be preferable over HLA match in the PTCy era: a study from the ALWP of the EBMT. Blood. 2024;143(24):2534–2543. doi: 10.1182/blood.2023023697. [DOI] [PubMed] [Google Scholar]
- 20.Shaffer BC, Gooptu M, DeFor TE, et al. Post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis attenuates disparity in outcomes between use of matched or mismatched unrelated donors. J Clin Oncol. 2024;42(28):3277–3286. doi: 10.1200/JCO.24.00184. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Ayuk F, Beelen DW, Bornhauser M, et al. Relative impact of HLA matching and non-HLA donor characteristics on outcomes of allogeneic stem cell transplantation for acute myeloid leukemia and myelodysplastic syndrome. Biol Blood Marrow Transplant. 2018;24(12):2558–2567. doi: 10.1016/j.bbmt.2018.06.026. [DOI] [PubMed] [Google Scholar]
- 22.Shaw BE, Mayor NP, Szydlo RM, et al. Recipient/donor HLA and CMV matching in recipients of T-cell-depleted unrelated donor haematopoietic cell transplants. Bone Marrow Transplant. 2017;52(5):717–725. doi: 10.1038/bmt.2016.352. [DOI] [PubMed] [Google Scholar]
- 23.Beauvais D, Drumez E, Blaise D, et al. Scoring system for clinically significant CMV infection in seropositive recipients following allogenic hematopoietic cell transplant: an SFGM-TC study. Bone Marrow Transplant. 2021;56(6):1305–1315. doi: 10.1038/s41409-020-01178-6. [DOI] [PubMed] [Google Scholar]
- 24.Nakamae H, Kirby KA, Sandmaier BM, et al. Effect of conditioning regimen intensity on CMV infection in allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2009;15(6):694–703. doi: 10.1016/j.bbmt.2009.02.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Marty FM, Bryar J, Browne SK, et al. Sirolimus-based graft-versus-host disease prophylaxis protects against cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation: a cohort analysis. Blood. 2007;110(2):490–500. doi: 10.1182/blood-2007-01-069294. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Marty FM, Ljungman P, Chemaly RF, et al. Letermovir prophylaxis for cytomegalovirus in hematopoietic-cell transplantation. N Engl J Med. 2017;377(25):2433–2444. doi: 10.1056/NEJMoa1706640. [DOI] [PubMed] [Google Scholar]
- 27.Saint-Andre V, Charbit B, Biton A, et al. Smoking changes adaptive immunity with persistent effects. Nature. 2024;626(8000):827–835. doi: 10.1038/s41586-023-06968-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Yeh AC, Varelias A, Reddy A, et al. CMV exposure drives long-term CD57+ CD4 memory T-cell inflation following allogeneic stem cell transplant. Blood. 2021;138(26):2874–2885. doi: 10.1182/blood.2020009492. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Stern L, McGuire HM, Avdic S, et al. Immunoprofiling reveals cell subsets associated with the trajectory of cytomegalovirus reactivation post stem cell transplantation. Nat Commun. 2022;13(1):2603. doi: 10.1038/s41467-022-29943-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Takenaka K, Nishida T, Asano-Mori Y, et al. Cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation is associated with a reduced risk of relapse in patients with acute myeloid leukemia who survived to day 100 after transplantation: the Japan Society for Hematopoietic Cell Transplantation Transplantation-related Complication Working Group. Biol Blood Marrow Transplant. 2015;21(11):2008–2016. doi: 10.1016/j.bbmt.2015.07.019. [DOI] [PubMed] [Google Scholar]
- 31.Kawamura S, Nakasone H, Takeshita J, et al. Prediction of cytomegalovirus reactivation by recipient cytomegalovirus-IgG titer before allogeneic hematopoietic stem cell transplantation. Transplant Cell Ther. 2021;27(8):683.e1–683.e7. doi: 10.1016/j.jtct.2021.04.024. [DOI] [PubMed] [Google Scholar]
- 32.Cannon MJ, Schmid DS, Hyde TB. Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection. Rev Med Virol. 2010;20(4):202–213. doi: 10.1002/rmv.655. [DOI] [PubMed] [Google Scholar]
- 33.Hoehl S, Berger A, Ciesek S, Rabenau HF. Thirty years of CMV seroprevalence-a longitudinal analysis in a German University Hospital. Eur J Clin Microbiol Infect Dis. 2020;39(6):1095–1102. doi: 10.1007/s10096-020-03814-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Taniguchi K, Watanabe N, Sato A, et al. Changes in cytomegalovirus seroprevalence in pregnant Japanese women-a 10-year single center study. J Clin Virol. 2014;59(3):192–194. doi: 10.1016/j.jcv.2013.12.013. [DOI] [PubMed] [Google Scholar]
- 35.Furui Y, Satake M, Hoshi Y, Uchida S, Suzuki K, Tadokoro K. Cytomegalovirus (CMV) seroprevalence in Japanese blood donors and high detection frequency of CMV DNA in elderly donors. Transfusion. 2013;53(10):2190–2197. doi: 10.1111/trf.12390. [DOI] [PubMed] [Google Scholar]
- 36.Bate SL, Dollard SC, Cannon MJ. Cytomegalovirus seroprevalence in the United States: the national health and nutrition examination surveys, 1988-2004. Clin Infect Dis. 2010;50(11):1439–1447. doi: 10.1086/652438. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Iftikhar R, Farhan M, Khan M, et al. Cytomegalovirus infection post-allogeneic stem cell transplantation: experience from a country with high seropositivity. Transplant Cell Ther. 2023;29(8):521.e1–521.e7. doi: 10.1016/j.jtct.2023.04.023. [DOI] [PubMed] [Google Scholar]
- 38.Liu YC, Lu PL, Hsiao HH, et al. Cytomegalovirus infection and disease after allogeneic hematopoietic stem cell transplantation: experience in a center with a high seroprevalence of both CMV and hepatitis B virus. Ann Hematol. 2012;91(4):587–595. doi: 10.1007/s00277-011-1351-8. [DOI] [PubMed] [Google Scholar]
- 39.Grandjean Lapierre S, Vallieres E, Rabaamad L, Labrecque M, Chartrand C, Renaud C. Evaluation of the Abbott ARCHITECT cytomegalovirus IgM/IgG, rubella IgM/IgG, and syphilis treponemal antibodies enzyme immunoassays in a mother and child health center population. Diagn Microbiol Infect Dis. 2019;94(3):231–235. doi: 10.1016/j.diagmicrobio.2018.12.017. [DOI] [PubMed] [Google Scholar]
- 40.Lagrou K, Bodeus M, Van Ranst M, Goubau P. Evaluation of the new architect cytomegalovirus immunoglobulin M (IgM), IgG, and IgG avidity assays. J Clin Microbiol. 2009;47(6):1695–1699. doi: 10.1128/JCM.02172-08. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Nielsen SL, Ronholm E, Sorensen I, Andersen HK. Detection of immunoglobulin G antibodies to cytomegalovirus antigens by antibody capture enzyme-linked immunosorbent assay. J Clin Microbiol. 1986;24(6):998–1003. doi: 10.1128/jcm.24.6.998-1003.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
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