Improving haematopoietic cell transplantation outcomes by selection of an HLA-matched unrelated donor is best practice; however, donor selection by secondary characteristics is controversial. We studied 1271 recipients with haematological malignancies who underwent T-cell-depleted allografts and had complete data on HLA-matching status for six loci (HLA-A, -B, -C, -DRB1, -DQB1, -DPB1) and clinical outcome data. Five-year overall survival was 40.6%. HLA mismatching (at HLA-A, -B, -C, -DRB1, -DQB1) relative risk (RR) 1.22, 95% confidence interval (CI) 1.2–1.5, P=0.033 for 1 mismatch and RR 1.46, 95% CI 1.1–1.9, P=0.009 for >1 mismatch) and CMV mismatching (RR 1.37, 95% CI 1.2–1.6, P<0.001) were significantly associated with inferior survival. Donors aged <30 years showed a trend towards better survival. The multivariate model for mortality, combining CMV and HLA-match status, found an RR of 1.36 (95% CI 1.1–1.7, P=0.003) for HLA matched/CMV mismatched, an RR of 1.22 (95% CI 0.99–1.5, P=0.062) for HLA mismatched/CMV matched and an RR of 1.81 (95% CI 1.4–2.3, P=<0.001) for HLA/ CMV mismatched, compared with the HLA/CMV-matched recipients. These data suggest that HLA and CMV matching status should be considered when selecting unrelated donors and that CMV matching may abrogate the effect of an HLA mismatch.
Haematopoietic cell transplantation (HCT) is curative for many recipients suffering from haematological and immunological disorders. Survival using unrelated donors (UD) has improved significantly over time and is now equal to that of sibling transplants in many settings.1 A reason for this improvement is the enormous expansion in the internationally available UD pool, with >25 million donors listed on Bone Marrow Donors Worldwide in 2015 (http://www.bmdw.org/). HLA matching for 10/10 loci is often considered the gold standard, but the importance of HLA-DQB1 matching has been questioned.2, 3 Conversely, the additional benefit of matching for DPB1 has been increasingly studied.4, 5, 6 In addition, studies report a differential impact of single allele mismatches on transplant outcomes.2, 7, 8 Owing to the expansion in volunteer donor numbers, recipients now often have a choice between several equally HLA-matched donors and in this setting secondary donor characteristics such as donor age, gender, parity, CMV serostatus and ABO type should be taken into account.3, 9 Although these factors may currently be considered by the team making the final donor selection, no widespread internationally agreed selection algorithms are available. Selection of these factors has changed significantly over time. CMV seronegative donors (D−) were originally chosen for all recipients. More recently, a CMV seropositive donor has been preferred for a CMV-positive recipient; however, this remains controversial, despite some studies supporting it.10, 11 Studies show that younger donors generally result in improved outcomes, but the impact of ABO mismatches and the use of female donors have produced conflicting results.3, 9
The aim of this study was to analyse the impact of HLA and non-HLA donor factors on transplant outcomes and to identify those factors important in donor selection.
Material and methods
The final study population includes 1271 UK recipients, both children and adults, transplanted for a haematological malignancy, from September 1996 to October 2011, from an UD through the Anthony Nolan Research Institute. One thousand three hundred and seventy paired samples that were collected pretransplant or predonation for recipients and donor, respectively, and stored in the sample repository were successfully typed; however, 99 recipients were not included in the final study population owing to incomplete clinical data. Both recipient and donor were required to have two field (previously four digit) allele typing results at six HLA loci (HLA-A, -B, -C, -DRB1, -DQB1, -DPB1). Clinical data were collected by the Anthony Nolan Research Institute in collaboration with the British Society for Blood and Marrow Transplantation, using standard posttransplant reporting forms. Standard definitions for primary graft failure (PGF), GVHD and non-relapse mortality (NRM) were used. Relapse was defined as clinical evidence of disease. The European Group for Blood and Marrow Transplantation (EBMT) score was calculated based on the publication by Gratwohl.12 CMV prophylaxis was not routinely given, instead screening and preemptive treatment strategies were used.
The study has ethical approval from the United Kingdom’s National Research Ethics Service (www.myresearchproject.org.uk, application number MREC 01/8/31). All recipients and donors signed informed consent.
Probability curves were calculated using the Kaplan–Meier method for survival and the cumulative incidence procedure for NRM and relapse. Time intervals were calculated relative to the date of transplantation, until the event of interest (or competing event) or until the date of last follow-up. Groups were compared using either log-rank test or Gray’s test as appropriate. Factors found to be significant at the P<0.1 level were entered into either Cox regression or Fine and Gray13 models, using a backward stepping procedure to find the best model. Incomplete time to event data for PGF and grade 2–4 acute GVHD resulted in these outcomes being described as simple proportions, with logistic regression analysis being utilised to find significant factors associated with each outcome. All analyses were performed using either SPSS version 22 software (SPSS, Inc., Chicago, IL, USA) or R.14 All statistical tests were two sided, and P<0.05 was used to indicate statistical significance.
Recipient and donor factors are shown in Table 1 arranged by transplantation era. Diseases for which transplantation was performed were acute leukaemia (581, 46%), myelodysplasia (221, 17%), chronic leukaemia (174, 14%), lymphoma (198, 16%), myeloma (46, 4%) and other (51, 4%). 94% of the population received T-cell depletion (TCD) with Alemtuzumab. As expected, the use of myeloablative conditioning decreased over the eras with a corresponding increase in the use of PBSC. Recipients were significantly older in the later eras. There was a reduction in the number of HLA-mismatched donors over time. Donors were also more likely to be younger and CMV seropositive donors (D+) were more likely to be selected for CMV seropositive recipients (R+) in the later eras.
The 5-year probability of survival for the whole group was 40.6%, with NRM at 1, 3 and 5 years of 26.5, 34.3 and 37.4% respectively. The relapse risk at 1, 3 and 5 years was 29.2, 39.2 and 42.1%, respectively. Overall PGF rate was 3.8%. Acute GVHD was present in 28% of recipients (grade 2 in 18%, grade 3/4 in 10%).
Factors implicated in recipient survival and mortality
Results of the univariate analysis of recipient and donor factors are shown in Table 2. Older recipients (P=0.005), R+ (P=0.013), those who had a previous autograft (P=0.001) and intermediate or poor EBMT risk status (P<0.001) had a worse overall survival (OS). There was a trend to a worse OS with the use of bone marrow (BM) compared with PBSC (P=0.078).
Recipients matched for 10/10 HLA alleles had significantly better OS and reduced NRM compared with those matched at 9/10 or <9/10 (5-year OS: 43.1% vs 35.6% vs 28.4%, respectively, P=0.001 (Figure 1) and NRM at 1 year: 20.3% vs 26.0% vs 33.4%, respectively, P=0.007). Considering individual locus mismatches compared with 10/10 matched recipients, mismatching for HLA-B (P=0.011) and -DQB1 (P=0.03) resulted in a significantly worse survival, while mismatching for HLA-A (P=0.17), HLA-C (P=0.28) or HLA-DRB1 (P=0.75) resulted in no statistically significant difference in survival (Table 2).
HLA-DPB1 matching was not associated with a statistically significant survival advantage (5-year OS for 12/12 was 46.5% vs 42.5% in 10/10 matches, P=0.1). Non-permissive HLA-DPB1 T-cell epitope (TCE) matching status was associated with a trend towards worse survival and a significantly higher NRM. 5-year OS in DPB1 TCE-matched, allele-matched or TCE-mismatched pairs was 43.0, 41.5 and 36.9% respectively, P=0.054, and NRM at 1 year was 19.3, 23.6 and 26.4%, respectively, P=0.028 (Table 2).
There was no impact of donor CMV on either OS or NRM as an independent variable; however, a significant effect was observed for CMV-matching status between recipient and donor. Recipients who had a CMV-matched donor had an OS of 44.1% vs 32.2% for those who were mismatched (P<0.001). Survival in the R+/D+ setting was 40.5% compared with 30.0% in the R+/D−. We also noted a difference in the CMV-negative recipient where R−/D− had a survival of 45.3% compared with 37.9% in the R−/D+ (Table 2). NRM at 1 year was 19.1% vs 30.4% for the CMV-matched vs -mismatched recipients (P<0.001) (Table 2). Use of donors aged <30 years resulted in a better survival (45.3% vs 38.6%, P=0.01) and a trend to lower NRM (19.2% vs 27.9%, P=0.075). An ABO match or minor mismatch was preferential to a major or bidirectional mismatch (OS: P=0.011and NRM: P=0.040).
In multivariate analysis (Table 3), the only recipient factor resulting in worse OS was older age. Recipients with a previous autograft and/or intermediate or poor EBMT disease risk score had a worse OS. OS and NRM were significantly worse in those who had a transplant prior to 2004 and 2000, respectively. HLA matching remained significant as those who had >1 HLA mismatch with their donor had a relative risk (RR) of 1.43 (95% confidence interval (CI) 1.1–1.9, P=0.016) for mortality and 1.59 (95% CI 1.1–2.4, P=0.028) for NRM. Although there remained a survival detriment when comparing a single mismatch to recipients with a 10/10 matched donor (OS: RR 1.21 (95% CI 1.1–1.5), P=0.042), there was no significant impact on NRM: RR 1.24 (95% CI 0.9–1.6), P=0.14). Recipients who were CMV mismatched with their donor had a significant survival detriment (OS: RR 1.40, 95% CI 1.2–1.6, P<0.001; NRM: RR 1.63, 95% CI 1.3–2.1, P<0.001). Use of donors >30 showed a trend towards worse OS (RR 1.17 (95% CI 0.98–1.4, P=0.078) but no impact on NRM. In contrast, recipient/donor gender matching did not impact on OS, while a female donor into a male recipient showed a trend to higher NRM compared with all other gender combinations (RR 1.38, 95% CI, 0.99–1.9, P=0.063). Recipient donor ABO matching status and the DPB1 TCE were not significant for either OS or TRM.
Four factors were shown to be associated with an increase in disease relapse in univariate analysis, including recipients of a prior autograft (5 years: 54.2% vs 40.0%, P<0.001), earlier transplant era (P=0.012), BM vs PBSC (45.2% vs 38.7%, P=0.024) and the use a DPB1 TCE or allele-matched donor vs a TCE-mismatch donor (P=0.036). CMV status of either the patient or donor, or the combinations, were not associated with relapse risk. In multivariate analysis, donor CMV status was the only donor factor associated with relapse (D+: RR 1.23 95% CI 1.1–1.5, P=0.035), while prior autograft and era retained significance (Table 4).
CMV status in the context of HLA matching
We further examined the relationship between recipient/donor CMV and HLA matching (Figure 2a). Outcomes differed significantly based on the four possible combinations (P⩽0.001). In the HLA-matched setting, survival was significantly better in those who were CMV matched (n=676) compared with CMV mismatched (n=223) (5-year OS 45.9% vs 35.9%, P=0.007). Likewise, in the HLA-mismatched setting, CMV-matched recipients (n=207) again had a better survival than those who were CMV mismatched (n=122) (5-year OS 38.6% vs 25.8%, P=0.002). These findings were consistent when adjusted for other significant variables in a multivariate analysis (Figure 2b). When compared with the HLA-matched, CMV-matched recipients: there was an RR 1.36 (95% CI 1.1–1.7, P=0.003) for HLA matched and CMV mismatched, an RR 1.22 (95% CI 0.99–1.5, P=0.062) for HLA mismatched and CMV matched and an RR 1.81 (95% CI 1.4–2.3, P<0.001) for HLA and CMV mismatched.
Impact of donor factors on other outcomes
In multivariate analysis, a mismatch of more than one HLA allele (RR 2.9, 95% CI 1.2–7.3, P=0.02) and the use of BM (RR 2.9, 95% CI 1.2–7.3, P=0.02) resulted in significantly higher PGF. HLA matching (OR 0.63 95% CI 0.5–0.8, P=0.002), the use of BM (OR 0.59, 95% CI 0.4–0.8, P=0.001) and CMV seronegative donors (OR 0.65, 95% CI 0.5–0.9, P=0.006) were associated with a lower risk of grade 2–4 acute GVHD (Table 4).
Our results show that donor factors remain a critical determinant of outcome in UD HCT, despite the changing trends in transplant practice over recent eras. We found both HLA matching and the recipient/donor match status for pretransplant CMV serostatus to be the most significant factors determining survival and report the novel finding that avoiding a CMV mismatch may offset the negative impact of an HLA mismatch. In addition, we confirmed the previous observations that HLA matching and donor age impact survival.
Although the relationship between CMV and HLA matching in this study is a novel finding, it is consistent with observations and proposed mechanisms made in several recent studies. Historically, it is well recognised that recipient CMV seropositivity (R+) is associated with an inferior transplant outcome,15, 16 but studies regarding the impact of donor status have produced controversial results3, 9, 17 and recommendations for donor selection based on this criteria have changed over time. In recent years, there has been developing consensus around the selection of a CMV seromatched donor for an HCT recipient.
Individual study results are not consistent with regard to subgroups in which this selection may be relevant. Two recent large EBMT studies report results similar to ours. In 2003, Ljungman et al.10 reported that a transplant from a D+ was associated with improved OS, event-free survival and decreased TRM compared with a D− in UD SCT. They did not find any difference in GVHD in the seronegative vs seropositive groups. In that study, the positive effect of D+ was abrogated by TCD using antithymocyte globulin, but recipients receiving Alemtuzumab (as in our study) were not included. More recently, the same group11 showed an improved survival in R+ transplanted with a D+, however, only in the recipients receiving myeloablative conditioning regimens. Although CMV reactivations (and GVHD) were not directly addressed, they found that deaths owing to viral causes were less likely in R+/D+, leading them to suggest that the presence of CMV-specific T cells was mediating a protective effect of D+ on survival. Interestingly, there was no impact of TCD noted in this study. Neither study addressed the HLA-match status.
As shown in our results, the negative effect of an HLA mismatch may be abrogated somewhat by matching for CMV. The combined immunological effects as well as potential poor graft function owing to treatment of CMV and an HLA mismatch (GVHD, immunosuppression and immune deficiency) are likely to be critical and may explain some of the discrepancies in earlier studies. This is supported by the fact that donor CMV serostatus does not appear to have major significance in HLA-identical sibling transplantation outcomes10, 11 as well as the finding that CMV reactivations are higher in the setting of an HLA mismatch.18 Although the overall rates of clinically significant GVHD were low, HLA mismatching was associated with a significant increase in GVHD as expected.
Some,10, 18, 19 but not all,20, 21 studies have shown that CMV reactivation and disease are more common in the setting of a CMV mismatch (that is, R+/D− compared with R+/D+). In the late 1980s, it was reported that cells from D+ could result in better outcomes in the TCD setting through reduction in CMV disease.22 CMV-specific T cells transferred with the donor graft could protect against progressive or recurrent CMV reactivation19, 21 and therefore be associated with better outcomes. This effect could be abrogated or lost by extensive TCD (ex vivo or antithymocyte globulin) or the need for ongoing and intensive immunosuppression such as in GVHD.
Although, in vivo TCD with Alemtuzumab was used in >90% of the recipients in our study, it is well recognised that this does not eradicate all T cells and that a degree of CMV-specific immunity is retained in this setting. CMV-specific T cells may also be of recipient origin. Sellar et al.23 have recently shown that, in the majority of R+/D− recipients receiving TCD (mostly sibling) reduced intensity conditioning HCT, recipient-derived T cells provide protection from recurrent CMV infection in the absence of GVHD. However, they stress the importance of avoiding GVHD in this setting to prevent CMV-associated toxicities. In our registry-based study, we unfortunately do not have data on CMV reactivations, immune reconstitution (IR) or the chimeric status of recipients after transplant. However, in line with the findings of Sellar et al.,23 the negative effect of donor serostatus (R+/D−) in our study is seen predominantly in those recipients with a co-existing HLA mismatch and consequently an increase in clinical GVHD (data not shown).
Another possible mechanism for improved outcome may be through a direct24, 25, 26 or indirect (through earlier IR)27 effect of CMV on reduction of disease relapse after transplant, although this remains controversial.28, 29, 30 Early and robust IR in general has been shown to be associated with improved transplant outcomes.31 Not surprisingly, CMV-specific IR has an important association with a reduction in CMV reactivation and infections.20, 32 However, donor CMV status has also been shown to influence the strength of IR33 and Zhou et al.19 showed that CMV-specific T-cell populations from R+/D+ contained higher levels of functional subsets than R+/D− recipients. We found that the use of CMV seronegative donors was associated with a lower relapse risk.
HLA matching is important for survival; however, in contrast to our previous studies,5, 34 we did not find a similar survival between a 10/10 and 9/10 matched transplant but rather findings similar to the paper by Lee et al.2 showing an incremental survival disadvantage with additional HLA mismatches. Possible reasons for this include a reduction in Alemtuzumab doses in the recent era35, 36 as well as the larger numbers now included in our study giving us greater power to detect a difference. We did see an impact of DQB1 matching on both OS and NRM. This differed from the study by Lee et al.2; however, it is consistent with the report from the German group,9, 37 which found a higher mortality associated with DQB1 mismatching, in particular if these mismatches were at an antigenic level. As in many studies, the type of mismatch may thus be of significance and may differ in the European vs American populations. Based on these differences, we would recommend that matching status continue to be considered for DQB1 as the impact of mismatches remains somewhat controversial. Matching should also be prioritised for HLA-B. A caution is that the number of mismatches in this study was small. Although survival was improved when either allele level or epitope matching for DPB1 was performed as has been previously shown,4, 6 this was not a significant factor in multivariate analysis. Previously, the impact has been seen most commonly in transplant pairs matched for the other HLA alleles, with less of an impact of DPB1 mismatching in ⩽9/10 matched transplants and we did not perform subset analysis.
Donor age was significantly associated with transplant outcomes, although the effect in multivariate analysis was borderline. These findings are consistent with several other studies9, 37 and suggest that this factor should be taken into account in donor selection. Although donor gender and ABO matching status both had some impact on transplant outcomes in univariate analysis, these effects were not seen in multivariate analysis. Several other studies have shown conflicting results related to these factors and it is possible that the impact may differ based on the characteristics of the population studied. In addition, small statistical effects may be more difficult to appreciate in smaller data sets.
In conclusion, our results add to the recent consensus that survival is improved by selecting a CMV-matched donor for an UD HCT recipient. We significantly extend these findings by including the influence of HLA matching on this variable and suggest that these factors are closely inter-related.
Based on these results, and those from recent studies, several donor selection strategies could be proposed. A 10/10 HLA-matched donor remains the best and selection of a CMV-matched donor is preferable. This is particularly relevant in the setting of a R+ in the HLA-mismatch setting. If no D+ is available in this setting, an alternative stem cell source, such as umbilical cord blood that has been shown to be associated with less GVHD, should be considered. Where a R+/D− combination cannot be avoided, active strategies to avoid GVHD should be undertaken. Finally, our results suggest that donor characteristics should not be considered in isolation but as a ‘package’ and individualised based on recipient characteristics.
Ottinger H, Ferencik S, Beelen D, Lindemann M, Peceny R, Elmaagacli A et al. Hematopoietic stem cell transplantation: contrasting the outcome of transplantations from HLA-identical siblings, partially HLA-mismatched related donors and HLA-matched unrelated donors. Blood 2003; 102: 1131–1137.
Lee S, Klein J, Haagenson M, Baxter-Lowe L, Confer D, Eapen M et al. High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation. Blood 2007; 110: 4576–4583.
Pidala J, Lee SJ, Ahn KW, Spellman S, Wang HL, Aljurf M et al. Nonpermissive HLA-DPB1 mismatch increases mortality after myeloablative unrelated allogeneic hematopoietic cell transplantation. Blood 2014; 124: 2596–2606.
Fleischhauer K, Shaw BE, Gooley T, Malkki M, Bardy P, Bignon J-D et al. Effect of T-cell-epitope matching at HLA-DPB1 in recipients of unrelated-donor haemopoietic-cell transplantation: a retrospective study. Lancet Oncol 2012; 13: 366–374.
Shaw BE, Mayor NP, Russell NH, Apperley JF, Clark RE, Cornish J et al. Diverging effects of HLA-DPB1 matching status on outcome following unrelated donor transplantation depending on disease stage and the degree of matching for other HLA alleles. Leukemia 2010; 24: 58–65.
Burt C, Parker A, McQuaker G, Copland M, Brierley C, Little AM et al. In a 12-allele analysis HLA-DPB1 matching is associated with improved OS in leukaemic and myelodysplastic patients receiving myeloablative T-cell-depleted PBSCT from unrelated donors. Bone Marrow Transplant 2014; 49: 657–663.
Morishima Y, Kashiwase K, Matsuo K, Azuma F, Morishima S, Onizuka M et al. Biological significance of HLA locus matching in unrelated donor bone marrow transplantation. Blood 2015; 125: 1189–1197.
Woolfrey A, Klein JP, Haagenson M, Spellman S, Petersdorf E, Oudshoorn M et al. HLA-C antigen mismatch is associated with worse outcome in unrelated donor peripheral blood stem cell transplantation. Biol Blood Marrow Transplant 2011; 17: 885–892.
Kollman C, Howe C, Anasetti C, Antin J, Davies S, Filipovich A 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: 2043–2051.
Ljungman P, Brand R, Einsele H, Frassoni F, Niederwieser D, Cordonnier C . Donor CMV serologic status and outcome of CMV-seropositive recipients after unrelated donor stem cell transplantation: an EBMT megafile analysis. Blood 2003; 102: 4255–4260.
Ljungman P, Brand R, Hoek J, de la Camara R, Cordonnier C, Einsele H 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: 473–481.
Gratwohl A . The EBMT risk score. Bone Marrow Transplant 2012; 47: 749–756.
Fine J, Gray R . A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 1999; 94: 496–509.
R Core Team. R: A Language and Evnironment for Statistical Computing. R Foundation for Statistical Computing: Vienna, Austria, 2014. https://www.r-project.org/.
Craddock C, Szydlo RM, Dazzi F, Olavarria E, Cwynarski K, Yong A et al. Cytomegalovirus seropositivity adversely influences outcome after T-depleted unrelated donor transplant in patients with chronic myeloid leukaemia: the case for tailored graft-versus-host disease prophylaxis. Br J Haematol 2001; 112: 228–236.
Spencer A, Brookes PA, Kaminski E, Hows JM, Szydlo RM, van Rhee F et al. Cytotoxic T lymphocyte precursor frequency analyses in bone marrow transplantation with volunteer unrelated donors. Value in donor selection. Transplantation 1995; 59: 1302–1308.
Bacigalupo A, Tedone E, Sanna MA, Moro F, Van Lint MT, Grazi G et al. CMV infections following allogeneic BMT: risk factors, early treatment and correlation with transplant related mortality. Haematologica 1992; 77: 507–513.
Jaskula E, Bochenska J, Kocwin E, Tarnowska A, Lange A . CMV serostatus of donor-recipient pairs influences the risk of CMV infection/reactivation in HSCT patients. Bone Marrow Res 2012; 2012: 375075.
Zhou W, Longmate J, Lacey SF, Palmer JM, Gallez-Hawkins G, Thao L et al. Impact of donor CMV status on viral infection and reconstitution of multifunction CMV-specific T cells in CMV-positive transplant recipients. Blood 2009; 113: 6465–6476.
Moins-Teisserenc H, Busson M, Scieux C, Bajzik V, Cayuela JM, Clave E et al. Patterns of cytomegalovirus reactivation are associated with distinct evolutive profiles of immune reconstitution after allogeneic hematopoietic stem cell transplantation. J Infect Dis 2008; 198: 818–826.
Pietersma FL, van Dorp S, Minnema MC, Kuball J, Meijer E, Schuurman R et al. Influence of donor cytomegalovirus (CMV) status on severity of viral reactivation after allogeneic stem cell transplantation in CMV-seropositive recipients. Clin Infect Dis 2011; 52: e144–e148.
Grob JP, Grundy JE, Prentice HG, Griffiths PD, Hoffbrand AV, Hughes MD et al. Immune donors can protect marrow-transplant recipients from severe cytomegalovirus infections. Lancet 1987; 1: 774–776.
Sellar RS, Vargas FA, Henry JY, Verfuerth S, Charrot S, Beaton B et al. CMV promotes recipient T-cell immunity following reduced-intensity T-cell-depleted HSCT, significantly modulating chimerism status. Blood 2015; 125: 731–739.
Elmaagacli AH, Steckel NK, Koldehoff M, Hegerfeldt Y, Trenschel R, Ditschkowski M et al. Early human cytomegalovirus replication after transplantation is associated with a decreased relapse risk: evidence for a putative virus-versus-leukemia effect in acute myeloid leukemia patients. Blood 2011; 118: 1402–1412.
Green ML, Leisenring WM, Xie H, Walter RB, Mielcarek M, Sandmaier BM et al. CMV reactivation after allogeneic HCT and relapse risk: evidence for early protection in acute myeloid leukemia. Blood 2013; 122: 1316–1324.
Ito S, Pophali P, Co W, Koklanaris EK, Superata J, Fahle GA et al. CMV reactivation is associated with a lower incidence of relapse after allo-SCT for CML. Bone Marrow Transplant 2013; 48: 1313–1316.
Admiraal R, Chiesa R, Lindemans CA, Nierkens S, Bierings MB, Versluijs AB et al. Leukemia-free survival in myeloid leukemia, but not in lymphoid leukemia, is predicted by early CD4+ reconstitution following unrelated cord blood transplantation in children: a multicenter retrospective cohort analysis. Bone Marrow Transplant. 2016; 51: 1376–1378.
Thomson KJ, Mackinnon S, Peggs KS . CMV-specific cellular therapy for acute myeloid leukemia? Blood 2012; 119: 1088–1090author reply 90–9.
Busca A, Passera R, Pini M, Zallio F, Dellacasa C, Audisio E et al. The use of ATG abrogates the antileukemic effect of cytomegalovirus reactivation in patients with acute myeloid leukemia receiving grafts from unrelated donors. Am J Hematol 2015; 90: E117–E121.
Mariotti J, Maura F, Spina F, Roncari L, Dodero A, Farina L et al. Impact of cytomegalovirus replication and cytomegalovirus serostatus on the outcome of patients with B cell lymphoma after allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2014; 20: 885–890.
Moscardo F, Sanz J, Carbonell F, Sanz MA, Larrea L, Montesinos P et al. Effect of CD8(+) cell content on umbilical cord blood transplantation in adults with hematological malignancies. Biol Blood Marrow Transplant 2014; 20: 1744–1750.
Ganepola S, Gentilini C, Hilbers U, Lange T, Rieger K, Hofmann J et al. Patients at high risk for CMV infection and disease show delayed CD8+ T-cell immune recovery after allogeneic stem cell transplantation. Bone Marrow Transplant 2007; 39: 293–299.
Avetisyan G, Aschan J, Hagglund H, Ringden O, Ljungman P . Evaluation of intervention strategy based on CMV-specific immune responses after allogeneic SCT. Bone Marrow Transplant 2007; 40: 865–869.
Shaw B, Gooley T, Malkki M, Madrigal J, Begovich A, Horowitz M et al. The importance of HLA-DPB1 in unrelated donor hematopoietic cell transplantation. Blood 2007; 110: 4560–4566.
Chakraverty R, Orti G, Roughton M, Shen J, Fielding A, Kottaridis P et al. Impact of in vivo alemtuzumab dose before reduced intensity conditioning and HLA-identical sibling stem cell transplantation: pharmacokinetics, GVHD, and immune reconstitution. Blood 2010; 116: 3080–3088.
Jardine L, Publicover A, Bigley V, Hale G, Pearce K, Dickinson A et al. A comparative study of reduced dose alemtuzumab in matched unrelated donor and related donor reduced intensity transplants. Br J Haematol 2015; 168: 874–881.
Kollman C, Spellman SR, Zhang MJ, Hassebroek A, Anasetti C, Antin JH et al. The effect of donor characteristics on survival after unrelated donor transplantation for hematologic malignancy. Blood 2016; 127: 260–267.
We thank all the transplant centre data managers and co-ordinators who provided clinical data or research samples for this study.
BES, NPM, SM and JAM designed the study, collected and curated the samples and data, performed the analysis and wrote the paper. BES, NPM and WPB performed the laboratory typing. RMS performed the statistical analysis. KK and JS collected and contributed the clinical data. BES, CA, AC, SM, DIM, AP, MNP, NHR and KT contributed patient data and samples. All of the authors contributed to the writing and review of the manuscript.
The authors declare no conflict of interest.
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Shaw, B., Mayor, N., Szydlo, R. et al. Recipient/donor HLA and CMV matching in recipients of T-cell-depleted unrelated donor haematopoietic cell transplants. Bone Marrow Transplant 52, 717–725 (2017). https://doi.org/10.1038/bmt.2016.352
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