Post-transplant cyclophosphamide and early mixed donor Chimerism in myeloid malignancies; a single-center experience

BackgroundAllogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative option for high-risk myeloid malignancies. Post-transplant cyclophosphamide (PT-Cy) has proven to be effective for graft versus host disease (GVHD) prophylaxis. Given that graft-versus-tumor (GVT) effect plays a major role in reducing the risk of disease relapse, the application of PT-Cy must balance the risk of relapse. Mixed chimerism (MC) refers to a state of concurrent presence of recipient and donor cells post allo-HSCT which may precede relapse disease.ObjectiveWe investigated the impact of PT-Cy on early MC (EMC) and disease relapse in patients with a myeloid malignancy post allo-HSCT.Study designThis retrospective single-center study included patients that underwent allo-HSCT between 2015 and 2021. Patient and disease characteristics were collected from the electronic health records. EMC was defined as <95% donor cells at day 90–120 post allo-HSCT.ResultsA total of 144 patient that received an allo-HSCT were included in the study. One hundred and eight (75%) patients received PT-Cy as part of the GVHD prophylaxis regimen. The majority underwent allo-HSCT for acute myeloid leukemia (62%) or myelodysplastic syndrome (31%). Sixty-five percent received allo-HSCT from a matched unrelated donor transplant and 65% received a myeloablative conditioning regimen. A lower rate of chronic GVHD (p = 0.03) and a higher rate of EMC (p = 0.04) were observed in patients that received PT-Cy. PT-Cy was not associated with overall survival (OS) and relapse-free survival (RFS). Multivariable analysis identified measurable residual disease status (p = 0.003), hematopoietic cell transplantation-specific comorbidity index (p = 0.012) and chronic GVHD (p = 0.006) as independent prognostic variables for OS. AML-adverse risk (p = 0.004) and EMC (p = 0.018) were independently prognostic for RFS. While EMC overall was not significantly associated with higher risk of relapse, EMC was associated with shorter RFS within adverse-risk AML patients.ConclusionOur study shows that PT-Cy was associated with an increased risk of EMC. The predictive value of EMC for relapse remains unclear and may depend on the underlying disease, which should be validated in a larger cohort.     

Outcomes of Busulfan,Fludarabine, and 400 cGy Total Body Irradiation Compared With Busulfan and Fludarabine Reduced-Intensity Conditioning Regimens for Allogeneic Stem Cell Transplantation in Adult Patients With Hematologic Diseases: A Single-Center Experience

BackgroundReduced intensity conditioning (RIC) regimens decrease the risk for nonrelapse mortality (NRM) in adult patients undergoing allogeneic hematopoietic stem cell transplantation for hematologic malignancies but increase the risk for relapse. The aim of this study was to compare the outcomes of fludarabine–total body irradiation (TBI) with fludarabine among patients with hematologic diseases.Patients and MethodsThis retrospective study of 137 patients with different hematologic malignancies compared the outcomes of 63 patients who received a conventional RIC regimen with 2 days of IV busulfan (3.2 mg/kg/d × 2 days) and fludarabine with 74 patients who received the same regimen plus 400 cGy of fludarabine and busulfan (FB)-TBI divided in 2 doses over 1 day (200 cGy BID). Median follow-up was 4.62 years.ResultsThe donors were either HLA-matched siblings (36%) or HLA-matched unrelated donors (64%). The FB-TBI showed trends toward improvement in progression-free survival (PFS) and overall survival (OS) over FB (5-year PFS rates 50% vs 34%, P = .06, and 5-year OS rate 53% vs 39%, P = .13). Acute graft-vs-host disease (aGVHD), relapse, and NRM were similar between the 2 groups. The 5-year cumulative incidence of chronic GVHD (cGVHD) was lower in the FB-TBI group compared with the FB group (29% vs 52%, P = .003). Multivariable analysis revealed that grade III-IV aGVHD was the only independent risk factor for worse OS (P = .001) in both groups. A high disease risk index was possibly associated with inferior OS (P = .07) in both groups.ConclusionsThe FB-TBI is a safe and effective intensified RIC regimen for adult patients with hematologic malignancies. It predicted a lower risk for cGVHD and showed possibly improved PFS and OS compared with FB.     

The recipient CCR5 variation predicts survival outcomes after bone marrow transplantation

The chemokine receptor CCR5 plays roles in the trafficking of effector cells towards the site of inflammation. We retrospectively examined the impact of the CCR5 variation (rs1800023, -2086A > G) on transplant outcomes in a cohort of 329 patients who underwent unrelated HLA-matched bone marrow transplantation (BMT) for hematologic malignancies through the Japan Marrow Donor Program. A multivariate analysis showed that the recipient CCR5 -2086A/A genotype was significantly associated with a lower relapse rate but not with the development of graft-versus-host disease (GVHD) or transplant-related mortality, thereby resulting in better disease-free and overall survival rates than other variations. The donor CCR5 -2086A/A genotype was associated with a lower incidence of grades 3–4 acute GVHD, which did not improve the survival outcomes. These findings suggest that the recipient CCR5 -2086A/A genotype affects the induction of the graft-versus-tumor effect without augmenting the development of GVHD. CCR5 genotyping in transplant recipients may therefore be a useful tool for evaluating pretransplantation risks.     

Impact of donor kidney function and donor age on poor outcome of living‐unrelated kidney transplantation (KT) in comparison with living‐related KT

Living‐unrelated donors (LURD) have been widely used for kidney transplantation (KT). We retrospectively reviewed 779 patients who underwent living‐donor KT from 2000 to 2012, to compare outcomes of 264 KT from LURD and 515 from living‐related donors (LRD), and to identify risk factors for living KT. Median follow‐up was 67 months. Mean donor age, total human leukocyte antigen (HLA) mismatches, and HLA–DR mismatches were higher, and mean estimated glomerular filtration rate (eGFR) was lower in LURD. Acute rejection (AR)‐free survival (p = 0.018) and graft survival (p = 0.025) were lower for LURD than LRD, whereas patient survival rate was comparable. Cox regression analysis showed HLA–DR mismatches (OR 1.75 for one mismatch; OR 2.19 for two mismatches), recipient age ≤ 42 yr, and donor age > 50 yr were significant risk factors for acute rejection. For graft survival, AR and donor eGFR (OR 1.90, p = 0.035) were significant. We also identified significant impact of recipient age > 50 yr and diabetes for patient survival. However, KT from LURD was not a significant risk factor for AR (p = 0.368), graft survival (p = 0.205), and patient survival (p = 0.836). Our data suggest that donor eGFR and donor age are independent risk factors for clinical outcomes of living KT, which can be related with poor outcome of KT from LURD.     

A high antithymocyte globulin dose increases the risk of relapse after reduced intensity conditioning HSCT with unrelated donors

The study included 110 consecutive patients with hematological malignancies receiving fludarabine‐based reduced intensity conditioning (RIC) and hematopoietic stem cell transplantation (HSCT) from matched unrelated donors. The median age was 55 yr (range 11–68) and all but 15 patients received peripheral blood stem cell grafts. Antithymocyte globulin (ATG) (Thymoglobulin, Genzyme) at a total dose of 6 mg/kg (n = 66) or 8 mg/kg (n = 44) was given to all patients according to protocol. The ATG dose did not affect time‐to‐neutrophil or platelet engraftment. The incidences of acute GVHD grades II–IV were 34% and 18% (p = 0.11) and of chronic GVHD were 40% and 26% (p = 0.46) in patients receiving 6 and 8 mg/kg of ATG, respectively. The five‐yr relapse‐free survival (RFS) was 61% and 36% (p = 0.14) in patients, given low and high ATG dose, respectively. In patients given low‐dose ATG, the incidence of relapse was lower compared to those given high‐dose ATG, 19% vs. 41% (p = 0.04). In multivariate analysis, age >50 yr (p < 0.001), absence of acute (p < 0.001) and chronic GVHD (p = 0.001) were correlated to relapse, and low‐dose ATG was associated with improved RFS (p < 0.05). A high dose (8 mg/kg) of ATG in RIC HSCT with unrelated donors increased the risk for relapse and reduced the RFS.     

Can donors with high donor risk indices be used cost‐effectively in liver transplantation in US Transplant Centers?

In an effort to quantify the impact of donor risk factors on recipient outcomes, the donor risk index (DRI) was developed. A high DRI correlates with poorer post‐transplant survival. In this study, high‐DRI donors are classified as those having DRIs >2.0, while low‐DRI donors have DRIs <2.0. The aim of this study was to evaluate the cost‐effectiveness of high‐DRI donor use in US Transplant Centers. A Markov‐based decision analytic model was created to simulate outcomes for an allocation scheme using only low‐DRI donors versus a scheme using both low‐ and high‐DRI donors. Baseline values and ranges were determined from published data and Medicare cost data. Sensitivity analyses were conducted to test model strength and parameter variability. An allocation scheme in which only low‐DRI donors were used generated 5.2 quality‐adjusted life years (QALYs) at a cost of $83 000/QALY. An allocation scheme using both low‐ and high‐DRI donors generated 5.9 QALYs at a cost of $66 000/QALY. Sensitivity analyses supported the use of an allocation scheme using both low‐ and high‐DRI donors. The overall contribution of high‐DRI grafts to the donor pool and the resultant reduction in wait‐list mortality make them cost‐effective.     

Relevance of HLA compatibility in living donor liver transplantation: the double‐edged sword associated with the patient outcome

HLA compatibility in living donor liver transplantation (LDLT) seems relevant to the acceptability of graft livers because LDLT recipients often share most or some part of HLAs with the respective donors. This study retrospectively investigated whether HLA compatibility affected the outcome of LDLT. Three hundred ninety LDLTs were performed in this hospital, and 346 pairs of HLAs (HLA‐A, B, DR) were retrieved from the medical record between October 1996 and March 2011. The dates of the deaths were censored when a recipient apparently died of or was retransplanted by other causes than graft failure because of host‐versus‐graft (HVG) response to purely analyze the outcomes of LDLT in view of HVG response. The relationship between HLA compatibility and graft‐versus‐host disease (GVHD) was also analyzed. No recipients with recipient‐against‐donor HLA mismatch (R→D MM) 0 experienced graft failure by HVG response. On the other hand, three of five recipients with “R→D MM 0” together with “donor‐against‐recipient MM 3” died of fatal GVHD. HLA compatibility in LDLT not only affected the long‐term acceptance of graft livers but also the risk of fatal GVHD.     

Effects of different serum-levels of ATG after unrelated donor umbilical cord blood transplantation

We determined total rabbit-IgG (r-ATG) levels in serum samples before (day 0) and after (day 11 and day 25) unrelated donor umbilical cord blood transplantation (UCBT). Most patients (27/41) suffered from a haematological malignancy. There were 25 children and 16 adults. All patients received rabbit anti-thymocyte globulin (ATG) at a total dose of 6 or 8mg/kg as part of the conditioning. No correlation between the dose of ATG and serum r-ATG levels post UCBT was found. The cumulative incidence of acute GVHD grades III-IV in patients given the 6 and 8mg/kg ATG dose was 15% and 13% (ns), respectively. Patients with r-ATG≤40μg/mL 11days after UCBT (n=19) had a higher incidence of grades III-IV acute GVHD (32% vs. 0%, p<0.01), higher TRM (69% vs. 7%, p=0.005), less relapse (17% vs. 82%, p<0.01) but similar relapse-free survival (RFS) (10% vs. 18%, p=0.4) compared to those with r-ATG>40μg/mL (n=17). Low serum-levels of r-ATG early after transplantation seem to be a strong predictor for acute GVHD grades III-IV, TRM and a low incidence of relapse in patients treated with thymoglobulin before unrelated donor UCBT.     

The effect of HLA disparity on clinical outcome after HLA-haploidentical blood and marrow transplantation

The relative importance of various human leukocyte antigen (HLA) loci has not been established for unmanipulated HLA-mismatched/haploidentical transplantation. To address this question, we analyzed the impact of HLA-A, HLA-B, HLA-DRB1, HLA-DRB3, HLA-DRB4, and HLA-DRB5 on the outcome of HLA-haploidentical transplantation. Four hundred and eighty-one donor-recipient pairs were fully typed before transplantation. In univariate analysis, HLA-B mismatch not only demonstrated significant adverse effects on acute graft-versus-host disease (GVHD) and transplant-related mortality but also was associated with reduced overall survival and leukemia-free survival (LFS). In multivariate analysis, HLA-B mismatch remained the independent risk factor for acute GVHD and transplant-related mortality. The high risk of disease and the female donor were found to be significant factors for reduced overall survival and LFS. Furthermore, multiple mismatch of the HLA locus was found to have no synergistic adverse effect on outcomes. Our results suggest that prospective matching of patients and donors for HLA-B antigen in the unshared HLA haplotype is warranted for HLA-mismatched/haploidentical transplantation.     

HLA‐DR/DQ molecular mismatch: A prognostic biomarker for primary alloimmunity

Alloimmune risk stratification in renal transplantation has lacked the necessary prognostic biomarkers to personalize recipient care or optimize clinical trials. HLA molecular mismatch improves precision compared to traditional antigen mismatch but has not been studied in detail at the individual molecule level. This study evaluated 664 renal transplant recipients and correlated HLA‐DR/DQ single molecule eplet mismatch with serologic, histologic, and clinical outcomes. Compared to traditional HLA‐DR/DQ whole antigen mismatch, HLA‐DR/DQ single molecule eplet mismatch improved the correlation with de novo donor‐specific antibody development (area under the curve 0.54 vs 0.84) and allowed recipients to be stratified into low, intermediate, and high alloimmune risk categories. These risk categories were significantly correlated with primary alloimmune events including Banff ≥1A T cell–mediated rejection (P = .0006), HLA‐DR/DQ de novo donor‐specific antibody development (P < .0001), antibody‐mediated rejection (P < .0001), as well as all‐cause graft loss (P = .0012) and each of these correlations persisted in multivariate models. Thus, HLA‐DR/DQ single molecule eplet mismatch may represent a precise, reproducible, and widely available prognostic biomarker that can be applied to tailor immunosuppression or design clinical trials based on individual patient risk.     

Toll-like receptor 1 variation increases the risk of transplant-related mortality in hematologic malignancies

Toll-like receptor 1 (TLR1) genetic variant (rs5743551, − 7202A > G) has been reported to be associated with susceptibility to various infectious diseases. We retrospectively examined the impact of TLR1 variation on transplant outcomes in a cohort of 320 patients who underwent unrelated HLA-matched bone marrow transplantation (BMT) for hematologic malignancies. A multivariate analysis showed that the G/G genotype in the recipients and the donors was associated with a significantly lower 3-year transplant-related mortality (TRM). The recipient G/G genotype also resulted in a better 3-year progression-free survival. This study suggests that the recipient and donor TLR1 G/G genotypes are comparably associated with a reduced risk of death that was not related to relapse. Thus, TLR1 genotyping may be useful for selecting the donor, managing patients in a risk-adapted manner, and creating therapeutic strategies to prevent complications after hematopoietic stem cell transplantation.     

Impact of amino acid substitution at residue 9 of HLA‐A2 on the development of acute GVHD in Korean pediatric patients receiving unrelated hematopoietic stem cell transplantation

Incompatibility of human leukocyte antigen (HLA) alleles between donors and recipients of unrelated hematopoietic stem cell transplantation (UHSCT) increases the risk of acute graft‐versus‐host disease (GVHD). We evaluated the positional effect of amino acid substitutions in HLA molecules on severe acute GVHD in Korean pediatric recipients of UHSCT. All of 64 donor–recipient pairs were serologically matched for HLA‐A, ‐B, and ‐DR loci. Only substitution at residue 9 resulting from an HLA‐A*02 polymorphism was significantly associated with the risk of severe acute GVHD in patients (OR = 7.0, P = 0.033) on multivariate analysis. Recipients of this mismatched HLA also showed shortened overall survival (HR = 9.7, P < 0.001) and increased risk for transplant‐related mortality (HR = 9.1, P = 0.027). Structural modeling showed that the amino acid substitution could alter the peptide preference of the ligand‐binding pocket. A single amino acid substitution at position 9 was a major predictor of severe acute GVHD in Korean pediatric patients.     

Impact of vitamin D receptor gene polymorphisms on clinical outcomes of HLA-matched sibling hematopoietic stem cell transplantation

We hypothesized that polymorphisms of the vitamin D receptor (VDR) gene might affect clinical outcomes of allogeneic hematopoietic stem cell transplantation (HSCT). Three VDR gene polymorphisms (BsmI G>A, ApaI G>T, and TaqI T>C) were genotyped in 147 patients who underwent HLA-matched sibling allogeneic HSCT. Frequencies of infection, graft-vs.-host disease (GVHD), overall survival (OS), and disease-free survival (DFS) were compared according to genotypes and haplotypes. Infection and acute GVHD had trends to be less frequent in patients with ApaI TT genotype than non-TT genotypes (p = 0.061 and p = 0.059, respectively). For TaqI genotypes, there were no statistical differences in frequency of infection and acute GVHD (p = 0.84 and p = 0.30, respectively), but TC genotype was associated with longer OS and DFS than TT genotype (p = 0.022 and p = 0.038, respectively). In the ApaI-TaqI haplotype analysis, patients with TC haplotype had significantly longer OS and DFS than those without TC haplotype (p = 0.022 and p = 0.038, respectively). In multivariable analysis, TaqI genotype and ApaI-TaqI haplotype of recipients were independent prognostic factors for both OS and DFS. This study suggests that the genotype and haplotype of VDR in recipient might be associated with clinical outcome of sibling HLA-matched HSCT.     

Prediction of graft versus host disease by frequency analysis of cytotoxic T cells after unrelated donor bone marrow transplantation

HLA "matched" unrelated donor bone marrow transplants are associated with an increased incidence and severity of graft-versus-host disease in comparison with HLA-identical sibling transplants. This is presumably due to HLA and non-HLA histocompatibility differences between donor and recipient. Using a limiting dilution assay, we have previously demonstrated a relationship between cytotoxic T lymphocyte precursor frequency and HLA disparity. In this study we have compared CTL-p frequencies with clinical GVHD, and demonstrate for the first time a significant correlation (P less than 0.005) between high CTL precursor frequency prior to BMT and severity of acute GVHD after HLA A, B, DR "matched" unrelated donor transplants using T cell depleted marrow. This assay system may be of value in the final selection of HLA "matched" unrelated donors for BMT.     

The negative impact of female donor/male recipient combination in allogeneic hematopoietic stem cell transplantation depends on disease risk

Optimal donor selection is one of the key factors to enhance the success rate of allogeneic hematopoietic stem cell transplantation (HSCT). The effect of sex mismatch, especially the effect of Y chromosome mismatch in graft‐versus‐host disease (GVHD) direction (female donors to male recipients: denoted as FtoM mismatch) on overall survival (OS) has been controversial and not examined out of the patient population in Western countries. We retrospectively analyzed 225 cases of allogeneic HSCT and showed that FtoM mismatch confers a highly significant impact on OS (P < 0.005) in Japanese population. We demonstrated that this effect depends on the disease risk; for standard risk cases, this effect was significantly associated with poor outcome (for OS, P = 0.021), while for high risk cases, it had no effect on the results (for OS, P = 0.26). We further showed that FtoM mismatch was associated with nonrelapse mortality (P = 0.019) and most of them were GVHD‐related in standard risk cases. In conclusion, FtoM mismatch has a significant impact on transplant outcome, especially in standard risk cases.     

One-way donor-recipient HLA-matching as a risk factor for graft-versus-host disease in living-related liver transplantation

Abstract Although one-way matching between an HLA-homozygous donor and a haploidentical recipient is a recognized risk factor in transfusion-associated graft-versus-host disease (GVHD), its impact in living-related liver transplantation (LRLT) has so far not been investigated. We present a case of fatal acute GVHD in our LRLT program that was attributed to one-way HLA matching between donor and recipient. Although the disappearance of donor cells in peripheral blood was suggested by genetic analysis, severe septicemia led to a fatal outcome. We further reviewed 280 LRLT cases and correlated one-way HLA matching with outcome. A total of 8 out of 280 donors (2.9%) and 11 out of 278 recipients (4.0%) were completely HLA homozygous in our LRLT program. Complete one-way HLA matching linked to GVHD was observed in four cases, including the present case. Although other contributing factors also need to be clarified, one-way HLA matching is a definite risk factor for GVHD in LRLT. We advocate caution before proceeding with one-way HLA donor-recipient combinations.     

Evidence for the alloimmune basis and prognostic significance of Borderline T cell–mediated rejection

Prognostic biomarkers of T cell–mediated rejection (TCMR) have not been adequately studied in the modern era. We evaluated 803 renal transplant recipients and correlated HLA‐DR/DQ molecular mismatch alloimmune risk categories (low, intermediate, high) with the severity, frequency, and persistence of TCMR. Allograft survival was reduced in recipients with Banff Borderline (hazard ratio [HR] 2.4, P = .003) and Banff ≥ IA TCMR (HR 4.3, P < .0001) including a subset who never developed de novo donor‐specific antibodies (P = .002). HLA‐DR/DQ molecular mismatch alloimmune risk categories were multivariate correlates of Banff Borderline and Banff ≥ IA TCMR and correlated with the severity and frequency of rejection episodes. Recipient age, HLA‐DR/DQ molecular mismatch category, and cyclosporin vs tacrolimus immunosuppression were independent correlates of Banff Borderline and Banff ≥ IA TCMR. In the subset treated with tacrolimus (720/803) recipient age, HLA‐DR/DQ molecular mismatch category, and tacrolimus coefficient of variation were independent correlates of TCMR. The correlation of HLA‐DR/DQ molecular mismatch category with TCMR, including Borderline, provides evidence for their alloimmune basis. HLA‐DR/DQ molecular mismatch may represent a precise prognostic biomarker that can be applied to tailor immunosuppression or design clinical trials based on individual patient risk.     

Acute Graft-Versus-Host-Disease in Kidney Transplantation: Case Report and Review of Literature

Graft-versus-host-disease (GVHD) is a complication of solid organ transplantation, most commonly of the small bowel or liver. Herein, we have presented a case of GVHD in a 27-year-old man who underwent an human leukocyte antigen (HLA) minor mismatch renal transplantation from his father. After the procedure, the patient presented with a fever, skin rash, and watery diarrhea. An allograft kidney biopsy demonstrated no sign of rejection; however, anti-A antibody was detected in plasma and progressive anemia was attributed to hemolytic anemia owing to a passenger lymphocyte syndrome. From those findings, we suspected that the clinical symptoms were caused by acute GVHD. An endoscopic biopsy of the colon revealed apoptotic cells consistent with the disease. We found reports of only 5 other GVHD cases after kidney transplantation. Several risk factors are associated with GVHD, such as transfer of graft lymphocytes, donor HLA homozygosity, and a relationship between recipient immunogenicity and immunosuppression. In this case, detection led to early diagnosis of donor-derived GVHD due to passenger lymphocyte syndrome. It is important keep GVHD in mind and to understand its risk factors as the mortality rate is high.     

Graft versus host disease after stem cell allotransplantation with low-dose total body irradiation, fludarabine, and antithymocyte globulin

BACKGROUND: We previously showed that antithymocyte globulin (ATG) given with total body irradiation (TBI) 200 cGy and fludarabine results in high rate of donor engraftment. Its influence on acute and chronic graft versus host disease (GVHD) and on graft versus tumor effect is less known. METHODS: Sixty-five patients underwent nonmyeloablative stem cell transplant with ATG, TBI 200 cGy, and fludarabine. GVHD prophylaxis was mycophenolate mofetil and cyclosporine. Forty-two patients (pts) (65%) had match related donors, 18 (27%) match unrelated, 1 (1.5%) mismatch related, and 4 (6%) mismatch unrelated donors. RESULTS: At a median follow-up of 862 days, 24 patients (37%) developed GVHD. The median age of the patients with and without GVHD was 56 years respectively. Acute GVHD grade II-IV developed in 19 pts (29%). Fatal GVHD of liver and/or gut occurred in nine pts (14%). Forty-one pts survived more than 100 days. Five pts (12%) had chronic GVHD, two had extensive, and three had limited involvement. Relapsed disease was observed in 22 pts (34%). Infections occurred in 15 pts (23%) and were fatal in 13 (20%). CONCLUSIONS: The addition of ATG to TBI 200cGy and fludarabine resulted in a modest incidence of GVHD. The best transplant outcomes were observed in pts with lymphoid malignancies.     

The center effect in liver transplantation in the Eurotransplant region: a retrospective database analysis

Apart from donor and recipient risk factors, the effect of center‐related factors has significant impact on graft survival after liver transplantation (LT). To investigate this effect in Eurotransplant, a retrospective database analysis was performed, including all LT's in adult recipients (≥18 years) in the Eurotransplant region from 1.1.2007 until 31.12.2013. Additionally, a survey was sent out to all transplant centers requesting information on surgeons’ experience and exposure. In total, 10 265 LT's were included (median follow‐up 3.3 years), performed in 39 transplant centers. Funnel plots showed significant differences in graft survival between the transplant centers. After correction for donor and recipient risk, with the Eurotransplant donor risk index (ET‐DRI) and the simplified recipient risk index (sRRI) and random effects, these differences diminished. Mean historical volume (in the preceding 5 years) was a significant (P < 0.001), nonlinear marker for graft survival in the multivariate analysis. This study demonstrates that funnel plots can be used for benchmarking purposes in LT. Case‐mix correction can be performed with the use of the ET‐DRI and sRRI. The center effect encompasses the entire complex process of preoperative workup, operation to follow‐up.