Donor-recipient Sex Mismatch Research Articles

Premature cyclosporine cessation and TBI-containing conditioning regimen increase the risk of acute GvHD in children undergoing unrelated donor hematopoietic stem cell transplantation.

Acute graft-versus-host disease (aGvHD) is a potentially fatal complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Identifying its risk factors would enable the proper prophylaxis and management, which may significantly improve the general outcome of children treated with HSCT. The aim of this single-center, retrospective cohort study was to assess the potential risk factors for grades II-IV of aGvHD in children after the 1st allo-HSCT from an unrelated donor (UD), performed as a result of an underlying malignant disease. From among patients who received HSCT in our center in the years 2004-2015, 237 were included in the study cohort. All the patients received standard aGvHD prophylaxis consisting of cyclosporine (CsA) and a short course of methotrexate (MTX). Various clinical and epidemiological features, the transplant proceedings, graft composition, conditioning regimens, as well as the duration and coherence of aGvHD prophylaxis were analyzed as potential risk factors for aGvHD. The incidence of II-IV aGvHD in the study cohort was 58.6%. The median time of the diagnosis of aGvHD was 18 days post-HSCT. In the multivariate analysis, risk factors significantly associated with grades II-IV of aGvHD were: myeloablative conditioning regimen containing total body irradiation (TBI-MAC) (RR (relative risk): 1.69; p = 0.03), premature termination of CsA administration due to its toxicity (RR: 1.99; p = 0.0003) and HSCT performed before the year 2009 (RR: 1.97; p = 0.0001). Donor and recipient age, donor-recipient sex mismatch, stem cell source, risk of disease, and amount of infused CD34+ cells seem to be insignificant as risk factors for aGvHD. The overall survival (OS) of patients with aGvHD was noticeably worse that in those who were aGvHD-free: 60.8% vs 74.1% (p = 0.08). The conditioning regimen and the proper aGvHD prophylaxis, including continuous CsA administration, have a major impact on aGvHD occurrence. According to our results, the termination of CsA therapy should be carefully considered, and avoided if possible.

Blood donor–recipient sex mismatch: outcomes impacted?

Background and objectivesA number of recent publications have questioned whether female donor transfusions (particularly of red cells) or donor–recipient sex mismatch are associated with increased risk for mortality. A systematic review was conducted to further explore this concern.Materials and methodsA literature search was performed to identify original studies linking red‐blood‐cell transfusion donor or recipient gender to mortality risk. Exclusion criteria included (1) absence of a focus on gender mismatch and mortality outcomes, (2) nonclinical studies, (3) non‐English language studies.ResultsThe initial search strategy yielded 136 results and 8 studies met all selection criteria. An additional 2 studies were found by supplemental search. Six of the ten studies reported increased mortality risk with sex mismatch, while four reported no increase in mortality. Study end‐points varied, thus limiting generalizability. Conflicting evidence was noted in regard to female donor sex, sex mismatch, directionality of risk, age of donors and recipients, and transfusion burden.ConclusionAdditional studies are needed to resolve this issue. As the majority of studies relied upon a ‘big data’ approach, there is concern for subtle confounding.

Impact of Donor-Recipient Sex Mismatch on the Incidence of Allograft Rejection in Clinical Lung Transplantation: A Review of the United Network of Organ Sharing Database

Purpose It is well-known that female animals mount immune responses against male-specific antigens, thought to be principally derived from proteins whose genes are Y chromosome-encoded. Although organ transplantation frequently involves donor-recipient sex mismatch, the immunological sequelae of such mismatches, particularly from male donor organs transplanted into female recipients, are unclear. Methods A review of the United Network of Organ Sharing (UNOS) database was conducted from 10/1987 to 12/2016. Recipient and graft survivals, and the incidences of acute rejection (AR)-related hospitalization and bronchiolitis obliterans syndrome (BOS), were determined across four groups: male donor-male recipient (dMrM, n = 12095), female donor-female recipient (dFrF, n=7444), female donor-male recipient (dFrM, n=3962) and male donor-female recipient (dMrF, n = 5766). Results AR-related hospitalization was specifically increased only in the dMrF group (p=0.006). In addition, severe BOS (Grade 3) was specifically increased only in the dMrF group (p Conclusion In clinical lung transplantation, female recipients of male allografts specifically exhibited significantly increased rates of AR and BOS. These findings are consistent with well-established immunological concepts and evidence, and have implications for donor-recipient matching in order to achieve optimal outcomes.

Gender Differences in Pre-Transplant Characteristics and Short-Term Clinical Outcomes Post Heart Transplantation

Purpose Women comprise 1 in 4 of all heart transplant (HT) recipients. Sex/gender differences affect cardiovascular disease burden and outcomes with important potential to impact patient care. As an initial step towards developing personalized therapy, we evaluated differences in HT clinical characteristics and outcomes between men and women. Methods A retrospective review was performed of consecutive adult patients who underwent HT at the University of Ottawa Heart Institute (Ontario, Canada) between 2012 and 2016. We determined patient characteristics in women and men at transplant and outcomes post transplant including death, graft function, rejection, infection and hospitalization. Results A total of 121 HT patients were evaluated: 29 (24%) female, mean age 53.6±12.3 years, 39 (32%) for ischemic cardiomyopathy (Table). Compared to men, women had lower body mass index, increased donor-recipient sex mismatch, and higher sensitization. There were no differences in the use or dose of induction or maintenance immunotherapy, however, women received a higher mean dose of Valganciclovir for cytomegalovirus (CMV) prophylaxis: 12.1±4.1 vs. 9.5±4.2 mg/kg/day, p=0.05. Over a mean follow-up of 3.0±1.9 years, there were 12 (10%) deaths, and no difference in survival or graft function between men and women. Compared to men, women had significantly higher rates of infection (62% vs. 41%, p=0.05) and hospitalization for infection (31% vs. 13%, p=0.03). Leukopenia (white cell count Conclusion Clinical characteristics and short-term outcomes post HT differ among women and men. Prospective evaluation and long-term follow-up of larger cohorts are needed to determine strategies to improve care in women following HT.

Splenomegaly May Increase Rejection Rates in Matched-Related Transplants for Thalassemia, This Effect Is Mitigated by Additional Immunosuppression.

Background Severe thalassemia syndromes (ST) are highly curable by BMT but rejection may occur in 5 to 30% of cases. Splenomegaly was shown to increase the risk of rejection even in low risk transplant setting in our earlier review (https://ash.confex.com/ash/2017/webprogram/Paper104001.html). Objective To assess the impact of splenomegaly on rejection and study the effectiveness of increased immunosuppression in the preparative regimen. Methods We compared transplant outcomes in patients with splenomegaly between two conditioning regimens: Our earlier protocol (Regimen A) and a more recent modified one (Regimen B) (Fig 1). Our BMT network used Regimen A between August 2013 and Dec 2016 which comprised of busulfan (14 mg/kg oral, not adjusted to serum levels), cyclophosphamide (200 mg/kg) and anti-thymocyte globulin (ATG) (Genzyme 4 mg/kg or Fresenius 16 mg/kg on days -12 to -10). Regimen B consisted of same backbone as Regimen A except Fludarabine total dose of 150 mg was added upfront and ATG dose was increased to 7 mg/kg in case of splenomegaly and or sex mismatched transplants (Jan 2017 to Jun 2108). G-CSF-primed bone marrow (5 μg/kg/dose twice daily for 3 to 5 days prior to harvest) was the source of hematopoietic stem cells in all cases. All patients were considered low risk based on liver size 3 by ultrasound measurement adjusted for height. All sibling couples were HLA-compatible. Results In total of 168 patients analyzed, 87 for Regimen A and 81 with Regimen B. Regimen A had 11 patients and Regimen B had 20 patients with significant splenomegaly. There was noticeable overall improvement in rejection rates between Regimen A and Regimen B patient groups (Fig 2) (p = 0.028) while improvement in rejection rates within the splenomegaly group between Regimen A and Regimen B was far more significant (Fig 3) (p = 0.0045). We could not detect any difference in variables potentially associated with rejection risk such as donor-recipient sex mismatch (p = 0.4), serum ferritin at BMT (p = 0.17), pre-BMT blood transfusions (p = 0.37), age at BMT (p = 0.59), ABO mismatch (p = 0.53) and spleen Z scores measured by ultrasound at BMT(p = 0.54) by univariate analysis. The median total nucleated cell dose was higher on Regimen B (9.45, IQR 7.065 – 11.815) compared to Regimen A (6.47, IQR 5.725 – 8.102) (p = 0.023) and the median follow up was shorter (median 15.8 vs 9.35 months) factors which may have contributed to improved results in Regimen B. Conclusion The increased risk of rejection related to splenomegaly can be decreased by adding fludarabine to the standard ATG- Bu-Cy protocol without significantly increasing transplant-related morbidity and mortality or resorting to splenectomy pre-BMT.

Factors Associated With Graft Rejection in the Cornea Preservation Time Study

To identify factors related to graft rejection following Descemet stripping automated endothelial keratoplasty (DSAEK) in the Cornea Preservation Time Study (CPTS). Cohort study within a multicenter randomized clinical trial. A total of 1330 eyes of 1090 subjects undergoing DSAEK were randomized to receive a donor cornea with preservation time (PT) of 0-7days (n=675) or 8-14days (n= 655) and followed for 3 years. Central endothelial cell density (ECD) was determined by a central image analysis reading center. Multivariable Cox models adjusted for PT, recipient diagnosis, and surgeon effect were used to identify factors associated with rejection. Cumulative probability of definite graft rejection was 3.6% (99% confidence interval 2.5%-5.3%). Younger recipient age was associated with graft rejection (P < .001; hazard ratio: 0.53 [0.33, 0.83] per decade). PT, donor-recipient sex mismatch, recipient diagnosis, recipient race, graft size, discontinuation of topical corticosteroids and immune-modulators, prior immunizations within 3months, and prior glaucoma surgery were not associated with rejection (P > .01). Among clear grafts with an ECD measurement at baseline and 3 years (n= 913), endothelial cell loss (ECL) was greater in eyes that experienced a rejection episode (n= 27) than in those that did not (n= 886) (48% vs 38%, P= .03). Twelve of 44 eyes (27%) with definite graft rejection subsequently failed, comprising 15% of the 79 failures in the CPTS. Graft rejection is uncommon after DSAEK and more likely with younger age, in a study cohort mostly > 50 years old. Rejection increases ECL, but it is not a leading cause of DSAEK failure.

Sex-Related Differences in Outcomes of Thoracic Organ Transplantation and Mechanical Circulatory Support.

Sex-Related Differences in Outcomes of Thoracic Organ Transplantation and Mechanical Circulatory Support.

Young Female Donors Do Not Increase the Risk of Graft-versus-Host Disease or Impact Overall Outcomes in Pediatric HLA-Matched Sibling Hematopoietic Stem Cell Transplantation

Optimal donor selection is critical in hematopoietic stem cell transplantation (HSCT). Donor–recipient sex mismatch, donor age, and female donor–donor parity are known to impact graft-versus-host disease (GVHD) and outcomes in adults. Minor histocompatibility antigens encoded by the human Y chromosome can result in specific antibody formation in some female donors, may increase in frequency with increasing donor age, and may be contributory to the increased incidence of GVHD. To better understand the role of donor age/sex and sex matching in HSCT outcomes, we conducted a retrospective study of pediatric patients receiving their first myeloablative sibling donor HSCT (n = 244) from 1998 to 2012. Observed rates of GVHD were low: 17% of patients surviving past engraftment (n = 243) developed grades II to IV acute GVHD (aGVHD) and 14% surviving ≥ 100 days (n = 229) developed chronic GVHD (cGVHD). On multivariate analysis the risk of aGVHD, cGVHD, and death increased with patient age as expected. Female donor sex and sex mismatch (female donor–male recipient) had no impact on the development of aGVHD. cGVHD was increased with female donors only if the donor was ≥12 years old. No cGVHD was observed among 109 patients aged < 10 years who received a 6/6 HLA-matched marrow HSCT, regardless of donor age or sex. Survival was mostly driven by diagnosis. Results suggest that in pediatric HSCT, young HLA-matched siblings are equivalently good donors regardless of sex or donor–recipient sex mismatch.

Donor Type and Disease Risk Predict the Success of Allogeneic Hematopoietic Cell Transplantation: A Single-Center Analysis of 613 Adult Hematopoietic Cell Transplantation Recipients Using a Modified Composite Endpoint

The composite endpoint graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) has recently been introduced as a tool to assess the success of allogeneic hematopoietic stem cell transplantation (HSCT) and has been incorporated into recent randomized trials of GVHD prophylaxis by the Blood and Marrow Transplant Clinical Trials Network. As developed, GRFS incorporates “chronic GVHD requiring systemic immunosuppression” as a measure of clinically significant chronic GVHD (cGVHD). However, the decision to start patients on immunosuppressive therapy for cGVHD is subjective and physician-dependent. We elected to assess a modification of the GRFS (m-GRFS) that uses a potentially more objective measure of cGVHD, specifically the development of National Institutes of Health grade moderate or severe cGVHD. A total of 613 patients who underwent a first allogeneic HSCT after an HLA-identical sibling (matched related donor [MRD]; n = 212), an 8/8 matched unrelated donor (MUD; n = 251) or T cell-replete haploidentical donor (HID) transplant with post-transplantation cyclophosphamide (n = 150) were included in this analysis. In the HID group, 86 patients (54%) received peripheral blood stem cells as the graft source. The median duration of follow-up was 50.2 months. The unadjusted Kaplan-Meier estimates for 1- and 2-year m-GRFS were 36% (95% confidence interval [CI], 32% to 40%) and 28% (95% CI, 25% to 32%), respectively. The 2-year m-GRFS was 30% (95% CI, 24% to 36%) for MRD graft recipients, 24% (95% CI, 19% to 30%) for MUD graft recipients, and 33% (95% CI, 26% to 41%) for HID graft recipients. A multivariate Cox model for m-GRFS identified donor type, Disease Risk Index (DRI) risk, donor-recipient sex mismatch, and year of transplantation as significant predictors of m-GRFS. Patients who received a MUD graft had worse m-GRFS compared to MRD graft recipients (hazard ratio [HR], 1.39; P = .003), whereas HID graft recipients had a similar m-GRFS as MRD graft recipients (HR, 1.10; P = .43). HID was associated with better m-GRFS compared with MUD (HR, .79; P = .046). These data show that m-GRFS is significantly affected by several modifiable factors, including donor type, donor-recipient sex match, and DRI. Adjusting donor choice and earlier referral of patients for evaluation of transplantation to improve the DRI can potentially overcome the negative impact of these factors.

Ocular surface analysis in hematological patients before and after allogeneic hematopoietic stem cell transplantation: implication for daily clinical practice

PurposeTo evaluate ocular surface parameters before and after hematopoietic stem cell transplantation (HSCT) and to correlate them with clinical and transplant variables.MethodsThis is a retrospective analysis of data from 93 patients affected by hematological malignancies undergoing HSCT. Values from Ocular Surface Disease Index, Schirmer test, Break-up Time, ocular surface staining, and Meibomian Gland Dysfunction score obtained before HSCT and 3-6 months after were retrieved from charts. Diagnosis and staging of dry eye (DE) disease was performed according to Dry Eye WorkShop criteria. Graft-versus-host-disease (GVHD) was classified according to the NIH criteria. Odds ratios for DE onset after HSCT were estimated for demographic, ocular, hematological and transplant variables.ResultsDE was diagnosed before HSCT in 50 (53%) of the patients, mostly of hyperevaporative profile. After HSCT, all ocular parameters significantly worsened with no change in DE profile. A 51% incident cases (22 of the 43 non-DE subjects) were reported. Increasing recipient age and female sex, higher CD34+ cells infused, donor-recipient sex mismatch (males receiving from females), related donors, and peripheral blood cells as stem cell source were associated with a significant higher incidence of DE after HSCT. Systemic chronic GVHD was diagnosed in 42% while ocular GVHD in 35.5% of the patients, which decreased to 12% when taking into account only incident cases.ConclusionsHigh DE prevalence was shown already before HSCT. A pre-HSCT ocular surface assessment is recommended for early DE diagnosis and treatment. This new protocol also influences the prevalence of ocular GVHD.

Donor Type and Disease Risk Predict the Success of Allogeneic Hematopoietic Cell Transplantation (HCT): A Single Center Analysis of 613 Adult HCT Recipients Using a Modified Composite Endpoint

Donor Type and Disease Risk Predict the Success of Allogeneic Hematopoietic Cell Transplantation (HCT): A single Center Analysis of 613 Adult HCT Recipients Using a Modified Composite EndpointIntroductionThe success of allogeneic HCT is based on long term survival, free of relapse or morbidity as commonly encountered when patients develop graft versus host disease (GVHD). The Bone marrow transplant clinical trials network (BMTCTN) recently incorporated a composite endpoint to determine success rate in ongoing clinical trials. The new composite endpoint of GVHD free, relapse free survival (GRFS) includes the factors of acute GVHD grade 3-4, relapse, death and chronic GVHD requiring systemic immunosuppression. As the decision to start patients on immunosuppression for chronic GVHD can be subjective and physician dependent, we elected to assess the success of allogeneic HCT using a more objective endpoint m-GRFS where the clinically significant negative events are acute GVHD grade 3-4, moderate-severe chronic GVHD, disease relapse and Death at 1 and 2-year post HCT.MethodsSix hundreds and thirteen patients who underwent a first allogeneic HCT after a HLA-identical sibling (MRD, n=212), 10/10 matched unrelated donor (MUD, n=251) or T-replete haploidentical donor with post-transplant cyclophosphamide (HIDT, n=150) were included in this analysis. Patient, Disease and Transplant related variables were prospectively documented and obtained from our institutional database. The Kruksall-Wallis test was used to compare continuous variables and the Chi-squared test for categorical variables. OS, DFS and m-GRFS were estimated by the Kaplan-Meier (K-M) method. Log-log transformed confidence intervals for OS, DFS and GRFS were calculated. Comparison of m-GRFS between demographic subgroups and between clinical subgroups were evaluated using the log-rank test for the entire study period and using the Wald test for a select time point. Competing risks analysis was performed to disentangle the components of GRFS. Grade III/IV acute GVHD, mod-severe chronic GVHD, relapse and death were considered as competing risks and cumulative incidences of these endpoints were calculated. Patients were considered to have met the endpoint once any of the components occurred. Cox regression analysis was conducted to examine the impact of donor, demographic and clinical factors on the primary endpoint of modified GRFS. The proportional hazards assumption was checked by temporarily including and testing time-dependent variables and the variables in the final model passed the proportionality test. The adjusted GRFS for one characteristic was calculated as the average survival of the whole sample, assuming that everyone in the sample had this characteristic.ResultsThe median follow-up was 50.2 months. Patients characteristics were as follows: median age 53 years (18-77), male 56%, reduced intensity/non-ablative 49%, AML 37%, ALL 13%, MDS/MPD 24%, bone marrow graft 19%, HCT-comorbidity index >=3 in 39%, and high/very high DRI 34%. The unadjusted Kaplan-Meier estimates for 1- and 2-year m-GRFS were 36% (95%CI 32%-40%) and 28% (95%CI 25%-32%). The 2-year m-GRFS for MRD recipients was 30% (24-36%), MUD 24% (19-30%) and HIDT 33% (26-41%). The most common event at 2 years post HCT was chronic GVHD (39%) followed by relapse (31%), acute GVHD 3-4(20%) and death (10%). After adjusting for age, gender, diagnosis, conditioning intensity, donor type, cell source, HCT-CI, DRI , donor-recipient gender mismatch and year of transplant, the multivariate cox model on m-GRFS showed donor type, DRI risk , donor recipient sex mismatch and year of transplant to be significant predictors of m-GRFS (table 1). Patients who received a MUD had worse GRFS compared to MRD (HR 1.39, p=0.003) whereas HIDT had similar GRFS to MRD (HR 1.10, p=0.43). HIDT had better GRFS than MUD (HR 0.79, p=0.046). The adjusted 1- and 2- year m-GRFS showed donor type (MUD vs MRD), DRI, donor-recipient sex mismatch and transplant year to be associated with worse GRFS (table 2).Conclusionsm-GRFS is a useful measure of transplant success. It appears to be significantly impacted by several modifiable factors including donor type, donor-recipient sex match and also by DRI. Adjusting donor choice and early referral of patients for transplant evaluation to improve DRI can potentially overcome the negative impact of these factors. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Organ transplantation and gender differences: a paradigmatic example of intertwining between biological and sociocultural determinants.

Organ transplantation, e.g., of the heart, liver, or kidney, is nowadays a routine strategy to counteract several lethal human pathologies. From literature data and from data obtained in Italy, a striking scenario appears well evident: women are more often donors than recipients. On the other hand, recipients of organs are mainly males, probably reflecting a gender bias in the incidence of transplant-related pathologies. The impact of sex mismatch on transplant outcome remains debated, even though donor-recipient sex mismatch, due to biological matters, appears undesirable in female recipients. In our opinion, the analysis of how sex and gender can interact and affect grafting success could represent a mandatory task for the management of organ transplantation.

Influence of donor-recipient sex mismatch on long-term survival of pancreatic grafts.

To assess the role of sex mismatch on graft survival after pancreas transplantation. We evaluated 24,195 pancreas-transplant recipients reported in the Scientific Registry of Transplant Recipients over a 25-year period. Pancreatic graft survival (PGS) was analyzed according to donor–recipient sex pairing using Kaplan–Meier estimations. Hazard ratios were estimated using Cox proportional hazard models. A total of 14,187 male and 10,008 female recipients were included in final analyses. Mean follow-up was 8.3 ± 5.7 years. In multivariate analyses, neither recipient sex nor donor sex was associated with pancreatic graft failure (PGF), but donor–recipient sex mismatch (regardless of recipient sex) was an independent predictor of PGS (HR, 1.09; 95% CI, 1.04–1.14; p < 0.001). Compared with M → M sex-matched recipients in univariate analyses, M → F and F → M sex mismatches were associated with an increased risk of PGF. Adjustment for significant recipient and donor factors eliminated the association between F → M sex mismatch and PGF (HR, 1.02; 95% CI, 0.93–1.10; p = 0.752), but not M → F (1.09; 1.02–1.17; 0.020). Stratified analyses suggested that the negative effect of donor–recipient sex mismatch could be neutralized in older patients. These findings suggest that donor–recipient sex pairing should be taken into consideration in organ-allocation strategies.

Long-Term Outcomes of Living-Donor Liver Transplantation for Primary Biliary Cirrhosis: A Japanese Multicenter Study.

The factors that influence long-term outcomes after living-donor liver transplantation (LDLT) for primary biliary cirrhosis (PBC) are not well known. Compared with deceased-donor transplantation, LDLT has an increased likelihood of a related donor and a decreased number of human leukocyte antigen (HLA) mismatches. To clarify the effects of donor relatedness and HLA mismatch on the outcomes after LDLT, we retrospectively analyzed 444 Japanese patients. Donors were blood relatives for 332 patients, spouses for 105, and "other" for 7. The number of HLA A-B-DR mismatches was none to two in 141, three in 123, and four to six in 106 patients. The 15-year survival rate was 52.6%, and PBC recurred in 65 patients. Recipient aged 61 years or older, HLA mismatches of four or more (maximum of six), graft:recipient weight ratio less than 0.8, and husband donor were adverse indicators of patient survival. IgM 554 mg/dL or greater, donor-recipient sex mismatch, and initial immunosuppression with cyclosporine were significant risks for PBC recurrence, which did not affect patient survival. In subgroup analysis, conversion to cyclosporine from tacrolimus within 1 year diminished recurrence. Prospective studies are needed to determine the influence of pregnancy-associated sensitization and to establish an optimal immunosuppressive regimen in LDLT patients.

Allogeneic Hematopoietic Transplantation in Patients with CLL: Results of a Large Disease-Specific Risk Factor Analysis

Objectives: For medically-fit young patients with high-risk chronic lymphocytic leukemia (CLL) BTK-/PI3K-inhibitors or allogeneic stem cell transplantation (alloHCT) are considered. We hypothesized that given the choice between these drugs and transplantation in future only patients with a low risk of treatment failure will be selected for alloHCT. Therefore, we searched for risk factors for 2-year non-relapse mortality (NRM) and 5-year event-free survival (EFS) after alloHCT, the latter as a surrogate for long-term disease-control.Methods: Data from patients with CLL who had received a first alloHCT from a HLA-identical sibling (SIB) or unrelated donor between 2000 and 2011 were updated in an EBMT data quality initiative. Multivariable Cox regression models were fitted to assess the impact of baseline risk factors for NRM and EFS.Results: Data on 694 patients were included into the analysis. The median age of the cohort of patients was 55 years (19 years to 74 years). Seventy-nine percent of patients had a Karnofsky performance status of 90% or higher. A disease history of less than two years was reported in 20% of patients and 44% of patients had a disease history of more than 5 years. The median number of pretreatments was 3 (range, 0-15). Eleven percent of patients had received a previous autologous HCT. Only 9% of patients had never received purine-analogs (PA) during their treatment history. Sixty-three percent of patients had either PA-refractory disease or relapse within 24 months from the last PA-containing chemotherapy at the time of HCT. A deletion 17p had been diagnosed in 28% of patients in this cohort. Information on PA-sensitivity, early relapse after autologous transplantation or PA-combination therapy and del(17p)/TP53 is used to select patients for allogeneic HCT according to the EBMT 2007 consensus. EBMT consensus criteria were met in 76% of evaluable patients. Overall, the majority of patients analyzed in this subset of all registered patients had high-risk CLL.For the whole cohort 2-year NRM was 28% (95%-CI, 24% to 32%). The baseline risk factors age, Karnofsky performance status, donor type, and donor-recipient sex mismatch had a significant impact on 2-year-NRM. With the help of these risk factors the outcome of good risk and poor risk reference patients was predicted whose linear predictors were close to the 10th and the 90th percentile of all patients in the dataset. The good risk male reference patient has an age of 45 years, a Karnofsky performance index of 100%, is in partial remission at HCT and has a matched related male donor. The poor risk male reference patient has 55 years of age a Karnofsky performance index of 80%, SD/PD at HCT, and a matched unrelated female donor. The female reference patients had the same characteristics, apart from the donor sex. Two-year-NRM was predicted to be 11% (12%) for male (female) patients with a favorable risk compared to 40% (32%) with a poor risk profile (see Figure). The same approach was used to analyze risk factors for long-term disease control. Five-year-EFS was 37% (95%-CI, 33% to 41%) for all patients. Age, Karnofsky performance status, history of an autologous HCT, remission status, and donor-recipient sex mismatch had a significant impact. The model-based prediction of 5-year EFS was 54% (64%) for a male (female) patient with a favorable risk profile compared to 15% (30%) with a poor risk profile. Current knowledge suggests that allogeneic HCT can overcome the negative prognostic impact of high risk cytogenetic abnormalities, especially of a deletion(17p) or TP53 -mutation. Even in this large cohort we observed only a trend for a lower incidence of relapse/progression in patients without deletion(17p) CLL within the first two years after HCT with translated into a trend for better EFS at that time. The impact on long-term disease-control and mortality was even smaller.Conclusion: Information on predicted 2-year-NRM and 5-year-EFS for good and poor risk reference patients derived from a large CLL dataset may be instrumental to select patients for future alloHCT.Model-based prediction of non-relapse mortality and relapse/progression. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Donor Lymphocyte Infusions for Chronic Myeloid Leukemia Relapsing after Allogeneic Stem Cell Transplantation: May We Predict Graft-versus-Leukemia Without Graft-versus-Host Disease?

Donor lymphocyte infusions (DLI) are an effective treatment for relapsed chronic myeloid leukemia (CML) after allogeneic stem cell transplantation (alloSCT). Leukemia resistance and secondary graft-versus-host disease (GVHD) are major obstacles to success with DLI. The aim of this study was to identify pre-DLI factors associated with prolonged survival in remission without secondary GVHD. We retrospectively analyzed 500 patients treated with DLI for CML relapse (16% molecular, 30% cytogenetic, and 54% hematological) after alloSCT. The overall probabilities of failure- and secondary GVHD–free survival (FGFS) were 29% and 27% at 5 and 10 years after DLI, respectively. The type of relapse was the major factor influencing FGFS (40% for molecular and/or cytogenetic relapse and 20% for hematological relapse at 5 years, P < .001). Chronic GVHD before DLI and an interval <1 year between alloSCT and first DLI were independently associated with inferior FGFS in patients with molecular and/or cytogenetic relapse. Consequently, FGFS was 13%, 35%, to 56% at 5 years in patients with 2, 1, and 0 adverse features, respectively. In patients with hematological relapse, independent adverse prognostic factors for FGFS were initial dose of CD3+ cells ≥ 50 × 106/kg, donor-recipient sex mismatch, and chronic GVHD before DLI. FGFS was 0%, 17%, 33%, to 37% in patients with 3, 2, 1, and 0 adverse features, respectively. The probability of survival in remission without secondary GVHD was highest (>50% at 5 years) when DLI were given beyond 1 year from alloSCT for molecular and/or cytogenetic CML relapse that was not preceded by chronic GVHD.

Cardiac Size and Sex-Matching in Heart Transplantation: Size Matters in Matters of Sex and the Heart

This study evaluated whether worsened outcomes in sex mismatch are related to mismatch of organ size in heart transplantation.Sizing for organ allocation in heart transplantation currently incorporates only body weight differences between the donor and recipient. Weight correlates poorly to cardiac size, and donor–recipient weight differences are not associated with differential survival. Heart size correlates with sex, and donor–recipient sex mismatch conveys worse-than-expected outcomes.We performed a retrospective cohort study of 31,634 donor–recipient adult heart transplant pairings from the United Network for Organ Sharing transplantation registry. We used predictive models to calculate the predicted total heart mass (pHM) for recipient and donor pairs. We assessed organ size mismatch by calculating the percent difference between the donor and recipient pHM as [(pHM(recipient) – pHM(donor))/(pHM(recipient))]*100.The most-undersized pHM septile demonstrated higher mortality during the first year post-transplantation (hazard ratio [HR]: 1.27; p < 0.001), which remained robust in adjusted models (HR: 1.25; p = 0.03). Survival did not vary across septiles of weight differences. On univariate analysis, sex mismatch was associated with higher mortality in male patients, but not in female patients. Controlling for differences in pHM reversed these associations. Adjusted models demonstrated worse survival associated with sex mismatch in female patients (1-year HR: 1.28; p = 0.02) but no difference in male patients (1-year HR, 1.00; p = 1.0).Differences in donor–recipient pHM modulated the survival associated with donor–recipient sex mismatch and identified donor heart undersizing as an otherwise occult and potentially preventable cause of mortality following orthotopic heart transplantation.

Early onset, EBV− PTLD in pediatric liver-small bowel transplantation recipients: a spectrum of plasma cell neoplasms with favorable prognosis

AbstractEBV− posttransplantation lymphoproliferative disorders (PTLDs) are rare compared with EBV+ PTLDs, occur later after transplantation, and have a poor response to treatment. Few studies have reported EBV− PTLD in pediatric solid-organ transplantation recipients. We describe 5 cases of EBV− PTLD in recipients of combined liver and small bowel allografts ranging in age from 16 months to 7 years. EBV− PTLD developed 9-22 months (median, 15) after transplantation. Morphologically, the lesions ranged from atypical plasma cell hyperplasia (a term not currently included in the World Health Organization classification) to plasmacytoma like. In all cases, in situ hybridization for EBV was negative, and molecular studies demonstrated clonal IgH gene rearrangements. Protein electrophoresis showed multiple clonal paraproteins in 4 of 5 cases. In 2 cases with a donor-recipient sex mismatch, FISH cytogenetics demonstrated that the plasma cells were of mixed donor/recipient origin. One patient died before therapy. Four patients were treated with high-dose dexamethasone, and 1 patient subsequently required thalidomide. All 4 remain in remission 75-128 months (median, 86) after diagnosis. In contrast to reports of EBV− PTLD in adults, these plasma cell lesions occurred early after transplantation and resolved completely after minimal treatment.

Donor–Recipient Sex Mismatch in Kidney Transplantation

The lack of reliable human proxies for minor (ie, non-HLA) histocompatibility loci hampers the ability to leverage these factors toward improving transplant outcomes. Despite conflicting reports of the effect of donor-recipient sex mismatch on renal allografts, the association between acute rejection of renal allografts and the development of human alloantibodies to the male H-Y antigen suggested to us that donor-recipient sex mismatch deserved re-evaluation. To evaluate whether the relationships between donor sex and allograft failure differed by recipient sex. We studied recipients of deceased-donor (n = 125,369) and living-donor (n = 63,139) transplants in the United States Renal Data System. Using Cox proportional hazards models stratified by donor type, we estimated the association between donor-recipient sex mismatch and death-censored allograft failure with adjustment for known risk factors, with and without the use of multiple imputation methods to account for potential bias and/or loss of efficiency due to missing data. The advantage afforded by male donor kidneys was more pronounced among male than among female recipients (8% vs 2% relative risk reduction; interaction P < 0.01). This difference is of the order of magnitude of several other risk factors affecting donor selection decisions. Donor-recipient sex mismatch affects renal allograft survival in a direction consistent with immune responses to sexually determined minor histocompatibility antigens. Our study provides a paradigm for clinical detection of markers for minor histocompatibility loci.

Donor–recipient sex mismatch portends poor 10-year outcomes in a single-center experience

Several studies have indicated that survival after heart transplantation is affected by donor-recipient sex matching. In most studies, male recipients of a female heart have the poorest survival rates, whereas survival of female recipients is not affected by donor sex. The purpose of the current study was to determine the long-term outcomes of recipients at a large single center on uniform immunosuppression therapy in the current era. We reviewed the records of 857 patients transplanted at a single center between 1994 and 2008. Patients were divided into 4 groups based on donor-recipient sex: male donor to male recipient (male/male, n = 506); female donor to female recipient (female/female, n = 113); male donor to female recipient (male/female, n = 106); and female donor to male recipient (female/male, n = 132). Ten-year outcomes were assessed for: survival; freedom from cardiac allograft vasculopathy (CAV); and freedom from non-fatal major adverse cardiac events (NF-MACE). Ten-year actuarial survival was comparable in male/male and female/female groups, at 69% and 71%, respectively (p > 0.05). Compared with the male/male group, 10-year actuarial survival was significantly lower in the sex-mismatch groups: 58% in the male/female group (p = 0.03) and 59% in the female/male group (p = 0.01). There was no significant difference in 10-year freedom from CAV or NF-MACE among the groups. Heart transplant patients with donor-recipient sex mismatch have lower survival, extending the results of prior studies to suggest that sex mismatch is undesirable in female, as well as male, recipients. This may impact donor selection and recipient wait time to transplantation.