Unrelated Donor Hematopoietic Stem Cell Research Articles

Retrospective Analysis of Hemorrhagic Cystitis After Unrelated Donor Hematopoietic Stem Cell Transplantation In a Chinese Population.

AbstractAbstract 4546Hemorrhagic cystitis (HC), occurring mostly within first month after allogeneic hematopoietic stem cell transplantation (allo-HSCT), is a common complication which often requires prolonged hospitalization, considerable expense, and occasionally causes significant morbidity. The data from different transplantation centers about this complication are different in the incidence, risk factors, therapeatic strategies and outcome. In this study, we retrospectively analyzed the incidence, risk factors, prophylaxis and treatment regimens of HC after unrelated donor HSCT(URD-HSCT)in our center From October 2000 to February 2008, 168 consecutive patients underwent URD-HSCT were enrolled,including 113 male patients and 55 female patients. The median age was 26 years (range,8-52 years). The main myeloablative conditioning regimens used were busulfan/cyclophosphamide (BuCy) without total body irradiation (TBI); Reduced-intensity conditioning regimens (RIC) were predominantly fludarabine-based combinations without irradiation. Anti-thymocyte globulin(ATG) were added to the conditioning regimen in the patients receiving HLA-mismatched URD-HSCT. The prophylaxis regimen for HC included intravenous mesna,hyperhydration and intermittent diuretic. The diagnosis of HC was based on the presence of sustained microscopic or macroscopic hematuria in the absence of other clinical conditions such as urinary bacteria and fungi infection. It could be clinically graded to I to IV according to hematuria and divided into early onset (EOHC) and delayed (LOHC) according to the time of onset. In total, 27 of 168 patients (16.1%) developed HC at a median interval of 40 days post engraftment (range, 8–89 days). Among them,11 patients developed grade I (6.5%), 10 patients developed grade II (6.0%), 6 patients developed grade III (3.6%), while no patients with grade IV. Five patients(2.98%) presented EOHC and 22 patients (13.17%) presented LOHC. We discovered that in 27 patients with HC only 3 were female (11.1%), however in 141 patients without HC, 52(36.9%) were female (P<0.05). Patients with HC had a higher incidence of acute graft-versus-host disease (aGVHD) (92.6% vs 47.5%, P<0.001) and grades II-IV aGVHD (P<0.001), which is consist with previous reports. Furthermore, 16 patients (59.3%) with HC were ≥30-year-old, 50 patients (35.5%) without HC, were ≥30-year-old (P<0.05). Multivariate analysis showed that primary disease type, donor ‘s gender or age, stem cell source, myeloablative or nonmyeloablative conditioning regimen, HLA or ABO blood mismatching, the existence of CMV seropositivity were not significantly associated with the risk of HC. All patients achieved excellent response after being treated with alkalinization of the urine, hyperhydration with intravenous fluid. Several patients also received urethral catheterization to bladder washout. No patient died of HC. In conclusion, our results demonstrated that recipient ‘s gender, aGVHD and recipient's age(≥30-year-old), were three risk factors associated with HC. Other risk factors which had been reported to be related to HC in literatures did not show significant impact in our study. Although effective prophylaxis has significantly decreased the incidence of HC, up to date, the precise pathogenesis of HC has not been well elucidated. More clinical and mechanisms researches should to be explored. Disclosures:No relevant conflicts of interest to declare.

Permissive HLA-DPB1 Mismatching Compared to a Non-Permissive Mismatching Significantly Improves Overall Survival Following Allogeneic Transplantation In Patients with Both 10/10 and 9/10 Matched Unrelated Donors

AbstractAbstract 227It is well established that the use of a donor matched for 9–10/10 alleles at HLA-A,-B,-C,-DRB1,-DQB1 significantly improves overall survival (OS) after unrelated donor (UD) haematopoietic stem cell transplantation (HSCT). Whilst the matching status for HLA-DPB1 alleles has been shown to influence transplant complications (relapse and graft-versus-host disease (GVHD), its impact on survival has not been well defined. The current unmet need in clinical practice is an approach to stratify selection criteria when a clinician is confronted with the choice between several 10/10 or 9/10 matched unrelated donors.There is now considerable interest in exploring different types of matching criteria to define permissive HLA-DPB1 mismatches which may be associated with an improved outcome. We have previously shown that HLA-DPB1 permissiveness can be functionally defined by the characterization of shared T cell epitopes (TCE) recognized by alloreactive T cells. In this model, allelic HLA mismatches are classified as permissive if they do not involve TCE disparities, and as non-permissive if they do. Using this concept, we developed two overlapping algorithms of permissivity for allelic HLA-DPB1 mismatches, on the basis of 3 (TCE3) or 4 (TCE4) groups of DPB1 alleles encoding immunogenic TCE. Data from relatively small prospective studies has shown a worse outcome to be associated with non-permissive DPB1 TCE disparities.Here, we present outcomes in 9123 UD-HSCT pairs, collected through the International Histocompatibility Working Group (IHWG). The cohort was comprised of 5809 10/10 matched transplant pairs and 3314 9/10 matched pairs. Within the 10/10 and 9/10 matched pairs three groups of patients were identified: 1. Zero DPB1 mismatches (i.e. allele matched), 2. Permissive DPB1 mismatch, 3. Non-permissive DPB1 mismatch. The model was adjusted for disease severity, source of stem cells, conditioning regimen, use of T-cell depletion, patient/donor gender and patient age.In line with DPB1 allele frequencies in worldwide populations, the number of transplants scored as permissive was higher for TCE3 (4398/7270 [60.4%]) than for TCE4 (2577/7270 [35.4%]). Using the DPB1 permissive mismatch transplants as the reference group (either 10/10 or 9/10 matched), we showed that DPB1 allelic matches resulted in similar survivals to DPB1 permissive mismatches, both in the 10/10 (HR 0.96, p=0.498 for TCE3 and HR 0.99, p=0.85 for TCE4) and the 9/10 setting (HR 0.97, p=0.70 for TCE3 and HR 0.99, p=0.96 for TCE4).In contrast, survival was significantly worse in the presence of a non-permissive TCE3 or TCE4 mismatch, both in the 10/10 (HR 1.15, p=0.0005 for TCE3 and HR 1.13, p=0.0035 for TCE4) and in the 9/10 matched setting (HR 1.13, p=0.0140 for TCE3 and HR 1.11, p=0.0448 for TCE4). The survival detriment appeared to be due to a significantly increased non-relapse mortality (TCE3: 10/10 HR 1.27, p<0.001 and 9/10 HR 1.21, p=0.0001; TCE4: 10/10 HR 1.24, p<0.001 and 9/10 HR 1.13, p=0.0514), as well as an increase in grades II-IV acute GVHD (TCE3: 10/10 HR 1.17, p<0.001 and 9/10 HR 1.29, p<0.001; TCE4: 10/10 HR 1.12, p=0.0035 and 9/10 HR 1.19, p<0.0001). There was no significant difference in disease relapse between permissive and non-permissive mismatched pairs. Finally, using the 10/10 DPB1 permissive mismatched group as a reference, we found survival to be similar for 10/10 DPB1 non-permissive (HR 1.15) and 9/10 DPB1 permissive (HR 1.20) or DPB1 allele matched (HR 1.17) transplants.In conclusion, our results suggest that extending donor selection to include HLA-DPB1 both allelic and functional TCE matching may result in better prediction of survival for patients. These findings provide an attractive new algorithm to stratify donor choice when several well-matched UD are identified. Disclosures:No relevant conflicts of interest to declare.

How I treat Philadelphia chromosome–positive acute lymphoblastic leukemia

AbstractThe Philadelphia chromosome is present in approximately 20% to 30% of adults with acute lymphoblastic leukemia (ALL). The poor prognosis of this relatively uncommon acute leukemia has led to the rapid adoption of treatment strategies such as unrelated donor hematopoietic stem cell transplant and tyrosine kinase inhibitors into clinical practice, despite a relative paucity of randomized clinical trials. Recently, there has been a surge of interest in the underlying biology of ALL. In combination with an accumulation of more mature clinical study data in Philadelphia-positive ALL, it is increasingly possible to make more rational and informed treatment choices for patients of all ages. In this article, I review available data and indicate how I personally interpret current evidence to make pragmatic treatment choices with my patients, outside of clinical trials. My strongest recommendation is that all physicians who are treating this rare disease actively seek appropriate clinical trials for their patients wherever possible.

Outcome of Chinese children with unrelated donor hematopoietic stem cell transplantation

To evaluate the prognostic factors and outcomes in Chinese children undergoing unrelated donor hematopoietic stem cell transplantation (UDT). Retrospective analysis of clinical data from 53 consecutive children who received UDT from November 2002 to December 2007 in our center. The median recipient age was 8.4 years (range 1.5-21). With a median follow-up of 36 months (range 18-80), the probability of 3-year overall survival (OS) was 71.5%. Treatment-related mortality (TRM) was 19.0%, and 9.5% died after post-transplant leukemia relapse. Incidence of grades I-II, III-IV acute and chronic graft versus host disease (GVHD) was 63%, 29%, and 46%. There was significant difference in OS between patients older or younger than 10 years (50.0% vs. 84.8%, P = 0.003), patients with different underlying diseases (ALL, AML, CML, and non-malignant disease: 36.4%, 80.0%, 61.5%, and 100%, P = 0.001) and patients receiving either HLA 0-1 versus 2-3 loci high-resolution mismatched UDT (83.3% vs. 53.3%, P = 0.034). The OS was not affected by the stem cell source (peripheral stem cell 70.3%, bone marrow 87.5% vs. cord blood 62.5%, P = 0.542) or the severity of acute GVHD (grade 0-II 77.8% vs. grade III-IV 60.0%, P = 0.140). The important prognostic factors for OS after UDT were the degree of HLA match, the age of patient and the type of underlying disease. Patients < 10-year with non-malignant disease receiving 0-1 locus high-resolution mismatched UDT had the most favorable outcomes.

Unrelated hematopoietic stem cell donors as research subjects

Unrelated hematopoietic stem cell donors as research subjects

European Marrow Donor Information System: Concept and Praxis

Hematopoietic stem cell transplantation is an increasingly used treatment option for patients with severe disorders of hematopoiesis. In roughly two thirds of the cases, an unrelated donor must be sought in international databases. These searches would nowadays be unimaginable without the support of information technologies. Reliable communication and data transfer of donor and patient records between all partners in this huge network is one of the most important success factors in stem cell transplantation. The European Marrow Donor Information System (EMDIS) is an open computer network for data exchange among different unrelated hematopoietic stem cell donor registries that covers 85% of all potential unrelated stem cell donors and cord blood units worldwide. The network has spread also to North America, Australia, Asia, and Africa. The Czech Stem Cell Registry in Prague became a member of the EMDIS community at the end of 2003, when it manually processed about 300 preliminary search requests per year and exported 32 stem cell products to other countries. In 2008, it has automatically processed >14,000 preliminary requests with a doubled 63 number of exported stem cell products.

Abstract B77: Ethnicity and hematopoietic stem cell transplantation (HSCT) outcomes in British Columbia, Canada

Abstract Purpose: There are documented ethnic disparities in cancer care access, use and clinical outcomes in North America; however, the role of ethnicity on different outcomes of unrelated donor hematopoietic stem cell transplantation (HSCT) as an established treatment for many hematological and non-hematological malignancies has not been studied for Canadian patients. Patients and Methods: We reviewed the registry data of 395 patients receiving first time unrelated donor HSCT for hematological malignancies at leukemia/BMT center of British Columbia (BC) between 1988 and 2008. They were reported to be white (N=340), Asian (N=32), native (N=8), Hispanic (N=3), black (N=2), mixed (N=9) and other- not specified (N=1) which were further categorized as white (N=340) and non-white (N=55). Different HSCT outcomes were compared by log-rank test and Cox proportional hazard regression adjusting for significant patient, disease and transplant related factors at 95% significance level. Results: Univariate and multivariate analysis didn't show any statistically significant difference for overall survival, disease-free survival, relapse, acute graft versus host disease (aGVHD) grade 2+ and chronic graft versus host disease (cGVHD) rates between whites and non-whites. We reanalyzed a subset of 115 cases (88 whites and 27 non-whites) who received their HSCT after June 2001 (start date for application of high resolution DNA-based HLA matching in the study center) and their underlying diagnosis was acute myeloid leukemia, acute lymphoid leukemia, chronic myeloid leukemia and myelodysplastic syndrome. The results showed a higher risk of cGVHD for non-whites in univariate analysis (HR1.82, 95% CI1.07-3.12, P=0.03), however; adjusting for covariates in the multivariate analysis resolved this difference (P = 0.09). Conclusion: According to our data, HSCT clinical outcomes are comparable between white and non-white ethnic minorities in BC. The contrasting result with that of US studies might be due to different ethnic composition of BC and using a heterogeneous non-white ethnic group as the comparator (to increase the power of study) which could mask any unsought differences in the subgroups. Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):B77.

Long-term outcomes of HLA-matched sibling compared with mismatched related and unrelated donor hematopoietic stem cell transplantation for chronic phase chronic myelogenous leukemia: a single institution experience in China

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative therapy for chronic myelogenous leukemia (CML). In this study, the long-term outcomes of HLA-matched sibling donor (MSD) with mismatched related donor (MRD) and unrelated donor (URD) transplantation for CML in the first chronic phase (CML-CP1) using different graft vs. host disease (GVHD) prophylaxis regimens according to donor source and the degree of HLA matching were compared. The data of 91 patients with CML-CP1 were analyzed with respect to GVHD, overall survival (OS), and transplant-related mortality (TRM). The incidence of grade II-IV acute GVHD was 25.5% in the MSD and 40.5% in the MRD/URD group (P = 0.133). The 1-year cumulative incidence of chronic GVHD was not different between the MSD and the MRD/URD groups, while extensive chronic GVHD was different between the two groups (31.9% vs. 10.8%, P = 0.023). The 5-year cumulative relapse rate was not different between the MSD and the MRD/URD groups, while TRM was different between the two groups (6.6% vs. 26.3%, P = 0.010). The 5-year cumulative OS was 90.9%, 71.5%, and 85.4% in the MSD, the MRD/URD, and the HLA allele-matched URD transplantation, respectively (MSD vs. MRD/URD, P = 0.013; MSD vs. HLA allele-matched URD, P = 0.437). In conclusion, survival in HLA allele-matched URD is equivalent to MSD, but in MRD and mismatched URD is inferior to MSD in patients with CML-CP1 undergoing allo-HSCT using different GVHD prophylaxis regimens according to donor source and degree of HLA matching. Patients undergoing MRD/URD transplantation have an equal quality of life as patients undergoing MSD transplantation.

110-P: Donor-Specific (DSA) Anti-DP Antibodies Associate With Graft Failure (PGF) in Unrelated Donor Hematopoietic Stem Cell Transplantation (MUDHSCT)

110-P: Donor-Specific (DSA) Anti-DP Antibodies Associate With Graft Failure (PGF) in Unrelated Donor Hematopoietic Stem Cell Transplantation (MUDHSCT)

GVHD after unrelated cord blood transplant in children: characteristics, severity, risk factors and influence on outcome

We reviewed our experience in 79 children who had unrelated cord blood transplant (UCBT) between 1996 and 2007 with a major focus on GVHD, comparing both traditional and National Institute of Health (NIH) criteria. The cumulative incidence (CI) of acute GVHD (aGVHD, by day +100) was 0.42 for grade II-IV and 0.22 for grade III-IV. The CI of all aGVHD (NIH, that is, no time limit) at 1 year was 0.45 for grade II-IV and 0.32 for grade III-IV. Infused CD34 cell dose (>1 × 10(5)/kg), pretransplant bacterial infection and nonmalignant disorders were risk factors for grade II-IV aGVHD on univariate analysis. Infused CD34 cell dose remained significant on multivariate analysis. At 1 year, the CI of chronic GVHD (cGVHD) using the Seattle criteria was 0.27, whereas that for cGVHD (NIH) was 0.08. By NIH criteria, the classic form of cGVHD was uncommon (5%) after UCBT. Instead, the acute (71%) and overlap (24%) GVHD variants predominated. Grade II-IV aGVHD was a significant risk factor for cGVHD by both Seattle and NIH criteria. We conclude that GVHD after day +100 after UCBT typically carries features of aGVHD. Moreover, and in marked contrast to adult unrelated donor hematopoietic stem cell transplantation, the GVHD observed in this series did not adversely affect survival.

One-Antigen Mismatched Related versus HLA-Matched Unrelated Donor Hematopoietic Stem Cell Transplantation in Adults with Acute Leukemia: Center for International Blood and Marrow Transplant Research Results in the Era of Molecular HLA Typing

Approximately 13% of patients lacking an HLA-identical sibling have a one-antigen-mismatched related donor (MMRD). Historically, outcomes from the use of a one-antigen MMRD were considered equivalent to those from the use of a matched unrelated donor (UD). Recent improvements in UD stem cell transplantation (SCT) resulting from better molecular HLA matching justifies investigating whether UD should be preferred over MMRD in adult patients with acute leukemia. Here, we compared the outcomes of MMRD (n = 89) and HLA-A, -B, -C, and -DRB1 allele-matched UD (n = 700) SCT reported to the Center for International Blood and Marrow Transplant Research between 1995 and 2005. The patients underwent transplantation for acute myelogenous leukemia or acute lymphoblastic leukemia in first or second complete remission. Donor type was not associated with hematologic recovery. Univariate and multivariate comparisons of MMRD versus HLA-matched UD transplants showed no statistically significant differences in overall survival, disease-free survival, treatment-related mortality, relapse, or 100-day grade III-IV acute graft-versus-host disease (GVHD). MMRD SCT was associated with a lower rate of chronic GVHD at 1 year (35% vs 47%; P = .03), which was confirmed by multivariate analysis (relative risk, 0.58; 95% confidence interval, 0.39-0.85; P < .01). According to our data, HLA-matched UD and MMRD SCT are associated with comparable survival. Given that less chronic GVHD was observed in the MMRD transplantations, this option, when available, remains the first choice in patients with acute leukemia without an HLA-identical sibling in need of allogeneic SCT.

The impact of HLA genotyping on survival following unrelated donor haematopoietic stem cell transplantation

One of the major factors that have contributed to improving the outcomes of Stem Cell Transplantation is progress made in the field of human leucocyte antigen(s) (HLA). This is evident not only in developing techniques for rapid and accurate tissue typing, but also in the greatly improved understanding of the HLA system and the impact of HLA matching on transplant complications. It is now accepted that high-resolution HLA matching for transplant recipients and unrelated donors is associated with the best clinical outcomes. The most important HLA determinants are the six 'classical' polymorphic HLA loci: HLA-A, -B, -C, -DRB1,-DQB1, -DPB1. For several years, based on the outcome of numerous studies, a 10/10 matched donor (HLA-A, -B, -C, -DRB1, -DQB1) was considered the ideal. The impact of HLA-DPB1 has been less clear, in view of reduced likelihood of patient/donor matching for this locus. More recently, several large studies have questioned the importance of HLA-DQB1 matching on outcome. Based on the findings of recent studies, the current gold standard unrelated donor is believed to be one matched for 8/8 alleles at high resolution i.e. matched for HLA-A, -B, -C, -DRB1, however, in certain circumstances, mismatches may be tolerated and/or permissive.

Higher CD34 + and CD3 + Cell Doses in the Graft Promote Long-Term Survival, and Have No Impact on the Incidence of Severe Acute or Chronic Graft-versus-Host Disease after In Vivo T Cell-Depleted Unrelated Donor Hematopoietic Stem Cell Transplantation in Children

The aim of our study was to compare the results of unrelated donor (UD) peripheral blood stem cell transplantation versus UD bone marrow transplantation and to analyze the impact of infused CD34(+) and CD3(+) cell doses on survival and incidence of severe graft-versus-host disease (GVHD) in 187 children who underwent UD hematopoietic cell transplantation with the use of in vivo T cell depletion (antithymocyte globulin or CAMPATH-1H). HLA typing was performed at the "high-resolution" level. Patients receiving > or =10 x 10(6) CD34(+) cells/kg and > or =4 x 10(8) CD3(+) cells/kg had better overall and disease-free survival. Multivariate analysis has shown that both infused CD34(+) cell dose <10 x 10(6)/kg and CD3(+) cell dose <4 x 10(8)/kg were independent risk factors for mortality (relative risk [RR] 1.8 and 1.71, P = .009 and .016, respectively). Regarding disease-free survival, multivariate analysis has revealed another independent risk factor for poor outcome apart from the 2 earlier-mentioned cell doses, which was the use of donors mismatched at 2 HLA antigens or 3 HLA allele/antigens (RR 2.5, P = .004). In age groups 0-10 years and 10-20 years, CD34(+) cell doses higher than the age-adjusted median dose clearly favored survival. Higher infused doses of CD34(+) and CD3(+) cells did not result in an increased rate of severe GVHD. The use of mismatched donors was the only independent risk factor for the incidence of severe acute GVHD (RR 2.2, P = .046). The report demonstrates for the first time in a pediatric cohort, that higher doses of transplanted CD34(+) and CD3(+) cells lead to an improved survival without an increased risk of severe GVHD. The study findings may be limited to the population of patients receiving in vivo T cell depletion, which is now broadly used in unrelated donor setting in Europe.

Comparison between an artificial neural network and logistic regression in predicting acute graft-vs-host disease after unrelated donor hematopoietic stem cell transplantation in thalassemia patients

There is growing interest in the development of prognostic models for predicting the occurrence of acute graft-vs-host disease (aGVHD) after unrelated donor hematopoietic stem cell transplantation. A high number of variables have been shown to play a role in aGVHD, but the search for a predictive algorithm is still ongoing. Artificial neural networks (ANNs) represent an attractive alternative to multivariate analysis for clinical prognosis. So far, no reports have investigated the ability of ANNs in predicting HSCT outcome. We compared the prognostic performance of ANNs with that of logistic regression (LR) in 78 beta-thalassemia major patients given unrelated donor hematopoietic stem cell transplantation. Twenty-four independent variables were analyzed for their potential impact on outcomes. Twenty-six patients (33.3%) developed grade II to IV aGVHD. In multivariate analysis, homozygosity for donor KIR haplotype A (p = 0.03), donor age (p = 0.05), and donor homozygosity for the deletion of the human leukocyte antigen-G 14-bp polymorphism (p = 0.05) were independently significantly correlated to aGVHD. The mean sensitivity of LR and ANNs (capability of predicting aGVHD in patients who developed aGVHD) in test datasets was 21.7% and 83.3%, respectively (p < 0.001); the mean specificity (capability of predicting absence of aGVHD in patients who did not develop aGVHD) was 80.5% and 90.1%, respectively (p = NS). Although ANNs are unable to calculate the weight of single variables on outcomes, they were found to have a better performance than LR. A combination of these two methods could be more efficient in predicting outcomes and help tailor GVHD prophylaxis regimens according to the predicted risk of each patient. Whether ANN technology will provide better predictive performance when applied to other datasets remains to be confirmed.

Unrelated hematopoietic stem cell donors as research subjects

Requests for participation of unrelated stem cell donors in research transplant protocols are becoming more frequent. World Marrow Donor Association calls on donor registries to participate in research activities. Here, we discuss various implications of research participation and make some recommendations as how to make this possible.

Outcome Of Chinese Children With Unrelated Donor Hematopoietic Stem Cell Transplantation: A Single Center Experience

Outcome Of Chinese Children With Unrelated Donor Hematopoietic Stem Cell Transplantation: A Single Center Experience

Simultaneous human herpesvirus 6-associated encephalitis and Guillain-Barré syndrome in a patient after matched unrelated donor haematopoietic stem cell transplantation

Viral infections are still a serious diagnostic and therapeutic problem in patients undergoing alternative donor transplants. β-Herpesviruses (especially human herpesvirus type 5, 6 and 7) are recognized pathogens in this group of patients and may cause central nervous system disease. Guillain-Barré syndrome (GBS) is a very rare complication among stem cell transplant recipients and usually has been attributed to infection. We report a case of resolving simultaneous GBS and HHV-6-associated encephalitis in a haematopoietic stem cell transplant recipient with preceding reactivation of cytomegalovirus (CMV) infection. According to our knowledge this well-documented case is probably the first report from Poland.

High Impact of Human Leukocyte Antigen Matching On Overall Survival and Transplant Related Mortality in Allogeneic Hematopoietic Stem Cell Transplantation for CLL: Long-Term Study From the EBMT Registry.

Abstract 2286Poster Board II-263 Background:The outcomes of related and unrelated donor hematopoietic stem cell transplantations (HSCT) are strongly affected by the degree of human leukocyte antigen (HLA) matching between the transplant recipient and the donor or cord blood unit. HLA matching plays an important role in engraftment, incidence and severity of graft-versus-host disease (GVHD) and also in overall survival; although this factor is still not validated yet in many hematological malignancies. Objective:To evaluate the impact of HLA matching and difference in matching degree among transplants from unrelated donors (UD) on different outcomes in chronic lymphocytic leukemia (CLL). Materials & methods:We have analyzed 370 CLL patients who underwent an allogeneic HSCT reported to the EBMT registry. There were 280 males (75%) and 90 females with a median age of 53 years (24-69). Forty-five patients (12%) have received a previous HSCT. At transplant, 294 among 317 evaluated patients had a good performance status (PS) (93%), 43 patients were in CR (12%), 160 in PR (46%), 44 in SD (13%) and 103 in PD (29%) among 349 evaluated patients. Two hundred and sixty six patients received a reduced intensity conditioning regimen (RIC) and 103 a standard (Std) conditioning; 313 patients received PBSC, 56 BM and 2 cord blood cells from 198 HLA siblings, and 172 unrelated donors (UD). There were 136 (36%) sex-mismatched (91 F/M and 45 M/F), 150 pairs (40%) had an ABO incompatibility (61 minor, 89 major) and for CMV: 78 pairs were +, 146 - and 111 mixed. The median interval between diagnosis and transplantation was 53 months (3-308). According to the registry, there were 198 HLA siblings, 135 matched UD (MUD) and 37 mismatched UD (MMUD). We focused on UD and re-analyzed all HLA typings for patients and donors, after classification we found: 24 well matched (10/10 in high resolution), 28 partially matched (7/7, 8/8 or 9/9 in high resolution), 30 matched in low resolution and 90 mismatched in high resolution, which was different from the registry classification. Results:After transplantation, 359 patients engrafted, 199 developed an AGVHD (gr I: 74, gr II: 79, gr III: 29 and gr IV: 17) and 171 presented a cGVHD (83 limited and 88 extensive). The cumulative incidence of AGVHD for the total population was 22% for gr II and 13% for gr > II. [Siblings: 19% and 12%; well & patially matched: 37% and 10%; low resolution & MMUD: 19.6% and 15.3% for grII & gr > II respectively]. At 1 year after transplant for the total population, the cumulative incidence of limited and extensive cGVHD was 17 % (15-19) and 18.4% (16.4-20.4)[ Siblings: 16.2% (13.6-19) and 17.2% (14.5-20); well & patially matched: 23% (17.2-29) and 23.1% (17.2-29); low resolution & MMUD: 15.8% (12.3-19.1) and 18.3% (14.8-21.8)] respectively. With a median follow up of 48 months, the probability of 3 and 5-years overall survival (OS) for the total population were 62% (56-67) and 52% (45-57) respectively. We found a high significant difference in term of OS between the siblings, well & partially matched groups versus low & MMUD groups (p=0.002) (figure 2). [OS at 3 & 5 years; Siblings: 68.3% (61.8-75.5) and 57.2% (49.8-65.6); well & patially matched: 60.8% (47.6-77.7) and 53.3% (39.2-72.4), low resolution & MMUD: 49% (40.3-59.5) and 38.5% (29.5-50.2) respectively]. We observed also a high significant difference in term of transplant related mortality (TRM) between the same groups (p=0.0022) (figure 4). The multivariate analysis using Cox model studying age, pre-transplant status; gender, PS, cells source, ABO compatibility, conditioning and different HLA groups, showed a significant impact of 4 factors on OS: age: HR=1.04 (1.01-1.6) p=0.001, disease status (PD): HR=3.08 (1.2-7.1) p=0.02, PS: HR=2.37 (1.1-5.1) p=0.02 and HLA MMUD group: HR= 1.62 (1.02-2.59) p=0.03. The same factors were also highly significant in multivariate analysis in term of TRM (age: HR=1.04 (1.001-1.07) p=0.009, disease status (PD): HR=5.49 (1.29-23.4) p=0.02, PS: HR=3.8 (1.7-8.4) p=0.01 and HLA MMUD group: HR= 1.9 (1.07-3.37) p=0.02. Conclusion:This large retrospective analysis pointed out the high impact of HLA matching in terms of OS and TRM (in addition of age, disease status and PS), without any difference between HLA siblings, MUD and partially matched groups. Moreover, we demonstrated the importance of HLA classification when registering patients in the EBMT registry and its impact on different outcomes. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Selection of Adult Unrelated Hematopoietic Stem Cell Donors: Beyond HLA

HLA matching is the dominant controllable donor-recipient factor determining the outcome of adult unrelated donor hematopoietic cell transplantation. Beyond HLA, donor selection is often based on donor characteristics such as age, sex, parity, cytomegalovirus (CMV) serostatus, and ABO blood type. The published evidence to suggest these additional factors are important determinants of survival is weak and is sometimes conflicting. Other factors may be more important for optimal donor selection than the traditional non-HLA factors. These include the donor's geographic location, the performance history of the groups managing the donor, a priori knowledge of the donor's willingness/availability, and others. Implementation of tools to expose this additional donor-related information could significantly alter and aid unrelated donor selection practices.

Association of functional polymorphisms of the transforming growth factor B1 gene with survival and graft-versus-host disease after unrelated donor hematopoietic stem cell transplantation

Many genetic factors play major roles in the outcome of hematopoietic stem cell transplants from unrelated donors. Transforming growth factor beta1 is a member of a highly pleiotrophic family of growth factors involved in the regulation of numerous immunomodulatory processes. We investigated the impact of single nucleotide polymorphisms at codons 10 and 25 of TGFB1, the gene encoding for transforming growth factor beta1, on outcomes in 427 mye-loablative-conditioned transplanted patients. In addition, transforming growth factor beta1 plasma levels were measured in 263 patients and 327 donors. Patients homozygous for the single nucleotide polymorphism at codon 10 had increased non-relapse mortality (at 3 years: 46.8% versus 29.4%, P=0.014) and reduced overall survival (at 5 years 29.3% versus 42.2%, P=0.013); the differences remained statistically significant in multivariate analysis. Donor genotype alone had no impact, although multiple single nucleotide polymorphisms within the pair were significantly associated with higher non-relapse mortality (at 3 years: 44% versus 29%, P=0.021) and decreased overall survival (at 5 years: 33.8% versus 41.9%, P=0.033). In the 10/10 HLA matched transplants (n=280), recipients of non-wild type grafts tended to have a higher incidence of acute graft-versus-host disease grades II-IV (P=0.052). In multivariate analysis, when analyzed with patients' genotype, the incidences of both overall and grades II-IV acute graft-versus-host disease were increased (P=0.025 and P=0.009, respectively) in non-wild-type pairs. We conclude that increasing numbers of single nucleotide polymorphisms in codon 10 of TGFB1 in patients and donors are associated with a worse outcome following hematopoietic stem cell transplantation from unrelated donors.