HLA Compatibility Research Articles

Macrophage Colony-Stimulating Factor Attenuated the Severity of Chronic Graft-Versus-Host Disease after Unrelated Bone Marrow Transplantation

Macrophage colony-stimulating factor (M-CSF) is a growth factor for cells from the monocyte-macrophage lineage and has been used in Japan after chemotherapy and bone marrow transplantation (BMT) to induce early recovery of neutrophils and to reduce the incidence of febrile neutropenia. A tolerogenic action of M-CSF was recently reported during induction of dendritic cells from cord blood. To study the effects of M-CSF administration on the long-term outcomes of unrelated BMT, We retrospectively analyzed the data of patients who had undergone their first BMT through the Japan Marrow Donor Program between 1993 and 2005 and for whom complete data concerning age, sex, HLA compatibility, and colony-stimulating factor were available. Fifty-four patients received M-CSF administration within 8 days of undergoing a BMT for a median length of 13 days, and the data of 500 patients who did not receive any CSF was used as the control. There were no significant differences in the patients' age, sex, donor's age, ATG administration, infused nucleated cell number, GVHD prophylaxis, or HLA compatibility. The M-CSF cohort (M) received more transplants from male donors (M, 77.8% vs. control, 62.3%, p = 0.020), and contained more standard-risk diseases than the control cohort (M, 64.8% vs. control, 47.8%, p = 0.014). Overall survival of the M cohort was superior to that of the control cohort (M, 57.7% vs. control, 46.4% at 5 years after transplantation), but the difference was not significant (log rank test, p = 0.084). There were no significant differences in the incidence or grade of acute GVHD between the two cohorts (log rank test, all acute GVHD, p = 0.710; grade 2 to 4, p = 0.680; grade 3 to 4, p = 0.653). The incidence of chronic GVHD was lower in the M cohort than in the control, but the difference was not significant (log rank test, p = 0.224). The incidence of extended type chronic GVHD of the M cohort was significantly lower than in the control (log rank test, p = 0.004). The observed occurrence of extended type chronic GVHD was 8.9% in the M cohort and 24.3% in the control. Multivariate analysis revealed that M-CSF administration was a significant factor (relative risk: 0.73, 95% CI: 0.55 – 0.94, p = 0.012), as was the age of patients and donors, underlying disease, and acute GVHD. Although chronic GVHD is associated with a lower relapse rate of the underlying malignant disease, we did not observe any increase of relapse in the M cohort (log rank test, p = 0.067). Our observation suggests the potential clinical use of M-CSF for preventing severe chronic GVHD.In patients with chronic GVHD, both the serum IL-10 level and IL-10 production from mononuclear cells have been shown to decrease after stimulation. After stimulation with LPS, M-CSF-induced macrophages are known to produce large amounts of IL-10 instead of IL-12. Recent reports have shown that M-CSF induced dendritic cells (DCs) with IL-4 in a culture from human cord blood and that these DCs produced high amounts of IL-10, but no IL-12, a pattern similar to that seen in M-CSF-induced macrophages. The low incidence and severity of both acute and chronic GVHD after cord blood transplantation regardless of HLA disparity is well documented. M-CSF is elevated during pregnancy and in cord blood. Taken together the above statements offer possible explanations for the low incidence and severity of GVHD in cord blood transplantation. In this context, our observation suggests that M-CSF administration after UR-BMT might decrease the severity of chronic GVHD through the induction of certain types of macrophages and DCs.

Ciclosporine and Metotrexate Reduce the Risk of High Grade Acute Gvhd after Busulfan, Fludarabine and Anti-Thymocyte Globulin conditioning Regimen in Comparison with Cyclosporine Alone

We have performed a study in 137 adult pts who were transplanted with BFA (busulfan 8 mg/kg, fludarabine 150 mg/m^2 and ATG (Thymoglobuline Genzyme)) conditioning regimen in our centre between 11/1998 and 12/2007. The aim of the study was to evaluate the prognostic factors in this cohort of pts. The group consisted of 87 men and 50 women, median age was 54.5 yo (17–66). The diagnosis was AML (43), Myelodysplasia/Myeloproliferative disease (20), CML (2) (Myeloid group, MG: 65), ALL (14), Multiple Myeloma (MM: 30), Lymphoma (LYM: 28). Pts had received a median of 2 lines of treatment before transplantation (0–6). Sixty-four pts (47%) had previous autologous transplants (50 pts one and 14 pts 2 autologous transplants). At time of transplant, 80 pts were in CR, 38 in PR and 19 refractory or in relapse. The donor was a sibling for 85 and a MUD in 52 pts with HLA compatibility 10/10 in 37pts and 9/10 in 15 pts (2 one A mm, 2 one B mm, 10 one C mm and 1 one DQ mm). Graft consisted of PBSC in 128 pts, the median number of CD34 cells infused was 6.3 × 10^6/kg (0.92–25.47). The median of nucleated cells infused in 9 pts grafted with bone marrow cells was 1.5 × 10^8/Kg (0.71–3.42). The ATG dose was 2.5 mg/kg in 49, 5 mg/kg in 54 and more than 5 mg/kg in 34 pts. GVHD prophylaxis was with CSA in 67 pts, CSA-MTX in 70 pts. With a median FU of surviving pts of19 m (1.5–103 m) the 3y OS and PFS were 50 and 40% respectively. Four pts with refractory disease at transplantation had no engraftement. The remaining 133 pts experienced neutrophil recovery at a median time of 18 days (0–30), and platelet recovery at a median time of 11 days (0–130). Sixty-one pts died. The 2 main causal factors being: relapse in 37 of the cases (59%), GVHD and infection in 16 cases (26%). The probability of TRM at 100 days and 1 y were 6% and 15% respectively. The 3 y probability of relapse was 45%. 58 pts (42%) developed aGVHD (grade I–II, n=37, 27%; grade III–IV, n=21, 15%). One hundred and ten pts were evaluable for cGVHD. The incidence of cGHVD was 42% (46 pts) and the incidence of its extensive form was 18% (20 pts). Fourteen pts received DLI for progressive disease (6 MM, 3 AML, 2 follicular Lymphoma, CLL, HD, ALL 1 each). The complete remission was obtained in patients with follicular lymphoma and CLL. Only one pt with MM reached the CR post Mel 100 and DLI. Two pts received the DLI for mixed chimerism with successes. The OS and PFS at 3y were significantly higher in patient who had a cGVHD, disease in CR, received higher than median of CD34, and without grade III–IV aGVHD (p<0.05). The study revealed that the dose of ATG has little influence on PFS (2.5mg/kg: 44%, 5 mg/kg: 48%, >5mg/kg: 26%) (p=0.1). The multivariate analysis showed a significant association between OS and cGVHD (76 vs 43%), and grade III–IV aGVHD (56 vs 0%). PFS was significantly associated with the cGHVD (53 vs 37%), grade III–IV aGVHD (45 vs 0%), CD34 numbers (50 vs 30%) and dose of ATG. GVHD prophylaxis regiment with CsA alone (23 vs 10%) is the only factor increasing the incidence of grade III–IV aGVHD. In univariate analysis two factors associated with high risk of cGVHD were presence of all grade aGVHD and use of CsA alone in GVHD prophylaxis but in multivariate analysis only presence of aGVHD increase the cGVHD incidence significantly. In univariate analysis, the TRM was higher in pts with advanced disease, receiving lower doses of CD34 and with grade III–IV aGVHD. In multivariate analysis, high grade aGVHD (55 vs 11%) and low dose of CD34 (30 vs 10%) significantly increase the TRM. The relapse rate was high in patients receiving a high dose of ATG, low dose of CD34 (58 vs 36%) and without cGVHD (53 vs 38%) and in multivariate analysis, it depends on presence of cGVHD and number of CD34 infused. In this retrospective study, presence of cGVHD and number of infused CD34 cells were the most important factors influencing the outcome. This was borne out by their positive effect on both the OS ans PFS data. The primary cause increasing mortality in the study group was identified as relapse. The cGHVD reduced the relapse risk and increase the OS probably due to the Graft versus Disease reaction. These results show that prophylaxis of GVHD by CsA and MTX reduced the incidence of grade III–IV aGVHD, without affecting the incidence of cGVHD, and more than 5 mg/kg of ATG decrease the PFS.

Impact of HLA High-Resolution Matching on Outcomes of Myeloablative Unrelated Donor Hematopoietic Stem Cell Transplantation in Chinese Population

Unrelated donor hematopoietic stem cell transplantation (URD-HSCT) is more frequently associated with severe graft-versus-host disease (GVHD) or graft rejection, and the success of URD-HSCT is influenced by the degree of HLA compatibility between the donor and patient. However, HLA mismatched unrelated donors should to be considerable for patients awaiting allogeneic HSCT who lack a suitable related donor or matched unrelated donor. The purpose of the study was to observed the impact of HLA-A, -B, -DRB1/B3 high-resolution matching on outcomes of URD-HSCT in Chinese population.Patients and methods: 182 patients with hematological malignancies received URD-HSCT (bone marrow, n=130; peripheral blood stem cell, n=52) in our center between Nov. 1998 and May. 2008, and donors were from Chinese Marrow Donor Program (Chinese Mainland) and Tzu Chi Stem Cells Center (Chinese Taiwan), and the median age of all patients was 26 years (range 8–52 years). The selection of unrelated donor relied on donor-recipient HLA-A, -B, -DRB1/B3 matching by high-resolution molecular typing by PCR-SSP or PCR-SSO, with 121 cases of HLA 6/6 alleles matched, 51 cases of 1/6 allele mismatched and 10 cases of 2/6 alleles mismatched. The distribution of single HLA class I or class II mismatching was as follows: 37 HLA class I mismatching with 21 HLA-A and 16 HLA-B, and 14 HLA class II mismatching with 12 HLA-DRB1 and 2 HLA-DRB3. All of the patients were received Bu/Cy or Bu/Cy modified myeloablative conditionging regimen. MMF combined with CsA and short course MTX were performed as aGVHD prophylaxis, while other 18 patients received additional anti-CD25 monoclonal antibody to prevent severe aGVHD.Results: After a median follow-up of 14.9 months, 170 patients achieved sustained engraftment with the engraft failure of 6.6%, early treatment-related mortality (TRM) of all patients was 14.4% at 100 days after transplant, and clinical relapse was observed in 8 patients (16.5%). aGVHD developed in 106 (58.2%) patients of all with grade I–II 82 (45.1%) and grade III–IV 24 (13.1%). By Kaplan-Meier method, the accumulative probability of 5-year overall survival (OS) and disease free survival (DFS) of all patients was 51.65±4.15% and 47.38±4.05%, respectively. The incidences of aGVHD was a little higher in HLA 1–2 alleles mismatched group (n=61) compared to HLA matched group (n=121) (67.2% vs 53.7%, p>0.05), and the incidences of grades I–II and III–IV aGVHD in HLA mismatched transplants were 45.9% and 21.3% respectively, while those in HLA matched transplants were 44.6% and 9.1% respectively. Comparing the outcomes between HLA 1–2 alleles mismatched and HLA matched transplants, the engraft failure were 9.8% and 5.0% (P>0.05), and early TRM were 18.0% and 12.4% (P>0.05), respectively. The Kaplan-Meier probability OS at 5 years were 44.31±6.86% and 55.66±5.11% in HLA mismatched and matched group (P>0.05) respectively. In HLA 2 alleles mismatched URD-HSCT, the incidence of engraft failure and aGVHD were 30.0% and 80.0%, and the outcomes were really inferior to HLA matched transplants. The impact of single HLA class I (n=37) or HLA class II mismatched (n=14) on the results of URD-HSCT had been also studied, and incidences of aGVHD in HLA class I or class II mismatched transplants was not significantly different compared with HLA matched transplants. In HLA class I and class II mismatched URD-HSCT, the engraft failure were 5.4% and 7.1% (p>0.05), and early TRM were 13.5% and 35.7% (p>0.05), respectively. The probability OS at 5 years in single HLA class II mismatched transplants was significantly lower compared with HLA matched transplants (23.81±12.94% vs 55.66±5.11%, p<0.01).Conclusion: URD-HSCT could be optimized by comprehensive and precise donor-recipient alleles matching, however, HLA mismatching was associated with the risk of URD-HSCT. Moreover, HLA 2 alleles mismatches of donor-recipient HLA-A, B, DRB high-resolution matching was correlated with an inferior clinical outcome. For patients with high-risk diseases without a suitable matched unrelated donor, alternative methods to URD-HSCT with a single HLA mismatch may permit early treatment before disease progression. In our study, it also demonstrated that HLA class I mismatching was correlated with a high incidence of aGVHD, and HLA class II mismatching was associated with an inferior overall survival in Chinese population, however, larger studies would have to dissect out the magnitude of the risk incurred with specific mismatches more clearly owing to small patient numbers in each group.

Unrelated Transplants for Poor Prognosis Adult Acute Lymphoblastic Leukemia: Long-Term Comparative Analysis Based on the Hematopoietic Progenitor Source.

Background: Adults with high risk ALL features at diagnosis, slow responders or with recurrent disease have a poor outcome with standard chemotherapy and are considered for unrelated transplants in most centers if a matched sibling donor is not available. Unrelated cord blood (UCB) has emerged as an option for unrelated transplant in adult patients.Aim of the study: to compare the outcome of adult patients with unrelated transplant for poor prognosis ALL based on the hematopoietic source used for transplant.Patients and Methods: One hundred and forty- nine adult patients (median 29 years [15–59], 90M/59F) with poor prognosis ALL received an unrelated transplant in 13 Spanish institutions from 2000 to 2007. Patients in 1st CR at transplant met at least one adverse prognostic factor (adverse cytogenetics, hyperleukocytosis or a slow-responder). ALL was of precursor B lineage in 111 (74%), T-cell lineage in 28 (19%) and undetermined lineage in 10 (7%) patients. ALL was in 1st CR in 81 (54%) patients, in 2nd CR in 37 (25%), in 3rd CR in 11 (7%) and overt disease in 20 (13 %) patients. Both groups were comparable for the main clinical and biologic ALL features except for patients with more overt disease in UCB transplant group. Conditioning therapy consisted on TBI-CY in 68 (46%), BU-CY in 9 (6%), Thiotepa- BU-CY/FLU in 60 (40%) patients (all of them UCB transplants) and other regimens in 12 (8%) patients (6 of them were non-myeloablative). The source of hematopoietic progenitors was UCB in 62 (41%), mobilized PB in 41 (28%) and BM in 46 (31%) patients. HLA compatibility requirements for selecting unrelated donors (BM and mobilized PB) were 7–8 out of 8 allelic identities, and for UCB were 4–6 out of 6 A / B antigenic and DR allelic identities.Results: Acute GVHD was most frequent after PBSCT and BMT thanin UCBT. There was no significant difference for limited and extensive chronic GVHD between UCBT and PBSCT/BMT. The median follow-up was 16 months (0.3–101.4). DFS estimated at 5 years for patients transplanted with any source was not significantly better in transplants in 1st CR versus 2nd CR or more advanced disease (median 12 [2–22] vs 5 [2–9], p=0.106). There was no statistical difference in OS or DFS at 5 years between UCB and PBSCT/BMT). TRM was significantly lower in UCB transplants (p=0.021). The relapse probability was 17% for the PBSCT/BMT versus 29% for UCBT (p=0.088). The use of TBI as conditioning therapy was not associated with a lower relapse rate.5y-OS (95%CI)Median OS (month, 95%CI)5y-DFS (95%CI)Median DFS (month, 95%CI)5y-TRM (95%CI)Whole series26% (17–35)10 (4–17)21% (13–29)7 (3–11)54% (44–64)PBSCT/BMT22% (11–33)9 (2–17)21% (11–31)5 (2–9)63% (50–76)*UCBT33% (18–48)15 (7–22)22% (8–36)9 (1–17)39% (25–53)*1st CR ALL30% (16–44)12 (0–29)24% (11–37)12 (2–22)57% (43–71)PBSCT/BMT27% (9–45)27 (2–51)24% (8–40)12 (2–22)63% (44–82)UCBT35% (14–56)10 (0–23)24% (4–44)10 (0–26)50% (31–69)*p=0.021GVHD was the main cause of death for unrelated PBSCT/BMT in contrast with infection and relapse for UCBT (p=0.001).Conclusions: UCB transplant and unrelated PBSCT/ BMT are equivalent options for poor prognosis adult ALL patients without a sibling donor. However, all modalities are associated with high transplant related mortality.

Comparison of Outcomes of HLA-Matched Related, Unrelated, or HLA-Haploidentical Related Hematopoietic Cell Transplantation following Nonmyeloablative Conditioning for Relapsed or Refractory Hodgkin Lymphoma

We compared the outcome of nonmyeloablative allogeneic hematopoietic cell transplantation (HCT) for patients with relapsed or refractory Hodgkin lymphoma (HL) based on donor cell source. Ninety patients with HL were treated with nonmyeloablative conditioning followed by HCT from HLA-matched related, n=38, unrelated, n=24, or HLA-haploidentical related, n=28 donors. Patients were heavily pretreated with a median of 5 regimens and most patients had failed autologous HCT (92%) and local radiation therapy (83%). With a median follow-up of 25 months, 2-year overall survivals, progression-free survivals (OS)/(PFS), and incidences of relapsed/progressive disease were 53%, 23%, and 56% (HLA-matched related), 58%, 29%, and 63% (unrelated), and 58%, 51%, and 40% (HLA-haploidentical related), respectively. Nonrelapse mortality (NRM) was significantly lower for HLA-haploidentical related (P=.02) recipients compared to HLA-matched related recipients. There were also significantly decreased risks of relapse for HLA-haploidentical related recipients compared to HLA-matched related (P=.01) and unrelated (P=.03) recipients. The incidences of acute grades III-IV and extensive chronic graft-versus-host disease (aGVHD, cGVHD) were 16%/50% (HLA-matched related), 8%/63% (unrelated), and 11%/35% (HLA-haploidentical related). These data suggested that salvage allogeneic HCT using nonmyeloablative conditioning provided antitumor activity in patients with advanced HL; however, disease relapse/progression continued to be major problems. Importantly, alternative donor stem cell sources are a viable option.

Ocular surface reconstruction: recent innovations, surgical candidate selection and postoperative management

Intricate homeostasis maintains the rich complexity and functionality of the ocular surface. Severe ocular surface diseases cause significant morbidities, including blindness. Ocular surface reconstruction strategies restore this homeostasis. Patients with limbal deficiency may benefit from limbal stem cell transplantation to alleviate persistent epithelial defects, maintain conjunctivalization regression and corneal avascularity, and restore vision. Amniotic membrane and other substrates function as tissue surrogates and substrates for expansion of stem cells. Maximum graft survivability necessitates aggressive and comprehensive preoperative management of inflammation, infection, microtrauma, dry eye conditions and HLA compatibility. Restoration of lacrimal gland function is important, as is implementation of aggressive immunosuppression. Future advancements in stem cell biology, tissue engineering, bioartificial microsystems or regenerative medicine will supplement the therapeutic armamentarium. The next decade will be an exciting time for corneal surgeons.

Classification of HLA-Matching for Retrospective Analysis of Unrelated Donor Transplantation: Revised Definitions to Predict Survival

The best unrelated donors (URD) for hematopoietic cell transplantation (HCT) are alleles matched at HLA-A, -B, -C, and DRB1. Earlier studies mostly used incomplete or lower resolution HLA typing for analysis of transplant outcome. To understand the impact of incomplete HLA characterization, we analyzed 14,797 URD HCT (1995-2006) using multivariable regression modeling adjusting for factors affecting survival. Of 21 matching cohorts, we identified 3 groups with significantly different outcomes. Well-matched cases had either no identified HLA mismatch and informative data at 4 loci or allele matching at HLA-A, -B, and -DRB1 (n = 7477, 50% of the population). Partially matched pairs had a defined, single-locus mismatch and/or missing HLA data (n = 4962, 34%). Mismatched cases had ≥2 allele or antigen mismatches (n = 2358, 16%). Multivariate adjusted 5-year survival estimates were: well-matched: 54.1 (95% confidence interval), 52.9-55.4), partially matched: 43.7 (42.3-45.2), and mismatched: 33.4 (32.5-36.5), P < .001. A better matched donor yielded 10%-11% better 5-year survival. Importantly, intermediate resolution -A, -B, and -DRB1 alleles matched “6/6 antigen matched” HCT had survival outcomes within the partially matched cohort. We suggest that these proposed HLA subgroupings be used when complete HLA typing is not available. This improved categorization of HLA matching status allows adjustment for donor-recipient HLA compatibility, and can standardize interpretations of prior URD HCT experience.

Distribution of HLA antigens in families of patients with leukaemias

Since the discovery of major histocompatibility complex influence on cause leukaemia in 1964, an HIA association with leukaemia in humans has been considered as a possible genetic risk factor that contributes to development of leukaemia. In addition to associations of several HLA antigens with leukaemias, it has been observed that patients with leukaemia have an increase in the frequency of HLA identical siblings, higher degree of HLA compatibility with their parents as well as higher parental HLA sharing rate in comparison to the families without patients suffering from leukaemia. To test hypothesis that susceptibility to leukaemia can be caused by influence of a recessive genes associated with the major histocompatibility complex in man, we analysed the distribution of I class HLA antigens in 77 families of patients suffering from different types of leukaemia. In the affected families and in 72 families of healthy controls, we investigated HLA identical sibling frequency, parental sharing of one, two or three HLA antigens and degree of compatibility of parents and offsprings: existence of haploidentity, compatibility in l' and 4/4 HLA antigens of A and B loci. We have found that in families with affected persons there is a statistically significant difference in number of HLA identical siblings in comparison to the group of healthy controls (t = 2.63). Also the results have shown that among the parents of affected persons there is a statistically significant difference in mutual compatibility in one (t = 3.012) and two (t = 2.4) HLA antigens. In addition, we observed an increase in the frequency of higher rate of compatibility between patients and their parents (t = 3.88) in l' HLA antigens, to their mothers (t = 2.83) and to their fathers (t = 2.55), respectively, in comparison to the healthy control group. The results of this study show that in families with persons suffering from leukaemia there are possible recessive factors associated with HLA system which could cause distorsion of HLA antigens segregation and as a possible genetical risk factor contribute to development of leukaemia.

Cord Blood Transplantation after Non Myeloablative Conditioning (Minneapolis Protocol): Impact on Transplant Outcomes in 112 Adults with Hematologic Malignancy. A French Multicentric Study of the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC) and Eurocord.

The aim of this retrospective multicentric study was to assess the results of 112 consecutive umbilical cord blood transplantations (UCBT) following nonmyeloablative conditioning (NMA) performed in 20 French centres, between October 2003 and March 2007.Characteristics of the patients : Underlying disease: acute leukaemia: myeloid 60, lymphoblastic 17, lymphoma: 15, myelodysplasia: 5, myeloma: 4, Hodgkin: 4, chronic leukaemia: myeloid 3 and lymphoid 3 and 1 solid tumor. Median age at transplantation: 44 y (16–69), median weight: 62 kg (42–125), male: 49 (43%), CMV seropositivity: 64% ; 32 pts had received previous autologous and 3 allogeneic transplantation. The time between diagnosis and transplant was 19 months (3–174). Disease status at transplantation was early (31%), intermediate (37%) and advanced (32%). Median follow-up was 7 months (2–38). The original Minneapolis conditioning regimen was used in 106 (96%) pts and modified in 6 (4 or 6 Gy TBI: 4 pts; ATG: 2). Characteristics of the grafts: A single unit was infused in 77 pts (69%), two in 35 (31%). HLA compatibility was 6/6 in 6 pts, 5/6 in 36, 4/6 in 60, ≤ 3/6 in 6 ; 43 pts were ABO matched. Infused nucleated cells (NC) was 3.1×107/kg (1–9): 2.9 × 107/kg in single units and 3.7 × 107/kg in double units. Results: Neutrophils recovery was 85±4% at a median of 19 days (0–48) ; 14% pts experienced autologous recovery; 14% had mixed and 72% full donor chimerism at D+100. Univariate analysis indicated the low weight, previous transplantation, double units and HLA compatibility as significant factors for neutrophil recovery; however multivariate analysis did not find any significant factor. Acute GVHD was observed in 34±5% of pts: 21, 12 and 5 pts had grade II, III or IV aGVHD respectively and chronic GVHD in 16%. Non relapse mortality was 12±3% at 6 months ; relapse: 22±5% ; overall survival: 72±5%. Causes of death were relapse in 17 pts, GVHD in 2 pts, venocclusive disease and multiorgan failure in 5, infections in 4 and other toxicity in 3. DFS at 6 and 24 months were 68±5% and 65±5%, respectively. By univariate analysis, risk factors for DFS were age (>44y), weight, previous transplant, HLA disparity (0+1 vs 2+3), and NC dose (<3.1× 107/kg). Multivariate analysis identified 3 independent risk factors: HLA disparity, cell dose and age were still significant. This French experience of UCBT after NMA confirms the good results of the Minneapolis group (Brunstein et al. Blood 2007). Few events were observed between 6 and 24 mo and DFS remains high, however a longer follow up is needed. A prospective study of UCBT after NMA conditioning in AML is ongoing in France to identify the risk factors for DFS in a more homogeneous group of pts.

Clinical Outcome by Acute Graft-Versus Host Disease (GVHD) Prophylaxis in Patients Underwent Allogeneic Bone Marrow Transplantation from Unrelated Donors: Nationwide Survey in Japan.

Acute GVHD is one of the most serious complications and the main cause of morbidity and mortality for patients undergoing allogeneic bone marrow transplantation (BMT). So choice of GVHD prophylaxis has great impact on transplant outcome. We performed large-scale retrospective study for acute GVHD by using the data on patients who underwent BMT from unrelated donors (UR-BMT) facilitated by Japan Marrow Donor Program (JMDP). From January 1993 to September 2004, 4,999 patients were registered in the JMDP. The study population consisted of 3,410 out of 4,999 patients who received UR-BMT from HLA A,B,DR genotyping matched or HLA DR DNA allele mismatched donors(2,626 and 784, respectively). We evaluated the effect of age, HLA compatibility, disease status, GVHD prophylaxis (Cyclosporine:CsA+Methotrexate:MTX or Tacrolimus:FK+MTX), severity of acute GVHD and other factors. The Kaplan-Meier estimates of over all survival(OS) were higher for the FK group than for the CsA group in the case of HLA A,B,DR genotyping matched BMT with 5-year survival rates of 54 and 51.4% (P<0.05) and also in the case of HLA DR DNA allele mismatched BMT, 53.2 and 43.4% (P<0.05), respectively. Those of OS were higher for the FK group than for the CsA group in HLA A,B,DR genotyping matched patients with standard-risk leukemia with 5-year survival rates of 65.9 and 60.8% (P<0.05) but in those patients with high-risk leukemia were not different significantly between FK and CsA group (27.4 and 31%: p=0.61). Those of OS in HLA DR DNA allele mismatched patients with standard-risk leukemia were higher for the FK group than for the CsA group with 5-year survival rates of 64.1 and 52.2%(P<0.05) and also in those patients with high-risk leukemia were higher for the FK group than for the CsA group with 5-year survival rates of 42.4 and 27%(P<0.05). Those of OS in patients under 16 years were higher for the FK group than for the CsA group with 5-year survival rates of 78% and 62.2%(P<0.005) and in patients of 16 and over were comparable for the FK and CsA groups with 5-year survival rates of 48.3% and 45.2%(p=0.179). During the first 100 days post-transplant the incidence of grade I- IV acute GVHD was lower in the FK group compared with CsA group (65.8% and 72.7%, respectively: P<0.005), but the incidence of grade II- IV acute GVHD was similar between FK and CsA groups (40.3% and 41.5%, respectively). The incidence of grade I- IV acute GVHD was lower in the HLA A,B,DR genotyping matched group than in the HLA DR DNA allele mismatched group (68.5% and 74.7%, respectively: P<0.001). Multivariate analysis demonstrated that OS was higher for the younger age group (<16 y/o) than for the older age group (≥16 y/o)(HR:1.86, 95%CI:1.58–2.18) and for the standard-risk leukemia group than for the high-risk leukemia group(HR:2.27, 95%CI:1.58–2.59). These findings indicate that the use of FK for acute GVHD prophylaxis is beneficial for patients undergoing UR-BMT, especially for patients under 16 years and with standard-risk leukemia.

Long-Term Survival after Reduced Intensity Conditioning (RIC) Allogeneic Stem Cell Transplantation in AML-Patients Is Consistently Sustained and Influenced by Donor Type Selection.

A total of 46 patients (24 female, 22 male) with acute myeloid leukemia (AML) received RIC allogeneic blood stem cell transplants from either fully HLA-compatible family donors (n=14) or unrelated HLA-compatible donors (n=32) between 3/1999 and 3/2007. The unselected consecutive single centre study patients (median age: 52 years, range: 22–64) were at high risk for treatment-related complications (older age, previous infectious complications, impaired organ function). 67% (n=31) of the cohort were not in first remisson but in an advanced status of AML. All patients received 30 mg·m−2 Fludarabine i.v. day −10 to −5, Busulfan 4mg·kg−1 orally day −5 to −4, and 10 mg·kg−1 i.v. Antithymocyteglobulin (ATG-Fresenius®) day −4 to −1 as RIC prior to allogeneic stem cell transplantation. A median of unselected 6.8 x 106 CD-34 positive stem cells (range: 1.9–14.3) were given. GvHD-prophylaxis consisted of Cyclosporin 3mg·kg−1 continuous infusion in case of 10/10 HLA compatibility donor situation (n=34), with the addition of mycophenolate mofetil 2gr. i.v. primarily starting from day +10 in one antigen mismatched HLA-unrelated donor situation (n=12). Nine patients (19.6%) died of therapy related mortality, due to GvHD (n=3), infections (n=4), or both (n=2). Relapses occurred in 18 patients (39%), in five patients even more than one year after transplantation. The median observation time of the study group was 19 months (range: 3–101), the product-limit estimates (Kaplan-Meier) of overall survival (OS) at 36 months were 0.48 (±0.08), of event-free survival (EFS) 0.44 (±0.08), respectively. [Display omitted] Disease-status (remisson vs. advanced) failed to have a significant impact in OS or EFS, whereas donor status (related vs. unrelated) resulted in OS at 24 months 0.76 (±0.12) for related donors and 0.4 (±0.09) for unrelated donors (p=0.017, log-rank test). RIC with Fludarabine/Busulfan/ATG prior to allogeneic stem cell transplantation results in a consistently sustained long-term outcome for this otherwise adverse patient subgroup, favouring family-matched donor selection.

Comparison of 6586 Unrelated Bone Marrow Transplants (UBMT) and 2713 Unrelated Cord Blood Transplants (UCBT) in Japan.

Background We compared 6586 UBMT (1993–2005) and 2713 UCBT (1997–2005) in Japan, where genetic background is more homogeneous and medical practices are more uniform than in USA or European countries. Patients and Methods Data on UBMT were collected by JMDP and UCBT by JCBBN. Patients were divided into children under 16 years, young adults (16–49 years) and elderly (50 years or older). Proportion of underlying diseases was similar in each group, except that transplants in severe aplastic anemia and chronic myelogenous leukemia were less in UCBT than in UBMT. The proportion of second or more transplants was higher in UCBT than in UBMT (22.9% vs 5.4%, p<0.001). Therefore, comparisons between UBMT and UCBT were made only in the first transplants. HLA compatibility was analyzed by allele typing.Results1.Engraftment1.Neutrophil(500/μl); median days in UBMT and in UCBT were 18 vs 23 (children), 17 vs 25 (young adults), and 17 vs 24 (elderly). Differences were statistically significant (p<0.001).2.Platelet (50K/μl):31 vs 59 (children), 30 vs 54 (young adults), and 32 vs 73 (elderly). (p<0.001)GVHD1.Acute GVHD ≥II; probability in UBMT and in UCBT were 50% vs 47% (children), 45% vs 44% (young adults), and 46% vs 44% (elderly). No significant differences.2.Chronic GVHD; 40% vs 20% (children), 50% vs 30% (young adults), and 47% vs 24% (elderly). (p<0.001)Survival in childhood non-malignant diseases1.Overall survival; 75%(N=56) vs 69% (N= 54) (immunedeficiency, n.s.), 81%(N=197) vs 51%(N=15) (aplastic anemia, P=0.001), and 75%(N=56) vs 69%(N=54) (inborn error of metabolism, n.s.).2.Event free survival (EFS); 64% vs 53% (ID, n.s.), 69% vs 32% (SAA, p<0.001), and 62% vs 19% (IEM, p=0.001).5-year-EFS in malignant diseases1.childhood ALL; 1+2CR: 66% (HLA matched BM, N=179), 56% (mismatched BM, N=106), 63% (MA CB, N=19) and 45% (MM CB, N=127) (p<0.001). Non CR: 25%(MA BM, N=53), 18%(MM BM, N=45), 12% (MM CB, N=30). (n.s.)2.childhood AML; 1+2CR: 65% (MA BM, N=100), 58% (MM BM, N=47), and 53% (MM CB, N=50) (n.s.) Non CR: 16% (MA BM, N=30), 20% (MM BM, N=25) and 15% (MM CB, N=40).(n.s.)3.young adult ALL; 1+2CR: 52% (MA BM, N=374), 36% (MM BM, N=188), and 38% (MM CB, N=96).(p<0.001) Non CR: 15% (MA BM, N=135), 14% (MM BM, N=112), and 12% (MM CB, N=40). (n.s.)4.young adult AML; 1+2CR: 60% (MA BM, N=421), 53% (MM BM, N=171), and 55% (MM CB, N=106).(p<0.001) Non CR: 20% (MA BM, N=235), 21% (MM BM, N=161), and 13% (MM CB, N=112). (p=0.012.)5.elderly ALL; 1+2CR: 52% (MA BM, N=48), 48% (MM BM, N=16), and 33% (MM CB, N=39).(p<0.001) Non CR: 6% (MA BM, N=20), 20% (MM BM, N=10), and 12% (MM CB, N=17). (n.s.)6.elderly AML; 1+2CR: 37% (MA BM, N=68), 51% (MM BM, N=23), and 32% (MM CB, N=47).(p<0.001) Non CR: 7% (MA BM, N=64), 26% (MM BM, N=18), and 14% (MM CB, N=92). (n.s.)Conclusion HLA allele matched UBMT gave better outcome than mismatched UBMT or matched/mismatched UCBT, but allele mismatched UBMT and UCBT were not different. UCBT should be chosen in early stages of the disease if UBMT from an HLA allele matched unrelated donor cannot be scheduled in the suitable period.

Unrelated Cord Blood Transplantation after Reduced Intensity Conditioning (RIC) in Adults with Hematological Malignancy. An EBMT-Eurocord-Netcord, Société Française de Greffe de Moelle et de Thérapie Cellulaire and University of Minnesota Collaborative Study.

Single center studies have demonstrated promising results in recipients of unrelated umbilical cord blood transplantation (UCBT) treated with a reduced intensity conditioning (RIC). However, little is known about risk factors for outcomes with this strategy. We retrospectively evaluated outcomes after RIC-UCBT in 176 patients with hematological malignancies: 116 had acute leukemia (21 ALL, 77 AML, 18 secAML), 36 lymphoid/plasma-cell diseases (6 Hodgkin, 24 NHL, 4 CLL and 2 Myeloma) and 24 myelodysplastic/myeloproliferative diseases (14 MDS and 10 CML). Median follow-up was 12 months (3–80) and median age 45 years (16–76). At transplant, 51% of patients were in advanced phase of disease and 30% had a previous autologous transplants. The conditioning regimen varied according to disease and centre; however, 95% received Fludarabine (FLU)-containing regimen, 55% being FLU-CY-TBI(2Gy), and ATG/ALG was added in 23%. GVHD prophylaxis consisted most commonly (72%) of CsA+MMF. All received a single UCB unit graft that was HLA identical (6/6) (HLA A and B low resolution and DRB1 allelic typing) in 6%, 5/6 in 27%, 4/6 55% and 3/6 in 11%. The median total nucleated cell dose infused was 2.7 × 107/kg. Median time to neutrophil recovery was 20 days (5–56) and probability of neutrophil recovery was 78±3% at day-60. Chimerism analysis at 3 months was complete in 64%, mixed in 16% and absent (autologous reconstitution) in 19%. In multivariate analysis, cell dose (<vs >2.7 × 107/kg, HR=1.6, p=0.02), HLA compatibility (5–6/6 vs 3–4/6, HR=1.5, p=0.04) and use of FLU+CY+TBI versus other regimens (HR=1.7, p=0.01), were independently associated with neutrophil recovery. At day-100, probability of acute GVHD II–IV was 30% (18% grade II; 6% grade III, 6% grade IV), and no risk factor was associated with its incidence. At 1 year, probability of chronic GVHD was 30%. TRM was 38% at 1 year, being 19% for patients given low dose TBI (<6Gy), vs 61% for those without TBI and 40% for those given a low cell dose (<2.7 × 107/kg), vs 21% for the remainder. In multivariate analysis, both factors were associated with TRM. Probability of relapse at 1 year was 41% and it was associated with disease status and aGVHD (26% in those with and 47% in those without aGVHD, p=0.02). DFS at 1 year was 41% for patients with acute leukaemia, 31% for MDS/CML and 42% for lymphoid/plasma diseases. For those treated with FLU-CY-TBI, DFS was 51% as compared to 28% for those treated with other RICs (p=0.0002). In a multivariate analysis, advanced disease status (HR=1.6, p=0.03) and conditioning regimens other than FLU-CY-TBI (HR=1.9, p=0.004) were associated with decreased DFS. In conclusion, cell dose plays a critical role on engraftment and risk of TRM after UCBT in the RIC setting. Specific RIC regimen, namely FLU-CY-TBI, provides better engraftment, reduced TRM and better DFS. These results support the use of FLU-CY-TBI and UCBT as a strategy for broadening the application of transplant to patients previously excluded on the basis of age, co-morbidities and/or absence of a HLA-matched unrelated donor.

Unrelated Cord Blood Transplantation Using Myeloablative Regimen for Acute Leukemia Patients Aged between 50 and 55 Years: Single Institutional Retrospective Comparison with Patients Less Than 50 Years of Age.

Background: Increasing age has been well-known as an obvious risk factor for graft-versus-host disease (GVHD) and transplant-related mortality (TRM) resulting negative impact on allogeneic transplantation including cord blood transplant (CBT). The incidence of sever GVHD after CBT, on the other hand, is lower than that after transplants using graft from adult cells, so we have expected the better results of CBT in older patients.Objectives and Methods: This study aimed to evaluate safety and efficacy of CBT using myeloablative regimen for older patients with acute leukemia.Patients and Methods: We retrospectively compared outcomes of older patients with acute leukemia with younger adults in our institute. Nineteen elderly patients (median age 52, range 50–55) and 81 young patients (median 49, range 16–49) received myeloablative conditioning regimen including 12 Gy of total body irradiation. GVHD prophylaxis comprised cyclosporine with (N=96) or without (N=4) methotrexate.Results: Comparisons of characteristics in the 2 age groups showed similar distributions for weight, gender ratio, diagnosis [de novo acute myeloid leukemia (AML), myelodysplastic syndrome related secondary AML, or acute lymphoblastic leukemia], disease status at transplantation, total nucleated cell dose and CD34+ cell dose in the graft before cryopreservation and proportions of HLA and sex compatibility between donors and recipients. The median period of follow-up for survivors after CBT was 730 days for older group and 1331 days for younger group, respectively. Grade II to IV acute GVHD occurred in 10 of 17 evaluable older patients and 49 of 75 evaluable younger patients (P = 0.61), while no older patients, but 6 younger patients developed grade III to IV acute GVHD. Extensive-type chronic GVHD occurred in 4 of 15 evaluable older patients and 18 of 69 evaluable younger patients (P = 0.96), respectively. The cumulative incidence of TRM at 100 days was 5% versus 6% (P = 0.70), and of relapse at 3 years was 29% versus 20% (P = 0.33) and the estimated disease-free survival at 3 years was 67% and 71% (P = 0.53) for older or younger patients, respectively. There was no significant difference in GVHD, TRM, relapse, and DFS between 2 age groups.Conclusion: The use of cord blood as a stem cell source might contribute to be decreased in the incidence of acute and chronic GVHD resulting in decreased TRM in older patients. Our results suggest that myeloablative CBT might be as safe and effective in patients with acute leukemia aged between 50 and 55 years as in younger patients.

Classification of HLA-Matching for Retrospective Analysis of Unrelated Donor Transplantation: Revised Definitions To Predict Survival.

Unrelated donor (URD) hematopoietic cell transplantation (HCT) is best performed using a donor who is allele-matched with the recipient at HLA-A,B,C and DR. Earlier reports analyzing outcomes of HCT have been limited by incomplete or lower resolution typing at some HLA loci. Excluding these incompletely typed pairs from studies decreases the power of analyses because of smaller sample size. If adjustment for known and unknown HLA-matching status could be accomplished, these patients could be retained in most analyses where HLA-matching is not the primary research focus. To understand the impact of incompletely characterized major histocompatibility antigens on the success of HCT, we analyzed 15,867 URD HCT using multivariable regression modeling adjusting for HLA and non-HLA factors affecting 1 year and 5 year survival. Of 26 independent matching groups defined by the completeness and resolution of donor:recipient pair matching we identified 3 distinct groups with significantly different outcomes: well matched, partially matched, and mismatched. Well-matched cases had no identified HLA mismatch and informative, though not necessary high-resolution data at all 4 loci or allele matching at HLA-A,B & DRB1 (n=7,753, 49% of the study population). Partially matched pairs had a defined, single locus mismatch at any of the 4 loci and/or missing HLA-C data [including 6/6 low/intermediate resolution A,B matched plus DRB1 allele matched] (n=5,396, 34%). Mismatched cases had 2 or more identified allele or antigen mismatches (n=2,692, 17%). Multiple-variable-adjusted one- and five-year survival estimates are shown in the Table. Using these HLA matching categories, we identified independently significant, 7–8% better 5 year survival using a better matched donor (between these 3 categories) stratified across patient subgroups of recipient age, disease stage, and using either myeloablative or non-ablative conditioning. Notably, the common term “6/6 antigen matched” [6/6 low/intermediate resolution A,B matched plus DRB1 allele matched] had survival outcomes within the partial matched cohort. We suggest that these HLA subgroups should be used in analyses of URD HCT outcomes when complete HLA typing is not available. This improved categorization of HLA matching status allows adequate adjustment for HLA donor-recipient HLA compatibility in retrospective studies and will help standardize interpretations of prior URD HCT experience.HLA Matching Group1 Year Survival (95% CI)*5 Year Survival (95% CI)*Well Matched53.5 (52.3–54.7)34.9 (33.5–36.3)Partially Matched41.5 (40.1–42.9)27.0 (25.7–28.5)Mismatched31.0 (29.3–32.9)18.3 (16.7–19.9)* p<0.001

Autologous Bone Marrow Transplantation as an Intensive Consolidation Therapy for Adult Patients in Remission from Acute Myeloid Leukemia.

Introduction: Autologous peripheral blood stem/progenitor cell transplantation (APBSCT) has been investigated as a potential therapeutic option to improve outcome in patients with acute myeloid leukemia. The optimal consolidation therapy for adults in remission without a histo-compatible donor has yet to be clearly established.Patients and Methods: This was a retrospective analysis of forty patients (23 females and 17 males) diagnosed with de novo acute myeloid leukemia, who were without a histo-compatible donor, that underwent APBSCT between the year 2000 and 2006 at a single institution. The patients' age ranged from 18 to 73 with a median age of 50. Cytogenetic analysis was available on 37 of the patients. Complete remission (CR) was confirmed by bone marrow morphology and immunophenotype analysis by flow cytometry. Patients in remission were further consolidated with variable cycles of chemotherapy prior to stem cell transplantation. For stem cell mobilization, patients received high-dose cytarabine (2000mg/m2) and etoposide (5mg/kg) for three days followed by G-CSF at 10μg/kg, starting 10 days after the chemotherapy, before the peripheral stem cell collection. The preparative regimen prior to transplantation with unpurged stem/progenitor cells consisted of a combination of intravenous busulfan (0.8 mg/kg for 16 doses) and cyclophosphamide (60 mg/kg for two doses) (37 patients) or busulfan and melphalan (3 patients). Patients were then followed for treatment-related mortality, disease free survival, and overall survival. The analysis was stratified according to age, cytogenetic risk, and remission state.Results: There was no treatment-related mortality. Nineteen out of forty patients had relapse of their disease. The relapse rate was lowest in the low risk cytogenetic group who were under the age of 60 and highest in the high risk cytogenetic group who were over the age of 60. The overall 5 year survival for all patients was 47%. When stratified for cytogenetic risk and age, the overall survival for low, intermediate, and high cytogenetic risk patients under the age of 60 were 67%, 59%, and 75% respectively. The overall survival for intermediate and high cytogenetic risk patients over the age of 60 were 33% and 0% respectively. The projected rate of disease free survival at 5 years was 40%. When stratified for cytogenetic risk and age, the disease free survival for low, intermediate, and high cytogenetic risk patients under the age of 60 were 33%, 52%, and 50% respectively. Disease free survival for intermediate and high cytogenetic risk patients over the age of 60 were 33% and 0%. Comparing patients in CR1 versus patients in CR2, the overall survival was 47% in CR1 and 50% in CR2. The disease free survival, when grouped as above, were 41% for those in CR1 and 33% for those in CR2.Conclusion: APBSCT is a reasonable and safe intensive consolidation therapy for those patients without a compatible HLA matched donor in first or second complete remissions, notably for those under the age of 60 regardless of their cytogenetic risk. The number of standard consolidations prior to APBSCT may be an important variable predicting outcome.

Double Cord Blood Transplantation in Bone Marrow Failure Syndromes.

The outcome of severe aplastic anemia, refractory to immunosuppressive therapy or observed in case of Fanconi anemia (FA), is usually poor in the absence of Hematopoietic Stem Cell Transplantation (HSCT). Umbilical cord blood is an alternative stem cell source for patients without matched related or unrelated donors. However, single cord blood unit is associated with high transplant related mortality due to the low cell dose infused in previous highly transfused patients. We have driven the hypothesis that double cord blood transplantation (dCBT) could circumvent the cell dose problem. For the purpose of this study, we have studied 13 patients with bone marrow failure syndromes given 2 partially matched dCBT from 2004 to 2007. The diagnoses were FA (n=9), SAA (n=4) and PNH (n=1). Among those patients, 5 (39%) received a dCBT as a rescue of previous rejected transplants (2 SAA and 3 FA). All patients received a fludarabine-based regimen, with TBI (2 Gy) for 4 patients. Cord blood units were a 4/6 or 5/6 HLA A, B and DR match with the patient except one which was 3/6. Graft versus host disease (GVHD) prophylaxis consisted in CSA+MMF. Steroids were given from day 7 to day 14 and stopped in case of no GVHD. Five male (39%) and 8 female (61%) with a median age of 16 years (range 7–31) were treated. The cell doses infused were a median of 5.0 × 107 NC/Kg (4–9) and 5.3 × 105 CD34+ cells/Kg (2–8). Graft rejection was seen in 5 patients (2 previously allotransplanted). Among those patients, one displayed a temporary mixed chimerism before rejection and another presented an autologous reconstitution. Among the remaining 8 patients, the median time to an absolute neutrophils count > 500 was 25 days (range 14–42) and the median time to a platelet count > 20,000 was 39 days. In these last patients, we observed a complete donor chimerism with one cord blood unit during 100 days after dCBT. Acute GVHD grade II–III was scored in 9 patients (69%) (7 grade II, 2 grade III). No patients presented acute GVHD grade IV. Four patients out of 8 developed Chronic GVHD (3 limited and 1 extensive). Four patients died (1 GVHD, 2 fungal infection, 1 thrombotic microangiopathy). With a median follow-up of 13 months (range 1 to 19 months), the overall survival was 55% (±15%) for all patients. The median survival of patients who were transplanted twice was 50% (±25%). In conclusion, dCBT seems to be an option to treat patients with bone marrow failure syndromes and without a suitable compatible HLA donor. Those results need to be established on a large number of patients to warrant the inclusion of dCBT in the treatment strategy of diseases with high risk of rejection.

Dissection and molecular analysis of alloreactive CD8+ T cell responses in allogeneic haematopoietic stem cell transplantation.

We applied a cDNA expression screening procedure with cryopreserved non-clonal CD8+ T cell populations (Lennerz et al., Proc. Natl. Acad. Sci. USA 102:16013-8, 2005) to the identification of candidate antigens for graft-versus-host disease (GvHD) and graft-versus-leukaemia (GvL) effects in allogeneic haematopoietic stem cell transplantation (allo-HSCT). In a patient-donor model system with HLA class I disparities, we identified an HLA-B*44 mismatch allele, HLA-B*4405, as the dominant target of alloreactive T cells expanded in vitro from donor peripheral blood mononuclear cells (PBMC). HLA-B*4405-reactive T cells were detectable after multiple in vitro stimulations in the patient's post-HSCT PBMC. In a patient-donor model with full HLA compatibility, the major target antigen of donor lymphocytes stimulated in vitro with the respective patient's pre-HSCT PBMC was restricted by HLA-A*0201 and was encoded by TRIM22-442 C, a newly detected polymorphic allele of the tripartite motif family member TRIM22 (synonym: STAF50), preferentially expressed in cells of the haematopoietic system. An arginine(R)-to-cysteine(C) exchange at position 442 generated an immunogenic T cell epitope equivalent to a minor histocompatibility antigen (mHag). TRIM22-442C-specific T cells persisted long-term in the patient's post-HSCT PBMC. Approximately, 1.3% of Caucasians carry TRIM22.442 C in association with HLA-A*0201. In particular, the knowledge of a large and diverse panel of such mHags may be crucial for further improvement of donor selection and adoptive T cell transfer strategies. The procedure applied herein will help to accelerate and facilitate their identification.

Research of Updating Method of HLA Compatibility of Multi-Element Model in Simulation

Research of Updating Method of HLA Compatibility of Multi-Element Model in Simulation

Simultaneous Renal Transplantation and Native Nephrectomy in Patients With Autosomal-Dominant Polycystic Kidney Disease

Our objective was to study the influence on transplant outcome of unilateral native nephrectomy of massively enlarged kidneys at the time of renal transplantation among patients with end-stage renal disease owing to autosomal-dominant polycystic kidney disease (ADPKD). Patients and Methods We studied 159 renal transplants in patients with ADPKD divided into two groups according to the need to perform a unilateral native nephrectomy owing to enlarged kidneys (N+; n = 143) versus those not (N0; n = 16) needing this procedure. Parameters related to the donors, grafts, recipients, and operative data were correlated with short- and long-term outcomes. The groups were homogeneous in terms of recipient and donor ages, genders, HLA compatibilities, and length of pretransplant dialysis. Results When no nephrectomy was needed surgery length was shorter (N0, 3.01 vs. N+, 4.23 hours; P < .001), less intraoperative crystalloids were infused (N0, 1.84 vs. N+, 2.76 L; P < .001), and less plasma (N0, 2.07 vs. N+, 2.93 U; P < .05), or blood (N0, 1.05 vs. N+, 1.81 U; P < .05) transfusions were required. Hospital stay was similar (N0, 12.70 vs N+, 16.50 days; P not significant [NS]). There was only one urologic complication in the nephrectomy group. There were no differences ( P = NS) in rates of delayed graft function (N0, 19.9%; N+, 12.5%), acute rejections (N0, 25.5%; N0, 33.3%), chronic allograft dysfunction (N0, 15.8%; N+, 28.6%). Graft function at 1 month as well as 1 and 5 years were comparable. Patient and graft survivals were similar at 1 and 5 years. There were no differences in the causes of graft loss or patient death. Conclusion In patients with ADPKD native nephrectomy of massively enlarged kidneys may be safely performed during the transplant procedure with no repercussions on the length of hospital stay, graft short- and long-term function and patient survival. However the procedure eads to a longer operative time and greater need for fluids and blood products.