Sibling Allogeneic Hematopoietic Stem Cell Research Articles

Efficacy of Triple Prophylaxis for Prevention of Graft-Versus-Host Disease in Matched Sibling Allogeneic Peripheral Blood Hematopoietic Stem Cell Transplantation in Pediatric Patients

BACKGROUND: Graft-versus-host disease (GVHD) continues to compromise the overall success of allogenic hematopoietic stem cell transplantation. It is the most important cause of morbidity and non-relapse mortality after allogeneic hematopoietic stem cell transplantation for malignant disease. In adults, post-transplant cyclophosphamide (Cy-PT) has been shown to be a feasible, economically accessible, and effective strategy to reduce the incidence of GVHD in matched sibling hematopoietic stem cell transplantation in combination with a calcineurin inhibitor plus mycophenolate mofetil (MMF). AIM: Demonstrate the clinical benefit of Cy-PT plus a calcineurin inhibitor combined with MMF for GVHD prophylaxis in HLA-matched, related peripheral blood stem cell transplants in pediatric patients with malignant hematologic neoplasms compared to standard therapy in historical controls. METHODS: A retrospective study was conducted on 22 pediatric patients with malignant hematologic neoplasms who underwent HLA-matched related peripheral blood allogenic stem cell transplantation (alloSCT) between July 2012 and December 2022. A comparison was made between two groups, one with triple prophylaxis using Cy-PT, cyclosporine (CsA), and MMF, and a historical cohort that received standard GVHD prophylaxis based on CsA and methotrexate (MTX). Patients were identified from a hospital registry. Descriptive and inferential statistics will be reported, using SPSS version 25 for analysis. RESULTS: Twenty-two patients received HLA-matched alloSCT from first-degree relatives genotypically identical in HLA-A, HLA-B, and HLA-DRB1 alleles. The demographic characteristics of both groups are summarized in the table. No patient experienced primary graft failure, sinusoidal obstructive syndrome, or hemorrhagic cystitis. Acute GVHD grade II-IV did not develop in patients who received Cy-PT, whereas in the CsA/MTX prophylaxis group, 1 (9%) grade IV patient was observed who died due to this cause before day 100. Two patients (18%) developed Moderate/Severe GVHD in the CsA/MTX group, and 1 (9%) had moderate GVHD in the Cy-PT group. Two-year overall survival was similar between the two groups (Cy-PT 53% and CsA/MTX 67%), as was event-free survival (PTCy 48% vs. CsA/MTX 61%). CONCLUSION: Peripheral blood represents a feasible option in our setting due to rapid graft engraftment, short hospital stays, and low incidence of primary graft failure, but with a higher incidence of GVHD as reported in the literature. We explored the efficacy and safety of triple prophylaxis for HLA-matched alloSCTs from peripheral blood using Cy-PT + CsA + MMF in a small group of patients, with outcomes slightly better than standard prophylaxis. These preliminary results motivate us to continue with this new regimen.

A retrospective comparative cohort study on the routine pre-engraftment use of granulocyte colony-stimulating factor in allogeneic hematopoietic stem cell transplantation

Objective: Myeloid growth factors have been often used in allogeneic hematopoietic stem cell transplantation settings. There are some controversies about increased graft versus host disease, relapse, and delayed platelet engraftment with those growth factors in the pre-engraftment period. In this study, we aimed to compare the transplantation outcomes of allogeneic hematopoietic stem cell transplantation recipients according to their myeloid growth factor support status.
 Materials and Methods: Sixty-seven adult acute myeloid leukemia/myelodysplastic syndrome and acute lymphoblastic leukemia patients who underwent allogeneic peripheral blood stem cell transplantation from HLA-identical matched sibling donors were analyzed retrospectively. All-cause mortality at day 100, day 180, and at 1-year were the primary outcome measures. Secondary outcome measures were the engraftment kinetics, length of hospital stay, and graft-versus-host disease incidences.
 Results: Growth factor supported group was younger (p=0.001), and the first complete remission status at transplantation was seen more compared to the unsupported group (p=0.04). Myeloablative conditioning was used more in growth factor supported group (p=0.004). Faster neutrophil engraftment (p=0.008) and delayed platelet engraftment (p=0.022) were seen in growth factor supported group. Graft-versus-host disease, relapse incidences, and all-cause mortality at day 100, day 180, and at 1-year were not different between groups. Steroid-resistant graft-versus-host disease was the only factor related with relapse (OR: 0.196, p=0.043).
 Conclusion: This real-life study shows colony-stimulating-factors are safe in HLA-identical sibling allogeneic hematopoietic stem cell transplantation. Further prospective randomized controlled studies for different stem cell sources, different donors, and different conditioning and graft-versus-host disease prophylaxis regimens are mandatory.

Comparative Outcome of Reduced Intensity and Myeloablative Preparative Regimen in HLA Identical Sibling Allogeneic Hematopoietic Stem Cell Transplantation for Patients Older Than 50 Years of Age with Acute Myeloblastic Leukaemia: A Retrospective Survey from the Acute Leukemia Working Party (ALWP) of the European Group for Blood and Marrow Transplantation (EBMT).

Results of reduced intensity preparative regimen (RIC) hematopoietic stem cell transplantation (HSCT) in the HLA identical HSCT setting have not been compared to myeloablative HSCT (MA) in patients with AML over 50 years of age. With this aim, outcomes of 315 RIC were compared with 407 MA HSCT recipients from 182 transplant centers. The majority of RIC was fludarabine-based regimen associated to Busulfan (BU) (53%) or low dose TBI (24%). Multivariate analyses of outcomes were used adjusting for differences between both groups. The median follow-up was 13 months. Cytogenetics, FAB classification, WBC count at diagnosis and status of the disease at transplant were not statistically different between the two groups. However, RIC patients were older (median 57 years versus 54 years), transplanted more recently, and more frequently with peripheral blood allogeneic stem cells as compared to MA recipients. In multivariate analysis, Incidence of grade II-IV acute GvHD (aGvHD) was significantly lower after RIC: 22% compared to 31% after MA HSCT (p=0.003) but not Grade III-IV (8% versus 12%, respectively)(p=0.12). the risk of chronic GVHD was lower following RIC (RR=0.69; 95% CI,=0.51 to 0.94, p=0.02). Transplant-related mortality was significantly decreased(18% versus 32%) (p<10−4; RR=0.48, CI= 0.33 to 0.68), and relapse incidence was significantly higher (41% versus 24%) (p=0.0003; RR=1.78, CI=1.3 to 2.43) after RIC transplantation. Leukaemia-free survival (LFS) was not statistically different between the two groups. These results may set the grounds for prospective trials comparing RIC with other strategies of treatment in elderly AML.

The impact of chimerism on DNA-based human identification from skin surface cells of post-allogenic hematopoietic stem cell transplantation (HCST) patients

The use of biological traces recovered from touched or handled items increased with the advance of the forensic analysis system. Thus, DNA profiles obtained from touch DNA became a useful tool in forensic investigation. However, a chimeric person with more than one chromosomal population can be challenging for a forensic analyst. We investigated the genetic profile in blood, buccal swab, and skin swabs from twenty-four recipients aged 21–63 years who underwent a matched sibling allogeneic hematopoietic stem cell transplantation with no sign of skin graft versus host disease. Autosomal short tandem repeats genotyping was performed to evaluate chimerism status at 15 loci along with gender marker Amelogenin. According to our results, donor chimerism was detected in all recipient's blood samples, while in buccal swabs, five recipients showed no presence of donor-derived cells in their genotype. Epithelial cells swabbed from hand fingertips were not devoid of donor-derived cells since all recipients showed high chimerism (39.69%–96.66%) in their genotypes. A significant change in chimerism was seen among various types of biological samples (p<0.05). No correlations were observed between chimerism and recipient age, gender, or time after transplant (p> 0.05). The loci D21S11, D8S1179, and FGA were the most informative, whereas D13S317, Vwa, and TOPX were the least informative STR markers. We concluded that touch DNA from a person who has undergone a successful allogeneic HSCTs should not be considered as reliable evidence for human identifications. Therefore, necessary precautions must be taken to avoid false identification and miscarriage of justice.

Combination of HLA-Matched Sibling Allogeneic Hematopoietic Stem Cell Transplantation With Unrelated Cord Blood Unit in Patients Aged 35 to 50 Years With Severe Aplastic Anemia: Preliminary Summary of a Single-Arm Trial

This study reports a single-arm trial in the interim phase in 4 patients with median age of 40.5 years who have undergone combined HLA-matched sibling donor (MSD) stem cell graft and an unrelated cord blood (UCB) unit for the treatment of severe aplastic anemia (SAA). The median time was 10 days for neutrophil engraftment (9-18 days) and 17 days for platelets (12-24 days). Median follow-up of 22 months (ranging from 16 to 29 months) showed survival of the 4 patients with complete hematological response. Acute graft-vs-host disease (GVHD) (grade II) occurred only in 1 patient, yet chronic GVHD was free. One patient showed a pattern of transient MSD graft followed by dominant UCB chimerism, and another 1 achieved mixed chimerism in the first 6 months after allogeneic hematopoietic stem cell transplantation (allo-HSCT) then evolved to a stable MSD graft. The other 2 patients sustained a full MSD graft during the post-HSCT period. Nevertheless, none of the patients developed primary and secondary graft failure up to the final follow-up. Although this is a small cohort, the dual transplantation combining HLA-matched sibling allogeneic hematopoietic stem cell transplantation with unrelated cord blood unit may deserve further exploration for treatment of SAA patients aged 35 to 50 years old.

Transfusion support for matched sibling allogeneic hematopoietic stem cell transplantation (1993-2010): factors that predict intensity and time to transfusion independence.

Patients undergoing allogeneic hematopoietic stem cell transplant require variable, often extensive transfusion support. Identification of factors that predict urgent, intensive, or special needs should improve management of these patients. This is a retrospective study of red blood cell (RBC) and platelet transfusion support provided for sequential matched sibling donor allogeneic transplants conducted at the Clinical Center, National Institutes of Health, from 1993 through 2010. Factors potentially important for predicting quantity of RBC and platelet transfusions, and time to transfusion independence through Day 200 following hematopoietic stem cell transplantation were evaluated. Subjects (n = 800) received 10,591 RBC and 10,199 platelet transfusions. Multivariable analysis demonstrated that the need for RBC pretransplant, CD34+ dose, transplant year, diagnostic category, and ABO match were significantly independently associated with quantity of RBC transfusions during Days 0 through 30. Only pretransplant need for RBCs, CD34+ dose, and transplant year had significance during Days 0 through 100. Similar analyses for quantity of platelet transfusions demonstrated that for both Days 0 through 30 and 0 through 100 significant factors were need for platelet support before transplant, CD34+ dose, transplant year, and transplant regimen. Of note, long term, during Days 101 through 200, only CD34+ dose remained significant for quantity of RBC and platelet transfusions. Analysis of time to transfusion independence demonstrated that patients with ABO major mismatches required longer to achieve freedom from RBC transfusion support compared to identical matches or those with minor mismatches. Patient-specific factors including CD34+ dose and ABO match of the graft should be given particular consideration by transfusion services when planning support of patients receiving allogeneic hematopoietic stem cell transplant.

Role of thymoglobulin in matched sibling allogeneic hematopoietic stem cell transplantation with busulfan and fludarabine conditioning in myeloid malignanicies.

In vivo T-cell depletion using anti-thymocyte globulin (ATG) is widely used in allogeneic hematopoietic stem cell transplantation (HSCT) for prophylaxis of GvHD. We investigated the influence of thymoglobulin dose (an ATG) on GvHD following matched sibling donor (MSD) HSCT with a busulfan and fludarabine preparative regimen. Medical records of 180 patients who received MSD HSCT with a conditioning regimen of busulfan, fludarabine, and ATG (BuFluATG) were reviewed retrospectively. The median age was 53 years (range 18-68). Initial diagnoses were acute myeloid leukemia (73.3%) and myelodysplastic syndrome (26.7%). Forty-four and 68 patients (24.4 and 37.7%) experienced acute and chronic GvHD of any grade, respectively. High-dose (⩾4.5 mg/kg) ATG was independently associated with decreased risk of acute GvHD (hazard ratio=0.36, 95% confidence interval (CI): 0.15-0.84, P=0.019) compared to low-dose ATG (<4.5 mg/kg). Although ATG dose was associated with the risk of acute GvHD, it was not associated with the risk of chronic GvHD in our study. A higher dose (⩾4.5 mg/kg) of ATG decreases the risk of acute GvHD but had no significant impact on disease-free survival in MSD HSCT patients conditioned with BuFluATG. The optimal dose of ATG should be further investigated in a large prospective study context.

Effect of Antithymocyte Globulin Source on Outcomes of HLA-Matched Sibling Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Severe Aplastic Anemia

We wanted to evaluate efficacy of porcine antithymocyte globulin (ATG) in HLA-matched sibling donor allogeneic hematopoietic stem cell transplantation (MSD-HSCT) for patients with severe aplastic anemia (SAA). The clinical data of 113 SAA patients who received MSD-HSCT from January 2005 to November 2016 were analyzed retrospectively. Of these, 58 patients received rabbit ATG as a part of conditioning regimen (R-ATG group), whereas the other 55 patients received porcine ATG (P-ATG group). Patient baseline characteristics and donor conditions of the 2 groups were similar, except patients were older and more received peripheral blood stem cell transplantation in the P-ATG group. All patients engrafted in 2 groups. There were significant differences in the incidence of acute (20.7% ± 5.3% versus 43.4% ± 7.0%, P = .015) and chronic graft-versus- host disease (GVHD; 20.1% ± 5.8% versus 46.0% ± 7.9%, P = .003) between the R-ATG and P-ATG groups. However, there were no significant differences in terms of 3-year overall survival (93.1% ± 3.3% versus 84.4% ± 5.7%, P = .235), grades III to IV acute GVHD (3.4% ± 2.4% versus 12.3% ± 4.7%, P = .098), moderate to severe chronic GVHD (12.6% ± 4.9% versus 11.5% ± 4.9%, P = .905), or graft rejection (7.4% ± 3.6% versus 5.5% ± 3.1%, P = .852). There was also no significant difference with regard to the incidence of severe bacterial infection (P = .075), invasive fungal disease (P = .701), or cytomeglovirus viremia (P = .770). P-ATG showed satisfactory efficacy and safety compared with R-ATG in the setting of MSD-HSCT for SAA patients. P-ATG could be a potential alternative preparation for R-ATG, further offering the advantage of lower costs.

Rabbit ATG Plus Cyclophosphamide with or without Fludarabine Is Superior Conditioning Regimen for Patients with Severe Aplastic Anemia Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Objective: To compare rabbit antithymocyte globulin (ATG) containing conditioning regimen (group A) with horse antilymphocyte globulin (ALG)-based regimen (group B) for sibling allogeneic hematopoietic stem cell transplant (HSCT) outcome, disease free survival, rejection and complications in severe aplastic anemia patients.Methods: We analysed 205 aplastic anemia patients undergoing allogeneic HSCT from HLA matched sibling donors from July 2001 to April 2016. Group A (n=169) received conditioning with ATG plus Cyclophosphamide (CY) 200 mg/Kg with Fludarabine (Flu) 120mg/m2 (n=100) or without Flu (n=69), whereas group B comprised of CY plus ALG (n=36). The stem cell source was bone marrow (43.9%); PBSC (8.3%) and bone marrow plus PBSC (47.8%). Cyclosporin (CsA) was given as GVHD prophylaxis in 129 patients, while methotrexate (MTX) was added to CsA in 76 cases. Chi-square test was used to compare categorical variables. Kaplan Meier survival curves with log rank test was applied to compare the groups for survival analysis.Results: Overall survival was 78.7% in Group A compared to 69.4% in group B (p=0.23). Patients in group A had significantly better disease free survival (DFS) (75.1%) than group B (55.6%) (p=0.018). The incidence of acute GVHD was 18.3% in Group A compared to 22.2% in Group 2 (p=0.64), while chronic GVHD was significantly higher in Group 2 (22.2%) as compared to Group A (9.5%) (p= 0.04). Likewise frequency of Mucositis was high in Group B (30.5%) compared to Group A (10.7%) (p = 0.006). Moreover, patients receiving ALG-based conditioning had more frequent infections (86%) compared to ATG-based group (67.4%) (p=0.03). There was no significant difference within group A with respect to use of fludarabine as part of conditioning.Conclusion: Rabbit ATG containing conditioning regimen is associated with less complications and better survival in patients with severe aplastic anemia undergoing allogeneic HSCT. DisclosuresNo relevant conflicts of interest to declare.

Cyclosporine (CsA) Pharmacogenetics Post HLA-Matched Sibling Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Myeloid Leukemia: Value of CYP3A4 Gene Polymorphism

Cyclosporine (CsA) Pharmacogenetics Post HLA-Matched Sibling Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Myeloid Leukemia: Value of CYP3A4 Gene Polymorphism

Impact of the GSTA1 Gene Polymorphism on Clinical Outcomes of HLA-Matched Sibling Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Myeloid Leukemia

Impact of the GSTA1 Gene Polymorphism on Clinical Outcomes of HLA-Matched Sibling Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Myeloid Leukemia

Role of the Methylenetetrahydrofolate Reductase (MTHFR) A1982C Gene Polymorphism in Predicting Clinical Outcomes of HLA-Matched Sibling Allogeneic Hematopoietic Stem Cell Transplantationin Patients with Myeloid Leukemia

Role of the Methylenetetrahydrofolate Reductase (MTHFR) A1982C Gene Polymorphism in Predicting Clinical Outcomes of HLA-Matched Sibling Allogeneic Hematopoietic Stem Cell Transplantationin Patients with Myeloid Leukemia

Impact of Donor and Recipient Sex on Outcomes of HLA-Identical Sibling Allogeneic Hematopoietic Stem Cell Transplantation

Background: hematopoietic cell transplantation (HCT) is well established as therapy for hematologic malignancies as well as many non-malignant disorders. Donor selection is an important way to decrease the risks after HSCS and is therefore a key component of the clinical practice of transplantation. There are many criteria proved or hypothesized to affect outcomes after SCT and one of these, sex is the most controversial. Some investigators have found an increased risk of acute or chronic graft-versus-host disease (GVHD) associated with donor sex. Transplantation of stem cells from a female donor to a male recipient is a special circumstance in which donor T cells specific for minor H antigens, encoded by genes on the recipient Y-chromosome that are polymorphic to their X-chromosome homologues, may make a contribution to GVHD and GVL activity.Objective: investigate the effect of donor and recipient sex mismatch on outcomes of HLA-identical sibling allogeneic stem cell transplantation.Methods: this study was carried on 82 patients selected from patients who had underwent a myelo-ablative preparative regimen for a hematologic malignancy and received HSC transplant from an HLA-identical sibling being divided into 2 groups: 1st one with a female donor to a male recipient and 2nd one include otherwise. Both groups will be subjected to HLA tissue typing, CBC, Bone marrow aspirate evaluation, PT & PTT, blood culture when needed, SGPT, SGOT, ALP, blood urea, s.creatinine, urine analysis, pulmonary function tests, chest x-ray, echocardiography ECG, CMV-, EBV-, VZV-, Toxoplasma- antibodies (IgG , IgM), HBs-Ag, HBs-Ab, and HCV-Ab.Results: after variables controlling for patient and donor, there was an increased risk of acute GVHD in patients who received grafts from female donor being 18% for patients receiving grafts from female compared with 8% for recipients of male grafts. Donor sex was also an important influence on risk of developing chronic GVHD with cumulative incidences of chronic GVHD 9.7% for patients receiving transplants from male donors grafts compared to 24.3% for recipients of female donor grafts.Conclusion: we found that male recipients of grafts from female donors had a significantly higher probability for acute and chronic GVHD than male recipients with male donors or female recipients with female donors and despite the beneficial GVL effect observed in male recipients with female donors, these patients had significantly reduced survival compared with all patient/donor sex combinations, suggesting that other variables, particularly GVHD, contribute to transplantation-related mortality.

Comparison of Unrelated Cord Blood Transplantation and HLA-Matched Sibling Hematopoietic Stem Cell Transplantation for Patients with Chronic Myeloid Leukemia in Advanced Stage

This is the first report to present a clinical comparison of unrelated cord blood transplantation (CBT) and HLA-matched sibling allogeneic hematopoietic stem cell transplantation for patients with chronic myeloid leukemia (CML) in advanced stage (accelerated phase or blast crisis). A total of 32 consecutive patients with advanced CML received unrelated CBT (n = 16) or HLA-matched sibling allogeneic peripheral blood stem cell or bone marrow transplantation (allo-PBSCT/BMT) (n = 16) between 2002 and 2011. The median day to neutrophil engraftment and the median day to platelet engraftment were longer in the unrelated CBT group. The cumulative incidence of grades 1 to 2 acute graft-versus-host disease (aGVHD), grades 3 to 4 aGVHD, and chronic graft-versus-host disease did not differ significantly between the 2 cohorts. The cumulative incidence of transplantation-related mortality (TRM) at day +180 was higher in CBT group (37.5% versus 12.5%, P = .013). The risk of relapse was lower in CBT patients compared with that of allo-PBSCT/BMT patients (14.2% versus 42.7%, P = .03). The long-term survival in CBT group patients was slightly better than that of allo-PBSCT/BMT group, although the difference did not reach statistical significance: the 5-year overall survival for CBT patients and allo-PBSCT/BMT patients was 62.5% and 48.6%, respectively (P = .10), whereas the 5-year leukemia-free-survival rate was 50% and 40.5%, respectively (P = .12). Our comparisons suggest that patients with advanced CML receiving unrelated CBT had a lower relapse rate, a slightly better long-term survival, but a higher early TRM than those receiving HLA-matched related allo-PBSCT/BMT.

Comparative outcome of reduced intensity and myeloablative conditioning regimen in HLA identical sibling allogeneic hematopoietic stem cell transplantation for acute leukemia patients: A single center experience

Due to the high transplant related morbidity and mortality (TRM), relatively younger acute leukemia patients that have a good performance status and no comorbidity are eligible for myeloablative conditioning (MAC) followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT). The outcomes of 84 consecutive adult patients with ALL (n=38) or AML (n=46) who underwent allo-HSCT from their HLA-identical siblings were evaluated retrospectively. The median age at transplantation was 34 (17-58 years) for the whole patient population. Of these, 24 patients received a MAC and 60 patients received a fludarabine-based reduced intensity conditioning regimen (RIC). After a median follow-up of 32 months (range, 1-119), for the entire group, the 3-year estimated overall survival (OS) was 57.5% and the disease-free survival (DFS) was 51.5%. The OS for ALL and AML patients were 53.9% vs 62.1%: and DFS were 50.5% and 53.4%, respectively. The 3-year estimated OS for RIC and MAC patients were 63.2% and 41.7%; and DFS were 57.1% and 34.7%, respectively. In ALL patients, conditioning regimens (RIC vs MAC) led to similar OS and DFS; however, in AML patients both OS (70.1% vs 21.4%) and DFS (59.3% vs 42.9%) were found to be higher in RIC patients compared to MAC recipients. Overall, the TRM at day 100 was 1.7% and has increased up to 5.1% at 1st year. In multivariate analysis, the diagnosis (p=0.03) and RIC regimen (p=0.027) were the prognostic variables for prolonged OS in all patients; and RIC regimen (p=0.031) was the only prognostic factor for prolonged OS in AML patients. The first complete remission (CR1) was correlated with a prolonged DFS as an independent variable for all patients (p=0.09). Eleven of the RIC patients (18.3%) and 6 of the MAC patients (25%) developed acute graft-versus-host disease (GvHD). Seventeen of the RIC patients (33.3%) and 4 of the MAC patients (16.7%) developed chronic GvHD. In conclusion, RIC conditioning regimens may provide a longer OS and DFS, especially in patients with AML who are in first CR, not eligible for MAC conditioning.

Similar Survival, but Better Quality of Life After Myeloablative Transplantation Using Unrelated Cord Blood Versus Identical Sibling Hematopoietic Cells in Adults with Hematologic Malignancies: A Single Institute Analysis.

AbstractAbstract 3134HLA-identical sibling allogeneic hematopoietic stem cell transplantation (HSCT) is the best therapeutic option for high-risk hematological disease, but it is limited by lack of availability of a suitable donor for most candidate patients. At our institution our center, unrelated cord blood transplantation (UCBT) was used as the first alternative option for patients who lack an HLA-matched related donor in the last decade. We retrospectively analyzed the clinical outcomes of UCBT versus HLA-identical sibling HSCT for adult patients with hematologic malignancies.Between April 2000 and May 2012, 194 consecutive adult patients with malignant hematological diseases received UCBT (77 patients; median age 21y, r 14–46; male 49) and related bone marrow transplantation (BMT) and/or peripheral blood stem cells transplantation (PBSCT) (117 patients; median age 30y, r 14–53; male 75). Diagnoses in two groups (UCBT/Sibling) included de novo AML (n = 23/32), ALL (n = 30/26), CML (n = 17/47), MDS/AML (n = 3/8), mixed phenotype acute leukemia (MPAL) (n = 3/1), NHL (n = 1/2), and MM (n = 0/1)). Overall rates of high-risk patients were 84.4% for UCBT recipients and 50.4% for BMT/PBSCT recipients(P<0.05). 11.6 percent of UCB grafts and 100% sibling grafts were HLA-identical (antigen level for HLA-A and B, allelic for DRB1, respectively). All patients received myeloablative conditioning regimens and CsA plus mycophenolate mofetil as GVHD prophylaxis.The median number of nucleated cells and CD34+ cells infused were 0.36 (r 0.19–0.69)×108 and 0.21(r 0.06–0.52)×106 per kilogram of the recipient’s body weight for UCBT recipients, and 5.68 (r 2.02–12)×108 and 3.63(r 0.67∼14.99)×106 per kilogram for BMT/PBSCT recipients (P=0.000). The primary engraftment rate was 96.1% (UCBT) and 100% (BMT/PBSCT). The median time to 0.5×109/L ANC was 19 days (r 12–35) and 12 days(r 10–18)(P = 0.000) and the median time to 20×109/L platelets was 36 days(r 14–90)and 15 days(r 11–17)(P = 0.001); hematopoietic recovery was significantly delayed after UCBT. The cumulative incidence of total acute GVHD (47.3% vs.22.2%, P = 0.001), early transplantation-related mortality (TRM) before day +100 (13.0% vs.3.4%, P<0.05), and infection (58.4%vs. 12.0%, P<0.05) was higher in UCBT recipients. Median follow-up was 42.2 months (range, 4.5–123.2 months) for BMT/PBSCT recipients and 22.2 months (range, 3.0–110.2 months) for UCBT recipients. There was no significant difference in cumulative incidence of grades ?to ? acute GVHD (9.4% vs. 5.0% P = 0.247), relapse rate (14.3% vs. 14.5%, P=0.962), and 3 year over survival (OS) (59.6% vs. 64.1%, P=0.123). But the cumulative incidence of chronic GVHD (18.8% vs. 44.1%) and extensive chronic GVHD (0% vs. 18%) was lower in UCBT recipients (P<0.05). The estimated 9-M CI of discontinuing immunosuppressive therapy (IST) while alive was 80%, and long-term survivors of UCBT had better quality of life.Our data shows similar survival, but better quality of life after myeloablative transplantation using UCB versus identical sibling hematopoietic cells in adults with hematologic malignancies. HLA-mismatched cord blood should be considered an acceptable source of hematopoietic stem-cell grafts for adults in the absence of an HLA-matched adult donor. Disclosures:Sun:Anhui Provincial “115” Industrial Innovation Program (2009): Research Funding; the Fund of the Key Medical Project of Anhui Provincial Healthy Department (2010A005): Research Funding; Key Scientific and Technological Project of Anhui province “Twelfth Five-Year Plan” (11010402164): Research Funding.

In Situ Detection of HY-Specific T Cells in Acute Graft-versus-Host Disease–Affected Male Skin after Sex-Mismatched Stem Cell Transplantation

HY-specific T cells are presumed to play a role in acute graft-versus-host disease (aGVHD) after female-to-male stem cell transplantation (SCT). However, infiltrates of these T cells in aGVHD-affected tissues have not yet been reported. We evaluated the application of HLA-A2/HY dextramers for the in situ detection of HY-specific T cells in cryopreserved skin biopsy specimens. We applied the HLA-A2/HY dextramers on cryopreserved skin biopsy specimens from seven male HLA-A2(+) pediatric patients who underwent stem cell transplantation with confirmed aGVHD involving the skin. The dextramers demonstrated the presence of HY-specific T cells. In skin biopsy specimens of three male recipients of female grafts, 68% to 78% of all skin-infiltrating CD8(+) T cells were HY-specific, whereas these cells were absent in biopsy specimens collected from sex-matched patient-donor pairs. Although this study involved a small and heterogeneous patient group, our results strongly support the hypothesis that HY-specific T cells are actively involved in the pathophysiology of aGVHD after sex-mismatched stem cell transplantation.

Structural Basis of Mannan-Binding Lectin Recognition by Its Associated Serine Protease MASP-1: Implications for Complement Activation

Complement activation contributes directly to health and disease. It neutralizes pathogens and stimulates immune processes. Defects lead to immunodeficiency and autoimmune diseases, whereas inappropriate activation causes self-damage. In the lectin and classical pathways, complement is triggered upon recognition of a pathogen by an activating complex. Here we present the first structure of such a complex in the form of the collagen-like domain of mannan-binding lectin (MBL) and the binding domain of its associated protease (MASP-1/-3). The collagen binds within a groove using a pivotal lysine side chain that interacts with Ca(2+)-coordinating residues, revealing the essential role of Ca(2+). This mode of binding is prototypic for all activating complexes of the lectin and classical pathways, and suggests a general mechanism for the global changes that drive activation. The structural insights reveal a new focus for inhibitors and we have validated this concept by targeting the binding pocket of the MASP.

Kaposi’s sarcoma developed after allogeneic hematopoietic stem cell transplantation

A 33-year-old Chinese male patient with severe aplastic anemia received matched sibling allogeneic hematopoietic stem cell transplantation using antithymocyte globulin containing conditioning regimen after 4 months of unsuccessful treatment with cyclosporine A. Following transplantation, the patient was immunosuppressed demonstrated by intermittent infections, including a varicella 3 months after transplantation. Although DNA-STR results on day +30 confirmed complete donor engraftment, repeat DNA-STR analysis performed more than 3 months after transplantation showed a mosaic phenotype. Cyclosporine tapering commenced early, but the last DNA-STR result confirmed complete graft rejection. On day +198, the patient presented with fever, skin boil in the right temporal region, severe pancytopenia, intrabodominal lymphadenopathy and hepatosplenomegaly. Within 1 month, superficial lymphadenopathy and right exophthalmos developed. Excisional lymph node biopsy pathology confirmed Kaposi's sarcoma (KS). The patient succumbed due to intracranial bleeding as a result of thrombocytopenia. This is the first study of KS that developed following stem cell transplantation for severe aplastic anemia. The precipitating factors underlying KS development in this case and its differentiation from post-transplant lymphoproliferative disorders are analyzed.

Early Prediction of Acute Gvhd Based on Molecular Profiling at the Time of Engraftment after Hematopoietic Stem Cell Transplantation.

Allogeneic hematopoietic stem cell transplantation is an important last resort therapy for hematological diseases. Unfortunately, the success of a large proportion of these transplants is limited by graft-versus-host disease (GVHD). Currently known risk factors for acute GVHD (histoincompatibility, sex mismatch, older patients, previous pregnancies) do not provide a precise estimate of individual patient risk and do not help for individualization of the therapy. Although GVHD may have beneficial graft-versus-tumor effects, observational studies have identified GVHD as the main cause of non-relapse mortality. Thus, early identification of those patients who will develop aGVHD may allow for individualized treatment, and also for the reduction of unnecessary treatment for those patients not at risk. Nowadays, however, there is no diagnostic method that allows prediction of aGVHD. Thus, the goal of our study was to reveal a gene expression profile that would predict the occurrence of aGVHD.Material and methods: Between May 2004 and August 2007, we collected blood samples from 89 recipients of myeloablative (N=71) and non-myeloablative (N=17) HLA-identical sibling allogeneic hematopoietic stem cell transplants at the time of successful engraftment (2–3 weeks after transplantation). Acute GVHD prophylaxis was cyclosporine plus short course of methotrexate and cyclosporine plus mycophenolate mofetil in myeloablative and non myeloablative transplants, respectively. Forty patients (45%) experienced acute GVHD (Glucksberg criteria). All the patients had acute GVHD before the first three months after transplantation (median 31 days; range 21–88 days). We isolated total RNA from the peripheral blood mononuclear cells, amplified it, labeled, and co-hybridized to the microarray slides containing probes for 22,000 genes. We used BRB ArrayTools for data analysis. The patients were divided into training and test groups, the former used to build a model discriminating patients with and without aGVHD and the latter - to test the model on independent samples. We selected the informative genes using “recursive feature elimination” method followed by six different multivariate classification algorithms (compound covariate predictor, diagonal linear discriminant analysis, 1- and 3-nearest neighbor predictor, nearest centroid predictor, support vector machine, Bayesian predictor) in order to establish a molecular classifier in the training set. Then we validated this new classifier in the test set of patients. Because multiple classification algorithms may give different results, we considered a result being robust and a patient being “classifiable” when at least five out of seven algorithms were concordant. The other patients were considered as “unclassifiable” because no reliable prediction regarding development of aGVHD could be made.Results: We found a molecular classifier comprised by 244 gene probes in the training set of samples which were selected based on the most accurate classification. In the test group of samples, we found that 80% of patients could be classified based on the concordance between classification methods as described above. For these patients, the classifier showed 78% of a predictive accuracy (75% of sensitivity and 80% of specificity).Conclusion: Our results show that molecular profiling is able to identify patients under high risk of acute GVHD at the time of engraftment. Establishing of a predictive diagnostic method for aGVHD is the first step of individualization of therapeutic strategy after hematopoetic stem cell transplantation.