Cord Blood Stem Cell Transplantation Research Articles

Comparison of Unrelated Cord Blood and Peripheral Blood Stem Cell Transplantation in Adults with Myelodysplastic Syndrome after Reduced-Intensity Conditioning Regimen: A Collaborative Study from Eurocord (Cord blood Committee of Cellular Therapy & Immunobiology Working Party of EBMT) and Chronic Malignancies Working Party

Hematopoietic stem cell transplantation (HSCT) remains the only curative treatment in patients with higher risk myelodysplastic syndrome (MDS), but the choice of the optimal alternative stem cell source is still a subject of debate in patients lacking an HLA-matched sibling donor. Here, we report on a large series of patients with MDS (N = 631) transplanted either with mobilized peripheral stem cells (PBs) from unrelated donors (n = 502) or with umbilical cord blood transplant (UCB, n = 129) as alternative grafts after reduced-intensity conditioning. Neutrophil engraftment was higher after PB (98% versus 78%, P < .0001). Acute graft-versus-host disease (GVHD) was similar after PB (31%) and UCB (29%), and chronic GVHD incidence was higher after PB (41% versus 23%). Two-year nonrelapse mortality was lower after PB (31% versus 42% P = .03). There was a better overall survival (OS) and disease-free survival (DFS) after PB (49% ± 2% versus 30% ± 4%, P < .0001 and 44% ± 2% versus 28% ± 4%, P < .0001). Multivariate analysis confirmed the advantage of PB for treatment-related mortality, OS, and DFS, whereas relative risk of chronic GVHD was similar. A multivariate analysis comparing PB from a 10/10 HLA-matched donor, PB from a 9/10 HLA-matched donor, and UCB showed an advantage on treatment-related mortality, DFS, and OS only in 10/10 PB. We conclude that in MDS patients lacking an HLA-matched sibling donor, PB from a 10/10 HLA-matched unrelated donor is the preferred source of hematopoietic stem cells. HLA-mismatched unrelated donor or cord blood seem to give similar inferior results except for neutrophil engraftment, which is delayed after UCB.

Unrelated Donor (UD) Cord Blood (CB) Stem Cell Transplantation (SCT) from a Single CB Unit in Older Adults: Excellent Engraftment and Low Early Mortality with a Preparative Regimen of Melphalan (M), Thiotepa (T), Fludarabine(F), and Rabbit (r) Anti Thymocyte Globulin (ATG)

▪Background:Success of single unit UD-CBSCT has been limited by graft failure, delayed engraftment and high early mortality. Preparative regimen of Busulfan with TF and horse ATG has reduced early mortality and improved engraftment in single unit UD-CBSCT in adults (Sanz. BMT 2012: 47; 1287-1293). M with TF and r-ATG has previously been used as a preparative regimen in double expanded UD-CBSCT in adults (De-Lima. NEJM 2012: 367; 2305-2315). Outcomes of this regimen will be of interest in single unit UD-CBSCT.Methods:We retrospectively analyzed the outcomes of all patients that underwent UD-CBSCT from single unit using MTF-rATG conditioning at UMass Memorial Medical Center.Results:Twenty five underwent single unit UD-CBSCT from January 2009 to June 2014. There were 15 males and 10 females. The median age was 63 years (range, 28 -81) and median weight was 68.9 kg (range, 58.9 - 119). Nine patients (36%) were over age 65 years. Diagnosis was AML/MDS (n= 18), CLL (n= 2) and others (n=5)- ALL/Aplastic Anemia/MM/NHL/Blastic NK cell malignancy. Disease status CR1 (n=11), CR2 (n=1) and persistent disease (n=13). Four patients had undergone a prior autologous SCT.Preparative regimen consisted of T (5-10 mg/kg) day -7, F (30 mg/m2) from day -6 to -2, M (100-140 mg/m2) day -1 and r-ATG (3 mg/kg). Graft versus host disease (gvhd) prophylaxis consisted of mycophenolate mofetil (day -1 to 56) and tacrolimus (level 5-15 ng/ml) starting day -1. Tacrolimus was replaced in 2 patients: Sirolimus (n=1) and Cyclosporine (n=1). HLA matching was 6/6 (n=1), 5/6 (n=1) and 4/6 (n=23). The median total nucleated cell (TNC) dose based on pre-cryopreserved sample was 3x10e7/kg (range, 1.9 - 5.3). The median TNC and CD34 cells infused was 2.5x10e7/kg (range, 1.3-4.2) and 1.13x10e5/kg (range, 0.16-3.05) respectively.Day 100 mortality was 16% (CI,6-37%). Cumulative incidence of neutrophil engraftment (NE) was 92% (CI, 62- 99%) and that of platelet engraftment (PE) was 84% (CI, 57- 95%) Figure 1 & 2. The median time of NE was 19 days (range, 13-37) and that of PE was 40 days (range, 24-73). All 23 patients surviving beyond day 10 engrafted their neutrophils. “Transplant Success“ defined by a composite end point (NE by day 26, PE by day 60 and survival at day 100) was 60% (CI,38% -77%). The incidence of acute gvhd (I &II only) was 18% (CI,6-41%) and that of chronic gvhd was 25% (CI10-49%). 9 patients are currently alive at a median followup of 932 days (range, 97-1875 ) .All survivors are gvhd free and off immune suppression.The 2 year overall survival (OS) based on Kaplan Meier estimate is 36 %(CI,18-55%). Figure 3Discussion:Preparative regimen of MFT-rATG results in excellent engraftment, low early mortality and acceptable “Transplant Success” in single unit UD-CBSCT in older adults. Our outcomes in high risk older adults compare favorably to other studies using “double cord” or “cord blood expansion” strategies. [Display omitted] [Display omitted] [Display omitted] DisclosuresNath:Celgene: Consultancy, Honoraria. Off Label Use: Thiotepa,Melphalan,rabbit ATG,Fludarabine, mycophenolate mofetil All these have been used in preparative regimens and gvhd prophylaxis for allogeneic stem cell transplantation. Cerny:Incyte: Consultancy, Honoraria; Ariad Pharmaceuticals: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria.

Readmissions following umbilical cord blood stem cell transplantation.

272 Background: Readmission within 30 days of discharge has been perceived by the Centers for Medicare and Medicaid Services to be an indicator of poor healthcare quality, however it is unclear how accurately this applies to oncology patients. Patients treated with allogeneic hematopoietic stem cell transplantation (HSCT) have high rates of readmission, but the incidence following umbilical cord blood transplantation (UCBT) is poorly described. The goal of this study was to identify the incidence, reasons, and risk factors for readmission following UCBT. Methods: A retrospective review of patients receiving an UCBT at Dana-Farber/Brigham and Women’s Hospital between January 1, 2004 and December 31, 2013 was performed. The 30-day and the day +100, a traditional assessment point in transplantation, readmission rates were examined. Reasons for readmission, as well as sociodemographic and disease and stem cell transplant related variables were evaluated. Predictors of readmission were identified using multivariate regression analysis. Results: 33.6% (42/125) of patients were readmitted within 30 days of discharge. Of patients who survived until day +100, 46.7% (57/122) were readmitted within 100 days of UCBT. The most common cause for readmission was infection (38.3%), followed by fever without a source (14.8%) and graft vs. host disease (GVHD) (8.6%) (Table). A multivariate logistic regression model of the probability of being readmitted within 30 days and by day +100 suggested that infection during transplant admission was a significant risk factor for readmission (OR: 5.1, p=0.003 and OR: 2.9, p=0.014, respectively). Conclusions: There is a high rate of readmission within 30 days and by day +100 following UCBT. The most common causes of readmission were infection and fever without a source. Infection during the transplant admission predicted a higher risk of readmission, suggesting a possible group to target for interventions aimed at reducing readmissions and improving quality of care. [Table: see text]

Haplo-Cord Transplantation Using CD34+ Cells from a Third-Party Donor to Speed Engraftment in High-Risk Patients with Hematologic Disorders

Among the strategies to optimize engraftment of cord blood (CB) stem cell transplantation (SCT), single CB with the coinfusion of CD34+ stem cells from an HLA-mismatched auxiliary donor (haplo-cord) provides a valid alternative for adult patients without a suitable donor. A total of 132 high-risk adult patients with hematological malignancies from 3 Spanish institutions underwent myeloablative haplo-cord SCT. The median age was 37 years and median weight was 70 kg; 37% had active disease. The median number of postprocessing CB total nucleated and CD34+ cells was 2.4 × 107/kg (interquartile range [IQR], 1.8 to 2.9) and 1.4 × 105/kg (IQR, .9 to 2), respectively. Neutrophil engraftment occurred in a median of 11.5 days (IQR, 10.5 to 16.5) and platelet engraftment at 36 days (IQR, 25.5 to 77). Graft failure was 2% overall and only 9% for CB. Cumulative incidence of acute graft-versus-host disease (GHVD) grades II to IV was 21% and cumulative incidence of chronic GVHD was 21%. Median follow-up was 60 months (range, 3.5 to 163). Overall survival was 43.5%, event-free survival was 38.3%, nonrelapse mortality was 35%, and relapse was 20% at 5 years. Myeloablative haplo-cord SCT results in fast engraftment of neutrophils and platelets, low incidences of acute and chronic GVHD, and favorable long-term outcomes using single CB units with relatively low cell content. Moreover, CB cell dose had no impact on CB engraftment and survival in this study. Therefore, haplo-cord SCT expands donor availability while reducing CB cell dose requirements.

Related allogeneic cord blood and bone marrow hematopoietic stem cell transplantation for Fanconi anemia: a case report

Successful cord blood and bone marrow hematopoietic stem cell transplantation for Fanconi anemia described. The feature of this clinical case is using cord blood unit from private cord blood bank. Private cord blood banks in the future can make a significant contribution to the structure of the autologous and allogeneic transplantations in oncohematology.

Cord blood banking and transplantation

A review of articles published since January 2012 on the topic of cord blood banking and cord blood stem cell transplantation was conducted for this the 25th anniversary year of the first cord blood transplant performed in a human. Cord blood banking is performed throughout the world. Umbilical cord blood (UCB) transplantation is recognized as an acceptable alternative stem cell source for paediatric and adults requiring a haematopoietic transplant, particularly for patients of racial and ethnic minorities. To further advance the use of UCB, methods to enhance UCB stem cell expansion, engraftment and maintenance may be required. Controversy on the most effective and economically sustainable model for banking and storing an optimal UCB product continues to persist. Cord blood banking and transplantation of cord blood stem cells has advanced rapidly over the initial 25 years, as more than 30 ,000 patients have benefited from the therapy. New concepts on the use of methods to expand UCB stem cells for transplantation and use for nonhaematopoietic indications may increase demand for UCB over the next few decades.

Treatment of Fanconi Anemia with Transplantation of Umbilical Cord Blood stem Cells: One Case Report and Literature Review

Objective To study the curative effect of transplantation of umbilical cord blood stem cells on Fanconi anemia (FA).Methods One patient with FA aged 15 was enrolled in this study in our center on May 10th 2012.The FA patient was transplanted with umbilical cord blood stem cells.Conditioning procedure included fludarabine (Flu) +-cyclophosphamide (CTX) +-rabbit anti-human T-lymphocyte immunoglobulin (ATG).Therapeutic effect of transplantation was reported with its relevant literature reviewed.Results The times to neutrophil ＞0.50 × 109/L and platelet ＞ 20 × 109/L engraftment were 16 d and 21 d,respectively.At the same,the patient achieved full donor chimerism (FDC).No severe infection and other complications occurred.Conclusions Transplantation of umbilical cord blood stem cells is a safe and effective treatment modality for this FA patient. Key words: Fanconi anemia; Umbilical cord blood; Hematopoietic stem cell transplantation

Clinical analysis of umbilical cord blood stem cell transplantation in the treatment of decompensated hepatic cirrhosis

Objective To observe the clinical effect of umbilical cord blood stem cell transplantation in the treatment of decompensated hepatic cirrhosis .Methods The umbilical cord blood of healthy puerperal women was collected,and stem cells were isolated and injected into liver through hepatic artery to treat 20 patients withdecompensated＆nbsp;cirrhosis.Blood,liver function,coagulation changes ,indicators of clinical symptoms and adverse events were observed after transplantation 1 week,2 weeks,4 weeks and 8 weeks.Results 1 week after transplantation ,the fatigue,loss of appetite situation were improved in more than 80% patients,but the changes were not significant （ t=0.88,0.80, 0.20,0.23,0.56,all P〉0.05）.2 weeks after transplantation,the bloating of 60% patients was improved,ALB in-creased significantly（t=2.03,P〈0.05）.After 4 weeks,the bloating of 70%patients relieved,50%of patients with ascites subsided.ALB,ALT,PT were significantly improved （t=3.84,P 〈0.01;t =1.75,3.02,all P〈0.05）;8 weeks later,75%of patients with ascites subsided .Except for AST was not obvious ,other indicators were improved significantly（t=2.20,2.22,5.93,all P〈0.05）.Except for one case had low fever ,there were no other adverse reac-tions.Conclusion Cord blood stem cell transplantation in the treatment of decompensated cirrhosis can achieve a certain short-term treatment effects , especially in increasing the level of ALB and reducing PT , could resume liver damage and has relatively high security at the same time . Key words: Cord blood stem cells; Hepatic cirrhosis

Pilot trial of risk‐adapted cyclophosphamide intensity based conditioning and HLA matched sibling and unrelated cord blood stem cell transplantation in newly diagnosed pediatric and adolescent recipients with acquired severe aplastic anemia

Cyclophosphamide-based conditioning regimens and allogeneic hematopoietic stem cell transplantation (AlloHSCT) from matched related donors (MRD) has resulted in the highest survival rates in children and adolescents with acquired severe aplastic anemia (SAA). Time to transplant has consistently been associated with decreased overall survival. Reduced toxicity conditioning and AlloHSCT has been used successfully in other pediatric non-malignant diseases. We piloted a risk-adapted AlloHSCT approach, using fludarabine and anti-thymocyte globulin based conditioning with high (200 mg/kg) and low (60 mg/kg) dose cyclophosphamide as upfront treatment in newly diagnosed pediatric patients with acquired SAA incorporating alternative donor sources, including cord blood. Average risk for non-engraftment patients with <10 transfusions received low dose cyclophosphamide (60 mg/kg); High Risk, those with ≥10 transfusions received conditioning regimen with higher intensity cyclophosphamide (200 mg/kg). Seventeen patients were enrolled and underwent AlloHSCT including 12 males and 5 females with mean age of 8 years (range 3-16), and median follow-up time of 39 months (range 1-135). Donor sources included MRD BM (6/6 [n = 9], 5/6 [n = 2]) and unrelated CB (5/6 [n = 4], 4/6 [n = 2]). Five year OS was 67.6% (37.9-85.4). Three secondary graft failures (17.6%) occurred in the low dose cyclophosphamide arm. Upfront treatment with risk-adapted cyclophosphamide conditioning AlloSCT is well tolerated for the management of newly diagnosed pediatric and adolescent patients with acquired SAA. However, the increased risk of graft rejection in the lower dose arm warrants additional research regarding the optimal intensity of cyclophosphamide-based conditioning regimen to reduce toxicity without increasing graft failure.

New Technology May Improve Survival of Blood Cancer Patients Who Require Umbilical Cord Blood Stem Cell Transplants

New Technology May Improve Survival of Blood Cancer Patients Who Require Umbilical Cord Blood Stem Cell Transplants

Celiac Disease Transmitted By Unrelated Cord Blood Stem Cell Transplantation (CBST)

Celiac disease is due to intolerance to certain cereal proteins leading to immune-mediated small bowel villous atrophy and malabsorption. Specifically, the gliadin component of wheat, and the prolamin component of rye and barley are implicated in causing disease. BMT and CBST have been known to transmit immune associated diseases such as diabetes mellitus immune thrombocytopenic purpura from an affected donor to transplant recipient. We observed the occurrence of Celiac disease in a patient a year following cord blood stem cell transplantation (CBST) for acute myelogenous leukemia (AML- FAB M2) in complete second remission (CR-2). The patient had no history of celiac disease prior to CBST nor any family member. The cord donor was HLA-identical unrelated male donor with HLA types: A3, B7 (w6), DR (B1), DR (B5). The family history of the donor was unavailable for celiac disease. The CBST was complicated by grade 2 skin Graft versus Host Disease (GVHD), which responded to steroid therapy. A year post transplantation she developed persistent mucous diarrhea with tinge of blood associated with abdominal cramps. Investigations for infectious causes such as CMV enteritis were negative and colonsocopy did not reveal any evidence of GVHD. Gastrointestinal symptoms persisted and did not respond to steroid and prograf therapy. Subsequent duodenal and jejunal biopsy revealed subtotal villous atrophy with cryptic hyperplasia suggestive of celiac disease. Antigliadin IgA and IgG, reticulin IgA and Endomysial IgA andibodies were elevated. A diagnosis of post-CBST coeliac disease was made. She responded well to gluten-free diet and became symptom-free. A literature review identifies only from donor to recipient one previous example of transmission of celiac disease following HSCT. This case could be the second case of celiac disease following transplantation and the first one post CBST. An association of celiac disease with some HLA types, including DQA1.0501, and DQB1.0201, in conjunction with the haplotypes A30, B18, DR3, DRw52, and DQ2 was recently noted. The donor of this case exhibit HLA DQ A1.0501 and DQ B1.0201 alleles. The findings suggest transfer of celiac disease by cord stem cells and confirm the immune nature of the disease. In addition the propensity to develop T-cell non-Hodgkin lymphoma and transmission of celiac disease by CBST support T cell concept in celiac disease. Autoimmune enteropathy should be considered in patient with persistent diarrhea post hemopoietic stem cell transplant.

Clinical Features of Cutaneous Pre-Engraftment Syndrome in Patients Receiving Umbilical Cord Blood Stem Cell Transplantation

Clinical Features of Cutaneous Pre-Engraftment Syndrome in Patients Receiving Umbilical Cord Blood Stem Cell Transplantation

GRAFT-Versus-Host Disease Clinical Profile and Duration of Immunosuppression Among Patients WHO Received Cord Blood STEM CELL Transplant: A Single Center Experience

inflammatory cells, collagen deposition and expansion of airways in the lung despite showing no sign of acute illness or weight loss. Masson’s trichrome revealed increased fibrosis in the lung (Figure 2), but not in other organs. Conclusion: We have shown that in the NSG mouse, a combination of Cy/TBI with a lownumber of G-CSFmobilized human PBMCs causes chronic lung inflammation and fibrosis that can serve as an important pre-clinic model of lung cGVHD.

Preliminary clinical efficacy and safety of BMN 701, GILT-tagged recombinant human acid alpha glucosidase (rhGAA), in late-onset Pompe disease: results of an extension study

Metachromatic leukodystrophy (MLD) is a lysosomal disorder that results from the deficiency of the lysosomal enzyme arylsulfatase A. It is characterized by motor and developmental regression, seizures, deafness, blindness, dementia and premature death. There are three types of onsets: late infantile, juvenile, and adult. We performed a retrospective chart review of 71 patients (47 infantile, 23 juvenile) evaluated at the Program for Study of Neurodevelopment in Rare Disorders (NDRD) between January 2000 and August 2013. The patients were evaluated prospectively using a standardized protocol. The purpose of the study is to describe the natural course of the disease. In 31 patients only a baseline evaluation was available because they went on to receive umbilical cord blood stem cell transplantation. The data collected was extracted from the NDRD evaluations as well as any outside medical records that provided relevant information regarding symptoms and symptom onset. The results indicate that the patients with the late infantile form show severe deterioration over a short period of 36 months. The first symptoms for the late-infantile onset were reported at amedian age of 16months and included delay inwalking and changes in muscle tone. The median age for the children with juvenile onset was 60 months. While the patients with juvenile onset showed changes in muscle tone, attention and behavior problems were more often cited as the first cause of concern. The median age of diagnosis was 27 and 78.5 months for late-infantile and juvenile onset, respectively. The median age of walking was delayed at a median of 14 months for both groups. First words were reported at a median of 10 months for lateinfantile onset and 12 months for juvenile onset. In conclusion patients with MLD deteriorate very rapidly after the onset of symptoms. Currently there is an unacceptable delay between the parents initial concerns of their child and diagnosis, leaving a very small window of opportunity to treat the patient. Newborn screening will provide the opportunity for early diagnosis but since age of onset could vary recognizing first signs will be extremely important when counseling families about future interventions.

Treatment Adherence and Quality of Life of Thalassemic Children

Thalassemia is a genetic disease in which a defect occurs in the rate of synthesis of α or β chains of hemoglobin leading to premature death of RBCs. Children suffering from thalassemia major may become pale and listless and have poor appetite, unexplained fever within first months after birth. For survival, these children have to undergo blood transfusions every 2–4 weeks depending on the severity of illness combined with iron chelation therapy to remove excess iron from their body due to frequent blood transfusions. These children do not always adhere to the treatment regimen which not only affects their physical health but the overall quality of life and may lead to early death in children. Thalassemia can be cured completely using bone marrow transplantation and cord blood stem cell transplantation. However, this treatment is possible only for a small number of children because of suitable donor and cost of treatment. Care of thalassaemia has been included in 12th Five year Plan of the Government of India. Nurses play a major role in improving the quality of life of children by providing the awareness to parents and children and motivate them to follow the treatment regimen.

乳児ALL 臍帯血移植後にネフローゼ症候群を来した1 例

症例は9 か月男児。生後1 か月時に乳児急性リンパ性白血病と診断され寛解導入療法施行後，6 か月時に非血縁間臍帯血移植を施行。急性GVHD は軽快しシクロスポリン（CsA）を漸減，慢性GVHD 所見は認めず移植後101日目に退院。9 か月時（移植後115 日目），ネフローゼ症候群を来しステロイド内服を開始。しかし改善せず，ステロイド抵抗性ネフローゼ症候群と診断しステロイドパルス療法を3 クール施行し1 歳時（移植後6 カ月）に腎生検を施行。微小変化型と考え，CsA 増量と，ミゾリビン（MZR）を追加したうえでステロイドパルス療法を2 クール施行するが尿蛋白は陰性化を認めなかった。免疫抑制剤を多剤併用しており原疾患の再発も危惧されたが，原疾患がB 細胞性急性リンパ性白血病であったこともありリツキシマブ（RTX）を4 回投与したところ，尿蛋白陰性化し1 歳3 か月時に退院。その後は寛解を維持している。臍帯血移植後ネフローゼ症候群という稀な疾患を経験したため報告する。

StemEx®(Copper Chelation Based) Ex Vivo Expanded Umbilical Cord Blood Stem Cell Transplantation (UCBT) Accelerates Engraftment and Improves 100 Day Survival In Myeloablated Patients Compared To a Registry Cohort Undergoing Double Unit UCBT: Results Of a Multicenter Study Of 101 Patients With Hematologic Malignancies

BackgroundUCBT has proven effective in treating patients with hematologic malignancies (HM),but engraftment is slower and graft failure rates higher compared to other unrelated transplants. We have previously shown that incubation of UCB CD133+ cells with cytokines and the copper chelator TEPA (5µM), inhibits stem cell differentiation and results in a median of 89 and 30 fold expansion of CD34+ and CD34+CD38- cells, respectively (Cytotherapy 2004;6:344). Using this technology (StemEx®) we performed a prospective multicenter myeloablative UCBT trial in patients with HM. MethodologyPatients were transplanted with a single CBU of which CD133+ cells from a segregated portion of the CBU (20-50%) were cultured for 21 days with hematopoietic cytokines and TEPA and transplanted along with a minimum of 107nucleated cells (NC)/kg from the un-manipulated (UM) portion of the same unit (NCT00469729). The primary endpoint of this study was 100 day overall survival. Using an intent to treat design, outcome was compared to a 2006-2010 double UCBT (dUCBT) control group (n = 295) collected from and by the CIBMTR and Eurocord registries using identical eligibility criteria to the StemEx® study: lack of a 5/6 or 6/6 matched sibling donor, age 12-55 years with high risk AML or ALL in 1stCR or subsequent, advanced CML or after failing TKI, MDS with Int-2 or high risk features or chemosensitive relapsed lymphoma. GvHD prophylaxis included a calcineurin inhibitor and mycophenolate mofetil. Comparison of the primary endpoint was based on a logistic regression model that adjusts the treatment comparison for imbalance between the groups in important prognostic factors found to impact mortality: age, sex, CMV status and disease risk. Results25 centers in US, EU and Israel enrolled 101 eligible patients between Oct 2007-Feb 2012 with AML-43, ALL-30, MDS and CML-8 each, and lymphoma-12. Median age was 37 (12.6-55.8); median weight was 68 kg (42.5-128.5). The baseline NC and CD34 cell dose/kg were 3.06 (1.29-11.0) x 107 and 1.64 (0.24-9.23) x 105. 70% of the units were matched at 4/6 loci. Median NC and CD34 fold expansion were 400 (0-764) and 77 (6-280), respectively. StemEx yielded a median of 14-fold increase in the number of CD34+ infused, in comparison to the number of CD34+ cells the patients could have received from the entire UM CBU. In total, patients received a median dose of 2.2 x 107 NC/kg and 9.7 x 105CD34/kg. No significant acute toxicity was seen with the expanded cell infusions.The primary endpoint of this study has been met: 100 day survival was significantly higher in the StemEx® vs control group; 84.2 vs 74.6 % [95% CI 0.5 (0.26-0.95); p = 0.035]. Neutrophil and platelet engraftment rates were faster in the StemEx® vs control group: 21 vs 28 days (p< 0.0001) and 54 vs 105 days (p = 0.008), respectively. There was a trend in the reduction of engraftment failure from 14.4% in the control to 8.1% in the StemEx® group, p=0.086. Early engraftment (EE) (ANC ≤ day 20 and platelets ≤ day 60) was achieved more frequently in StemEx® (39.4%) than in the control arm (12.4%) , p<0.001. EE was associated with improved 100 day survival (p = 0.0028). Grade III/IV aGvHD and cGvHD rates did not differ between the study and control groups (19.4 vs 16.9%; p = 0.107) and 18.4 vs 16.0% (p = 0.731), respectively. Of the 101 patients, 16 patients died in the first 100 days. Causes of death were infection (5), multiorgan failure/ARDS (4), VOD (2) and relapse, acute GvHD, graft failure, hemorrhagic CVA and DIC (1 each). Importantly, the CD34+ cell dose from the StemEx expanded fraction was associated with time to ANC and platelet engraftment (p<0.001, 0.011, respectively) and inversely associated with grade III/IV infections during 100 day post-transplant (p = 0.023). ConclusionsThis multi-international study demonstrated the advantage of StemEx® over dUCBT historical controls,measured by a significant improvement in day 100 survival and faster engraftment of ANC and platelets. The robust associations obtained between CD34+ cell dose derived from the expanded portion and graft functionality provide additional support for the clinical benefit obtained over the dUCBT historical control arm. This technology holds the promise of increasing the number of UCBT being performed while potentially reducing its short term morbidity and mortality. Disclosures:Stiff:Gamida Cell Ltd: Consultancy, Honoraria, Research Funding. Peled:Gamida Cell: Employment. Landau:Gamida Cell Ltd: Employment. Rosenheimer:Gamida Cell Ltd: Employment. Mandel:Gamida Cell LTd: Employment. Hasson:Gamida Cell Ltd: Employment. Olesinski:Gamida Cell Ltd: Employment. Glukhman:Gmaida Cell Ltd: Employment. Snyder:Gamida Cell Ltd: Employment. Galamidi Cohen:Gamida Celll Ltd: Employment. Kidron:Gamida Cell Ltd: Employment. Bracha:Gamida Cell Ltd: Employment. Harati:Gamida Cell Ltd: Employment. Ben-Abu:Gamida Cell Ltd: Employment. Freind:Gamida Cell Ltd: Employment. Freedman:Gamida Cell Ltd: Consultancy. Olmer:Gamida Cell Ltd: Consultancy. Barishev:Gamida Cell Ltd: Consultancy. Nagler:Gamida Cell Ltd: Consultancy, Research Funding. Sanz:Gamida Cell Ltd: Consultancy, Honoraria, Research Funding.

CD133 Is a Positive Marker Of Human Cord Blood-Derived CD34-Negative Hematopoietic Stem Cells

BackgroundWe have previously identified very primitive human cord blood (CB)-derived CD34-negative (CD34-) severe combined immunodeficiency (SCID)- repopulating cells (SRCs) using the intra-bone marrow injection (IBMI) method (Blood 2003:101;2924). A series of our studies suggests that the identified CD34- SRCs are a distinct class of primitive hematopoietic stem cell (HSC) and that they are at the apex of human HSC hierarchy. Recently, we developed a high-resolution purification method for primitive CD34- SRCs using 18 lineage (Lin)-specific antibodies, which can enrich CD34- SRC at 1/1,000 level (Exp Hematol 2011: 39:203). In the present study, we tried to identify the positive marker of CD34- SRCs in order to further purify and characterize the CD34- SRCs (HSCs). Materials and MethodsFirst, we extensively analyzed candidate positive markers, including known HSC markers and various adhesion molecules by FACS using highly purified CB-derived 18Lin-CD34+/- cells. Finally, we identified CD133 as a positive marker of human CB-derived CD34- SRCs. Then, CB-derived 18Lin- CD34+/-CD133+/- cells were sorted by FACS, and hematopoietic stem/progenitor cell (HSPC) capacities of these four fractions of cells were extensively investigated. HSPC capacities were evaluated using (1) colony-forming cell (CFC) assays, (2) measurement of maintenance/production of CD34+ cell capacities in co-cultures with human bone marrow-derived mesenchymal stromal cells (BM-MSCs) (Blood 2010:24:162), (3) SRC activities using NOG mice, (4) limiting dilution analyses (LDA) to determine the SRC frequency in the 18Lin-CD34-CD133+ fractions, and (5) comparison of gene expression profiles between 18Lin-CD34+/-CD133+/- cells by real-time RT-PCR. ResultsSeventy-five percent of 18Lin-CD34+ and 13.5% of 18Lin-CD34- cells highly expressed CD133. In the CFC assays, the plating efficiencies of 18Lin-CD34+CD133+, CD34+CD133-, CD34-CD133+ and CD34-CD133- cells were 57%, 65%, 39% and 19%, respectively. Interestingly, most of 18Lin-CD34-CD133+/- cells formed erythroid-bursts (71% and 73%) and erythro/megakaryocytes-containing mixed colonies (25% and 27%). On the contrary, they formed few granulocyte/macrophage colonies (4.2% and 0%). Then, we co-cultured these four fractions of cells with human BM-MSCs. One thousand of 18Lin-CD34+/-CD133+/- cells were seeded into each well and cells were co-cultured for 7 days in the presence of SCF+TPO+FL+IL-3+IL-6 +G-CSF. Both the 18Lin-CD34-CD133+/- cells produced CD34+ cells. However, the percentage and absolute number of CD34+ cells produced from 18Lin-CD34-CD133+ cells (31.7 % and 3.2 x 104 cells) were greater than those of 18Lin-CD34-CD133- cells (13.2 % and 0.4 x 104 cells). In addition, both the 18Lin-CD34- CD133+/- cells generated higher percentages (13.5 % and 11.5%) of CD41+ cells compared to those of the 18Lin- CD34+CD133+/- (1.8% and 4.2%) cells. Collectively, 18Lin-CD34+/-CD133+/- cells showed different in vitro lineage differentiation potentials. Then, these four fractions of cells were transplanted into NOG mice by IBMI. We performed primary and secondary transplantations for up to 36 weeks. In the results, all of the mice received 18Lin-CD34+CD133+ cells (n = 5) or 18Lin-CD34-CD133+ cells (n = 9) showed primary and secondary human CD45+ cell repopulations. However, neither 18Lin-CD34+CD133- cells nor 18Lin-CD34-CD133- cells showed human cell repopulations (n = 6 in each group). These results clearly demonstrated that the CD133 expression clearly segregated SRC activities in the 18Lin-CD34+/- cells. Moreover, LDA demonstrated that the frequency of SRCs in the 18Lin-CD34-CD133+ fraction was 1/142. Interestingly, HSC self-renewal maintenance genes, such as Notch1, HoxB4, HoxA9, and Bmi-1, were highly expressed in both 18Lin-CD34+/-CD133+ cells. ConclusionThese results clearly demonstrated that CD133 is a positive marker of human CB-derived CD34- SRCs (HSCs). Furthermore, CD133 segregated SRC activities of 18Lin-CD34- as well as 18Lin-CD34+ cells in its positive fractions. More importantly, these findings suggest that number of CD133+ cells in cord blood units is a more appropriate marker to detect/predict HSC potentials in cord blood stem cell transplantation in comparison to currently used CD34+ cell numbers. Disclosures:No relevant conflicts of interest to declare.

Single Cord Blood Transplantation Combined With An HLA Mismatched Third Party Donor For High-Risk Hematological Patients With HIV Infection

BackgroundThe safety and usefulness of unrelated umbilical cord blood (CB) stem cell transplantation (SCT) in patients candidates for allogeneic SCT and HIV infection is unknown. Single CB with the co-infusion of CD34+ cells from a third party HLA-mismatched donor (TPD), or Haplo-cord SCT, has shown to reduce the period of post-transplant neutropenia and related early complications associated with single CB transplantation. This platform could potentially reduce the risk of early infections in this particular group of patients. On the other hand, the use of a cell source homozygous for the CCR5 delta32 allele mutation, which confers high resistance against HIV-1 acquisition, is of particular interest in HIV+ patients. Methods and ResultsWe report here on the first two patients with HIV infection and high-risk haematological malignancies who underwent haplo-cord SCT in two different centers: (Case 1) a 53 year-old male patient with high-risk MDS; (Case 2) a 34 year-old male with Burkitt lymphoma in CR2. Both CB transplants were performed using the haplo-cord platform with the co-infusion of mobilized and selected CD34+ cells from a TPD. Conditioning regimen were myeloablative in both cases. Case 1 had the additional potential benefit from the use of a CB unit with the homozygous CCR5delta32 mutation. Both cases achieved neutrophil and platelet engraftment similarly to previous haplo-cord SCT performed in HIV negative patients, as well as full CB chimerism. However, case 1 developed beside a severe lung infection, relapse of the underlying malignancy 2 months after SCT and died consequently. Case 2 presented one episode of bacterial sepsis with good response to antibiotics, and one episode of CMV reactivation controlled with valgancyclovir. Thirteen months after SCT, this patient is alive and in CR. Extensive analyses of viral and immunological compartments were performed showing the early viral dynamics in both patients. ConclusionsCB SCT is feasible in patients eligible for allogeneic SCT and HIV infection. The haplo-cord strategy with the co-infusion of auxiliary cells from a TPD seems to offer a fast neutrophil engraftment similarly to HIV negative patients. Therefore, this strategy should be considered in patients with HIV infection and indication for allogeneic SCT, whenever CB is the source of choice and especially if a CCR5 mutated unit is available. Disclosures:Kuball:Miltenyi: GMP product development Other.

Comparison Of Unrelated Cord Blood (CB) and Peripheral Blood Stem Cell (PB) Transplantation In Adults With Myelodysplastic Syndrome (MDS) After Reduced Intensity Conditioning Regimen (RIC): A Collaborative Study From Eurocord and Chronic Malignancies Working Party (CMWP-EBMT)

BackgroundOutcome of patients with intermediate or high risk IPSS myelodysplastic syndrome (MDS) is poor in the absence of hematopoietic stem cell transplantation (HSCT). Choice of the best stem cell source is debated in this poor risk population. Unrelated cord blood transplantation (UCBT) has been used for patients lacking an HLA identical donor. This is the first study comparing well matched unrelated adult peripheral blood (PB) stem cell transplant to mismatched UCBT for patients with MDS. MethodPatients with MDS transplanted from 2005 to 2011 with either unrelated CB or PB receiving a reduced intensity conditioning (RIC) were included. All PB donors were Human Leucocyte Antigens (HLA)-allele matched (10/10) or one allele mismatched (9/10) (-A, -B, -C, DRB1, -DQB1). Overall survival (OS) and disease-free survival (DFS) were estimated by Kaplan-Meier. Relapse incidence (RI), non-relapse mortality (NRM), engraftment, acute and chronic graft-versus-host disease (GVHD) were calculated using cumulative incidence (CInc) methods. Risk factors for outcomes were analyzed by Cox and Fine & Gray models. Results502 patients transplanted with PB or 129 with CB (80 with double units) were compared. Among the PB recipients, 363 (72%) were 10/10 matched and 123 (25%) 9/10 matched. Most CB (98%) recipients had at least one HLA mismatch on 6 antigens tested (-A, -B antigen level and DRB1 allelic level), 32% had one mismatch and 66% had 2 mismatches. Median follow-up was 12 months for PB and 24 months for CB. MDS was transformed into AML in 416 patients. MDS WHO classification was: RA in 37, RCMD in 31, RAEB1 in 50 and RAEB2 in 87 and unclassified in 10 patients. Considering only patients with MDS, cytogenetic according to IPSS was: good in 96, intermediate in 57 and poor in 65 patients. PB and CB groups were different for age, gender, incidence of secondary AML (CB: 71% vs PB: 64%) and conditioning regimen. CInc of engraftment was lower in CB patients, 78 vs 96% (p<0.0001). Grade II to IV acute GVHD was 29% and 31% for PB and CB. Chronic GVHD was more frequent after PB (42% vs 23%, p=0.001). The unadjusted 2-year OS and DFS were better in patients transplanted with PB (46% vs 30% and 43% vs 28%, p=0.0001). There was no statistical difference for OS and DFS between single and double UCBT. RI was not significantly different (25 vs 30%, p=0.09) whereas NRM was higher in patients transplanted with CB (42 vs 33%, p=0.02). In multivariate analysis, OS (Hazard ratio (HR): 0.59, 95% confidence interval (CI): 0.44-0.80) and DFS (HR: 0.57, 1.89, 0.79) were higher in patients transplanted with PB compared to CB. Furthermore, after adjustment, CB was also a risk factor for higher NRM ((PB, HR: 0.55, 95%CI: 0.37-0.80) and RI ((PB, HR: 0.62, 95%CI: 0.39-0.97).The analyses were performed using 3 groups of patients according to donor HLA type: PB 10/10, PB 9/10 and CB. The unadjusted 2-year OS and DFS were better with PB 10/10 than with PB 9/10 or CB: 49%, 37% and 30% (p=0.0001) and 45%, 36%, 28% (p<0.0001), respectively. NRM was not significantly different between CB and PB 9/10: 42% vs 36%. RI was similar after CB and PB 9/10: 28% vs 30%. Chronic GVHD was significantly lower after CB (PB 9/10: 37% vs CB 23%, p=0.004). The multivariate analysis showed an advantage of OS for PB 10/10 compared to PB 9/10 (HR: 1.45, 95%CI: 1.06-1.97, p=0.02) whereas there was no significant difference between PB 9/10 and CB (HR: 1.24, 95%CI: 0.84-1.83, p=0.29). Likewise, DFS was better after PB 10/10 (HR: 0.57, 95%CI: 0.43-0.77, p=0.05) and it was similar after PB 9/10 or CB (HR: 1.34, 95%CI: 0.92-1.97, p=0.13). In the 9/10 PB no differences in the results were observed according to the specific mismatched locus (A, B, DRB1, vs C, DQB1) ConclusionDespite the limitation of a retrospective registry based study and the short term follow up, our study shows that transplants with PB from matched unrelated donor gives the best outcomes. In the absence of a 10/10 unrelated matched PB donor, a 9/10 PB donor or mismatched CB give similar results. Therefore, for MDS patients without a HLA 10/10 unrelated donor a 9/10 regardless of the specificity of the locus where the mismatch occurs mismatched HLA locus or a HLA mismatched CB are both alternative options for transplantation. Disclosures:Gluckman:Cord use: Honoraria; gamida: Honoraria.