Cord Blood Transplantation In Children Research Articles

Incidence and Risk Factors of Chronic Graft-Versus-Host Disease After Unrelated Cord Blood Transplant In Children and Adults. A Retrospective Study on Behalf of EUROCORD and Late-Effect Working Party of EBMT

AbstractAbstract 219Chronic GvHD disease (cGvHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplant. Unrelated cord blood transplant (UCBT) is associated with a reduced incidence of chronic GvHD when compared to other sources of stem cells, however risk factors analysis for incidence is scarce in the literature. We retrospectively analyzed 792 patients, 447 children (age<18) and 345 adults, receiving first single (n=667) or double UCBT (n=125) in EBMT centers, between 1994 and 2009, for malignant and non-malignant diseases, who engrafted and survived at least 100 days from transplantation. Median age was 13 years (0.1-68); the most common disease was acute leukemia (62%), 18% of patients were transplanted for a non-malignant disease. Conditioning regimen was myeloablative (MAC) in 79% of cases (TBI>6Gy in 30%), RIC in 21%. Busulphan-based conditioning was used in 50% and ATG was added in 81% of cases. CsA+steroid was the most common GvHD prophylaxis (49%); CsA+mycophenolate mofetil was used in combination in 46% of adults. Eleven percent of units were HLA-identical (antigen level for HLA-A and B, allelic for DRB1), while 39% and 50% had 1 or 2–3 mismatches, respectively. Median total nucleated cell (TNC) infused was 4.5−107/kg. Median follow-up was 39 months (3-158). Cumulative incidence (CI) of cGvHD at 2 years in the whole population was 31±2% (n=251). Chronic GvHD was extensive in 53% of children and adults. Regarding cGvHD organ involvement, skin and gastro-intestinal tract were the most frequent organ affected, 64% and 38% of cases respectively followed by liver (15%) and lung involvement (7%). Eighty-six percent of patients were treated with systemic therapy. Out of 251 patients who developed cGvHD, 137 had previously acute GvHD (77 out of 113 children and 60 out of 138 adults). Factors associated with a decreased incidence of cGvHD were: 0–1 HLA mismatched units (p<0.001) and age<18 years (p<0.001). In fact, CI of cGvHD at 2 years was 24±2% in children and 40±3% in adults. Therefore, risk factors analysis was performed separately for children and adults. In children, in multivariate analysis, factors associated with decreased incidence of GvHD were: age less than 5 years at transplant (HR=0.64, p=0.01), TBI based-conditioning (HR=0.5, p=0.003) and no previous aGvHD (HR=0.24, p<0.001). In adults, in multivariate analysis, 0–1 HLA mismatched grafts (HR=0.86, p=0.016), TNC infused >2.2 ×10â‹€7/kg (HR=0.6, p=0.016) and no previous aGvHD (HR=0.49, p<0.001) were independent factors associated with a decreased incidence of cGvHD. At 3 years, CI of transplant-related mortality (TRM) after 100 days was 15±2% and 30±3% in children and adults respectively. Chronic GvHD, analyzed as time dependent variable, was an independent factor associated with an increased TRM in children (HR=3.03, p<0.001) and adults (HR=2.04, p=0.001). Estimated overall survival (OS) at 3 years after 100 days of UCBT was 71±2% and 49±3% in children and adults respectively. In multivariate analysis, in children factors independently associated with a decreased OS were: presence of chronic GvHD (HR=1.5, p=0.039), malignant disease (HR=2.26, p=0.001) and patient's CMV positive serology (HR=1.54, p=0.014). In adults, factors decreasing OS were: chronic GvHD (HR=1.42, p=0.042), advanced phase of disease (HR=1.5, p=0.016) and TNC infused <2.8 ×10â‹€7/kg (HR=1.4, p=0.045). Two hundred ninety-four patients died, in 39% of cases deaths were related to relapse of original disease, 53% to transplant related causes. In conclusion, after UCBT, incidence of cGvHD was decreased in children compared to adults, however the frequency of limited and extensive cGvHD was the same in both groups. An increased risk of cGvHD was associated with previous acute GvHD in both groups, whereas it was associated in children with older age (>5 years) and no use of TBI, and in adults with a mismatched CB unit (4/6 or more) and TNC infused <2.2 ×10â‹€7/kg. In children as well as in adults UCBT recipients, chronic GvHD increases TRM and decrease OS. Further prospective studies should evaluate better GvHD prophylaxis after UCBT. Disclosures:No relevant conflicts of interest to declare.

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

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

Impact of Viable CD45 Cells Infused on Lymphocyte Subset Recovery after Unrelated Cord Blood Transplantation in Children

We studied lymphocyte recovery in 88 children who consecutively underwent unrelated cord blood transplantation for malignant (n = 64) or nonmalignant (n = 24) diseases. All children but 3 received myeloablative conditioning regimens with pretransplant antithymocyte globulin. Median age was 5.6 years (0.1-18 years) and median follow-up was 40 months (10-136 months). The median dose of infused viableCD45(+) cells (vCD45) was 3.35 × 10(7)/kg with a ratio infused vCD45/collected total nucleated cell at 0.46. Immunologic endpoints were: time to achieve CD3(+) >500 and 1500/mm(3), CD4(+) >500/mm(3), CD8(+) >250/mm(3), CD19(+) >200/mm(3), natural killer >100/mm(3). These endpoints were analyzed through the use of cumulative curves for estimating incidence over time in the context of competing risks, and through Fine and Gray models to assess prognostic factors. The median time to reach these endpoints was 33, 97, 214, and 340 days for natural killer, B, CD8, and CD4 cells, respectively. In multivariate analysis, a high infused vCD45 cell dose improved CD3 (P = .014) and CD4 (P = .032) reconstitutions. A young recipient age also favored CD3 recovery (P = .013). With patients grouped according to vCD45 cell dose quartiles, the threshold for a better recovery was 3.35 × 10(7)/kg. Considering the ratio vCD45/TNC, this "immune recovery based" threshold corresponds to a higher cell dose than the minimum usually recommended dose for myelogenous engraftment. This may have important implication for UCB selection.

Double umbilical cord blood transplantation for children and adolescents

Umbilical cord blood transplantation (UCBT) with two units has been conducted with promising results in adults to overcome the limitation of low cell numbers. In an attempt to improve the outcomes, double UCBT was performed in children and adolescents. Sixty-one patients, including 44 acute leukemia, and 17 other hematologic diseases, received double UCBT. Donor-type engraftment achieved in 82% of patients. Except one patient with persistent mixed chimerism of two units, other 49 patients showed dominancy of one unit and only the CFU-GM was significant factor influencing dominancy. The event-free survival (EFS) of leukemia and other hematologic disease were 59% and 53%, respectively, and the EFS of acute leukemia patients who received transplant in first or second CR (68.6%) was significantly better than in those with advanced disease (22.2%) (P = 0.007). Among the factors influencing outcomes, low cell dose difference between two units (TNC difference/TNC of large unit <15%) were associated with higher TRM, relapse, and lower EFS. Double UCBT was a promising modality of transplant in children and adolescence. However, engraftment and other results were not so satisfactory yet. To improve the outcomes, development of new selection guideline, probably including cell dose difference between two units and technology to enhance engraftment and reduce transplantation-related mortality are warranted.

Comparison of Pre-Cryopreserved and Post Thaw and Wash Total Nucleated Cell Count On Major Outcomes Following Unrelated Cord Blood Transplant in Children.

Abstract 3336Poster Board III-224Engraftment and overall survival after umbilical cord blood transplant is highly dependent on the total nucleated cell count (TNC). Current standard post thaw processing includes a wash step to remove dimethyl sulfoxide (DMSO), lysed red cells and stroma. The contribution of the wash step to cell loss and ultimately the dose of cells available for transplant is not well described. To investigate the amount of cell loss after washing and its impact on major outcomes compared to pre-cryopreserved TNC, we analyzed data from 310 patients prospectively enrolled on a National Heart Lung Blood Institute (NHLBI) sponsored cord blood transplant study between 1999 and 2003. Dataset was obtained after signed agreement with the NHLBI and local IRB approval. There were 310 patients ≤18 years of age with malignant (N=217) or non-malignant (N=93) disease enrolled on this trial. Only single cord units were used. All cord blood units were thawed and washed using an identical process developed by Rubinstein et al. All patients received myeloablative preparative regimen with either total body irradiation or busulfan based regimens with cyclosporine and prednisone GVHD prophylaxis. All patients received anti-thymocyte globulin as part of their conditioning regimen. For the overall survival, Cox proportional hazard models were generated for pre-wash cell dose and post-wash cell dose separately and then combined in one model. All models included identical covariates. Total cell dose was modeled as a continuous variable with appropriate transformation using restricted cubic lines to account for non-linear relationships. For transplant related mortality (TRM) and neutrophil engraftment, competing risk analyses were used. These analyses were done with adjustment for age, gender, disease (malignant versus nonmalignant), performance status (<90 versus ≥90), HLA (3-4/6 versus 5-6/6 match), and CMV status. The median age was 4.59 years (range 0.04 – 17.90) with 188 (61%) male, 249 patients (80%) had a performance status of ≥90. 166 patients (54%) received a cord blood unit matched at 3/6 or 4/6 HLA antigens and 144 patients (46%) received a cord blood unit matched at 5/6 or 6/6 HLA antigens. The median pre-cryopreserved TNC per kg was 6.93 × 107/kg (range 1.5-80.9 × 107/kg). The median TNC recovery after thawing and washing (PTW) was 5.43 × 107/kg (range 1-31.6 × 107/kg). The average cell recovery was 89% after thawing and washing. Neutrophil engraftment was significantly associated with higher pre-cryopreserved (p=0,003) and PTW TNC infused (p=0.005); younger age (p=0.03), better HLA match (p=0.03). The risk of transplant related mortality was significantly higher among older patients (p=0.02), female patients (p=0.02) and those receiving 3-4/6 HLA matched cord units (p=0.02). Neither the pre-cryopreserved or PTW TNC were significant contributing factors. The risk of grade II-IV acute GVHD was significantly higher among older patients (p=0.04) and those receiving higher pre-cryopreserved TNC (p=0.02) but not higher PTW TNC (p=0.07). Overall survival was significantly better among younger patients (p=0.02), male recipients (p<0.001), patients with non-malignant diseases (p<0.001), patients with performance status >90 (p=0.04) and those receiving 5-6/6 HLA matched cord units (p=0.04). Pre-cryopreserved and PTW TNC did not influence overall survival. In conclusion, pre-cryopreserved and post thaw and wash TNC were equally predictive for major outcomes of unrelated cord blood transplant in children. DisclosuresNo relevant conflicts of interest to declare.

The Effect of Obesity On Outcome of Unrelated Cord Blood Transplant in Children with Malignant Diseases.

Abstract 2278Poster Board II-255Obesity has become a pandemic in the US, affecting both children and adults. In the adult population, evidence suggests that obesity has an adverse impact on outcomes of hematopoietic stem cell transplant for various malignancies. We investigated the influence of obesity on children undergoing unrelated cord blood transplant utilizing data from the Cord Blood Transplant Study. To our knowledge, no data exists on the effect obesity has on key prognostic indicators for cord blood transplant for malignant diseases in children. There were 191 patients '18 years of age with malignant diseases prospectively enrolled on a National Heart Lung Blood Institute (NHLBI) sponsored cord blood transplant study between 1999 and 2003. Data set was obtained after signed agreement with the NHLBI and local IRB approval. All patients received myeloablative preparative regimens with either total body irradiation and cyclophosphamide (N=172) or busulfan and melphalan (N=19). In addition, all patients received anti-thymocyte globulin as part of their conditioning regimens. Graft versus host disease (GVHD) prophylaxis included cyclosporine and prednisone. Children were classified into groups according to body mass index (BMI) percentile. Normal weight was defined as BMI between the 5th and 85th percentile, overweight between the 85th and 95th percentile, obesity above 95th percentile for age and gender according to the Center for Disease Control and Prevention (CDC) guidelines. For the overall survival (OS) and disease free survival (DFS), the Cox regression model was used to test the effect of BMI while controlling for age, gender, performance status (<90 versus ≥90), HLA match (≤4/6 versus ≥5/6 HLA match), total nucleated cell count (TNC) per kg infused and CMV status. For neutrophil and platelet engraftment, transplant related mortality (TRM), grade II-IV acute GVHD, and chronic GVHD, competing risks regression analyses were used to test effect of BMI while controlling for other covariates. The median age was 7.59 years (range 2.07 – 17.90) with 113 (59%) male. 160 patients (84%) had a performance status of ≥90. 51 patients (27%) had acute myelogenous leukemia (AML), 109 patients (57%) had acute lymphoblastic leukemia (ALL) and 30 patients (16%) had other malignant diseases. 119 patients (62%) received a cord blood unit matched at 3/6 or 4/6 HLA antigens and 72 patients (38%) received a cord blood unit matched at 5/6 or 6/6 HLA antigens. The median TNC per kg infused was 5.2 × 107/kg (range 0.15-80.9 × 107/kg). Of the 191 total patients who were classified by their BMI percentiles, 117 patients (61%) were normal weight, 35 patients (18%) were overweight and 39 patients (20%) were obese. The two groups were not significantly different in sex distribution (p=0.25), diagnosis (p=0.13), performance status (p=0.91), median TNC received (p=0.49) or CMV status (p=0.47). Obese patients were significantly younger with a median age of 5.7 years compared to 8.9 years in normal weight children (p=0.002). Time to neutrophil and platelet engraftment, TRM, risk of grade II-IV acute GVHD, DFS and OS were not significantly different in overweight or obese patients compared to normal weight patients. There was a trend towards increased risk of chronic GVHD in obese patients (p=0.045) compared to normal weight patients. In conclusion, obesity has no significant effect on multiple outcomes after unrelated cord blood transplant in children with malignant diseases. Disclosures:No relevant conflicts of interest to declare.

Improving cord blood transplantation in children

Umbilical cord blood transplantation (UCBT) is widely used to treat children affected by many disorders. In comparison to bone marrow transplantation, the advantages of UCBT are represented by lower incidence and severity of graft-versus-host disease, easier procurement and prompter availability of cord blood cells, and by the possibility of using donors showing human leucocyte antigen disparities with the recipient. Despite these advantages, the large experience gained over the last decade has clearly demonstrated that UCBT patients may be exposed to an increased risk of early fatal complications, due to the lower engraftment rate of donor haematopoiesis, delayed kinetics of neutrophil recovery and lack of adoptive transfer of pathogen-specific memory T-cells. An inverse correlation between the number of nucleated cord blood cells infused per kilogramme recipient body weight and the risk of dying from transplantation-related causes exists. Thus, it is not surprising that strategies aimed at increasing the number of cord blood progenitors, favouring stem cell homing, and transferring pathogen-specific lymphocytes, have been recently investigated. In particular, selection of the richest cord blood units, infusion of 2 units in the same recipient, intrabone injection of cord blood cells, and transplantation of ex-vivo expanded progenitors can contribute to improve the results of UCBT.

Unrelated cord blood transplantation in children with severe congenital neutropenia

SCN is an inherited hematological disorder with severe neutropenia and recurrent infections. Although there are some reports that recombinant rhG-CSF improves clinical outcome, allogeneic HSCT appears to be the only curative treatment for these patients. We report here two children with SCN successfully treated by CBT from unrelated donors. They were refractory to rhG-CSF treatment and have no identical family donor. Bu + CY were given as conditioning. Case 1 and Case 2 received 6/6 and 5/6 HLA-matched unrelated umbilical cord blood, respectively. The number of infused nucleated cells was 6, 18 x 10(7)/kg and CD34(+) cell number was 3, 74 x 10(5)/kg in Case 1. Those cell numbers were 8, 8 x 10(7)/kg and 5, 34 x 10(5)/kg for Case 2, respectively. Neutrophil/platelet engraftments were 45/49 days in Case 1 and 24/36 days in Case 2. Grade II cutaneous acute GVHD was seen in Case 2 that was treated successfully with prednisolone. Both patients are well with normal hematological findings and full donor chimerism for post-transplant 20 and 24 months, respectively. We conclude that UCB can be considered as a safe source of stem cell in patients with SCN who need urgent HSCT.

Unrelated umbilical cord blood transplantation in children with immune deficiency: results of a multicenter study

In the absence of a related donor, unrelated cord blood transplant (CBT) may be a potential option for patients with a primary immune deficiency (PID). Most published experience consists of single-center data using multiple preparative regimens and GVHD prophylaxis. We report the results of a multicenter prospective trial of unrelated CBT for PID. A total of 24 children with PID, with a median age of 1 year (range: 0.23-7.81 years) and a median weight of 10.5 kg (range: 4-24.4 kg) received unrelated CBT between 1999 and 2003. All patients received a fully ablative conditioning regimen with identical GVHD prophylaxis and supportive care. Most patients (79%) received a 1 or 2 HLA Ag-mismatched cord unit with a median nucleated cell infused of 9.3 x 10(7)/kg (range: 1.0-31.2) and a median CD34 of 2.7 x 10(5)/kg 2.9 (range: 0.6-84.5). The cumulative incidence of neutrophil engraftment by day 42 was 58% (95% CI: 38-79%) at a median of 19 days. Cumulative incidence estimates of grade III-IV acute GVHD at day 100 and chronic GVHD at 1 year were 29% (95% CI: 10-48%) and 24% (95% CI: 3-44%), respectively. The probability of survival at 180 days and 1 year was 66.7% (95% CI: 44.3-81.7%) and 62.5% (95% CI: 40.3-78.4%), respectively. Unrelated CBT should be considered in children with PID.

Unrelated cord blood transplantation in children with idiopathic severe aplastic anemia

Early results of unrelated cord blood transplantation (UCBT) for severe aplastic anemia (SAA) were poor with a high rate of engraftment failure. This was attributed to the combination of lower graft cell dose and intact host immune system. We performed UCBT in nine children (median age 9 years) with refractory SAA using increasingly immunosuppressive preparative regimens. The time from diagnosis to UCBT was 3.4-20 months (median age 7.2 years), with all children having failed at least one course of immunosuppression. Donor/recipient HLA matching was six of six (n=1), five of six (n=2) and four of six (n=6). The median nucleated cell dose infused was 5.7 x 10(7) cells/kg (range 3.5-20 x 10(7) cells/kg). Six patients were engrafted after the first UCBT. Two of the three patients without hematopoietic reconstitution were engrafted after a second UCBT. All children receiving >or=120 mg/kg of CY in the preparative regimen were engrafted. The median time to myeloid engraftment was 25 (17-59 days) days. Acute GVHD developed in two, and chronic GVHD in five patients. Five patients developed EBV viremia post transplant (lymphoproliferative disorder in three patients). At a median follow-up of 34 months, seven patients are alive and transfusion-independent. UCBT is a feasible treatment strategy for children with refractory SAA lacking a well-matched adult donor.

Indications and results of cord blood transplant in children with leukemia

Umbilical cord blood transplant (UCBT) is now used more frequently for transplanting children with high-risk malignancies. The advantages are the rapid availability of donor cells, the possibility of using HLA-mismatched transplants and the decreased risk of acute and chronic GvHD. The Eurocord registry has collected and analyzed data on unrelated CBTs performed in European Blood and Marrow Transplant Group (EBMT) and non-EBMT centers. The literature shows that after UCBT relapse rate (RR), disease-free survival and overall survival of children with acute leukemia are similar to other hematopoietic stem cell sources (matched unrelated BM). Disease status at the time of transplantation is found in several studies to be a very important determinant of long-term outcome. In conclusion, UCB is a valuable alternative source of hematopoietic stem cell transplantation in children with acute leukemia who need an allogeneic transplant, but lack a suitable sibling donor.

58: Risk Factor Analysis of Outcomes After Unrelated Cord Blood Transplantation for Children with Hurlers Syndrome. An EUROCORD-Duke University Collaborative Study

58: Risk Factor Analysis of Outcomes After Unrelated Cord Blood Transplantation for Children with Hurlers Syndrome. An EUROCORD-Duke University Collaborative Study

Cord Blood Transplantation from Unrelated Donors for Children with Acute Lymphoblastic Leukemia in Japan: The Impact of Methotrexate on the Clinical Outcome.

Cord blood transplantation (CBT) became one of the important alternatives in allogeneic stem cell transplantation for children with hematological malignancies. We have analyzed the clinical outcomes of CBT for children with acute lymphoblastic leukemia (ALL) in Japan and identified risk factors of transplant outcome, when they had no prior transplant. From 1997 to 2006, total 332 children with ALL have undergone CBT from unrelated donor and 270 of them had no prior transplant. They are 0–15 yrs (median 5) and 4 to 60kg of body weight (median 18). Serological disparities of HLA for graft-versus-host disease (GVHD) direction were 0(n=54), 1(n=168) and 2(n=47), and disease status at transplant were 1st complete remission (CR) (n=120), 2nd CR (n=71), and more advanced stages (n=75). The median number of nucleated cells in cord blood unit was 4.93×107/kg (1.35–24.9), and that of CD34+ cells was 1.53×105/kg (0.17–15.0). As preconditioning, total body irradiation (TBI) was given in 194 patients and methotrexate (MTX) was given as GVHD prophylaxis in 159 patients. The neutrophil engraftment was achieved in 88.5% (95%CI: 84.1–91.8%) of patients and platelet engraftment (>50k) was obtained in 72.6% (95%CI: 66.8–77.7). The incidence of grade II–IV and III–IV acute GVHD was 45.6% (95%CI: 39.5–51.4) and 20.4% (95%CI: 15.8–25.4) respectively. Non-relapse mortality was observed in 22.6% (95%CI: 17.7–27.8) and 35.2% (95%CI: 29.2–41.3) of patients relapsed after CBT. The five year event free survival (EFS) of all patients was 38.1% (95%CI: 34.9–41.3); 47.4%(95%CI: 42.4–52.4) in 1st CR, 45.5%(95%CI: 38.9–52.1) in 2nd CR and 15.2%(95%CI: 10.8–38.9) in more advanced stages, respectively. The multivariate analysis revealed that the larger number of CD34+ cells (p<0.01) and administration of granulocyte colony stimulating factor after CBT (p<0.01) were associated with earlier neutrophil engraftment. Preconditioning with TBI (p<0.01) and absence of MTX (p=0.037) significantly affected the development of grade II-IV acute GVHD. Advanced disease at transplant was the most predominant factor for leukemic relapse (p<0.01). GVHD prophylaxis with MTX (p=0.042), less allele mismatches (p=0.013) and disease status of 1st and 2nd CR at transplant (p<0.01) were significantly associated with better EFS. Our results showed the favorable effect of MTX for the development of acute GVHD and EFS. In conclusion, GVHD prophylaxis including MTX is important in CBT for children with ALL.

Unrelated Cord Blood Transplantation for Children with Juvenile Myelomonocytic Leukemia.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment for children with juvenile myelomonocytic leukemia (JMML). A recent study from the European Working Group of MDS in Childhood (EWOG-MDS) reported a 5-year probability of event free survival of 55% (n=48), and 49% (n=52) in children transplanted from either an HLA identical sibling or an unrelated volunteer, mainly donating bone marrow (BM) cells. As in the EWOG-MDS analysis only 7 children received unrelated cord blood transplantation (UCBT), we decided to further investigate the role of UCBT in 42 children with JMML, reported to the Eurocord-EBMT and EWOG-MDS registries. Median age at transplantation of the 42 children was 2.6 years (range 0.6–7); 29 patients were males and 13 females. Cytogenetic analysis was available in all patients but one: 10 patients had monosomy 7, 4 other abnormalities, while the remaining 27 children had a normal karyotype. Seven patients underwent splenectomy before UCBT. Conditioning included Busulfan in 78% of patients, while the most common graft-versus-host disease (GVHD) prophylaxis consisted of Cyclosporin-A and steroids. In donor-recipient pairs, histocompatibility was determined by serology or low resolution molecular typing for HLA-A and -B antigens and by high-resolution DNA typing for DRB1 locus. The donor was HLA identical in 7 cases, 1-antigen disparate in 18 and with 2 or more disparities in 14. Median number of nucleated cells infused was 6.8 × 107/Kg (range 2–50). The 60-day cumulative incidence (CI) of engraftment was 76%%, with a median time to neutrophil and platelet recovery of 27 (range 14–51) and 50 (range 15–180) days, respectively. In multivariate analysis an age at UCBT younger than 2.6 years (hazard ratio, HR=0.27; 95% confidence interval=0.13–0.57; p=0.0005) and the use of a more HLA-compatible donor (HR=0.38; 95% confidence interval=0.16–0.89; p=0.03) predicted better engraftment. CI of grade II-IV acute and chronic graft-versus-host disease (GvHD), and of transplantation-related mortality (TRM) were 31%, 16%, and 33%, respectively. The CI of TRM of our cohort of patients is higher than the 2-year TRM CI of 16% in children with JMML given unrelated donor HSCT reported in the EWOG-MDS analysis. Eleven children relapsed, the 2-year CI of relapse being 22%. In comparison, in the EWOG-MDS study, the 2-year CI of relapse of unrelated HSCT recipients was 36%. The CI of relapse was 30% in patients with monosomy 7 as compared to 19% in the remaining children (p=0.64). With a median follow-up of 36 months (range 3–102), the 2-year disease-free survival (DFS) of the overall cohort was 45%; patients younger or older than 2.6 years had a DFS of 66% and 26% respectively, p=0.01. In multivariate analysis, only age at UCBT was associated with increased DFS (HR=2.98; 95% confidence interval=1.21–7.34; p=0.02). These data indicate that UCBT is a suitable option for children with JMML lacking an HLA-compatible relative and suggest that the search for an unrelated cord blood unit be initiated simultaneously to that for unrelated BM donors. Cord blood offers the advantage of nearly immediate availability of stem cells and allows to perform HSCT even in the presence of donor HLA disparities.

Risk Factor Analysis of Outcomes after Unrelated Cord Blood Transplantation for Children with Hurler's Syndrome. An Eurocord-Duke University Collaborative Study.

Hurler's syndrome (HS), the most severe form of mucopolysaccharidosis type-I causes progressive deterioration of the central nervous system and death in childhood. Allogeneic-stem cell transplantation (SCT) before the age of two years halts disease progression and prolongs life. Graft-failure and mixed-chimerism (40–50%) limit the success of SCT for HS. Unrelated-cord blood transplants (UCBT) are suggested to be a good alternative option for bone marrow, however, little is known about risk factors for outcomes after UCBT for this disease. We have analyzed 93 HS children that received an UCBT from 1995 to 2007 and were reported to EUROCORD or transplanted at Duke University. Median age at UCBT was 1, 3 (0, 2–4) yrs, and median follow up was 24 (3–140) mths. The donor was HLA-identical (HLA-A and -B by low resolution and HLA-DRB1 by high-resolution) in 13 cases (16%) and incompatible in 67 cases (84%: most with 1 (54%) and 2(26%) HLA disparities). The median nucleated cell dose/kg and CD34+/kg at infusion were respectively 7.2 (2–22) x 107 and 2, 3 (0, 5–17) x 105. With the exception of 5 patients, all received a Busulfan/Cyclophosphamide (+Fludarabine: 6) regimen. All patients received ATG or Campath (4).Results: Median days to neutrophil and platelet recovery were 22 (10–46) and 35 (13–82) days, respectively. Mixed-chimerism was found in only 6%. All patients had normal enzyme levels after engraftment. In multivariate analyses for neutrophil recovery, a CD34+-dose of >2.3x105/kg (HR=2.0; p= 0.015) was associated with increased probability of recovery. Acute-GvHD (grade II-IV) was observed in 27%, while chronic-GvHD was seen in 10% at 2 years. Two years overall survival (OS) and disease free survival were 78% and 70%, respectively. For 2 years OS, time from diagnosis to UCBT more than 6 months was associated with increased risk of death (6% for those children transplanted earlier and 30% for those transplanted later: p=0,04). Transplantation improved somatic features of HS. In conclusion, outcomes following UCBT for Hurler's syndrome are encouraging. UCB appears to be a good alternative allogeneic stem cell source to transplant children with HS. Earlier transplantation and higher cell dose are associated with better outcomes after UCBT for HS patients.

Risk Factors Analyses for Outcomes after Unrelated Cord Blood Transplantation for Children with Myelodysplastic Syndromes. An Analysis on Behalf of EWOG-MDS and Eurocord Groups.

Myelodysplastic syndromes (MDS) are very rare diseases in children and hematopoietic stem cell transplantation remains the only curative treatment. This is a retrospective registry-based study of 42 children with MDS (refractory cytopenia n=21, refractory anemia with excess of blasts n=15, and refractory anemia with excess of blasts in transformation n=6), who underwent unrelated cord blood transplantation (UCBT). Both databases from Eurocord and EWOG-MDS group were used. Diagnosis of MDS was established by each reporting center based on the WHO classification modified for pediatric patients. Median age was 7.4 years, median cell dose infused was 4.2 × 107/Kg and median follow-up was 39 months. All patients received one cord blood unit, with 0 or 1 HLA disparity in 22, and 2 or more in 20. Twenty-five children received a Busulfan-based conditioning regimen. The association of Cyclosporine A and prednisone was used in 69% of patients. The 60-day cumulative incidence (CI) of engraftment was 69±7%, in a median time of 25 days. In multivariable analysis, ABO match (Hazard Ratio=2.94, 95% Confidence Interval=1.23–6.66, p=0.01) and refractory cytopenia (HR=2.38, 95% Confidence interval=1.01–5.55, p=0.05) were favorable factors associated with neutrophil recovery. Thirteen patients developed acute GVHD grades II–IV. Moreover, 16 children had skin, 5 liver, 6 gastrointestinal involvements (stages 2–4). The 100-day CI of aGVHD was 29±7%. Of 20 evaluable patients, 10 developed chronic GVHD and the 1-year CI of cGVHD was 24±7%. The 2-y CI for treatment-related mortality was 56±8%. In univariable analysis, recipient's weight was the only statistical significant factor associated with TRM (47% for children weighting less than < 38Kg versus 80% for remainders, p=0.05). In addition, there was a trend of higher TRM for patients who received CBU with 2 or more HLA disparities (p=0.09). The 2-y overall survival and disease-free survival were 37±8% and 32±8% respectively. In multivariable analysis, OS improved when recipient's weight at UCBT was lower than 38kg (HR= 2.53, 95% confidence interval=1.16–5.55; p=0.02). In conclusion, since hematopoietic stem cell transplantation is the only treatment with curative potential, UCBT is a reasonable option for children without an identical sibling donor. Moreover, outcomes might be improved with better donor and patient's selection.

OP02 Unrelated cord blood transplantation in children and adults with leukemias and lymphomas

OP02 Unrelated cord blood transplantation in children and adults with leukemias and lymphomas

Reduced intensity allogeneic umbilical cord blood transplantation in children and adolescent recipients with malignant and non-malignant diseases

There is a significant amount of morbidity and mortality following myeloablative umbilical cord blood transplantation (UCBT). Reduced intensity (RI) conditioning offers an alternative to myeloablative conditioning before UCBT. We investigated RI-UCBT in 21 children and adolescents with malignant (n=14), and non-malignant diseases (n=7). RI conditioning consisted of fludarabine (150-180 mg/m2) with either busulfan (< or = 8 mg/kg)+rabbit antithymocyte globulin (R-ATG; n=16) or cyclophosphamide+R-ATG+/-etoposide (n=5). Human leukocyte antigen match: 4/6 (n=13), 5/6 (n=5) and 6/6 (n=3). The median total nucleated cell and CD34+ cell dose per kilogram were 3.58 x 10(7) and 2.54 x 10(5), respectively. The median time for neutrophil and platelet engraftment was 17.5 and 52 days, respectively. There were six primary graft failures (chronic myelogenous leukemia (CML), beta-thalassemia, hemophagocytic lymphohistiocytosis (HLH) and myelodysplastic syndrome (MDS)). The probability of developing grade II to grade IV acute graft-versus-host disease (GVHD) and chronic GVHD was 28.6 and 16.7%, respectively. Incidence of transplant-related mortality (TRM) was 14%. The 5 years overall survival (OS) in all patients was 59.8%. The 5 years OS for patients with average versus poor-risk malignancy was 77.8 versus 22.2% (P=0.03). RI-UCBT may result in graft failure in specific high-risk chemo-naïve patients (CML, beta-thalassemia, HLH and MDS), but in more heavily pretreated pediatric and adolescent recipients results in rapid engraftment and may be associated with decreased severe GVHD and TRM.

Unrelated cord blood transplantation in children with sickle cell disease: Review of four‐center experience

UCBT was performed in seven children with SCD and stroke (HLA match 4/6 n=5; 5/6 n=2). Four received myeloablative regimens (BU, CY, ATG plus FLU in one patient). One had primary graft failure, three had sustained engraftment, two with grade III-IV GVHD (one died, one developed chronic GVHD), one with stable mixed chimerism. Three patients treated with reduced-intensity regimens (FLU, BU or CY, ATG, TLI) failed to engraft; one engrafted after second UCBT (HU, TT, RXA, ALZ, TBI). Four patients (57%) developed viral infections. Engraftment, GVHD, and infection remain challenges.

Unrelated cord blood transplant in children with high-risk acute lymphoblastic leukemia: a long-term follow-up

The aim of this single center study was to assess the impact of pre-transplant factors on long-term follow-up in young patients affected by high-risk acute lymphoblastic leukemia (ALL) who underwent an unrelated cord blood transplant (CBT). The conditioning regimens, graft-versus-host disease (GVHD) prophylaxis and supportive policies were uniform for all patients. We analyzed the results of CBT performed in 30 patients, aged <18 years, affected by high risk ALL. As conditioning regimen, all patients received 12 Gy fractionated total body irradiation, etoposide, cyclophosphamide and horse anti-lymphocyte globulin. GVHD prophylaxis consisted of 6-methylprednisolone and cyclosporine A. RESULTS The cumulative incidence of engraftment was 93% (95% CI:0.85-0.93). The cumulative incidence of grade III-IV acute and chronic GVHD was 7% (95% CI:0.01-0.19) and 33% (95% CI: 0.17-0.64), respectively. The 9-year cumulative incidence of transplant-related mortality and relapse was 34% (95% CI:0.13-0.45) and 31% (95% CI:0.16-0.61), respectively. The 9-year overall survival, leukemia-free survival and event-free survival were 42% (95% CI:0.52-0.93), 47% (95% CI:0.25-0.61) and 46% (95% CI:0.33-0.61), respectively. A number of CFU-GM <1 x 10(4)/Kg of recipient body weight was the only factor that negatively affected all outcome parameters both in univariate and multivariate analyses. The infused cell dose expressed as in vitro progenitor cell growth represents the most important pre-transplant factor affecting the long-term outcome after an unrelated CBT in young patients with high risk ALL. The number of CFU-GM should thus be considered in the selection process of cord blood units for transplant.