This prospective study aimed to investigate the influence of pretransplant serum ferritin levels on the outcomes of allogeneic hematopoietic SCT (HSCT). In total, 190 patients with acute leukemia or myelodysplastic syndrome were consecutively enrolled. The patients were divided into two groups: low-ferritin group (<1000 ng/mL) and high-ferritin group (⩾1000 ng/mL). The primary end point was the cumulative incidence of infection within 100 days after HSCT, which was similar between the two groups: bloodstream infection, 35 vs 38%, P=0.65; bacterial infection, 44 vs 41%, P=0.68; and fungal infection, 6 vs 8%, P=0.71. The 1-year adjusted probability of OS of the high-ferritin group was significantly lower than that of the low-ferritin group (76 vs 63%, P=0.017). Using receiver operating characteristic curve, the threshold of pretransplant serum ferritin levels for bloodstream infection was 1400 ng/mL; the threshold for OS, EFS and non-relapse mortality was 1349 ng/mL. In conclusion, pretransplant serum ferritin levels of ⩾1000 ng/mL did not influence the incidence of infection but adversely affected OS after HSCT. A higher threshold of pretransplant serum ferritin levels may predict HSCT outcomes.

Donor-recipient sex incompatibility has been associated with transplant outcomes in allogeneic hematopoietic SCT. Such outcomes might be because mHA encoded by Y chromosome genes could be immunological targets for allogeneic T cells and B cells to induce GVHD, GVL effect and graft failure. However, its effect on the outcome of cord blood transplantation (CBT) is yet to be clarified. We retrospectively analyzed 191 adult patients who received single-unit CBT after myeloablative conditioning for malignant disease in our institute. In multivariate analysis, male recipients with female donors had a higher incidence of extensive chronic GVHD (hazard ratio (HR) 2.97, P=0.02), and female recipients with male donors had a lower incidence of platelet engraftment (HR 0.56, P=0.02) compared with female recipients with female donors as the reference. Nevertheless, there was no increase in mortality following sex-incompatible CBT. These data suggested that donor-recipient sex compatibility does not have a significant impact on survival after myeloablative CBT for hematological malignancies.

BACKGROUND:Acute kidney injury (AKI) is a common medical complication after myeloablative allogeneic stem cell transplantation (SCT). We have previously performed a retrospective analysis of AKI after cord blood transplantation (CBT) in adults, and found that the maximum of vancomycin (VCM) trough levels were significantly higher in patients with AKI. Following these results, we have monitored VCM serum trough concentrations more strictly, to not exceed 10.0 mg/L, since 2008.METHODS:In this report, we performed an analysis of AKI in a new group of 38 adult patients with hematological malignancies treated with unrelated CBT after myeloablative conditioning between January 2008 and July 2011.RESULTS:Cumulative incidence of AKI at day 100 after CBT was 34% (95% confidence interval 19-50). The median of the maximum value of VCM trough was 8.8 (4.5-12.2) mg/L. In multivariate analysis, no factor was associated with the incidence of AKI. No transplant-related mortality was observed. The probability of disease-free survival at 2 years was 83%.CONCLUSION:These findings suggest that strict monitoring of VCM serum trough concentrations has a beneficial effect on outcomes of CBT.

We studied the clinical outcomes of 87 adults with de novo acute leukemias who received unrelated cord blood transplantation (CBT) after myeloablative conditioning. Between August 1998 and July 2008, 55 patients with acute myelogenous leukemia (AML) and 32 patients with acute lymphoblastic leukemia (ALL) were treated with unrelated CBT. All patients received 4 fractionated 12 Gy total body irradiation (TBI) and chemotherapy as myeloablative conditioning and cyclosporine plus short term methotrexate as graft-versus-host disease (GVHD) prophylaxis. The median age was 38 years and the median number of nucleated cells was 2.38 x 107/kg. 16 patients were transplanted not in complete remission (CR). t(9;22) and 11q23 abnormalities were found in nine and seven, respectively. All patients received a single cord blood unit and grafts were selected from at least 4/6 serologically matched units in the Japan Cord Blood Bank Network. Variables considered in statistical analyses were age, gender, diagnosis, disease status at CBT, disease risk, cytogenetic subgroups, total nucleated cell (TNC) dose, sex mismatches, ABO mismatches, HLA mismatches (A and B by low resolution, DRB1 by high resolution), and blood levels of cyclosporine. With a median follow-up of 42 months (range 13-120), the probability of disease free survival (DFS) at 5 years was 67.1% (95%CI: 57.0-77.2%). The 5-year cumulative incidence of relapse was 23.1% (95%CI: 13.7-32.5%). In multivariate analysis, the risk factor identified for both DFS and the incidence of relapse was the numbers of HLA mismatches. The probability of DFS and the cumulative incidence of relapse in the subset of three HLA antigen mismatches (n = 25) were 89.6% and 9.9%, respectively. Several reports have shown that HLA matched CBT resulted in better outcome, but our study revealed superior outcome in recipients of grafts with three HLA antigen mismatches. Although this is a result from a Japanese single institute, we suggest that CBT from grafts with three HLA antigen mismatches may improve outcomes by reducing the incidence of relapse without increasing treatment related mortality (TRM) in adult patients with de novo acute leukemias.

Background: The NHS Improvement's Cancer Reform Strategy states that reducing length of stay (LOS) improves patient satisfaction and they have piloted a ’23 hour Breast Care Model’. In 2009, according to the Hospital Episode Statistics (HES) data, the Royal Bolton Hospital's mean LOS for breast surgery (excluding reconstruction) was 3.99 days. The national mean was 2.62 days. We implemented change aimed at reducing LOS and prospectively audited LOS and patient satisfaction.

We analyzed the disease-specific outcomes of adult patients with advanced myelodysplastic syndrome (MDS) treated with cord blood transplantation (CBT) after myeloablative conditioning. Between August 1998 and June 2009, 33 adult patients with advanced MDS were treated with unrelated CBT. The diagnoses at transplantation included refractory anemia with excess blasts (n=7) and MDS-related secondary AML (sAML) (n=26). All patients received four fractionated 12 Gy TBI and chemotherapy as myeloablative conditioning. The median age was 42 years, the median weight was 55 kg and the median number of cryopreserved nucleated cells was 2.51 × 107 cells per kg. The cumulative incidence of neutrophil recovery at day 50 was 91%. Neutrophil recovery was significantly faster in sAML patients (P=0.04). The cumulative incidence of plt recovery at day 200 was 88%. Plt recovery was significantly faster in CMV seronegative patients (P<0.001). The cumulative incidence of grade II–IV acute GVHD (aGVHD) and extensive-type chronic GVHD was 67 and 34%, respectively. Degree of HLA mismatch had a significant impact on the incidence of grade II–IV aGVHD (P=0.021). TRM and relapse at 5-years was 14 and 16%, respectively. The probability of EFS at 5 years was 70%. No factor was associated with TRM, relapse and EFS. These results suggest that adult advanced MDS patients without suitable related or unrelated BM donors should be considered as candidates for CBT.

Umbilical cord blood has several advantages of immediate availability, no risk to donors, a lower risk for acute and chronic GVHD despite major human leukocyte Ag (HLA) disparity, and a lower risk of transmitting infections. As a result of the early successes with pediatric cord blood transplantation (CBT), cord blood from unrelated donors have been increasingly used as an alternative stem cell source for adult patients with hematological malignancies. Recent single-institute and registry-based studies suggest that CBT is a safe, feasible and effective strategy for adult patients without suitable related or unrelated BM donors. In this review, we focus on recent results of myeloablative CBT in adults.

We analyzed outcomes and risk factors after unrelated cord blood transplantation (CBT) for 98 adult patients with acute leukemia. Between August 1998 and June 2007, 98 adult patients with acute leukemia were treated with unrelated CBT at The Institute of Medical Science, University of Tokyo. Diagnoses at transplantation included de novo AML (n = 55), ALL (n = 25), and MDS-related secondary AML (n = 18). 59 (60%) patients were transplanted in an advanced status of the disease (defined as acute leukemia in third or subsequent complete remission, not in remission, or with high-risk cytogenetics). All patients received four fractionated 12 Gy total body irradiation and chemotherapy as myeloablative conditioning. 95 patients received standard cyclosporine (CyA) and methotrexate, and 3 patients received CyA only as a graft-versus-host disease (GVHD) prophylaxis. Among the patients the median age was 40 years (range, 18–55 years), the median weight was 56 kg (range, 36–76 kg), the median number of cryopreserved nucleated cells was 2.46 × 10 7/kg (range, 1.16–5.29 × 10 7/kg) and the median number of cryopreserved CD34 positive cells was 0.93 × 10 5/kg (range, 0.15–8.97 × 10 5/kg). 92 patients had myeloid reconstitution and the median time to more than 0.5 × 10 9/L absolute neutrophil count was 21 days. A higher CD34 positive cell count was independently associated with faster neutrophil recovery (p = 0.0001). A self-sustained platelet count more than 50 × 10 9/L was achieved in 86 patients at a median time of 42 days. Acute GVHD greater than or equal to grade III occurred in 6 of 92 evaluable patients and chronic GVHD occurred in 67 of 84 evaluable patients. Among 67 chronic GVHD patients, 19 patients were extensive type. 69 patients are alive and free of disease at between 116 and 3322 days after CBT. With a median follow-up of 1677 days, the probability of disease-free survival (DFS) at 5 years was 68.5 ± 5%. The 5-year cumulative incidence of transplant related-mortality and relapse was 9.9 ± 4%, 24.8 ± 5%, respectively. In multivariate analyses, advanced disease status was an adverse factor for DFS (p = 0.001) and relapse (p = 0.007). These results suggest that adult acute leukemia patients without suitable related or unrelated bone marrow donors should be considered as candidates for CBT. We analyzed outcomes and risk factors after unrelated cord blood transplantation (CBT) for 98 adult patients with acute leukemia. Between August 1998 and June 2007, 98 adult patients with acute leukemia were treated with unrelated CBT at The Institute of Medical Science, University of Tokyo. Diagnoses at transplantation included de novo AML (n = 55), ALL (n = 25), and MDS-related secondary AML (n = 18). 59 (60%) patients were transplanted in an advanced status of the disease (defined as acute leukemia in third or subsequent complete remission, not in remission, or with high-risk cytogenetics). All patients received four fractionated 12 Gy total body irradiation and chemotherapy as myeloablative conditioning. 95 patients received standard cyclosporine (CyA) and methotrexate, and 3 patients received CyA only as a graft-versus-host disease (GVHD) prophylaxis. Among the patients the median age was 40 years (range, 18–55 years), the median weight was 56 kg (range, 36–76 kg), the median number of cryopreserved nucleated cells was 2.46 × 10 7/kg (range, 1.16–5.29 × 10 7/kg) and the median number of cryopreserved CD34 positive cells was 0.93 × 10 5/kg (range, 0.15–8.97 × 10 5/kg). 92 patients had myeloid reconstitution and the median time to more than 0.5 × 10 9/L absolute neutrophil count was 21 days. A higher CD34 positive cell count was independently associated with faster neutrophil recovery (p = 0.0001). A self-sustained platelet count more than 50 × 10 9/L was achieved in 86 patients at a median time of 42 days. Acute GVHD greater than or equal to grade III occurred in 6 of 92 evaluable patients and chronic GVHD occurred in 67 of 84 evaluable patients. Among 67 chronic GVHD patients, 19 patients were extensive type. 69 patients are alive and free of disease at between 116 and 3322 days after CBT. With a median follow-up of 1677 days, the probability of disease-free survival (DFS) at 5 years was 68.5 ± 5%. The 5-year cumulative incidence of transplant related-mortality and relapse was 9.9 ± 4%, 24.8 ± 5%, respectively. In multivariate analyses, advanced disease status was an adverse factor for DFS (p = 0.001) and relapse (p = 0.007). These results suggest that adult acute leukemia patients without suitable related or unrelated bone marrow donors should be considered as candidates for CBT.

Although infusion of cryopreserved bone marrow or peripheral blood stem cell is associated with a variety of symptoms, there have been no reports detailing the data of infusion-related toxicities of cryopreserved cord blood (CB) units. We prospectively evaluated the incidence and significance of infusion-related toxicities in 34 adult patients undergoing unrelated CB transplantation. Cryopreserved CB units were thawed and immediately infused, unfiltered, through a central intravenous catheter without further manipulation. Heart rate, blood pressure, oxygen saturation and clinical symptoms were recorded during and after infusion. Twenty-four percent of patients experienced non-cardiovascular toxicities related to infusion. The incidence of systolic and diastolic hypertension and bradycardia was 58, 64 and 32%, respectively. Although three patients (9%) with severe systolic hypertension after the infusion required treatment with antihypertensive agents, no patients experienced life-threatening side effects or needed discontinuation of CB unit infusion. Patient or transplant characteristics had no effect on the hypertension and bradycardia related to the infusion of CB. These data suggest that infusion of cryopreserved CB without further manipulation after thawing is safe and well tolerated. However, cardiovascular toxicities including hypertension and bradycardia were frequently observed.

Although unrelated cord blood transplantation (CBT) is increasing in number, the optimized immunosuppressive therapy for prevention of graft versus host disease (GVHD) has not been established. Cyclosporine A (CsA) is the most common immunosuppressant used for GVHD prophylaxis and individualization among types of stem cell source by using therapeutic drug monitoring (TDM) is essential to optimize pharmacotherapy. Cord blood lymphocytes are naïve and most of CBT are carried out with a human leukocyte antigen (HLA)-mismatched combination especially in adults. Our retrospective analysis showed CsA can be tapered earlier for recipients of CBT than for those of BMT. To optimize CsA administration in CBT, we analyzed proportion of IL-2 producing cells among CD4+ T lymphocytes using multi-color flow cytometric analysis before and after CsA administration. We analyzed 55 peripheral blood samples from 6 allogeneic BMT recipients as controls and 104 peripheral blood samples from 7 CBT recipients. Cells were cultured in the presence of phorbol 12-myristate 13-acetate, ionomycin, and monensin at 37°C for 4 hrs and then stained for surface markers and intracytoplasmic IL-2. Blood CsA levels were simultaneously measured. We found that the level of IL-2 production in CD4+ T lymphocytes was inversely proportional to blood CsA levels for both BMT and CBT. IL-2 production in CD4+ T lymphocytes of cord blood recipients can be inhibited by relatively lower CsA concentration compared with that of bone marrow recipients. To our most interest, there was dramatic difference in required blood CsA level for inhibition of IL-2 production by days after transplantation (e.g. before and after day45) in recipients of CBT, while there was no difference by days after transplantation in recipients of BMT. This finding can explain why earlier tapering of CsA is possible for cord blood recipients. Further analysis is needed to optimize blood CsA level on different days after CBT for GVHD prophylaxis.

Donor cell-derived hematological malignancy is a rare complication after allogeneic SCT. Earlier studies reported that 0.12–5% of patients developed donor cell leukemia (DCL) after allogeneic SCT.1, 2 Recently, several reports have shown that donor cell-derived hematological malignancy occurred in patients after cord blood transplantation (CBT).3, 4, 5, 6, 7, 8, 9 Here, we report an adult case with ALL that subsequently developed donor cell-derived myelodysplastic syndrome (MDS) after CBT.

The impact of ABO incompatibility between donor and recipient on engraftment and transfusion requirement was studied in 95 adults who underwent unrelated cord blood transplantation (CBT). The patients included 27 ABO-identical, 29 minor, 21 major and 18 bidirectional ABO-incompatible recipients. Neutrophil engraftment did not differ between ABO-identical/minor ABO-incompatible and major/bidirectional ABO-incompatible recipients ( hazard ratio (HR) 1.17, P = 0.48). Cumulative incidence of platelet engraftment in ABO-identical/minor ABO-incompatible recipients was higher than in major/bidirectional ABO-incompatible recipients ( HR 1.88, P = 0.013). In addition, fewer platelet transfusions were required during the first 60 days after CBT in ABO-identical/ minor ABO-incompatible recipients ( HR 0.80, P = 0.040). RBC engraftment did not differ between the two groups ( HR 1.25, P = 0.33). However, fewer RBC transfusions were required in ABO-identical/ minor ABO-incompatible recipients than in major/bidirectional ABO-incompatible recipients ( HR 0.74, P<0.005). No patients developed pure red-cell aplasia after CBT. These results indicate that ABO incompatibility affected platelet engraftment and transfusion requirement of RBC and platelet in CBT recipients. Further studies including larger patient numbers are required to elucidate the impact of ABO incompatibility on the clinical outcome of CBT.

Although allogeneic stem cell transplantation from a human leukocyte antigen (HLA)-identical related donor offers a potential cure for patients with acute myeloid leukemia (AML) not in remission, a suitably matched related donor is unavailable for approximately two-thirds of patients. Recently, umbilical cord blood from unrelated donors have been used as an alternative stem cell source for adult patients with AML. Here, we report our clinical results of unrelated cord blood transplantation (CBT) after myeloablative conditioning for 30 adult patients with AML not in remission. Between August 1998 and November 2005, 30 adult patients with AML not in remission were treated with unrelated CBT at The Institute of Medical Science, University of Tokyo. Diagnoses at transplantation included de novo AML (n=14) and MDS-related secondary AML (n=16). All patients received four fractionated 12 Gy total body irradiation and chemotherapy as myeloablative conditioning. 27 patients received standard cyclosporine (CyA) and methotrexate, and 3 patients received CyA only as a graft-versus-host disease (GVHD) prophylaxis. Among the patients the median age was 45.5 years (range, 19-55 years), the median weight was 55 kg (range, 36-76 kg) and the median number of cryopreserved nucleated cells was 2.43 × 107/kg (range, 1.16-5.29 × 107/kg). 28 patients had myeloid reconstitution and the median time to more than 0.5 × 109/L absolute neutrophil count was 21.5 days. A self-sustained platelet count more than 50 × 109/L was achieved in 23 patients at a median time of 42 days. Acute GVHD above grade II occurred in 15 of 28 evaluable patients and chronic GVHD occurred in 17 of 23 evaluable patients. Among 17 chronic GVHD patients, 7 patients were extensive type. 16 patients are alive and free of disease at between 280 and 2937 days after transplantation. With a median follow-up of 2013 days, the probability of disease-free survival at 5 years was 51.8%. These results suggest that adult patients with AML not in remission should be considered as candidates for CBT. Although allogeneic stem cell transplantation from a human leukocyte antigen (HLA)-identical related donor offers a potential cure for patients with acute myeloid leukemia (AML) not in remission, a suitably matched related donor is unavailable for approximately two-thirds of patients. Recently, umbilical cord blood from unrelated donors have been used as an alternative stem cell source for adult patients with AML. Here, we report our clinical results of unrelated cord blood transplantation (CBT) after myeloablative conditioning for 30 adult patients with AML not in remission. Between August 1998 and November 2005, 30 adult patients with AML not in remission were treated with unrelated CBT at The Institute of Medical Science, University of Tokyo. Diagnoses at transplantation included de novo AML (n=14) and MDS-related secondary AML (n=16). All patients received four fractionated 12 Gy total body irradiation and chemotherapy as myeloablative conditioning. 27 patients received standard cyclosporine (CyA) and methotrexate, and 3 patients received CyA only as a graft-versus-host disease (GVHD) prophylaxis. Among the patients the median age was 45.5 years (range, 19-55 years), the median weight was 55 kg (range, 36-76 kg) and the median number of cryopreserved nucleated cells was 2.43 × 107/kg (range, 1.16-5.29 × 107/kg). 28 patients had myeloid reconstitution and the median time to more than 0.5 × 109/L absolute neutrophil count was 21.5 days. A self-sustained platelet count more than 50 × 109/L was achieved in 23 patients at a median time of 42 days. Acute GVHD above grade II occurred in 15 of 28 evaluable patients and chronic GVHD occurred in 17 of 23 evaluable patients. Among 17 chronic GVHD patients, 7 patients were extensive type. 16 patients are alive and free of disease at between 280 and 2937 days after transplantation. With a median follow-up of 2013 days, the probability of disease-free survival at 5 years was 51.8%. These results suggest that adult patients with AML not in remission should be considered as candidates for CBT.