Reduced-intensity Umbilical Cord Blood Transplantation Research Articles

Radiation-sparing reduced-intensity unrelated umbilical cord blood transplantation for rare hematological disorders in children.

Graft failure is a major pitfall of unrelated umbilical cord blood transplantation (CBT) in children with rare hematological disorders other than acute leukemia, such as acquired and inherited bone marrow failure, myelodysplastic syndrome, juvenile myelomonocytic leukemia, and chronic myeloid leukemia. We developed a less-toxic conditioning regimen for CBT that achieves a higher rate of complete donor chimerism, and retrospectively compared it against two other conditioning regimens for CBT performed at our single institution. The engraftment rate with complete donor chimerism was 100% and 5-year event-free survival (5y-EFS) was 90.9% in patients using our latest regimen (n = 11) of reduced-intensity conditioning (RIC) containing fludarabine (Flu) 180mg/m2, melphalan (MEL) 210mg/m2, and low-dose rabbit anti-thymocyte globulin (LD-rATG) 2.5mg/kg without irradiation (regimen C). Outcomes were better than in patients (n = 10) treated with previous regimens involving irradiation (5y-EFS 30.0%, p = 0.004): regimen A, consisting of myeloablative conditioning containing cyclophosphamide (CY) and total body irradiation (TBI) with 8-12Gy, or regimen B, consisting of RIC with Flu, CY, horse ATG, and thoracoabdominal irradiation (TAI) with 6Gy. In conclusion, Flu/MEL/LD-rATG (regimen C) without TBI/TAI may be preferable as RIC for unrelated CBT in children with rare hematological disorders.

Successful sustained engraftment after reduced-intensity umbilical cord blood transplantation for adult patients with severe aplastic anemia

AbstractWe retrospectively analyzed 12 consecutive adult severe aplastic anemia patients who received unrelated umbilical cord blood transplantation after a reduced-intensity conditioning regimen (RI-UCBT). The conditioning regimen consisted of 125 mg/m2 fludarabine, 80 mg/m2 melphalan, and 4 Gy of total body irradiation. The median infused total nucleated cell number and CD34+ cell number were 2.50 × 107/kg and 0.76 × 105/kg, respectively. Eleven of the 12 patients achieved primary neutrophil and platelet engraftment. All patients who achieved engraftment had complete hematologic recovery with complete donor chimerism, except for one patient who developed late graft failure 3 years after RI-UCBT. Two of the 12 patients died of idiopathic pneumonia syndrome, and the remaining 10 patients are alive, having survived for a median of 36 months. Our encouraging results indicate that RI-UCBT may become a viable therapeutic option for adult severe aplastic anemia patients who lack suitable human leukocyte antigen-matched donors and fail immunosuppressive therapy.

Two cases of mycosis fungoides treated by reduced‐intensity cord blood transplantation

Mycosis fungoides is a cutaneous T-cell lymphoma, which is clinically divided into three stages: patch, plaque and tumor. Despite a variety of treatments the prognosis is poor in advanced mycosis fungoides. Recently, allogeneic hematopoietic stem cell transplantation has been successfully applied for such cases. We performed reduced-intensity umbilical cord blood transplantation for two advanced mycosis fungoides patients. Case 1 was a 56-year-old man and case 2 was a 30-year-old woman. Tumors of each case were refractory to conventional chemotherapy. Although radiation therapy was considerably effective, tumors relapsed after several months. Reduced-intensity umbilical cord blood transplantation was performed because case 1 had no human leukocyte antigen-identical siblings and the sibling of case 2 did not agree to be the donor. The male patient died of pulmonary failure 23 days after reduced-intensity umbilical cord blood transplantation. The case 2 patient succeeded in reduced-intensity umbilical cord blood transplantation and remained in complete/partial remission for 13 months. However, chemotherapy-resistant tumors relapsed, and allogeneic hematopoietic stem cell transplantation was performed at 17 months. She died of cerebral hemorrhage 23 days after the procedure. Reduced-intensity umbilical cord blood transplantation may be included in the treatments for advanced mycosis fungoides, where graft-versus-lymphoma effect seems to be a significant factor for the success of the treatment.

Successful engraftment after reduced-intensity umbilical cord blood transplantation for myelofibrosis

AbstractAlthough allogeneic hematopoietic stem cell transplantation has recently been applied to patients with myelofibrosis with reproducible engraftment and resolution of marrow fibrosis, no data describe the outcomes of umbilical cord blood transplantation. We describe 14 patients with primary (n = 1) and secondary myelofibrosis (n = 13) who underwent reduced-intensity umbilical cord blood transplantation. Conditioning regimens included fludarabine and graft-versus-host disease prophylaxis composed cyclosporine/tacrolimus alone (n = 6) or a combination of tacrolimus and mycophenolate mofetil (n = 8). Thirteen patients achieved neutrophil engraftment at a median of 23 days. The cumulative incidence of neutrophil and platelet engraftment was 92.9% at day 60 and 42.9% at day 100, respectively. Posttransplantation chimerism analysis showed full donor type in all patients at a median of 14 days. The use of umbilical cord blood could be feasible even for patients with severe marrow fibrosis, from the viewpoint of donor cell engraftment.

Clinical Characteristics and GVL Effect of Chronic Graft-Versus-Host disease Following Reduced-Intensity Umbilical Cord Blood Transplantation (RICBT).

Abstract 1162Poster Board I-184 BackgroundsUmbilical cord blood can be an alternative stem cell source for the patients of hematological diseases. However, little is known about chronic GVHD (cGVHD) and graft versus leukemia/lymphoma (GVL) effect in reduced-intensity cord blood transplantation (RICBT). We had been demonstrated that cGVHD in CBT is tolerable compared with that in BMT and that the occurrence of cGVHD could result in good prognosis. Here, we analyzed the clinical picture of chronic GVHD following RICBT and the GVL effect. MethodsWe reviewed medical records of 192 patients with hematological diseases who had received CBT between Jan. 2004 and Dec. 2008 who had been free from disease progression for more than 100 days after RICBT at Toranomon Hospital, Tokyo, Japan. Median age was 54 years (17-82). Most of them had diseases in advanced status (n=168). Most of the pre-transplant conditioning were reduced intensity consisted of fludarabine, melphalan and TBI 4Gy (n=157). GVHD prophylaxis were tacrolimus (Tac) alone (n=99) and Tac plus mycophenolate mofetil (MMF) (n=93). HLA disparities were as follows; 6/6 (n=9), 5/6 (n=38), 4/6 (n=142), and 3/6 (n=3). Underlying diseases were AML (n=58), myelodysplastic syndrome (n=36), ALL (n=23), lymphoma (n=64) and others (n=11). ResultsThe Median observation period after the transplantation was 924 days (range, 109–1944). Chronic GVHD was admitted in 114 patients (59.4%) consisted of limited type 88 (45.8%) and extensive type 26 (13.5%) in classical criteria, and mild type 96 (50.0%), moderate type 15 (7.8%), and severe type 3 (1.6%) in NIH consensus criteria of cGVHD. The target organs of cGVHD were skin 87.5%, liver 40.6%, and mouth mucous membranes 32.8 %, eye 23.4%, and the lungs only 7.8% (COP3 and BOS2). Except 21 cases ( 10.9%) required systemic steroid or MMF therapy. The median of Karnofsky score of cGVHD was 90%(40-100). During observation period, no patients except one patient caused by heart failure were died of cGVHD. In multivariate analysis, high-risk disease (p=0.019) and preceding acute GVHD (p=0.026) are related to the occurrence of cGVHD, and cGVHD increased overall survival (p<0.01) and suppressed recurrence of the disease (p<0.01). ConclusionAlthough the frequency of cGVHD was not low, the severity was mild, and the death related to cGVHD is rare in RICBT. NIH consensus criteria is useful for the evaluation of cGVHD severity. Some effect of GVL may play a role on better survival and lower relapse rate in RICBT. DisclosuresNo relevant conflicts of interest to declare.

Voriconazole Is Safe and Effective as a Prophylactic Regimen of Invasive Fungal Infections for High Risk Patients after Reduced-Intensity Umbilical Cord Blood Transplantation

Invasive fungal infections (IFI) are significant complications after allogeneic hematopoietic stem cell transplantation. We previously reported that 3-year cumulative incidence of IFI was 10.2 % and median onset of IFI was day 20 post reduced-intensity umbilical cord blood transplantation (RI-CBT) under the prophylaxis by fluconazole or micafungin (Biol Bone Marrow Transplant 2007; 13:771). In recent years, voriconazole (VOR) has been employed in IFI prophylactic regimens during bone marrow or peripheral blood stem cell transplantation in several clinical trials and reports, but the safety and efficacy during umbilical cord blood transplantation is unclear. In order to address this issue, we prospectively administered VOR to 46 high risk recipients of RI-CBT for IFI prophylaxis, between August 2007 and May 2008. All of the patients had no prior episode of IFI and were treated in reverse isolation in laminar airflow-equipped rooms. The plasma trough concentration of VOR and serum galactomannan index was obtained once a week. Chest CT scan was performed for persistent fever under the administration of broad antibiotics. Proven and probable IFI were defined according to revised EORTC/MSG criteria. Median age was 58 years old (range, 21–82). Twenty-three were AML, 10 were non-Hodgkin lymphoma, 6 were aplastic anemia, 5 were ALL, 1 was CML, and 1 was multiple myeloma. All patients were at high risk of IFI, except one patient with lymphoma in CR; 22 had high risk underlying diseases, 17 had prior transplantation, and 6 were very severe aplastic anemia. All patients received fludarabine-based preparative regimens. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus & mycophenolate mofetil in 30, tacrolimus alone in 15, and cyclosporine alone in 1. Additional immune suppressive therapy against pre-engfraftment immune reactions (Transplant 2005; 80:34) or GVHD were administered in 35 patients; 19 received corticosteroid (CS), 7 beclomethasone (BDP), 5 CS & BDP, 1 CS & BDP & infliximab, 1 CS & infliximab, 1 CS & BDP & etanercept, and 1 CS & methotrexate. Forty-two patients achieved neutrophil recovery > 500/uL on day 21 post-transplant at medium (range, 11–38). The median length of VOR prophylaxis from transplantation was 85 days (range, 6–422) for patients who survived longer than 100 days. The total number of patient-days on VOR was 4241 days. There were no proven IFI. Two patients developed probable pulmonary aspergillosis during VOR administration (at day 71 and 75; 1-year cumulative incidence 4.3 %.) No breakthrough infections by candida or zygomycetes were detected. VOR was well tolerated, except in 2 patients who discontinued VOR due to abnormal liver test and severe visual disturbance. Two patients developed probable pulmonary aspergillosis after switching from VOR to other antifungals (at day 80 and 263 under the administration of micafungin and itraconazole, respectively). Thus, VOR can be safely administered, and have reduced the incidence of IFI, with no breakthrough infections by candida or zygomycetes, indicating possible superiority of incorporating this drug as an IFI prophylactic regimen in RI-CBT.

HHV6-Associated Limbic Encephalitis after Reduced-Intensity Umbilical Cord Blood Transplantation.

Background: HHV6 reactivation has been increasingly recognized in allogeneic haematopoietic stem cell transplant recipients, particularly in umbilical cord blood transplantation. In adult recipients, HHV6 has been associated with limbic encephalitis (HHV6-LE), which causes anterograde amnesia and epilepsy. The CNS disorder confined to the hippocampal regions; the presence of abnormal MRI signals involving the hippocampus, and detection of HHV6 DNA inCSF. However, the clinical features of the syndrome have not been well characterized.Methods: In this study we retrospectively reviewed the medical records of 139 umbilical cord blood transplantation recipients with reduced-intensity conditioning between January 2006 and December 2007 at Toranomon Hospital in Japan to determine the incidence of HHV6-LE among these patients. The diagnosis was based on the acute development of retrograde amnesia, confusion, coma and seizures accompanied by charascteristic MRI findings of abnormal high signal intensity on flair and T2 weighted images in the hippocampus and mesial temporal lobes, and the detection of HHV6 DNA in CSF. Eighty-six were received foscarnet before the onset of HHV6-LE as prophylaxis. All the patients who manifested suspicious symptoms of HHV6-LE were treated with foscarnet.Results: HHV6-LE was diagnosed in 11/139 for a cumulative incidence of 7.2%. The median age was 49 years (range 36–82), 3 were female. Diseases treated were AML/MDS (8), ALL (1), diffuse large B-cell lymphoma (1), and aplastic anemia (1). All 11 were conditioned with fludarabine-based reduced-intensity regimen, and tacrolimus alone (5) or tacrolimus+mycophenolate mofetil (6) were used as GVHD prophylaxis. Five of them had started foscarnet before the onset of HHV6-LE as a prophylaxis. Median symptom onset was on day +20 (range, 12–50). Initial symptoms included confusion in 9, retrograde amnesia in 8, and seizures in 5. MRI demonstrated hyppocampal and mesial temporal lobe FLAIR/T2 high signal intensity in 8/11. Initial CSF analysis demonstrated a median WBC count was 7 (range, 1–21)/μl, median protein was 49 (range, 44–337) mg/dl, median glucose was 107 (range, 62–269) mg/dl. No positive results of bacterial or viral cultures were observed in any of the patients. Median HHV6 DNA levels in the CSF was 20000 (range, 200–80000) copies/ml. Median HHV6 DNA levels in peripheral blood was 200 (range, 0–300000) copies/ml. Remarkably, 7 patients were negative for HHV6 in peripheral blood even within 6 days prior to the onset of CNS symptoms. All were treated with foscarnet at 50–100mg/kg of body weight, and clinical symptoms improved in 9 evaluable patients (2 were not evaluable due to severe pulmonary complications). The virus was cleared in the CSF successfully in 7 patients evaluated. Seven died with the median survival of 32 days (range, 7–346) from diagnosis of limbic encephalitis. HHV6-LE was not a direct cause of death in any of them (2 were from infection, 2 from IP, 2 from relapse, and 1 from MOF). Four were alive as of July 31, 2008, and what is of extreme interest is that all were those who received foscarnet as a prophylaxis. None of the factors analysed failed to reach statistical significance regarding the impact on the onset of HHV6-LE.Conclusions: High incidence of HHV6-LE as well as reactivation of the virus was observed in CB recipients. HHV6 DNA monitoring in peripheral blood may not be sufficient to predict the development of HHV6-LE. Although clinical manifestations were severe in some cases, foscarnet therapy was effective in all evaluable cases. Possible positive impact of prophylactic foscarnet therapy on better survival was suggested, which needs further evaluation by prospective study.

Bloodstream Infection after Reduced-Intensity Umbilical Cord Blood Transplantation Versus Other Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation.

Blood stream infection (BSI) is a major cause of transplant-related mortality (TRM) following allogeneic hematopoietic stem cell transplantation, and to overcome it, reduced-intensity preparative regimens were developed in recent years. However, little information has been reported on BSI after reduced-intensity cord blood transplantation (RI-CBT). To clarify the characteristics of BSI after RI-CBT, we compared the incidence of microbiologically documented BSI before day 100 between RI-CBT and reduced-intensity non-cord blood allogeneic hematopoietic stem cell transplant (RI-non-CBT) recipients in Toranomon hospital, Japan. RI-non-CBT group includes related bone marrow (rBM), related peripheral blood stem cell (rPBSC) and unrelated bone marrow (uBM) transplantation. We retrospectively reviewed the first events of BSI in 211 consecutive adult patients between Jan 2004 and July 2006. One hundred and fifteen patients received RI-CBT and 96 patients received RI-non-CBT (4 from rBM, 34 from rPBSC and 58 from uBM). The median ages of patients in both groups were 55 years. All of the preparative regimens were fludarabine-based and prophylaxis against GVHD was tacrolimus alone in most of the RI-CBT recipients and combination of calcinurin inhibitor and short-term methotrexate in most of the RI-non-CBT recipients. The median time to achieve neutrophil engraftment was delayed in RI-CBT group (day 20 vs. day15). The cumulative incidence of engraftment at day 60 was 73.0% in RI-CBT group versus 90.6% in RI-non-CBT group. The cumulative incidence of BSI was 39.3% at day 100 and RI-CBT group tended to have more BSI compared to RI-non-CBT group (46.1% vs. 31.3%, p=0.0122), particularly at the early points after transplantation. Median day of positive culture for bacteremia was earlier (day 9 vs. day 14) in RI-CBT group. In spite of reduced-intensity preparative regimen, RI-CBT in adults is associated with higher rates of BSI at early time points after transplantation.

Value of pretransplant screening for colonization of Pseudomonas aeruginosa in reduced-intensity umbilical cord blood transplantation for adult patients

Value of pretransplant screening for colonization of Pseudomonas aeruginosa in reduced-intensity umbilical cord blood transplantation for adult patients

Double Unrelated Reduced-Intensity Umbilical Cord Blood Transplantation in Adults

Umbilical cord blood (UBC) stem cells are a useful stem cell source for patients without matched related or unrelated donors. Adult transplantation with single UBC units is associated with high transplantation-related mortality (TRM). In most cases, mortality is due to infection related to slow engraftment and immunoincompetence. In this study, we used a reduced-intensity conditioning regimen of fludarabine, melphalan, and antithymocyte globulin followed by 2 partially matched UBC units. The UBC units were a 4/6 HLA match or better with each other and with the patient and achieved a minimum precryopreservation cell dose of 3.7 × 10 7 nucleated cells/kg. A total of 21 patients (median age, 49 years) were treated. The median time to an absolute neutrophil count > 0.5 × 10 9/L was 20 days, and the median time to an unsupported platelet count > 20 × 10 9/L was 41 days. Two patients experienced primary graft failure and underwent a second UBC transplantation. One patient had a late graft failure. Acute graft-versus-host disease (GVHD) grade II-IV occurred in 40% of patients. The 100-day TRM was 14%, and the 1-year disease-free survival was 67%. Mixed chimerism was associated with a higher risk of chronic GVHD. Our findings indicate that adult patients can tolerate double UBC transplantation well and achieve sustained antitumor responses using this reduced-intensity conditioning regimen.

Impact of Human Leukocyte Antigen Compatibility on Engraftment in Adult Patients Receiving Reduced-Intensity Umbilical Cord Blood Transplantation Using Calcineurin Inhibitor Alone for GVHD Prophylaxis.

Despite the fact that the majority of cord blood grafts were human leukocyte antigen (HLA) disparate at one to two antigens, acute graft-versus-host disease (GVHD) was less severe after cord blood transplantation (CBT) compared to unrelated bone marrow transplantation. On the other hand, engraftment failure is a serious problem after CBT. We retrospectively analyzed the influence of HLA compatibility on engraftment after reduced-intensity umbilical cord blood transplantation (RI-CBT). We analyzed the clinical outcome of patients who underwent first RI-CBT at Toranomon hospital between January 2002 and December 2005. Those who had died within 28 days from the day of transplant were excluded from these analyses. All 156 patients had hematological malignancies including 41 with AML, 21 with ALL, 6 with CML, 19 with MDS, 31 with malignant lymphoma, 14 with adult T-cell leukemia/lymphoma, 6 with other diseases. Median age was 54 years (range, 17–79 years). All of them were considered to be inappropriate for conventional stem cell transplantation due to the lack of an HLA-identical related donor, age >50 years old and/or organ dysfunction. The preparative regimens were mainly composed of fludarabine 125 mg/m2, melphalan 80 mg/m2, and 4 Gy total body irradiation. GVHD prophylaxis was composed of cyclosporine or tacrolimus alone. Eight, 46, 98 and 4 patients received 6 of 6, 5 of 6, 4 of 6 and 3 of 6 HLA antigen matched cord blood in graft-versus-host (GVH) direction. Primary engraftment failure was diagnosed in 18 patients (11.5%). Median time to engraftment was 19 days (range, 11–55 days) for the total patient group. In GVH direction, the cumulative incidence of engraftment at day 100 were 94.4% in 5 to 6 of 6 antigen matched cord blood and 85.3% in 3 to 4 of 6 antigen matched cord blood (p=0.001). Median time to engraftment was 17 days (range, 11–36 days) in 5 to 6 antigen matched cord blood and 20 days (range, 11–55 days) in 3 to 4 antigen matched cord blood. In host-versus-graft direction, the cumulative incidence of engraftment at day 100 were 90.9% in 5 to 6 antigen matched cord blood and 87.5% in 3 to 4 antigen matched cord blood (p=0.5895). Median time to engraftment was 18.5 days (range, 11–55 days) in 5 to 6 antigen matched cord blood and 19 days (range, 11–49 days) in 3 to 4 antigen matched cord blood. In univariate analysis, both total cell dose (>3 x 107/kg) and CD34 positive cell dose (>1 x105/kg) were significantly associated with the engraftment (p=0.0009 and p=0.0005). Age, gender, risk, GVHD prophylaxis, blood type mismatch and early immune reaction were not associated with the engraftment kinetics. Multivariate analysis revealed 5 to 6 antigen mismatch in GVH direction was a significant independent factor for engraftment (p=0.0073), as well as CD34 positive cell dose. In conclusion, HLA disparities in GVH direction are associated with engraftment in adult patients receiving reduced-intensity umbilical cord blood transplantation using calcineurin inhibitor alone for GVHD prophylaxis.

Reduced-intensity Umbilical Cord Blood Transplantation in Adult Acute Myeloid Leukemia: Report of Four Cases

The outcome after unrelated cord blood transplantation (CBT) is similar to that of matched unrelated bone marrow transplantation in children, and the results of CBT in adult patients has recently shown improvement. In addition, the use of reduced-intensity conditioning regimens for CBT has shown stable engraftment and reduced treatment-related mortality (TRM). From May 2005 to Jan 2006, four adult patients with acute myelogenous leukemia were treated with CBT after reduced-intensity conditioning at our hospital. The mean age of patients was 53.8 yrs, and all patients received 2 HLA antigen mismatched single unit cord blood. The infused mean cell dose was 2.85×107/kg for total nucleated cells and 0.72×105/kg for CD34+ cells. All patients had engraftment. The mean number of days to WBC and platelet engraftment was D+20.3 and D+60.3, respectively. There was no TRM within 100 days after transplantation. At the last follow up, three of the four patients were alive. One patient transplanted in first complete remisson is alive in remission at day 413, but the other patients transplanted in advanced disease all relapsed. Reduced-intensity CBT is a feasible approach in selected adult patients with acute myeloid leukemia.

Intestinal thrombotic microangiopathy following reduced-intensity umbilical cord blood transplantation

Thrombotic microangiopathy (TMA) is a significant complication after hematopoietic stem-cell transplantation (HSCT); however, there is little information on it following reduced-intensity cord blood transplantation (RI-CBT). We reviewed the medical records of 123 adult patients who received RI-CBT at Toranomon Hospital between January 2002 and August 2004. TMA was diagnosed in seven patients based on intestinal biopsy (n = 6) or autopsy results (n = 1). While these patients showed some clinical symptoms such as diarrhea and/or abdominal pain, mental status alterations or neurological disorders were not observed in any of them. Laboratory results were mostly normal at the onset of TMA; >2% fragmented erythrocytes (n = 1), <10 mg/dl haptoglobin (n = 1), and >200 IU/dl lactic dehydrogenase (LD) (n = 4). On endoscopic examination, TMA lesions, consisting of ulcers, erosions, and diffuse exfoliation, were distributed spottily from terminal ileum to rectum. Intestinal graft-versus-host disease (GVHD) and cytomegalovirus (CMV) colitis were confirmed in five and four patients, respectively. With therapeutic measures including supportive care (n = 4), fresh frozen plasma (n = 1), and a reduction of immunosuppressive agents (n = 1), TMA improved in four patients. The present study demonstrates that intestinal TMA is a significant complication after RI-CBT. Since conventional diagnostic criteria can overlook TMA, its diagnosis requires careful examination of the gastrointestinal tract using endoscopy with biopsy.

Reduced Intensity Umbilical Cord Blood Transplantation(RI-UCBT) in Adult Patients with Graft Failure or Relapse after First Allogeneic Transplantation.

Background: Graft failure, graft rejection, or disease relapse post allogeneic hematopoietic stem cell transplantation(HSCT) is life-threatening and serious complication that necessitate consideration for a second transplantation. Graft failure has been more frequently reported in patients with aplastic anemia with T-cell depletion of the graft, in cord blood transplants, or when unrelated or HLA-mismatched related donors were used. In second allogeneic stem cell transplant setting, current questions include suitable stem cell source, additional conditioning, immunosuppression, and the use of a different donor, still remain unknown. We performed a feasibility study of reduced intensity umbilical cord blood transplantation (RI-UCBT) in adult patients with graft failure or disease relapse after first allogeneic transplantation.Patients and Methods: Nine patients (median age, 53 years; range 17–68) with advanced hematological diseases [AML (n=4), ALL (n=2), MDS (n=2), ATL (n=1)] who showed relapse or graft failure after first allogeneic transplantation underwent RI-UCBT with single cord blood unit at Toranomon Hospital between May 2003 and February 2004. Eight cases were in non-CR at transplant. A median time from first to second transplant was 226 days (range 31–475). The median number of mononuclear cells transfused was 2.3 x 107 /kg (range 1.8–3.5). HLA disparities were as follows; 5/6 in two cases, 4/6 in seven cases. Conditioning regimen mainly consisted of fludarabine 25 mg/m2 on days -7 to −3, melphalan 40mg/m2 (n=8) or busulfan 4mg/kg(n=1) day −3 to −2, and 4 Gy total body irradiation on day −1. Graft-versus-host disease (GVHD) prophylaxis was composed of ciclosporin alone (n=6) and tacrolimus alone (n=3).Results: All of them achieved primary neutrophil engraftment (>500/μL) after a median of 22 days (range, 15–32) and achievement of donor T-cell chimerism was confirmed. Four cases developed grade II-IV GVHD, and one case developed limited chronic GVHD. Of all the nine cases received RI-UCBT, seven died from relapse (n=4), sepsis (n=2), and TMA (n=1). Two survived without relapse for +232 and +81 days, respectively.Discussion: Although the number of patients is small and the follow-up period is short, our results corroborate that RI-UCBT for graft failure or relapse post first transplant is tolerated and may be worth considering for further evaluation. Neutrophil engraftment was achieved, however, disease relapse rate and treatment-related mortality is high. The management of disease status and development of ideal conditioning regimen will be the focus of future investigation.

Successful engraftment after reduced-intensity umbilical cord blood transplantation for adult patients with advanced hematological diseases.

The purpose of this research was to evaluate the feasibility of reduced-intensity unrelated cord-blood transplantation (RI-UCBT) in adult patients with advanced hematological diseases. Thirty patients (median age, 58.5 years; range, 20-70 years) with advanced hematological diseases underwent RI-UCBT at Toranomon Hospital between September 2002 and August 2003. Preparative regimen composed of fludarabine 25 mg/m(2) on days -7 to -3, melphalan 80 mg/m(2) on day -2, and 4 Gy total body irradiation on day -1. Graft-versus-host disease prophylaxis was composed of cyclosporin alone. Twenty-six patients achieved primary neutrophil engraftment after a median of 17.5 days. Median infused total cell dose was 3.1 x 10(7)/kg (range, 2.0-4.3 x 10(7)/kg). Two transplant-related mortalities occurred within 28 days of transplant, and another 2 patients displayed primary graft failure. Cumulative incidence of complete donor chimerism at day 60 was 93%. Grade II-IV acute graft-versus-host disease occurred in 27% of patients, with median onset 36 days. Primary disease recurred in 3 patients, and transplant-related mortality within 100 days was 27%. Estimated 1-year overall survival was 32.7%. Excluding 7 patients with documented infection, 19 patients displayed noninfectious fever before engraftment (median onset, day 9). Manifestations included high-grade fever, eruption, and diarrhea. The symptoms responded well to corticosteroid treatments in 7 of 13 treated patients. This study demonstrated the feasibility of RI-UCBT in adults.