ALBERT

Description: The immaturity of T cells in cord blood is well known in functional assays and phenotypic analyses. During the first several months after cord blood transplantation (CBT), the T cell compartment is recovered by peripheral expansion from those mature and naïve T cells in cord blood grafts and plays an important role in acute graft-versus-host disease (GVHD) and graft-versus-leukemia reaction. Recently, we have reported that adult patients with hematological malignancies receiving CBT from HLA-partially-mismatched unrelated donors (n=68) had a lower risk of severe acute GVHD (〉 grade II, 7% versus 26%) and transplant-related mortality (9% versus 29% at 1 year) and a higher probability of disease-free survival (74% versus 44% at 2 years) than HLA-matched unrelated bone marrow transplant (BMT) recipients (n=45) in our multivariate analysis (Takahashi et al., Blood, in press). We speculated that the immune reconstitution process over a period of several months after CBT might have contributed to these promising clinical results. Using four-color analysis with CD4, CD8, CD45RA, and CD62L, more than 90% of cord blood CD4+ and CD8+ T cells in the grafts belonged to the naïve fraction. Cytokine expression in cord blood T cells was also suppressed to 0.1% in CD4+ and to 0.9% in CD8+ with positive interferon-γ by intracellular staining, which were significantly lower than those in adult T cells (16.2% in CD4+ and 37.8% in CD8+). Circulating T cell counts normalized after 3 months for CD8+ and 4 months for CD4+ in our CBT recipients, both of which were significantly faster than in previously published studies, which were 9 months for CD8+ and 12 months for CD4+. After T cell recovery, peripheral blood T cells moved from the naïve to the central memory fraction immediately, and then moved to the effector memory fraction. A naïve subset of CD4+ T cells remained (median: 38 cells/μl on day 90, n=12) during the first 3 months, which was significantly higher than in the BMT control (median: 9 cells/μl on day 90, n=5, p=0.015), but showed a low level of CD8+ T cells (median: 14 cells/μl on day 90, n=12), almost the same as in BMT recipients (median: 13 cells/μl on day 90, n=5). Intracellular interferon-γ-producing T cells were detected at 3.4% (0.1–34.2%) in CD4+ and 32.3% (1.1–86.9%) in CD8+ at 1 month post-CBT (n=16), both of which were comparable to post-BMT. To investigate whether these T cells with memory phenotype are functional, we analyzed antigen-specific T-cell recovery using cytomegalovirus (CMV) as a specific antigen. CMV-responsive CD4+ T cells were detected within the first 4 months in all recipients with positive CMV antigenemia (n=13), but CD8+ T cells were detected only in 5 out of 13 cases, probably because of pre-emptive Gancyclovir administration in most antigenemia-positive patients. To conclude, naïve cord blood T cells rapidly increased in number and adopted a memory phenotype showing cytokine-production and antigen-recognition capacity in the early phase after CBT. These data suggest that mature T lymphocytes in cord blood have unique properties and contribute to the favorable clinical outcome of CBT.

Description: BACKGROUND Limited information is available on incidences and clinical features of acute graft-versus host disease (GVHD) after cord blood transplantation and large-sized researches have been awaited. METHODS We investigated the incidences and clinical features of acute GVHD in 2,015 patients reported to the Japan Cord Blood Bank Network, who underwent cord blood transplantation between June 1997 and August 2006. RESULTS Of 2,015 patients, 1481 patients (73%) achieved neutrophil engraftment at a median of day 22 (range, 6–81). Cumulative incidence of neutrophil recovery at day 100 was 0.74 (95%CI, 0.73–0.76). Of 2015 patients, 708 patients developed grade II-IV acute GVHD: grade II (n=423), grade III (n=237), and grade IV (n=48). The median onset was day 19 (range, 4–190). The cumulative incidences of grade II-IV and III-IV acute GVHD at day 100 were 0.35 (95% CI, 0.33–0.37) and 0.14 (95% CI, 0.12–0.15), respectively. Skin and gastrointestinal acute GVHD was documented in 1,006 and 405 patients, respectively, whereas liver GVHD was diagnosed in 149 patients. Multivariate analysis identified the following predictors of grade II-IV acute GVHD: the number of infused nucleated cells, transplantation from female donors to female recipients, TBI-containing preparative regimens, methotrexate-containing GVHD prophylaxis, and tacrolimus-based GVHD prophylaxis. Overall survival rates at three years of patients with grade 0-I, II and III-IV GVHD who survived 100 days or longer were 0.58 (95%CI, 0.53–0.63), 0.61 (95% CI, 0.54–0.67) and 0.40 (95%CI, 0.31–0.49), respectively. CONCLUSIONS Acute GVHD following cord blood transplantation is mild and has graft-versus malignancy effects. Probability of event free survival after cord blood tranplantation in the patients with grade 0-I, II and III-IV who survived 100 days or longer Event - free survival of the patients with grade 0-I, II and III-IV GVHD who survived 100 days or longer was 0.54 (95% CI, 0.49–0.59), 0.58 (95%CI, 0.52–0.65) and 0.41 (95%CI, 0.32–0.49),respectively,3 years after transplantation. Probability of event free survival after cord blood tranplantation in the patients with grade 0-I, II and III-IV who survived 100 days or longer Event - free survival of the patients with grade 0-I, II and III-IV GVHD who survived 100 days or longer was 0.54 (95% CI, 0.49–0.59), 0.58 (95%CI, 0.52–0.65) and 0.41 (95%CI, 0.32–0.49),respectively,3 years after transplantation.

Description: Umbilical cord blood transplantation (UCBT) is an alternative to bone marrow transplantation in adults when no sibling donor is available. Recently, UCBT after reduced-intensity conditioning (RI-UCBT) has been increasing in high risk adults not eligible for conventional conditioning. To evaluate the feasibility and effectiveness of RI-UCBT, we retrospectively analyzed the outcomes of 777 patients with hematologic diseases, who received RI-UCBT as the first allograft between 1997 and 2006 in Japan. Of 777 patients, 303 were women and 474 were men. Their median age was 56 years (range, 16–79 years). The patients’ diagnoses included 190 with acute myeloid leukemia, 66 with acute lymphoblastic leukemia, 22 with chronic myeloid leukemia, 172 with myelodysplastic syndrome, 193 with malignant lymphoma, 68 with adult T-cell leukemia/lymphoma, 44 with multiple myeloma, and 22 with aplastic anemia. Of 770 evaluable patients, 272 were defined as standard risk, whereas 498 were defined as high risk. Cord blood units were obtained from Japan Cord Blood Bank Network. The median total nucleated cell (TNC) number and median CD34+ cell number were 2.54 (range, 1.10–6.42) × 107/kg and 0.77 (range, 0.01–12.32) × 105/kg, respectively. Forty-two, 216, 512 and 4 patients received 6 of 6, 5 of 6, 4 of 6 and 3 of 6 serological HLA matched cord blood, respectively. The most frequently used conditioning regimens were fludarabine (Flu), alkylating agent (melphalan, busulfan or cyclophosphamide) with total body irradiation (TBI). The most frequently used prophylaxis regimens for graft-versus-host disease (GVHD) were calcineurin inhibitor (CI) alone in 431 patients and CI plus methotrexate in 206 patients. Cumulative incidence of neutophil engraftment was 67% at a median of 20 days after transplantation. Platelet recovery more than 20 × 109/L was observed in 47% at a median of 39 days. Among 542 evaluable patients, 206 developed acute GVHD of grade II or higher (cumulative incidence: 38%). The Kaplan-Meier estimates of overall survival (OS) and disease free survival at 2 years were 25% and 20%, respectively. Cumulative incidence of treatment-related mortality at day 100 was 36%. In univariate analyses, TNC number (〉2.5 × 107/kg) and CD34+ cell number (〉0.7 × 105/kg) were significantly associated with the neutrophil engraftment (P=0.0009 and P

Description: [Study purpose] We have reported that overall results of cord blood transplantation (CBT) were inferior to those of bone marrow transplantation (BMT) from unrelated donor in myelodysplastic syndrome (MDS) including transformed acute myelogenous leukemia (AML/MDS) (ASH 2007). Poor engraftment and higher incidence of relapse in CBT patients were serious problems. We now show here the impact of conditioning regimen and GVHD prophylaxis method on clinical outcomes of CBT, and then show the results when we looked for the appropriate graft selection in terms of human leukocyte antigen (HLA) compatibility and cell dose. [Patients and Methods] Clinical data of 333 patients with MDS including AML/MDS who received unrelated CBT without prior transplant history between 1998 and 2006 in Japan were collected by the Japan Cord Blood Bank Network (JCBBN). The median period of follow-up for survivors (n=148) after transplants was 13 (range, 1–99) months. We analyzed the hematopoietic recovery, incidences of acute and chronic graft-versus-host disease (GVHD), risks of transplant-related mortality (TRM) and relapse, and disease-free survival (DFS) using competing risk regression models. [Results] Both myeloablative conditioning regimen including 8Gy or more dose of total body irradiation (TBI) and GVHD prophylaxis as calcineurin inhibitor (cyclosporin or taclorimus) plus methotrexate (MTX) significantly (p

Description: Unrelated cord blood transplantation (u-CBT) may provide a treatment option for patients with malignant lymphoma (ML) who have failed other conventional therapies and do not have a compatible donor available. Japan Cord Blood Bank Network (JCBNW) has established a registry for u-CBT as a quality management and promotion of CBT. We have analysed 271 patients with ML (aggressive lymphoma=189, indolent lymphoma=52) transplanted from 1999–2006 and reported to JCBNW. The median follow-up was 19 months (1–85) and the median age was 47 years (1–75). At transplant, 83% of the patients are non-CR and 23% had received previous autologous transplants. The conditioning regimen varied according diasease and centers: reduced intensity conditioning regimens (RIC) were used in 49% and ATG/ALG was added in 5% of the cases. GVHD prophylaxis consisted of CsA alone (23%), CsA/sMTX (28%), TAC alone (18%), TAC/sMTX (11%) and others (20%). The median nucleated cell dose infused was 2.6 × 10^7/kg and the graft was HLA identical (6/6) (HLA A and B low resolution and DRB1 allelic typing) in 37 cases, 5/6 in 110, and 4/6 in 122. Median time to neutrophil recovery (〉500/mm3) was 22 days (0–61) and 39 days for platelets recovery (〉20.000/mm3). The probability of neutrophil recovery was 80%. Grades II–IV aGVHD was observed in 50%. Treatment-related mortality (TRM) was observed in 107 patients (39%), and 61% of them were related to infection. The overall survival (OS), disease-free survival (DFS), and cumulative incidences of disease progression at 2 years after u-CBT were 28%, 21%, and 11%, respectively. In a multivariate analysis, chemoresistance, bacterial infection, and cGVHD were identified as adverse prognostic factors for overall survival. The development of grades II–IV aGVHD was associated with higher rate of DFS, which suggested the existence of a graft versus lymphoma effect. Althouth u-CBT can be an effective therapeutic option for patients with refractory ML, more work is still needed to decrease TRM.

Description: Background: Allogeneic stem cell transplantation currently is the only potentially curative therapy for myelodysplastic syndrome (MDS). Cord blood and bone marrow from unrelated donors are considered as an acceptable alternative to hematopoietic stem cells. The result of single institutional analysis in Japan has shown cord blood transplantation (CBT) is promising in adults with hematologic malignancies including MDS and is comparable with bone marrow transplantation (BMT) from unrelated or related donors (Blood101: 4711, 2003, Blood104: 3813, 2004, Blood109: 1322, 2007). Objectives: This study aimed to use the data of MDS patients within JMDP and JCBBN registry database to evaluate safety and efficacy of both BMT and CBT from unrelated donors and relate those to biological and procedural factors. Methods: Clinical data of 965 patients with MDS including transformed acute myelogenous leukemia (AML/MDS) who received unrelated BMT (n=532) or unrelated CBT (n=433) between 1993 and 2006 were collected. The median period of follow-up for survivors after BMT was 21 months for BMT and 12 month for CBT, respectively. We analyzed the hematopoietic recovery, incidences of graft-versus-host disease (GVHD), risks of transplant-related mortality (TRM) and relapse, and disease-free survival (DFS) using Cox proportional hazards models. Results: Compared with BMT recipients, CBT recipients were older (52 years old versus 39 years old), included many patients with AML/MDS (58% versus 38%), used many non-myeloablative regimen (55% versus 18%), less human leukocyte antigen-matched donor (3% versus 67%) and less methotrexate (MTX)-containing GVHD prophylaxis (43% versus 91%). Multivariate analysis demonstrated slow neutrophil (P

Description: Abstract 3118 Introduction: Elderly patients with myelodysplastic syndromes (MDS) are often lack of suitable human leukocyte antigen (HLA)-matched related donors. Unfortunately, the data on the efficacy of allogeneic transplantation using alternative donor sources are limited. We retrospectively compared the outcomes of HLA 6/6 antigen-matched related bone marrow or peripheral blood progenitor cells (rBM/PBPC) transplantation (6/6rBM/PBPCT), HLA 8/8 allele-matched unrelated bone marrow (uBM) transplantation (8/8uBMT), HLA 7/8 allele-matched uBM transplantation (7/8uBMT), and HLA at least 4/6 antigen-matched single-unit umbilical cord blood (CB) transplantation (sCBT) for elderly patients with MDS. Method: The data were obtained from the Transplant Registry Unified Management Program, which includes data from the Japan Society for Hematopoietic Cell Transplantation, the Japan Marrow Donor Program, and the Japan Cord Blood Bank Network. Patients aged 50–70 years old at transplantation with MDS according to French-American-British (FAB) classification who received first allogeneic transplantation between January 1, 2001 and December 31, 2010 were included. Among 336 rBM/PBPC, 291 uBM, and 215 CB transplantation recipients with complete HLA data, 268 6/6rBM/PBPCT, 147 8/8uBMT, 90 7/8uBMT, and 211 sCBT recipients were included. Cox proportional-hazards regression model was used for adjusted comparisons of the donor sources on overall survival (OS). Fine and Gray proportional-hazards model was used for adjusted comparisons of the donor sources on non-relapse mortality (NRM), relapse, grade 2–4 acute graft-versus-host disease (aGVHD2–4), and neutrophil engraftment. Recipient age at transplantation (〉=60 or 50–59), recipient sex (male or female), performance status (PS) at transplantation (2–4 or 0–1), FAB classification at transplantation (refractory anemia with excess blasts (RAEB) and RAEB in transformation (RAEBt), or refractory anemia (RA) and RA with ringed sideroblasts), latest cytogenetics classification according to International Prognostic Scoring System (good, intermediate, poor, or unevaluable), transplant conditioning regimen (reduced-intensity conditioning or myeloablative conditioning), and the year at transplantation (2001–2005 or 2006–2010) were included in the multivariate models. Result: Median follow-up was 2.9 years. The unadjusted 3-year OS rates for recipients of 6/6rBM/PBPCT, 8/8uBMT, 7/8uBMT, and sCBT were 50.7%, 58.2%, 46.2%, and 28.4%, respectively. Multivariate analysis revealed that the OS for sCBT recipients was significantly inferior to those for 6/6rBM/PBPCT (relative risk (RR) [95% confidential interval], 1.9 [1.5–2.5]; P 1, FAB classification at transplantation as RAEB/RAEBt, and poor cytogenetics. The risk of relapse for sCBT recipients was comparable with that for 6/6rBM/PBPCT but significantly higher than those for 8/8uBMT (RR, 2.4 [1.5–3.8]; P

Description: Abstract 3095 Background: Although acute graft-versus-host disease (aGVHD) is a major cause of non-relapse mortality (NRM) after allogeneic hematopoietic cell transplantation (allo-HCT), there have been few reports on the influence of older age on NRM after aGVHD. Methods: We retrospectively analyzed 2954 patients with hematological malignancies who received their first allo-HCT between January 2005 and December 2009 and developed grade II to IV aGVHD, using the database of the Transplant Registry Unified Management Program (TRUMP) at the Japan Society for Hematopoietic Cell Transplantation. The median age of the patients was 48 years (range: 20–82) and the median follow-up period for survivors was 740.5 days after transplantation. The diagnosis included acute myeloid leukemia (n=1248, 42.2%), acute lymphoid leukemia (n=537, 18.2%), myelodysplastic syndrome (n=328, 11.1%), non-Hodgkin lymphoma (n=391, 13.2%), adult T cell leukemia/lymphoma (n=187, 6.3%), chronic myeloid leukemia (n=99, 3.4%), plasma cell neoplasms (n=56, 1.9%), myeloproliferative neoplasm (n=42, 1.4%), Hodgkin lymphoma (n=27, 0.9%), and other leukemia/lymphoma (n=39, 1.3%). High-risk disease was present in 1470 patients (49.8%). The stem cell sources were HLA-matched related donors in 689 patients (23.3%), mismatched related donors in 245 patients (8.3%), matched unrelated donors in 780 patients (26.4%), mismatched unrelated donors in 595 patients (20.0%), and cord blood in 645 patients (21.8%). Myeloablative conditioning was used in 1808 patients (61.2%). Cyclosporine- and tacrolimus-based GVHD prophylaxis was used in 1304 and 1600 patients (44.1% and 54.2%), and just 88 patients (3.0%) underwent in vivo T cell depletion. Five hundred and thirty-four patients (18.1%) had GVHD prophylaxis without methotrexate. At the onset of aGVHD, 2379 (80.5%), 234 (7.9%), and 958 patients (32.4%) had initial skin, liver, and gut involvement, respectively. The cumulative incidence of NRM was analyzed under the assumption that they represented competing risks, defining relapse as a competing event for NRM, and compared using Gray's test. The Fine-Gray proportional hazards model was used to test the statistical significance of several potential prognostic factors for NRM. Multivariate analysis was conducted with covariates with P-values

Description: We have little information on chronic graft-versus-host disease (GVHD) after cord blood transplantation (CBT). We investigated its clinical features in 1072 Japanese patients with hematologic malignancies who received a transplant through the Japan Cord Blood Bank Network. The primary end point was to investigate the incidence of any chronic GVHD. Median age of the patients was 33 years (range, 0-79 years). The cumulative incidence of chronic GVHD 2 years after transplantation was 28%. Chronic GVHD was fatal in 29 patients. Multivariate analysis demonstrated that development of chronic GVHD was favorably associated with both overall survival and event-free survival. Multivariate analysis identified risk factors of chronic GVHD: higher patient body weight, higher number of mismatched antigens for GVHD direction, myeloablative preparative regimen, use of mycophenolate mofetil in GVHD prophylaxis, and development of grades II to IV acute GVHD. Although chronic GVHD is a significant problem after CBT, it is associated with improved survival, perhaps due to graft-versus-malignancy effects.

Description: Background Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative treatment option for the patients with acute myeloid leukemia (AML), but a major obstacle to success is represented by the relapse of the disease. Donor T lymphocytes can induce graft-versus-leukemia (GVL) effect, and it contributes to eliminate leukemic cells. We retrospectively analyzed the risk of relapse after allo-HCT for the patients with AML. Purpose of this study is to determine the impact of donor sources for the risk of relapse and survival. Patients and Methods Clinical data were collected from the Transplant Registry Unified Management Program (TRUMP) in Japan. An individual patient data-based analysis was performed on patients with AML who underwent allo-HCT between 2006 and 2010. Patients with CR1 or CR2 were defined as having standard-risk disease, and patients with CR3≤ or non-CR were defined as having advanced-risk disease. Cox proportional hazards models were used to evaluate variables that may affect overall survival. Fine and Gray proportional-hazards model were used to evaluate variables that may affect morphologic relapse. Death in remission was treated as a competing risk when analyzing cumulative incidence of relapse. Death or relapse without GVHD was treated as a competing risk for acute and chronic GVHD. Results We analyzed a cohort of 3,829 patients with AML: 543 (14%) received bone marrow from related donors (RBM), 768 (20%) received peripheral blood from related donors (RPB), 1,576 (41%) received bone marrow from unrelated donors (URBM), and 942 (25%) received cord blood (CB). The median age at allo-HCT was 46 years (range, 16 to 65 years). The cumulative incidence of relapse at 5 years in all-risk patients, standard-risk disease, and advanced-risk disease were 36%, 22%, and 42%, respectively. The 5-year unadjusted OS rates in all-risk patients, standard-risk patients and advanced-risk patients were 44%, 61%, and 26%, respectively. In multivariate analysis, the uses of antigen matched URBM (HR 0.47, 95% CI 0.36-0.61, p