ALBERT

Description: Introduction: We have recently reported that the evaluation CD25 expression on leukemic blasts at the time of disease onset could be an alternative non-molecular tool for predicting transplant outcomes in patients with cytogenetically intermediate acute myeloid leukemia (AML). We herein focus on patients with refractory or relapsed AML and examine the clinical correlation of the surface CD25 expression measured by flow cytometry at the time of transplantation and subsequent transplant outcomes. Patients and methods: A total of 60 AML samples with primary induction failure (n = 32), first relapse (n = 23) or second relapse (n = 5) were analyzed by means of flow cytometric CD25 antigen expression on leukemic blasts at the time of transplantation. Survival outcomes were compared with regard to the CD25 expression. Overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan-Meiyer. Factors associated with at least borderline significance (p〈 0.10) on univariate analyses were subjected to multivariate analysis using backward stepwise proportional hazard modeling. Multivariate analysis was performed using the Cox proportional hazards regression model. Results: CD25 antigen expression (〉10%) on leukemic blasts was observed in 24 patients (40%). There was no significant difference between CD25 positive and negative groups in terms of clinical characteristics including cytogenetic risk, WHO classification, marrow or peripheral blasts % at transplantation, comorbidity, conditioning regimen, donor source or interval between diagnosis and transplantation. Although more early relapse cases within 180 days were observed in the CD25 positive group (p = 0.01), cumulative incidence of relapse, non-relapse mortality, acute or chronic graft-versus-host disease were not different between 2 groups. However, there was a significant difference in OS or PFS between 2 groups: 2-years OS; 8.3% vs. 34.0%, p=0.004 (Fig 1A), 2-years PFS; 8.3% vs. 26.3%, p=0.003 (Fig 1B). Moreover, multivariate analysis showed that CD25 expression was an independent adverse factor for OS (hazard ratio: 2.01, 95% confidence interval: 1.10-3.67, p = 0.02). Conclusion: Our cohorts with total 60 patients with refractory or relapsed AML showed that CD25 endowed these patients with an adverse prognostic impact, which might not be overcome even by transplantation. AML patients with residual CD25+ blasts at the time of transplantation might require additional therapy before or after transplantation for better survival. However, our small experience clearly desires larger series patients for evaluating the real impact of CD25 expression. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Description: Abstract 4508 Long-term follow-up data of the patients who underwent HSCT more than 2 years ago at a single institution in Japan was presented. The patients who received first allogeneic hematopoietic stem cell transplantation (HSCT) at Tokyo Metropolitan Komagome Hospital between January, 1990 and December, 2007 under hematology division were included. Follow-up data were obtained annually from the medical records if the patients visited our institution regularly. If the patients were not followed in our institution, follow-up data were requested to the hospitals where the patients had been followed or questionnaires were sent directly to the patients unless their addresses are not known. These letters were sent annually. The most recent laboratory data and any kind of complications under treatment including hypertension, hyperlipidemia, diabetes including usage of insulin, renal failure, dialysis, and any kind of malignancies were requested to be reported. Survival was the most primitive data and the reason of death was defined by one of the authors, HA. Chronic GVHD was excluded from the independent etiology of death. Progression of the disease or complications of the treatment for the progressive disease were considered to be due to relapse. The incidence of each complication was calculated using the number of the patients whose data are available. In total, 622 patients had received transplantation and 370 patients survived more than 2 years. During last two years, 211 patients had been followed in our institution while 74 patients by the institutions outside. Letters were sent directly to rest of surviving patients. As the result, 6 patients could not be reached by any method. Letters had been received without response in 15 patients. 72 patients died later than 2 years after transplantation. Relapse was the most important reason of death even more than 2 years after the transplantation. Although the incidence declined annually, the latest relapse was observed in the patient with CML almost 15 years after the transplantation. Pulmonary complications including bronchiolitis obliterans and infections followed. Secondary malignancy was the reason of death in 7 patients. Chronic kidney disease was already observed in 27 % of the patients who survived 2 years after transplantation and one of the devastating complications. In total of 7 patients needed to start regular dialysis or kidney transplantation and another 2 patients showed eGFR level of less than 15 ml/min/m2. Nephrotic syndrome was another renal complication observed in 4 patients. Hypertension was reported on 46/244 (19%) of the patients. Diabetes was reported on 27/241 (11.2%) and 13 of them were on regular insulin treatment. Definitive diagnostic criteria of diabetes were not indicated on this analysis suggesting higher incidence of glucose intolerance in these patients. There were 14 patients developed secondary malignancies diagnosed later than 2 years after transplantation and oral mucosa, tongue, esophagus and colon were the main organs involved. Physicians taking care of those patients were recommended to check kidney function and gastrointestinal tract including head/neck, esophagus and colon for secondary malignancy, as well as hematological status. Disclosures: No relevant conflicts of interest to declare.

Description: After allogeneic bone marrow transplantation (allo-BMT), recipient alveolar macrophages (AM) are gradually replaced by AM of the donor origin. An influx of mononuclear phagocytes of donor origin to the lung is responsible for the repopulation, but the detailed kinetics remain unclear. We therefore studied 24 BMT recipients who underwent bronchoalveolar lavage (BAL) from 24 to 83 days after BMT. AM cell number, size, morphology, proliferating ability, and genotype of AM were measured. Before day 50, the number and size of AM in BAL fluid were similar to those of normal nonsmokers. However, after day 50, the mean number of AM increased threefold and the mean cell size decreased due to the increase of small AM. These small cells are presumably of donor origin based on DNA fingerprinting analysis and based on fluorescence in situ hybridization for the Y chromosome in a sex-mismatched case. Immunohistochemistry and cell cycle analysis demonstrated that the increase in AM number coincided with a remarkable increase of AM expressing proliferating cell nuclear antigen, suggesting that small AM are proliferating. This is the first report representing that augmented proliferation of donor AM in situ may contribute to the reconstitution of AM population after BMT.

Description: Prognosis of patients with AML varies widely reflecting the heterogeneity of AML and the background of each patient. It is important for both physicians and patients to predict the response to chemotherapy to correctly select the therapeutic options. In the JALSG-AML97 study, patients were stratified using JALSG scoring system, and those who were categorized into the intermediate or adverse prognosis group were assigned to allo-HSCT during CR1 if they had an HLA-matched sibling. JALSG scoring contains several factors that have 1 or 2 points: 2 points, age 〈 50 years, WBC 50%; 1 point, PS

Description: We retrospectively analyzed results for 154 patients with acquired severe aplastic anemia who received bone marrow transplants between 1993 and 2000 from unrelated donors identified through the Japan Marrow Donor Program. Patients were aged between 1 and 46 years (median, 17 years). Seventy-nine donor-patient pairs matched at HLA-A, -B, and -DRB1 loci, as shown by DNA typing. Among the 75 mismatched pairs, DNA typing of 63 pairs showed that 51 were mismatched at 1 HLA locus (18 HLA-A, 11 HLA-B, 22 HLA-DRB1) and 12 were mismatched at 2 or more loci. Seventeen patients (11%) experienced either early or late graft rejection. The incidence of grade III/IV acute graft versus host disease and chronic graft versus host disease was 20% (range, 7%-33%) and 30% (range, 12%-48%), respectively. Currently, 99 patients are alive, having survived for 3 to 82 months (median, 29 months) after their transplantations. The probability of overall survival at 5 years was 56% (95% confidence interval, 34%-78%). Multivariate analysis revealed the following unfavorable factors: transplantation more than 3 years after diagnosis (relative risk [RR], 1.86; P = .02), patients older than 20 years (RR, 2.27; P = .03), preconditioning regimen without antithymocyte globulin (RR 2.28; P = .04), and HLA-A or -B locus mismatching as determined by DNA typing. Matching of HLA class I alleles and improvement of preparative regimens should result in improved outcomes in patients with severe aplastic anemia who receive transplants from unrelated donors.

Description: In Japan, unrelated bone marrow transplantations (U-BMT) for severe aplastic anemia (SAA) were first performed in 1993. Transplant regimens and patient selection have changed substantially since then. We aimed to determine the effect of these changes on transplant outcome. We retrospectively analyzed the outcome in patients with SAA who received U-BMT through the Japan Marrow Donor Program between 1993 and 2005. We selected 302 recipient-donor pairs in which molecular analysis of HLA-A, -B, -C, -DRB1, and DQB1 were performed. Patient ages ranged from 1 to 64 years (median, 17 years). Various preconditioning regimens were used by individual centers. Either tacrolimus with methotrexate or cyclosporine with methotrexate was used for the prophylaxis against graft-versus-host disease (GVHD) in 137 (45%) patients and 127 patients (42%), respectively. Of the 302 pairs, 104 (34%) were found to be matched at HLA-A, -B, -C, -DRB1, and DQB1; 97 (32%) were mismatched at a single HLA allele (23 HLA-A or -B, 42 HLA-C, 32 HLA-DRB1 or HLA-DQB1); 83 (28%) were mismatched at two HLA alleles (35 HLA-A or -B and HLA-C, 8 HLA-A or -B and HLA-DRB1 or -DQB1, 40 HLA-C and HLA-DRB1 or -DQB1); and 18 (6%) were mismatched at three HLA alleles. Currently, 210 of the 302 patients are alive with the median follow-up period of 722 days after transplantation. The incidence of graft failure was 2.2%; that of grade II/IV GVHD was 29.0%; that of III/IV acute GVHD was 13.8%; and that of chronic GVHD was 25.2%. Multivariate analysis revealed the following significant risk factors for survival: patients older than 15 years (RR, 1.98; range 1.17–3.35); HLA-A or -B + HLA-C or HLA-DQB1 or -DRB1 (RR 2.18; range 1.29–3.68); three loci mismatching (RR 3.14; range 1.47–6.69); prophylaxis against GVHD with tacrolimus with methotrexate (RR 0.45; range 0.28–0.73), ABO major mismatch (RR 1.67; range 1.05–2.63), and non-ATG-containing CY+TBI regimen (RR 2.17; range 1.16–4.03). Patients were divided into two cohorts based on years of transplantation and we compared patients transplanted within two time periods: 1993–2000 and 2001–2005. Five-year survival increased 55.9+/−4.6% in the 1993–2000 cohort (n=116) and 72.7+/−3.8% in the 2001–2005 cohort (n=186) (p=0.008). Patients and transplant characteristics that differed significantly between the two periods were patients’ age distribution, GVHD prophylaxis, HLA matching, and conditioning regimens. The percentage of patients older than 15 years was significantly larger in the recent period (p

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: The role of chemotherapy before allo-SCT remains unclear. We analyzed the data of 283 patients (median age 41 years, range 16–65 years) who underwent allo-SCT from an HLA-identical sibling donor for MDS that were reported to the Japan Society for Hematopoietic Cell Transplantation. One hundred eighty-eight patients had received chemotherapy before allo-SCT (Chemo group), whereas 95 had not (NoChemo group). The Chemo group included significantly higher proportion of patients with advanced disease and poor karyotype than the NoChemo group, (p