ALBERT

Description: Blood stream infection (BSI) is a major problem after cord blood transplantation (CBT). However we have little information on it after reduced-intensity cord blood transplantation (RICBT). This study aims to investigate clinical characteristics of BSI within 100 days of RICBT, and to identify its risk factors in the patient who received RICBT between January 2002 and March 2004 in Toranomon hospital. We reviewed medical records of 77 patients with advanced hematologic diseases who underwent RICBT at Toranomon Hospital between January 2002 and June 2004. Median age of the patients was 55 years (17-79). Median number of infused cells and CD34+ cells were 0.86 x 10E7 (range; 1.73–4.31) and 0.8x10E7/kg (range; 0.01–46.1), respectively. Conditioning regimen consisted of fludarabine (125–150 mg/m2), melphalan (80–140 mg/m2), and TBI 2–8 Gy. GVHD prophylaxis was cyclosporine or tacrolimus. BSI must have met at least one of the following criteria previously described. (O’Grady, NP et al., Infect Control Hosp Epidemiol 2002) Mortality was considered to be directly attributable to a bloodstream pathogen if the patient died within 7 day after the last positive blood culture without any other probable cause of death, The patient’s characteristics were compared between those with or without BSI by univariate analysis. 149 episodes of BSI were observed in 31 patients. Cumulative incidence within 100 days was 0.40. Median onset was day 13 (1–98) after RICBT. The causative organisms were P. aeruginosa (47), S. epidermidis (44), E. faecium (13), T. beigelii (6), S. maltophilia (6), E. faecalis (5), E. coli (3), A. xylosoxidans (3) and others (22). 8 patients died of septicemia directly associated with BSI. A mortality rate was 26%. The causative organism included P. aeruginosa, A. xylosoxidans, S. maltophilia, S, aureus and gram-positive rod. Use of corticosteroid (p=0.012) and time to engraftment (p=0.003) were associated with the development of BSI. BSI is a major complication in our series of RICBT. Use of corticosteroid and prolonged neutropenia might have increased the risk of incidence of BSI.

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: [Introduction] The effectiveness of allogeneic hematopoietic stem cell transplantation (allo-HSCT) against autoimmune disease has been suggested by studies in animal models and patients who had undergone transplantation for hematological disorders. However, its significant treatment-related mortality (TRM) has limited its application to life-threatening cases. Reduced-intensity stem cell transplantation (RIST) is a rapidly expanding treatment strategy and diminishes TRM by decreasing conditioning regimen toxicity compared to conventional myeloablative transplants. The benefit of RIST for autoimmune disease still remains unclear. [Purpose] The purpose of this study is to analyze outcomes of patients with autoimmune diseases treated with RIST for coexisting hematological diseases. [Patients and Methods] Between April 2001 and March 2004, 19 patients (median age, 53 y; range, 20-70) underwent RIST from allogeneic donor. All of the patients were considered inappropriate for conventional allo-HSCT due to age 〉 50 years and/or organ dysfunction (generally attributable to autoimmune disease-related). Stem cell sources were unrelated CB (n=10), unmanipulated related PB (n=7) and unmanipulated unrelated BM (n=2). The preparative regimens were Flu/Mel-based (n=11), Flu/Bu-based (n=7), and Flu/CY (n=1). The primary disease were NHL (n=7), MDS (n=4), AML (n=3), HD (n=2), ATL (n=2), and SAA (n=1). Concurrent autoimmune diseases were ulcerative colitis (n=4), psoriasis (n=3), rheumatoid arthritis (n=2), interstitial pneumonitis (n=2), atopic dermatitis (n=1), ITP (n=1), CIDP (n=1), polychondritis (n=1), SLE (n=1), and MCTD (n=1). Eleven out of 19 patients were active in autoimmune disease, and seven needed immunosuppressive therapy. [Results] Median follow up period is 174 days (range, 33–987). All patients achieved neutrophile engraftment (median 22 days; range 12–42) and sustained 100% donor chimerism without DLI. 13 patients (68%) developed grade II-IV acute GVHD, and six (31%) developed chronic GVHD. Nine patients (47%) who were treated with steroid, died of transplant-related toxicity; sepsis (n=7), GI bleeding (n=1), and multiple organ failure (n=1). One patient died of leukemia relapse. As of August 2004, ten patients are alive at median follow-up of 402 days, and the actuarial overall survival rate is 51 % at 2 years. Regarding the clinical response for autoimmune disease, no patients experienced flares of the disease: complete remission is observed in seven patients (70%) and they become therapy-free. In the other three patients (30%), disease remains stable. [Conclusion] Our results suggest that a strategy that incorporates RIST for autoimmune disease may be worth considering for further intense evaluation. It may have a considerable graft-versus-autoimmunity (GVA) effect due to the recipient lymphoablation and reconstitution of donor T cells. Organ failure due to autoimmune disease, impaired immune response, and GVHD may contribute to high TRM. Management of regimen-related toxicity and the control of GVHD will be the focus of future investigation.

Description: Purpose: In a phase I study to evaluate the feasibility and safety of non-TBI-RI-UCBT in patients with advanced hematological malignancies, who were ineligible for conventional allogeneic hematopoietic stem cell transplantation. Patients and Methods: We treated a total of 6 patients (2 Hodgkin disease, 3 Follicular Lymphoma, 1 MDS overt leukemia). There were 4 female and 2 male, with a median age of 52.5 (46–62) years old. At the transplantation, all patients were in progressive disease (high-risk). Two patients with lymphoma had failed one or more preceding autologous transplants and a patient with overt leukemia had failed an allogeneic transplant. Backbone agent in the conditioning regimen was fludarabine, in combination with melphalan (n=4), or melphalan and thiotepa (n=2). Graft-versus-host disease (GVHD) prophylaxis incorporated cyclosporine alone (n=3), or FK506 alone (n=3). All of the patients received 4 of 6 HLA -antigen-matched umbilical cord blood transplantation. The median number of infused total nucleated cell dose and CD34 plus cell dose before freezing were 3.18 x 107 (2.77–4.7) /kg and 0,85 x 105 (0.57–1.91) /kg, respectively. Results: All of the patients achieved primary neutrophil engraftment. The median time to reach 0.5 x 109/L neutrophils was 24 (13–31) days. Platelet counts above 20 x 109/L were achieved by 3 patients on median day of 40 (39–45) days. The median time to complete donor chimerism was 26.5 (16–35) days. Acute GVHD occurred in 2 of the 6 patients (grade I/II in 2). Chronic GVHD developed in none of the evaluable patients. Two of the 6 patients developed noninfectious fever before neutrophil engraftment. Three patients died of TRM (1 pneumonia, 1 thrombotic microangiopathy, 1 acute heart failure), and the other 2 patients died due to disease progression. At a median follow-up of 65.5 days (33–78), one of the 6 patients is currently alive in CR. Conclusion: Although this study is preliminary with a small number of patients and short follow-up, our findings demonstrated the successful engraftment of non-TBI-RI-UCBT for adult patients with relapsed/refractory hematological malignancies. Prospective study to further evaluate the efficacy of non-TBI-RI-UCBT for hematological malignancies is warranted.

Description: 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.

Description: Backgrounds: Cytomegalovirus (CMV) infection is a major complication after allogeneic transplantation; however clinical significance of CMV reactivation after cord blood transplantation remains unclear. Objective: We retrospectively investigated the incidence of CMV antigenemia, and CMV diseases, and its prognosis in adult patients who underwent reduced-intensity cord blood transplantation (RI-CBT) Patients/ Methods: We reviewed medical records of 77 patients who received RICBT at Toranomon Hospital between January 2002 and March 2004. Median age of the patients was 55 years (range 17–79). Underlying diseases were chemorefractory hematologic diseases (n=76) and severe aplastic anemia (n=4). Conditioning regimen comprised fludarabine (125 mg/m2), melphalan (80 mg/m2), and TBI 4-8Gy. GVHD prophylaxis was cyclosporine (n=69) or tacrolimus (n=11). Median total nucleated cells and CD34+ cells was 2.4×106 cells/kg (0.39–4.3), and 0.81×105 cells/kg (0.05–5.7) respectively. HLA disparity was 6/6 (n=3), 5/6 (n=12), 4/6 (n=63), and 3/6 (n=2). All patients were monitored CMV-antigenemia weekly and received pre-emptive gancyclovir or foscarnet. Results CMV antigenemia tested positive in 47 patients on a median of day 32 (range, 12–55) after RICBT. The cumulative incidence of CMV reactivation at day 100 was 0.70. Seven and 29 patients were treated with preemptive ganciclovir and foscarnet, respectively. Adverse events of them were myelosuppression in 3 patients given ganciclovir, and mild hyponatremia in a patient given foscarnet. CMV diseases developed in 15 patients on a median of day 39 (range 15–92); enterocolitis (n=13), pneumonia (n=1), and encephalitis (n=1). Seven of 15 patients were resolved with antiviral treatment, and the other patients were fatal with CMV infection. Univariate analysis showed any risk factors for CMV reactivation. Discussion CMV reactivation and diseases develop early after cord blood transplantation. Opitimal strategy for preventing CMV disease should be established in RICBT.

Description: Introduction Cord blood is an alternative stem cell source, and RICBT is investigated as a clinical trial. High incidence of infection is an obstacle to the spread of RICBT; however, the detail of infectious complication is not described. We retrospectively investigated the incidence and risk factor of IFI after RICBT. Patient and method A total of 102 patients received RICBT at Toranomon Hospital from March 2002 to May 2004. The median age of the patients was 57 years (range, 20–79). Underlying diseases included acute myeloid leukemia or myelodysplastic syndrome (n = 43), malignant lymphoma (n = 38), acute lymphoblastic leukemia (n = 12), multiple myeloma (n = 4), severe aplastic anemia (n = 3), chronic myeloid leukemia (n = 1) and idiopathic myelofibrosis (n = 1), and 90 (88%) patients had advanced or chemorefractory diseases. Preparative regimen comprised fludarabine 125mg/m2, melphalan 80 mg/m2 and 400 cGy total body irradiation. Graft-versus-host disease (GVHD) prophylaxis was cyclosporine (n = 80) or tacrolimus (n = 22). The median number of infused nucleated cell was 2.8 (range, 2.0 – 4.6) x 10E7 cells / kg, and HLA disparity was 0 (n = 1), 1 (n = 15) and 2 (n = 86). Patients were managed in laminar airflow-equipped rooms. All patients received fluconazole 200 mg/day for the prophylaxis of fungal infection. Proven or probable invasive fungal infections were defined according to the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC / MSG) criteria. Patients with possible IFI were not included in this analysis. The day of diagnosis of the fungal infection was the day on which the first positive diagnostic test was performed. For patients whose diagnosis was established after death, the date of death was considered to be the day of diagnosis. Result The median follow-up after RICBT was 8.5 months (range, 0.9–28). Eighty patients achieved primary engraftment, and the median time to engraftment was 20 days (range, 9–55). Nine (9%) patients developed IFI (Aspergillosis 8, Trichosporosis 1). Two patients had a history of IFI prior to transplant. The median time of diagnosis was 15 (range, 2–179) days after transplant. Six of the nine IFI developed during neutropenia. Four patients responded to treatment with amphotericin B and micafungin, and five patients died of IFI. No risk factor was identified in univariate and multivariate analysis. Discussion Different from recent reports on IFI after nonmyeloablative transplantation from adult donor, IFI develops early after RICBT. Because most of patients received multiple courses of myelosuppressive chemotherapy, patients possibly had latent IFI. In fact, two patients with history of IFI recurred after RICBT. Moreover, most of patients developed IFI in laminar-airflow equipped room. These facts suggest that early onset IFI might be an activation of latent fungal infection. On the other hand, increased incidence of bacterial and viral infection suggests the possibility that profound immunosuppression after RICBT causes early onset IFI. Conclusion IFI develops during neutropenia in RICBT. Prospective study to evaluate the risk factor of IFI and the effective fungal prophylaxis for RICBT is warranted.

Description: The potential role of RICBT in adults remains unclear. This study reports the results of RICBT for adults with hematological diseases. The 1st purpose of this report was to investigate the risk factors of non-relapse mortality (NRM) within day 100 of RICBT and the 2nd was to identify its prognostic factors. We reviewed medical records of 107 patients with advanced hematological diseases who had received RICBT between March 2002 and June 2004 at Toranomon Hospital, Tokyo, Japan. Median age of the patients was 55 years (17–79). Primary diseases were advanced (n=88) or standard (n=19). Median follow-up was 14 months (0.5–27). Conditioning regimen was fludarabine 125 mg/m2, melphalan 80 mg/m2 and TBI 4 Gy. GVHD prophylaxis was cyclosporine (n=87) or tacrolimus (n=26). Median total nucleated cells (TNC): 3.2 x 10^7 cells (1.7–4.3); Median CD34+: 1.4 x 10^5 cells (0.21–3.28); HLA match: 6/6 (n=4), 5/6 (n=3), 4/6 (n=95), 3/6 (n−1). Time to event curves were plotted by using the actuarial method of Kaplan-Meier, and differences between curves were analyzed by log-rank tests. The following factors were considered potential predictors of outcomes about 1st and 2nd purpose: age, weight, sex, risk, HLA disparities, TNC, CD34+, GVHD, pre-engraftment reactions (PER) that we have reported (Clin Cancer Res.10:3586-92, 2004), and use of steroids for PER. All factors were tested for the proportional hazards assumption. Neutrophile (〉500/μL) and platelet recovery (〉20,000/μL) were observed in 77.9% at day 60 (median; 19.5 day), 48.7% at day 100 (45.5 day), respectively. Primary graft failure was occurred in 8% of all cases. Cumulative incidence of acute GVHD (II-IV) and chronic GVHD were 39.8% and 21.1%, respectively. Causes of NRM included infections (n=30), regimen related mortality (RRM) (n=19), and GVHD (n=6). Incidence of NRM at day 100 was 51.6% (95% CI: 42–61), 33 patients with use of steroids for PER had NRM at day 100 of 75% (95% CI: 67–94), as compared to 39% (95% CI: 25–48) in 77 patients without use of steroids (p

Description: [Background] Non-myeloablative regimens have been proven to allow engraftment following allogeneic stem cells transplantation with minimal procedure-related toxicity and lower costs. Cord blood has emerged as an appealing alternative source of hematopoietic stem cells for unrelated donor transplantation, but delayed engraftment and frequent transfusion were reported. No studies have formally evaluated the cost of reduced-intensity cord blood transplantation (RICBT). [Purpose] To evaluate the relationship among costs, baseline patient characteristics, and major complications of RICBT, we performed an economic analysis of data in a clinical trial of RICBT for hematologic diseases at a single institution. [Patients and Methods] Ninety-three patients with hematological diseases (median age, 55y; range, 17–79: median body weight, 53kg; range, 38–75) underwent RICBT from March 2002 to May 2004 in Toranomon Hospital. Mean follow-up period was 77 days (range, 13–863). Data on resource use, including hospitalizations, medical procedures, medications, and diagnostic tests, were abstracted from subjects’ clinical trial records. Resources were valued using the Japanese national insurance reimbursement system for inpatient costs at one hospital and average wholesale prices for medications. Monthly costs were calculated and stratified by treatment group and clinical phase. [Results] The median initial inpatient cost was $80,400 (range, 41,300–154,700). When baseline variables were considered, disease status was significant predictor of costs. When clinical events were considered, in-hospital death was associated with higher costs. The mean length of total inpatient days was 78 days (range, 31–222), and the mean length of inpatient days post transplant was 51 days (range, 15–131). The mean units of transfused RBC, Platelet, and FFP were 27u, 224u, and 27u, respectively. [Discussion] This study firstly demonstrates that the cost of RICBT was much higher as compared to previous RIST using peripheral blood or bone marrow. RICBT is an attractive therapy, however, economic problem lies before prevalence of RICBT. The increased numbers of transfusions and supportive care would have effects on costs. The association between mortality and higher costs suggest that prevention of clinical complication may have significant economic benefits. Interventions that decrease these complications may have favorable cost-benefit ratios, and will be the focus of future investigation.

Description: Background: Based on its favorable effects on survival, azacitidine (AzaC) is now recognized as a first-line treatment option for higher-risk MDS. But the prognosis of patients who become resistant or intolerant to AzaC is still dismal (the median overall survival was 5.6 months, J Clin Onclol 2011;29:3322-7 Prebet T et. al.), and development of effective salvage therapies is eagerly awaited. A large number of tumor-associated antigens (TAAs) have been identified, and cancer vaccines utilizing their epitopes have shown some degree of clinical efficacies in various types of tumors. Wilms' Tumor 1 (WT1) is one of such promising TAAs with broad expressions in various tumors including MDS. WT4869 is a synthetic peptide vaccine derived from WT1 protein, and the phase 1/2 clinical study of WT4869 was conducted to evaluate the safety and efficacy in HLA-A*24:02+ MDS patients, with some exploratory biomarker analyses. Methods: The objectives of this study were to assess the tolerability of WT4869 treatment in MDS patients in phase 1 portion and evaluate the preliminary efficacy of WT4869 in higher-risk MDS patients in phase 2 portion. Higher-risk or transfusion-dependent lower-risk MDS patients including the AzaC-resistant population were enrolled in the study, and WT4869 at a dose of 5 to 1,200 µg/body was administered with intradermal injections every two weeks in dose-escalation cohorts according to the 3 + 3 design until discontinuation criteria were met. Clinical efficacy was evaluated according to the IWG response criteria 2006, and the time to acute myeloid leukemia and overall survival (OS) were also analyzed. We also evaluated immune responses including delayed type hypersensitivity and WT1-specific CTL induction. Expression of WT1 mRNA in peripheral blood and bone marrow cells were analyzed as surrogate markers for clinical efficacy. Results: Twenty six patients including 17 higher- and 9 lower-risk patients were enrolled in the study, and safety profiles were evaluated. Although dose-limiting toxicities (DLTs), including pneumonitis, muscle hemorrhage, pyrexia, and hypoalbuminemia, were observed in one patient at each dose of 50 and 400 µg/body, all of them were confirmed to be resolved or resolving, and no DLT was observed at other doses. As a result, WT4869 treatment was considered well-tolerated at the highest dose of 1,200 µg/body in MDS patients. Although there was no safety concern noted in phase 1 portion, further enrollment in phase 2 portion was not conducted to focus on the development with newly designed WT1 peptide vaccine. Twenty two out of 26 patients were analyzed for clinical efficacy. Decrease of bone marrow blasts was observed in one patient (marrow complete remission (mCR)), and 12 patients remained in stable disease (SD). Hematological improvement (HI) was observed in one mCR and three SD patients; two were in the erythroid lineages, one in the erythroid and neutrophil lineage and the other in the all three lineages. Very interestingly, two patients showed cytogenetic response, although hematopoietic improvement was not observed in these patients. In total, the overall response rate (mCR + any HI) was 18.2%, and the disease control rate (mCR + SD + any HI) was 59.1%. Though preliminary, prolongation of OS was observed in higher-risk patients and the median survival time in the AzaC-resistant higher-risk population was 13.0 months. CTL induction was observed in almost half of the treated population, and patients with any clinical response showed a trend of higher CTL induction. Conclusions: In the phase 1/2 study, WT4869 was well-tolerated in MDS patients, and preliminary but promising efficacy was suggested. WT1 peptide vaccination is expected to be a new treatment option for AzaC-resistant MDS. Further evaluations of WT1 peptide vaccination are warranted. Disclosures Ogura: Kyowa Hakko Kirin co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Phizer Japan Inc.: Research Funding; Janssen Pharmaceutical K.K.: Research Funding; GlaxoSmithKline K.K.: Research Funding; MSD K.K.: Research Funding; AstraZeneca K.K.: Research Funding; Takeda Pharmaceutical Company Limited: Research Funding; Symbio Pharmaceuticals Limited: Research Funding; Solasia Phama K.K.: Research Funding; Mundipharma K.K.: Research Funding; Celgene K.K.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding. Uchida:Eisai Co., Ltd.: Research Funding. Naoe:Kyowa Hakko Kirin Co., Ltd.: Patents & Royalties, Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Research Funding; Celgene K.K.: Research Funding; Toyama Chemical CO., LTD.: Research Funding; FUJIFILM Corporation: Patents & Royalties, Research Funding; Chugai Pharmaceutical Co., Ltd.: Patents & Royalties; Astellas Pharma Inc.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Pfizer Inc.: Research Funding. Kizaki:Ono Phranacutical Co., Ltd.: Consultancy; Nippon Shinyaku Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Chugai Phrarmaceutical Co., Ltd.: Research Funding. Tagashira:Sumitomo Dainippon Pharma Co.,Ltd.: Employment. Tsuchiya:Sumitomo Dainippon Pharma Co., Ltd.: Employment. Ohyashiki:Asahikasei: Research Funding; Teijin Pharma KK: Research Funding; Alexion Pharma KK: Research Funding; Asteras: Research Funding; Shinbaio Pharma KK: Honoraria; Toyama Kagaku KK: Speakers Bureau; Nippo Shinyaku KK: Speakers Bureau; MSD KK: Honoraria; Kyowa Kirin KK: Honoraria; Novartis Pharma KK: Honoraria, Research Funding, Speakers Bureau; Celegen KK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jansen Pharma KK: Honoraria, Research Funding, Speakers Bureau; Bristol Meyer Squib KK: Research Funding; Chugai Pharna KK: Research Funding; Sumitomo Dainippon: Membership on an entity's Board of Directors or advisory committees; Taiho Yakuhin KK: Research Funding. Miyazaki:Sumitomo Dainippon: Honoraria; Celgene Japan: Honoraria; Kyowa-Kirin: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Shin-bio: Honoraria.