ALBERT

Description: Background: Rituximab (R) plus CHOP (R-CHOP) is the standard of care for patients with diffuse large B-cell lymphoma (DLBCL). The International Prognostic Index (IPI) and revised IPI were reported as prognostic indicators for DLBCL in 1993 and 2007, respectively. Although they are widely accepted, the performance status (PS) factor is sometimes ambiguous or subjective. Therefore, we developed a new prognostic index, the SIL, that includes only three objective prognostic factors: the clinical stage (S), a soluble interleukin-2 receptor level 〉2,500 U/mL (I), and an elevated lactate dehydrogenase level (L) (Cancer Sci. 2012). This study was conducted to confirm the value of the SIL index in a larger cohort and in each risk stratification of patients and to validate the SIL index in an independent patient cohort. Methods: Between 2003 and 2012, we registered and treated 781 consecutive patients with DLBCL, excluding those with mediastinal large B-cell lymphoma, intravascular large B-cell lymphoma, and primary effusion lymphoma. All the included patients were scheduled to undergo primary therapy with six cycles of full-dose R-CHOP. Patients in whom the initial therapy dose was reduced by 〉20% were excluded. Finally, 572 of 781 patients were retrospectively analyzed. Patients with partial remission (PR) after the initial four cycles underwent eight R-CHOP cycles in total, whereas those who did not achieve PR after the initial four R-CHOP cycles or those who exhibited disease progression at any given time received salvage therapy. If deemed necessary by the attending physician, additional local irradiation was performed in patients with PR or complete remission.Furthermore, we verified the value of the SIL index in an independent cohort of 89 DLBCL patients. Results: The median age at diagnosis was 63 years (range, 18-89 years). The median number of therapy cycles was 6 (range, 1-8), and 90% of patients received 〉6 cycles. Sixty-one patients (11%) received radiation therapy as primary treatment, which was often used to treat sites of residual masses at the end of chemotherapy. The median observation time for survivors was 55 months (range, 1-131 months). For 572 patients, the 5-year progression-free survival (PFS) and 5-year overall survival (OS) rates were 70% and 81%, respectively. The 5-year PFS rate was significantly different as 86%, 73%, 63%, and 41% for 0, 1, 2, and 3 of SIL index, respectively (Fig 1; P 〈 0.0001). The 5-year OS rate was also significantly different as 92%, 87%, 78%, and 52% for 0, 1, 2, and 3 of SIL index, respectively (P 〈 0.0001). According to the SIL index, 367 (64%) and 205 patients (36%) were classified as having standard (SIL index: 0 or 1) and high (SIL index: 2 or 3) risks, respectively. In patients with a low/low-intermediate risk on the IPI, 84% were categorized as having standard risk according to the SIL index, whereas in patients with a high-intermediate/high risk on the IPI, 82% were categorized as having high risk according to the SIL index. Five-year PFS rates in the standard and high risk groups according to the SIL index were 79% and 53%, respectively (Fig 2; P 〈 0.0001). Five-year OS rates in the standard risk and high risk groups were 90% and 66%, respectively (P 〈 0.0001). Cox regression analysis of the SIL index, age (〉60 years), PS (2-4), sites of extranodal involvement (〉1), and sex showed that the SIL index (P 1), and sex, the SIL index was still a good prognostic indicator for PFS and OS in both groups. Lastly, when they were divided by the PS (0-1 and 2-4), the SIL index was effective in the good PS group. However, in the poor PS group, the SIL index showed a statistically significant difference in the OS, but not in the PFS. In the validation cohort analysis, 5-year PFS rates in the standard and high risk groups were 81% and 49%, respectively (Fig 3; P = 0.001). Five-year OS rates in the standard risk and high risk groups were 87% and 59%, respectively (P = 0.003). Conclusion: The SIL index is a simple and objective prognostic indicator for DLBCL patients treated with R-CHOP. Disclosures Fujita: Chugai Pharmaceutical CO.,LTD.: Honoraria.

Description: Background The percentage of blasts in the bone marrow in the early stage of remission induction therapy for acute myeloid leukemia (AML) has been reported to affect not only remission rate, but also long-term prognosis. If early post-treatment response to therapy was determined to affect prognosis, this finding could be a basis for selection of a proactive treatment such as hematopoietic stem cell transplantation; however, the proper assessment period and the percentage of blast cell survival vary among reports. Therefore, we retrospectively analyzed the relationship between prognosis and the percentage of blasts in the bone marrow in the early post-treatment stage in cases registered for the AML201 study conducted by the Japan Adult Leukemia Study Group (JALSG). Patients and Methods The JALSG AML201 study was a multicenter randomized study in which 1064 patients with newly diagnosed AML patients were registered between December 2001 and December 2005. For remission induction therapy, we compared standard-dose idarubicin or high-dose daunorubicin in combination with cytarabine. For consolidation therapy, we compared standard-dose multiagent chemotherapy or high-dose cytarabine alone, and no apparent differences were observed in overall survival (OS) between both treatment groups. The percentage of blasts in the bone marrow on day 15 was strongly associated with remission; using the receiver operating characteristic curve as a reference, we divided patients into a ≥5% and a

Description: Abstract 3028 Introduction: We performed a multicenter retrospective study of the significance of the addition of cytarabine (CA) or thiotepa (TT) to the myeloablative standard regimen consisting of total body irradiation (TBI) and cyclophosphamide (CY). Methods: Among the patients who underwent allogeneic hematopoietic stem cell transplantation between 2,000 and 2,010 in the four institutions related to Yokohama City University Hematology Group, a total of 365 patients who used the TBI/CY-based regimen were included to the cohort. Conditioning regimens were distributed to three groups: TBI/CY group (TC, n=82), TBI/CY/CA group (TCC, n=90), and TBI/CY/TT group (TCT, n=193). A standard TBI and CY regimen consisted of 12 Gy of TBI with four fractions and 60 mg/kg of CY for two days. Two days of CA (2 g/m2/day) or TT (200 mg/m2/day) were added to the TBI/CY regimen. A minimum dose reduction was permitted according to an older age or poorer co-morbidity. Overall survival (OS) and disease-free survival (DFS) were estimated by the Kaplan-Meier method. Gray's test was employed for comparison of cumulative incidence curves for relapse and non-relapse mortality (NRM). NRM and relapse were competing events. Adjusted multivariate Cox regression models were employed for each disease stage. Results: The median age was 42 years old (16–62). Diagnoses were acute myeloid leukemia (AML, n=219), acute lymphoid leukemia (ALL, n=105), and myelodysplastic syndrome (MDS, n=41). Complete remission or refractory cytopenia with multilineage dysplasia was defined as the standard stage (n=211), while the others were advanced (n=154). The stem cell sources were related bone marrow (RBM, n=79), related peripheral blood (RPB, n=51), unrelated bone marrow (UBM, n=161), and unrelated cord blood (UCB, n=74). As for patient characteristics, there was a deviation in the transplant year (P

Description: Abstract 1620 Few randomized prospective studies have been conducted on patients with localized DLBCL in the rituximab era. The SWOG 0014 study examined DLBCL patients treated with 3 cycles of R-CHOP followed by involved-field radiotherapy. Each of the patients had at least 1 of the 4 risk factors (nonbulky stage II, over 60 years of age, WHO performance status [PS] of 2, or elevated LDH), but showed 4-year progression-free survival (PFS) and 4-year overall survival (OS) rates of 88% and 92%, respectively. However, long-term observations showed that the PFS and OS curves did not plateau (Persky DO, et al. J Clin Oncol 2008). We retrospectively analyzed a series of patients with localized DLBCL treated with R-CHOP therapy alone. This study included 190 consecutive, untreated patients with localized DLBCL seen between 2003 and 2009 in 1 of the 7 participating hospitals. All the patients were scheduled to undergo primary therapy with 6 cycles of full-dose R-CHOP in 1 of the hospitals. Patients who required a dose reduction of more than 20% were excluded from the study, as were patients with special forms of DLBCL, such as intravascular lymphoma, primary mediastinal large B-cell lymphoma, and T-cell-rich B-cell lymphoma. Patients who achieved partial remission (PR) after the 4 initial cycles underwent a total of 8 R-CHOP cycles. Patients who did not achieve PR after the 4 initial cycles or those with disease progression at any time during the study underwent salvage therapy, and that time point was designated as the point at which the disease progression began. Additional local irradiation was allowed in patients with PR. Patients who received additional radiotherapy following CR in the decision of attending physicians were excluded from this study. Patients who achieved CR but who were initially at risk of central nervous system (CNS) involvement received 4 intrathecal doses of methotrexate (15 mg) and hydrocortisone (25 mg) for CNS prophylaxis. Central pathological reviews were not performed; only the individual institutional diagnoses were used. The study included 111 men and 79 women, with a median age at diagnosis of 63 years (range, 18–80 years). According to the IPI, 133 patients were classified as L; 49, as LI; 5, as HI; and 3, as H. Five patients received additional local irradiation after PR at the end of the R-CHOP therapy. CNS prophylaxis was performed in 15 patients who had an initial CNS risk and achieved CR. The median observation period for the living patients was 52 months. The responses to therapy were 180 CR, 8 PR, and 2 progression of disease (PD). The 5-year PFS and 5-year OS rates were 84% and 90%, respectively, and both plateaued (Figure 1). None of the patients experienced PD after 4 years of observation. Multivariate analysis revealed that the presence of bulky mass, which was evident in 18 patients, was an independent risk factor for PFS (P = 0.007, relative risk [RR] 3.5) and OS (P = 0.003, RR 5.8), along with poor performance status. During the observation period, 29 patients experienced PD. The progression sites included the primary sites in 15 patients, outside the primary sites in 10, and undetermined in 4. There were 16 deaths, 14 of which were due to the lymphoma. In 149 patients with at least one of the 4 risk factors used in the SWOG 0014 study, the 5-year PFS and 5-year OS rates were 86% and 94%, respectively. Six cycles of R-CHOP therapy alone were observed to be highly effective in attaining good survival results with plateaus. These results suggest that the “standard” strategy of 3 cycles of R-CHOP followed by involved-field radiotherapy for localized DLBCL should be replaced by R-CHOP alone. Disclosures: No relevant conflicts of interest to declare.

Description: Background: The prevalence of obesity has more than doubled between 1980 and 2014, worldwide. In Japan, 25% of adults aged ≥20 years (29 % of males and 20% of females) were overweight in 2013. Body mass index (BMI) assesses the proportion of weight versus height, and is commonly used to stratify underweight, normal, overweight, and obesity in adults. However, the prognostic impact of BMI in acute myeloid leukemia (AML) is debatable. In this retrospective study, we aimed to assess whether BMI was associated with clinical outcomes in AML patients in Japan. Patients and Methods: We identified 374 patients with newly diagnosed AML who had been administered either daunorubicin or idarubicin in combination with cytarabine as induction chemotherapy at any of the seven Japanese hospitals that collaborate to form the Yokohama City University Hematology Group from January 2000 to March 2015. Patients with acute promyelocytic leukemia were excluded from this study. BMI is defined as a person's weight in kilograms divided by the square of his height in meters (kg/m2). All patients were categorized in one of two groups according to their BMI: underweight (BMI

Description: Background: Since the introduction of rituximab, an anti-CD20 monoclonal antibody, the prognosis of patients with CD20-positive non-Hodgkin lymphoma has significantly improved. Recent reports have shown a gender-associated difference in rituximab clearance and clinical response, suggesting that rituximab may be more effective in female patients. However, the prognostic impact of gender with regard to rituximab clearance in diffuse large B-cell lymphoma (DLBCL) patients has not been elucidated thus far. Methods: We retrospectively analyzed data from 576 consecutive DLBCL patients, uniformly treated with standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP-21) therapy in 9 institutions in Japan, between 2001 and 2012. Patients with a dose reduction greater than 20%, mainly elderly patients with low performance status, were excluded from this study. The median age of the cohort was 63 years (range, 18–89 years), and 331 (57%) of the patients were male. Results: With respect to the International Prognostic Index (IPI) factors, a significantly higher proportion of female patients had elevated serum lactate dehydrogenase (sLDH) levels than male patients (57% vs. 48%, P = 0.03). A difference was also observed in the frequency of bone marrow (BM) involvement, which was primarily observed in male patients (8% in female vs. 15% in male, P= 0.006).No difference was observed between sexes in other baseline factors (other IPI factors, bulky mass over 10 cm, B symptoms). Complete remission rate for R-CHOP-21 was 86% in female patients and 85% in male patients (P = NS). After a median follow-up of 48 months, the 3-year progression-free survival (PFS) and overall survival (OS) rates were 73.7% and 84.3%, respectively. The IPI on diagnosis was low for 238 (41.3%) patients, low-intermediate for 152 (26.4%) patients, high-intermediate for 94 (16.3%) patients, and high for 92 16.0%) patients, with significant differences in survival among the 4 groups (3-year OS: 93.2%, 85.1%, 81.1%, and 63.6%, respectively, P 〈 0.001). Univariate analysis revealed that advanced clinical stage, poor performance status (PS 2-4), elevated sLDH, more than 1 extranodal involvement, BM involvement, bulky mass over 10 cm, and B symptoms had prognostic impact for both PFS and OS (all P

Description: Background: A soluble form of suppression of tumorigenicity 2 (ST2) has emerged as a biomarker for acute graft-versus-host disease (GVHD) and non-relapse mortality (NRM), whereas a clinical role of ST2 during the early phase of hematopoietic stem cell transplantation (HSCT) has not been fully elucidated. In addition, recent studies have demonstrated that high ST2 levels are associated with the development of thrombotic microangiopathy (TMA) and veno-occlusive disease (VOD) after HSCT. Therefore, we prospectively monitored soluble ST2 levels during the early phase of HSCT and evaluated the clinical association with transplant-related complications including acute GVHD, TMA, and VOD. Methods: Thirty-two adult Japanese patients who received first allogeneic HSCT for hematological diseases were enrolled consecutively between February 2014 and July 2015 at our university hospital or medical center that participate in Yokohama Cooperative Study Group for Hematology (YACHT). The selection of donor source and conditioning regimen was based on patients' hematological diagnosis, donor availability, and patients' clinical status. Soluble ST2 were measured by ELISA at fixed time points (before conditioning, on the day of HSCT (day 0) and days 14, 21, and 28 after HSCT). Serum IL-33 (the ligand of ST2), ferritin and C-reactive protein (CRP) levels were compared with ST2. Results: The median age was 50.5 years (range: 16-66). Acute myeloid leukemia was the main underlying disease (56%). Median soluble ST2 levels on the day of HSCT were higher than baseline and reached the maximum value (92.7 ng/mL (range: 0-419.7)) on day 21 after HSCT. ST2 levels were strongly correlated with ferritin and CRP levels in all samples (r = 0.456 and 0.615). Mainly, ST2 was well correlated with CRP at days 0, 14, and 21 (r = 0.717, 0.630, and 0.628). Serum IL-33 levels were under detection limits in most of the patients, resulting in no correlation of IL-33 with ST2 levels. With a median follow-up of 21.5 months (range: 0.9-35.4), nine patients developed grade II-IV acute GVHD. The optimal cut-off value of soluble ST2 on day 14 for predicting grade II-IV acute GVHD was determined as 100 ng/mL by the ROC analysis. We focused on day 14 ST2 levels as the earliest time point for predicting acute GVHD. The cumulative incidence of acute GVHD was 56.7% and 16.5% in the high and low-ST2 group, respectively (P 〈 0.01). Multivariate analyses showed that high-ST2 levels at day 14 were associated with a higher incidence of acute GVHD (hazard ratio: 9.35, 95% confidence interval: 2.92-30.0, P 〈 0.01). Although post-transplant CRP and ferritin levels were correlated with ST2, these markers did not influence the cumulative incidence of acute GVHD. Based on analyses for GVHD severity and the target organ involvement, ST2 levels were not associated with the grade of GVHD, whereas the cumulative incidence of gastrointestinal GVHD was significantly increased in the high-ST2 group (50% vs. 15%, P = 0.03). Finally, we evaluated the association of ST2 levels with other transplant-related complications and mortality. Severe non-GVHD complications were observed in 10 patients, including TMA (n = 2), VOD (n = 5), graft failure (n = 1), engraftment syndrome (n = 4), sepsis (n = 3), and pneumonia (n = 1), which were often overlapped. The cumulative incidence of NRM was increased in the high-ST2 group (33% vs. 0%, P 〈 0.01), but all the patients died of non-GVHD complications (sepsis, graft failure, TMA, and pneumonia, all of them overlapping with VOD). The two patients who had TMA and five who had VOD were all included in the high-ST2 group. Conclusion: Our detailed analysis regarding serial monitoring of ST2 following HSCT suggests that the early assessment of ST2 may be a predictive indicator for the onset of acute GVHD. Furthermore, we revealed that ST2 levels increased not only in patients with acute GVHD but also in those with other life-threatening complications, such as TMA and VOD, identified during patient monitoring. Although these complications often overlapped each other in the clinical settings for HSCT, gastrointestinal GVHD, TMA, and VOD, all of which are linked to endothelial injury, may be key complications related to high ST2 release. Further studies with larger sample sizes are needed to clarify the clinical value of ST2. Disclosures No relevant conflicts of interest to declare.

Description: Background: CD56 expression is reported to be associated with adverse prognosis in patients with acute promyelocytic leukemia (APL) treated with all-trans retinoic acid (ATRA) and chemotherapy (Murray et al, 1999, Ferrara et al, 2000, Montesinos et al, 2011, Ono T et al, 2014). However, the prognostic significance of CD56 has not been elucidated, particularly when more potent agents are used. We recently reported long term analysis of the Japan Adult Leukemia Study Group (JALSG) APL204 study and concluded that maintenance therapy with tamibarotene was more effective than ATRA by reducing relapse in APL patients (Takeshita et al, 2018). In this study, the clinical significance of CD56 was evaluated with other surface markers on APL cells. Patients and Methods: Newly diagnosed APL patients with documented cytogenetic and/or molecular evidence of t(15;17)/PML-RARA were registered to the APL204 study from April 2004 to December 2010. The eligibility criteria included age between 15 and 70 years, ECOG performance status between 0 and 3, and sufficient function of organs. Induction therapy was composed of ATRA and chemotherapy whose dose and duration were based on initial white blood cell (WBC) count. Patients who achieved molecular remission after three courses of consolidation therapy were randomly assigned to maintenance therapy with tamibarotene 6 mg/day for 14 days or ATRA 45 mg/day for 14 days, which was repeated every 3 months for 2 years. The primary endpoint was hematological or molecular relapse-free survival (RFS). Surface markers, including CD56, were defined as positive if more than 10% of the CD45-gated cells expressed a specific antigen. Clinical characteristics were compared by the chi-square test or the Fisher's exact test for categorical data and the Wilcoxon rank-sum test for continuous data. RFS, overall survival (OS) and event-free survival (EFS) were estimated by the Kaplan-Meier method, and compared using the log-rank test. Cumulative incidence of relapse (CIR) was compared by Gray's test. Multivariate analyses were also performed by the Cox-proportional-hazards-model. Clinical outcomes were renewed between January 2016 and June 2017 and the median follow-up period was 7.3 years. This study is registered at the University Hospital Medical Information Network Clinical Trials Registry as C000000154. Results: Of the 344 eligible patients, 319 (93%) achieved CR. After completing consolidation chemotherapy, 269 patients underwent maintenance random assignment; 135 to ATRA, and 134 to tamibarotene. Among 344 eligible patients, 325 were assessable for CD-phenotypes, and 45 (14%) were CD56-positive (CD56+). Among 269 patients who underwent the maintenance assignment, 34 (13%) were CD56+. CD56 expression was significantly associated with obvious bleeding (p

Description: Background: GF after allogeneic SCT is a life-threatening event. To clarify the clinical feature of patients with GF and the feasibility of second SCT for GF, we retrospectively investigated the patients who developed GF after SCT. Patients and Methods: we surveyed adult patients who received SCT in KSGCT between January 1994 and December 2005. Primary and Secondary GF were defined as a failure of absolute neutrophil count (ANC) ≥ 0.5x109/l for at least 3 consecutive days and a decrease of ANC 〈 0.5x109/l for at least 7 days consecutive days after initial engraftment, respectively. Results: Of the 1,963 patients, 60 patients (3.1%) were identified with GF. Their median age was 47 years (range, 16 to 63). There were 52 patients with hematological malignancies and 8 with aplastic anemia. The incidence of GF according to donor source was 9/597 patients (1.5%) in related donor-bone marrow (RBM), 1/359 (0.3%) in related donor-peripheral blood stem cells (RPBSC), 18/839 (2.1%) in unrelated donor-bone marrow (UBM), and 32/168 (19%) in unrelated cord blood (UCB). GF in UCB was significantly higher than that in other donors (P

Description: Background: Since FLT3-ITD is a poor prognostic factor for acute myeloid leukemia (AML), allogeneic hematopoietic stem cell transplantation (allo-HSCT) is practically performed. However, clinical usefulness of allo-HSCT at the first remission (CR1) has not been fully evaluated by the prospective study. To prospectively elucidate the role of allo-HSCT at CR1 in younger adult patients with FLT3-ITD positive AML and explore the prognostic impacts of clinical and genetic features, we conducted a phase II multicenter study (JALSG AML209-FLT3-SCT, UMIN Clinical Trials Registry UMIN000003433, http://www.umin.ac.jp/ctr/). Methods: A total of 49 patients 16 to 49 years of age with newly diagnosed de novo AML were enrolled in this study if they had a FLT3-ITD mutation and achieved complete remission within 2 courses of the standard induction therapies consisting of cytarabine and either daunorubicin or idarubicin. All patients were to be received allo-HSCT as soon as possible while continuing 4 courses of consolidation therapy combining cytarabine plus mitoxantrone, daunorubicin, aclarubicin or etoposide, vincristine, and vindesine. Patients received no further chemotherapy until allo-HSCT or relapse. Conditioning was selected according to each institutional standard from myeloablative regimens except for reduced intensity conditioning only in patients older than 40 years old or with higher HCT-CI than 1 point. GvHD prophylaxis was according to each institutional standard based on cyclosporine A or tacrolimus combined with short-term MTX. Targeted sequencing of 57 genes frequently identified in myeloid malignancies were analyzed using the preserved DNA extracted from AML cells at diagnosis. FLT3-ITD allelic ratio (AR) was quantified using DNA fragment analysis. Primary endpoint was 3-year disease-free survival (DFS). Results: Among 48 eligible patients with the median age of 38.5 (range, 17-49) years, 36 (75%) maintained CR1 to receive allo-HSCT at the median of 108 (range, 54-228) days after the achievement of CR1. Median follow-up was 1,726 (range, 983-2,974) days. The 3-year DFS rate was 43.8% (95% confidence interval [CI], 30-57%, Figure 1). The lower limit of 95% CI exceeded threshold response rate of 20%, concluding the treatment was effective. The 3-year overall survival, post-transplant DFS and non-relapse mortality rates were 54.2% (95%CI, 39-67%), 58.3 % (95%CI, 41-72%) and 25.0% (95%CI, 12-40%), respectively. There was no significant difference in DFS post allo-HSCT according to donor sources (related BM 64.6% vs. related PB 50.0% vs. unrelated BM 63.6% vs. UCB 60.0% at 3 years, P= .881). Neutrophil recovery was achieved in 94.3%. Cumulative incidences of grade II to IV and III to IV acute GvHD at day 100 were 21.2% (95%CI, 9-37%) and 9.1% (95%CI, 2-22%), respectively. Cumulative incidence of chronic GvHD at 1 year was 25.0% (95%CI, 12-40%). Mutations in NPM1 gene (65%) and genes associated with DNA methylation were frequently identified including DNMT3A (36%), IDH1 (6%), IDH2 (17%) and TET2 (17%, Figure 2). Median ITD AR was 0.344 (range, 0.006-4.099). There was no significant overlap of genetic alterations with high ITD-AR (≥ 0.5). No significant impact on DFS was observed by high ITD AR (≥0.5) (Hazard ratio [HR], 1.53; 95%CI, 0.58-4.06; P= .39) or other co-occurring genetic alterations including NPM1 mutations (HR, 0.78; 95%CI, 0.28-2.20; P= .64). Conclusions: This prospective study demonstrated the efficacy and safety of proceeding faster to allo-HSCT in CR1 for younger adult patients with FLT3-ITD positive AML, whose graft sources were not limited to HLA identical donors and the first available donor should be considered. Beyond FLT3-ITD mutations, no significant prognostic factor was identified in their genetic background or high ITD AR. Further study is required to improve the prognosis of AML patients with FLT3-ITD by establishment of an adequate therapeutic strategy using FLT3 inhibitors and allo-HSCT. Disclosures Atsuta: Kyowa Kirin Co., Ltd: Honoraria; Mochida Pharmaceutical Co. Ltd: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Janssen Paharmaceutical K.K.: Honoraria. Sawa:Asahi-Kasei: Honoraria; Celgene: Honoraria; Sumitomo Dainippon Pharma: Honoraria; MSD: Honoraria; Mochida: Honoraria; Ono Pharmaceutical Co., Ltd: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Sanofi: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; Kyowa-Hakko Kirin: Honoraria; Nippon Shinyaku: Honoraria; Pfizer Japan Inc.: Honoraria; Novartis: Honoraria; Eisai: Honoraria; Otsuka Pharmaceutical: Honoraria; Shire: Honoraria; Mundi Pharma: Honoraria. Ozawa:Kyowa-Hakko Kirin: Honoraria; Novartis: Honoraria; Pfizer Japan Inc.: Honoraria; Astellas Pharma Inc.: Honoraria. Tomita:Taiho Pharma: Research Funding; Kyowa Kirin: Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding. Maeda:Nippon Shinyaku Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K..: Honoraria. Usuki:Daiichi Sankyo Co., Ltd.: Research Funding, Speakers Bureau; Astellas Pharma Inc: Research Funding, Speakers Bureau. Matsuoka:Takeda Pharmaceutical: Research Funding; Novartis: Research Funding; Astellas Amgen Biopharma: Consultancy. Asou:SRL Inc.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Astellas Pharm Inc.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Asahi Kasei Pharma Co., Ltd.: Research Funding; Eisai Co., Ltd: Research Funding; Novartis Pharmaceuticals: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding. Matsumura:Otsuka Pharmaceutical: Consultancy, Research Funding; Novartis: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Pfizer: Research Funding, Speakers Bureau. Miyazaki:Kyowa-Kirin: Honoraria; Dainippon-Sumitomo: Honoraria; Chugai: Research Funding; Nippon-Shinyaku: Honoraria; Novartis: Honoraria; Otsuka: Honoraria. Kiyoi:Otsuka Pharmaceutical Co.,Ltd.: Research Funding; Astellas Pharma Inc.: Honoraria, Research Funding; Pfizer Japan Inc.: Honoraria; Zenyaku Kogyo Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Bristol-Myers Squibb: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Perseus Proteomics Inc.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Daiichi Sankyo Co., Ltd: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; FUJIFILM Corporation: Research Funding.