ALBERT

Description: Introduction: Bacterial infection is a major cause of early mortality after hematopoietic stem cell transplantation (HSCT). Currently, fluoroquinolones are widely used as prophylaxis against bacterial infection during neutropenia in HSCT. This strategy was established based on the results of several meta-analyses which showed that fluoroquinolones improved survival outcomes in patients receiving chemotherapy including HSCT when compared to placebo or no treatment. However, there was no evidence that the sole use of fluoroquinolones decreased mortality rates compared to other antibiotics. Intestinal flora has been investigated as a possible source of systemic infection during neutropenia through bacterial translocation from the intestinal tract. Some recent reports have shown that enterobacterial flora might be associated with bacteremia or graft-versus-host disease (GVHD) in HSCT. It was also shown in early trials that non-absorbable antibiotics which target intestinal flora improve the survival rate through decreased incidence of infection events in patients with neutropenia. However, it has been not sufficiently elucidated whether fluoroquinolones are able to reduce the infection rate more effectively than non-absorbable antibiotics, particularly in HSCT. Here we retrospectively compared systemic levofloxacin (LVFX) with non-absorbable polymyxin B (PB) in allogeneic HSCT. Patients and methods: This was a retrospective cohort study. We reviewed the charts of patients who underwent allogeneic HSCT where prophylaxis against bacterial infection was given using LVFX or PB from the start of conditioning until neutrophil engraftment. The study was conducted at our institute between 2005 and 2013. Results: A total of 226 (86 patients with PB and 140 patients with LVFX) patients were analyzed. Median age was 46 years (range: 16-69) with a 52:48 female/male ratio. The percentages for disease diagnosis, disease risk, and conditioning intensity were statistically similar. In the latter part of the study, significantly more patients were given LVFX. With the recent developments in HSCT procedure, cord blood or an HLA-mismatched donor was used as a stem cell source and drug combinations other than the classical combination, i.e., calcineurin+ short-term MTX, were used as GVHD prophylaxis in the LVFX group more frequently than in PB group. Median duration until neutrophil engraftment after HSCT was 16 days (range, 8-40) in the LVFX group and 15.5 days (range, 7-47) in the PB group (P= 0.74). The duration of prophylaxis was 11 days (range, 0-27) in the LVFX group and 12 days (range, 0-31) (P= 0.41) in the PB group. The type of antibiotic was changed in 96% of patients in the LVFX group and 94% in the PB group before engraftment, which was defined as failure of prophylaxis in this study (P=0.51). There was no significant difference in the incidence of clinically documented infection between the LVFX group (13%) and the PB group (17%) (P= 0.34). Microbiologically documented infection rates were 17% in the PB group and 11% in the LVFX group. The rate of resistance of etiological bacteria to LVFX was 100% in the LVFX group and 79% in the PB group (P=0.51). No significant difference was observed between the two groups in the cumulative incidences of prophylaxis failure (P= 0.36), clinically documented infection (P= 0.26), GVHD (P=0.50) and non-relapse mortality within the first 100 days after HSCT (P= 0.62). Furthermore, there was also no significant difference in overall survival between the two groups (P=0.72). Similar results were obtained in multivariate analysis adjusted for following factors: sex, age, transplant source, disease risk, donor type, HLA disparity, intensity of conditioning, type of GVHD prophylaxis, use of TBI or ATG. Conclusion: Our results indicate that prophylaxis against bacterial infection even with PB, a topical antimicrobial agent, might be as effective as LVFX in the early phase after allogeneic HSCT, suggesting the importance of inhibiting pathogenic bacteria in the intestine to prevent systemic infection probably due to the bacterial translocation. Antibacterial prophylaxis with PB might be a feasible strategy to preserve quinolone as an option for later use. Further optimization of oral prophylaxis against bacterial infection and/or a better understanding of influence of enterobacterial flora on after-transplant immunity are required. Disclosures Nakamae: Pfizer Inc.: Research Funding. Hayashi:Pfizer Inc.: Honoraria. Kakeya:Daiichi sankyo: Honoraria, Research Funding; Pfizer Inc.: Honoraria, Research Funding. Hino:Pfizer Inc.: Research Funding.

Description: INTRODUCTION HLA-haploidentical allogeneic hematopoietic cell transplantation (allo-HCT) using post-transplantation cyclophosphamide (PT/Cy-haplo) can be a standard of care in patients suffering from poor prognostic hematological malignancies without conventional donors. Regarding killer cell immunoglobulin-like receptor (KIR) and HLA information on optimal donor selection in PT/Cy-haplo settings, the following factors associated with improved survival have been reported: HLA-DR/HLA-DP mismatch, KIR receptor-ligand mismatch, KIR B/x haplotype with KIR2DS2, and inhibitory KIR gene mismatch (Willem 2019, Solomon 2018, Symons 2010). However, the results were still inconclusive. In addition, it remains unknown whether the graft-versus-leukemia/tumor (GVL) effect of donor KIRs or HLAs is modified by residual tumor burden at PT/Cy-haplo. METHODS We retrospectively examined consecutive patients who received PT/Cy-haplo at our institution between June 2009 and December 2018. In both patients and donors, 16 KIR genes were genotyped using KIR SSO Genotyping Test (One Lambda, Inc.) and HLA allele typing was performed at HLA-A, -B, -C, and -DRB1. Cumulative incidence of relapse (CIR) was estimated using a cumulative incidence curve with nonrelapse mortality as a competing risk and compared using the Gray's test. RESULTS A total of 91 patients with available KIR typing data were eligible. Of these, HLA typing data were unavailable for 5 patients (5.5%). In this cohort, 76 HLA-C mismatched transplants (88%) were included, and the frequencies of donor KIR ligand were 78 (90.7%) in C1/C1, 8 (9.3%) in C1/C2, and 0 in C2/C2. The median age was 48 years (range, 17 - 68 years). Median follow-up time among survivors was 1,271 days (range, 242 - 3,135 days) after PT/Cy-haplo. This study included 54 AML, 6 MDS, 2 CML, 13 ALL, and 16 NHL patients. Thirty-four patients (37%) showed complete remission (CR) at PT/Cy-haplo, and 37 on the secondor third transplant (40.7%). In CR population at PT/Cy-haplo, the patients who underwent PT/Cy-haplo from a KIR2DS1-positive donor had significantly lower rates of CIR than those from a KIR2DS1-negative donor (2-year CIR, 9.2% vs 42%; P = 0.037; Figure 1A). Due to unavailability of cases, we were unable to perform the subgroup analysis based on donor C1 or C2 status. In PT/Cy-haplo from a KIR3DS1- or KIR2DL5-positive donor, similar results were obtained, most likely due to genetic linkage disequilibrium among these genes. No other donor KIR genes were associated with CIR. Furthermore, PT/Cy-haplo from a KIR2DS1-positive donor was significantly associated with improved OS (2-year OS, 83% vs 34%; P = 0.01; Figure 1C). Also, PT/Cy-haplo from a B/x donor significantly increased OS (2-year OS, 77% vs 35%; P = 0.019), but did not decrease CIR (2-year CIR, 16% vs 40%; P = 0.122). These results suggested that donor KIR2DS1 could have a more crucial role in prevention of leukemia relapse than donor B/x haplotype. In non-complete remission (NCR) population at PT/Cy-haplo, however, PT/Cy-haplo from a KIR2DS1-positive donor and a B/x donor did not significantly improve CIR (Figure 1B) or OS (Figure 1D). Although we investigated the following previously reported models: KIR mismatch with ligand incompatibility model, receptor-ligand model, missing ligand model, inhibitory KIR gene model, and HLA-DRB1 disparity of graft-versus-host direction, none was found to be associated with significantly improved CIR or OS. CONCLUSION We found that in PT/Cy-haplo settings, with donor-recipient HLA-C mismatch in almost all cases, a KIR2DS1-positive donor significantly contributed to decreased CIR and increased OS in CR population at PT/Cy-haplo, but not in NCR population.　These results were consistent with the 2012 NEJM data by Venstrom et al in patients undergoing allo-HCT from HLA-matched or one-allele mismatched unrelated donors. Although the exact mechanism remains unclear, activating KIR2DS1, known as a player in the activation and tolerance of NK cells, could mediate NK-cell function and enhance GVL effect through NK alloreactivity in low tumor burden status at PT/Cy-haplo also in the PT/Cy-haplo setting. Our results may contribute to the establishment of an optimal donor selection algorithm. In future, elucidating the detailed mechanism of our findings could lead to the development of a novel preventive or therapeutic strategy for leukemia relapse. Disclosures Ido: MSD K.K.: Honoraria. Koh:Alexion: Honoraria; DAIICHI SANKYO COMPANY: Honoraria; MSD K.K: Honoraria; Takeda Pharmaceutical: Honoraria, Research Funding; NIHON PHARMACEUTICAL: Honoraria; Takeda Science Foundation: Research Funding; Chugai Pharmaceutical: Research Funding; Amgen Astellas BioPharma: Research Funding; Asahi Kasei Corporation: Research Funding; IQVIA Services Japan: Research Funding. Okamura:MSD K.K: Honoraria; Eisai Co., Ltd: Honoraria. Koh:Bristol-Myers Squibb: Honoraria. Nanno:Eisai Co., Ltd.: Honoraria; MSD K.K: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria. Nakamae:Novartis: Honoraria, Research Funding; Takeda Pharmaceutical Co., Ltd.: Honoraria; Japan Blood Products Organization: Honoraria; Kyowa-Hakko Kirin Co.,Ltd: Honoraria; Astellas Pharma Inc.: Research Funding; Bristol-Myers Squibb: Honoraria; Pfizer Japan Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai Pharmaceutical Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Nippon Shinyaku: Honoraria; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire Japan KK.: Honoraria. Nakashima:Novartis: Honoraria; Kyowa-Hakko Kirin Co.,Ltd: Honoraria; Eisai Co.,Ltd: Honoraria, Research Funding; Celgene Corporation: Research Funding; Bristol-Myers Squibb: Honoraria; Astellas Pharma Inc.: Research Funding; Amgen Astellas BioPharma K.K.: Honoraria, Research Funding; AbbVie Inc.: Research Funding. Nakane:Kyowa-Hakko Kirin Co.,Ltd: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; DAIICHI SANKYO COMPANY, LIMITED.,: Honoraria; Mundipharma K.K.: Honoraria; Novartis: Honoraria; Janssen Pharmaceutical K.K.: Research Funding; MSD K. K,: Research Funding; Pfizer Japan Inc.: Research Funding; Bayer Yakuhin, Ltd: Research Funding. Hino:Taiho Pharama: Research Funding; Takeda Pharmaceutical Co., Ltd: Honoraria, Research Funding; Astellas Amgen BioPharma: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Chugai Pharmaceutical Co., Ltd: Honoraria, Research Funding; Daichi-Sankyo: Honoraria, Research Funding; Eisai: Research Funding; Janssen: Honoraria; Japan Blood Products Organization: Honoraria, Research Funding; Kyowa-Hakko Kirin Co.,Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Consulting fee, Research Funding; Mochica Pharmaceutical Co., Ltd: Honoraria; Pfizer Japan Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria; Shire Japan KK: Honoraria; Sumitomo Dainippon Parma: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Other: Consulting fee, Research Funding; Otsuka Pharmaceutical: Honoraria, Research Funding; Nippon Shinyaku: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teijin: Research Funding; Nihon Pharmaceutical Co., Ltd: Research Funding; Astellas Pharma Inc: Honoraria, Research Funding; MSD: Honoraria, Research Funding; Mundipharma: Honoraria; Abbott: Research Funding; Alexion: Honoraria. Nakamae:Pfizer Japan Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka Pharmaceutical: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding; Nippon Shinyaku: Honoraria; Kwowa-Hakko kirin Co., Ltd.: Honoraria; Japan blood Products Organization: Honoraria; Janssen: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Astellas Pharma Inc.: Research Funding; Alexion: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria; Skire Japan KK.: Honoraria.

Description: Recently nonmyeloablative, haplo-identical T-cell replete bone marrow transplantation using high-dose cyclophosphamide (CY) post-BMT to control GVHD and prevent graft rejection by inducing bi-directional tolerance was reported. This strategy resulted in promising outcomes with low transplantation-related mortality (TRM) due to a low incidence of GVHD and infectious disease. However, the high relapse rate remained a major problem in high-risk hematological disease. We therefore planned a prospective pilot study of myeloablative or reduced intensity HLA haplo-identical allogeneic hematopoietic cell transplantation (HCT) using reduced doses of CY post-transplantation, followed by administration of peripheral blood stem cells (PBSC) instead of bone marrow, for those with a poor-prognosis or refractory leukemia and MDS. As of 30 June 2013, 17 patients had been enrolled in this prospective pilot study. Patients with a poor prognosis or refractory leukemia and MDS requiring prompt HCT were eligible for this study if they lacked a donor who was serologically HLA-identical or had a single antigen mismatch. The conditioning regimen consisted of fludarabine 15 mg/m2 and cytarabine 2.0 g/ m2 twice a day on days -11 and -10, thymoglobulin 2.0 mg/kg on days -8 and -7, and fludarabine 30 mg/ m2/day with intravenous busulfan 3.2 mg/kg/day on days -6 to -3 (n=11) or melphalan 100 mg (n=6) on day -2. Nine patients received a single dose of 25 mg/kg CY on day 3 and eight patients, double doses of 25 mg/kg CY on days 3 and 4 post-peripheral blood stem cell transplantation (PBSCT). Tacrolimus and oral mycophenolate mofetil was started after the completion of high-dose CY post-HCT. The median age of patients was 42 years (range 18–65). Disease diagnoses included AML (n=14), ALL (n=2) and MDS (n=1). In 12 (71%) of 17 patients, disease status was non-remission, with active disease at the time of PBSCT. Eight (47%) of 17 patients had a history of prior HCT. Donors were partially HLA-mismatched (haplo-identical) first degree relatives of the patients and differed from the patients at a median of 3/8 HLA loci in both the HVG and GVH directions. All patients received G-CSF-mobilized, unmanipulated PBSC containing a median of 3.0 x 106 CD34+cells/kg and 1.4 x 108CD3+T-cells/kg. Non-infectious fever due to PBSC infusion occurred in 14 (82%) patients and persisted until day 2 in most patients. Except for one patient who died soon after PBSCT due to disease progression, full donor T-cell chimerism was achieved at day 30 following PBSCT in all patients. Nine of 17 developed grade II-III acute GVHD. None developed grade IV acute GVHD. Three of nine patients receiving a single dose of CY, but only one of eight patients receiving double doses of CY developed grade III acute GVHD. In 12 of 16 evaluable patients, CMV reactivation was observed by day 100. Three patients developed CMV disease. BK virus cystitis occurred in four of eight patients receiving double doses of CY, however, none receiving a single dose of CY post-PBSCT developed BK virus cystitis. The cumulative incidence of TRM at one year was 13%. At one year, the overall survival of all patients, and the percentages of patients in remission and those with active disease were 43%, 75% and 31%, respectively. The results of our study demonstrated that our HLA haplo-identical transplantation using high-dose CY post-PBSCT resulted in a low incidence of TRM and was feasible even in patients with high-risk acute leukemia and MDS as an alternative stem cell source. Of note, the dose of CY post-PBSCT affected the incidence of both BKV cystitis and severe GVHD. The optimal dose of CY following HLA haplo-identical PBSCT and preparative regimen should be further explored to establish a standard regimen. Disclosures: Nakamae: Otsuka Pharmaceutical Co., Ltd.: Honoraria, Travel/accommodations/meeting expenses, Travel/accommodations/meeting expenses Other; Kyowa Hakko Kirin Pharma, Inc.: Research Funding, Speakers Bureau, Travel/accommodations/meeting expenses Other. Off Label Use: Mycophenolate mofetil was used as one of drugs for acute GVHD prophylaxis. Koh:Kyowa Hakko Kirin Pharma, Inc.: Travel/accommodations/meeting expenses Other. Nishimoto:Otsuka Pharmaceutical Co., Ltd.: Speakers Bureau; Kyowa Hakko Kirin Pharma, Inc.: Travel/accommodations/meeting expenses Other. Nakashima:Kyowa Hakko Kirin Pharma, Inc.: Travel/accommodations/meeting expenses Other. Nagasaki:Kyowa Hakko Kirin Pharma, Inc.: Travel/accommodations/meeting expenses Other. Nakane:Otsuka Pharmaceutical Co., Ltd.: Honoraria, Speakers Bureau; Kyowa Hakko Kirin Pharma, Inc.: Speakers Bureau, Travel/accommodations/meeting expenses Other. Nakamae:Kyowa Hakko Kirin Pharma, Inc.: Research Funding, Travel/accommodations/meeting expenses Other. Hino:Sanofi K.K.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Nippon Shinyaku Co.,Ltd.: Honoraria, Research Funding; Kyowa Hakko Kirin Pharma, Inc.: Honoraria, Research Funding, Travel/accommodations/meeting expenses Other.

Description: Background: Recent advance in genetic analysis has revealed that many mutations are associated with the development, progression and/or prognosis of core-binding factor acute myeloid leukemia (CBF-AML). Although KIT mutation is the most frequently identified in CBF-AML, its prognostic relevance remains controversial. We conducted the prospective, multicenter cooperative study (JALSG CBF-AML209-KIT, UMIN Clinical Trials Registry UMIN000003434, http://www.umin.ac.jp/ctr/) to evaluate the prognostic impact of KIT mutation, the incidence and clinical relevance of the other gene mutations and prognostic impact of the minimal residual disease (MRD) in CBF-AML. Methods: A total of 199 patients 16 to 64 years of age with newly diagnosed de novo AML were enrolled in this study if they had a RUNX1-RUNX1T1 or CBFB-MYH11 chimeric transcript 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 3 courses of high-dose cytarabine therapy (2 g/m2 by 3-hour infusion every 12 hours for 5 days) and no further chemotherapy until relapse. MRD level was evaluated in BM after the completion of the 3-course of consolidation therapy by the quantitation of RUNX1-RUNX1T or CBFB-MYH11 transcript in 112 patients. Target sequencing of 56 genes frequently identified in myeloid malignancies including exons 8, 10, 11 and 17 of the KIT gene were analyzed using the preserved DNA extracted from AML cells at diagnosis. Results: A total of 68 KIT mutations were identified in 63 of 199 patients (31.7%); 42 of 132 (31.8%) and 21 of 67 (31.3%) patients with RUNX1-RUNX1T1 and CBFB-MYH11, respectively. Mutation in exon 17 was the most frequently identified (73.5%), followed by in exon 8 (20.6%) and in exon 10-11 (5.9%). Mutation in exon 8 was more frequent in AML with CBFB-MYH11 (37.5%) than that with RUNX1-RUNX1T1 (11.4%, P=0.014). Although mutation at N822 residue in exon 17 was identified in 13/44 (29.5%) KIT mutations of the patients with RUNX1-RUNX1T1, no patient with CBFB-MYH11 had this mutation (P=0.008); however, mutation at the D816 residue was equally identified in patients with RUNX1-RUNX1T1 (21/44, 47.7%) and CBFB-MYH11 (13/24, 54.1%). The median BM blast percentage of the KIT mutation positive-patients (73.5%) was significantly higher than that of negative-patients (53.8%, P

Description: Background: There are several prognosis prediction models about allogeneic hematopoietic cell transplantation (allo-HCT) such as the hematopoietic cell transplantation specific comorbidity index (HCT-CI) and the refined disease risk index (R-DRI). Although HCT-CI and R-DRI are valuable and commonly used, further improvement of these models is desirable because the prognostic predictive abilities for post-allo-HCT survival remain suboptimal. Both brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-proBNP), are released from the ventricular and atrial walls, in response to the walls stretch into the blood. Plasma BNP and NT-proBNP levels are well-known biomarkers of the predictors of death in patients with cancer and heart disease. However, it is unclear whether these biomarkers are useful predictors for prognosis after allo-HCT. The main aim of our study was to evaluate the potential role of plasma BNP and NT-proBNP levels in predicting the mortality in allo-HCT patients. Methods: We retrospectively registered consecutive patients who underwent allo-HCT from January 2011 to December 2018. Plasma BNP and NT-proBNP examinations and echocardiography within 1 month from the start of conditioning regimen were performed in all transplant candidates as pretransplant work-up in our institution. Cox regression models were used to estimate the hazard ratios (HRs) with 95% confidence intervals (95% CI) in the univariate and multivariate analyses. Relapse/progression (Rel/Prog) and non-relapse mortality (NRM) were considered competing events. The Fine-Gray proportional hazard regression model was used for the univariate and multivariate analyses with competing risks. A p value 〈 0.050 was considered statistically significant. We estimated the two models using c-statistics on the basis of time to event, using the total follow-up period to compare the predictive accuracy of R-DRI or HCT-CI with BNP or NT-proBNP added models. Standard errors (SEs) for the c-statistics were estimated by applying a bootstrap procedure using 1000 bootstrap samples to confirm the reproducibility. The SEs for the difference in c-statistics between these two models were compared with the above bootstrap samples and used to compute a z-score and a p value for the difference, similar to that in several previous studies. Results: We enrolled 174 consecutive patients. The median age was 49 (range: 16-68) years. During the follow-up period, 64 patients died (36.8%). Both plasma BNP and NT-proBNP levels showed a significant association with OS and NRM, but not Rel/Prog in the univariate analysis. Next, we conducted multivariable analysis to evaluate the independence of plasma BNP and NT-proBNP levels by adjusting for not only those variables that were reported as prognostic factors in the previous research for OS, but also diastolic dysfunction that can be associated with plasma BNP and NT-proBNP levels. We constructed each two and three multivariable model, including either BNP or NT-proBNP to assess the effects of these biomarkers on OS and NRM according to the one-in-ten rule 6 to avoid overfitting (Table 1). The adjusted models for OS showed that higher plasma BNP and NT-proBNP levels were significantly associated with poorer outcomes. Moreover, the adjusted models for NRM showed that a higher plasma BNP level was significantly associated with the outcome. We also evaluated the prognostic significance of BNP, NT-proBNP, HCT-CI, or echocardiographic parameters, including ejection fraction (EF) and diastolic dysfunction, by adding to R-DRI via computation of the c-statistic. BNP or NT-proBNP showed significantly higher c-statistic estimates for OS as compared with R-DRI alone (c-statistic estimate 0.741, 0.759, and 0.674, respectively), but not EF or diastolic dysfunction (Table 2). Both plasma BNP and NT-proBNP levels had higher HRs for OS [HR per standard deviation (SD) 2.57 (95% CI: 1.75-3.76), p 〈 0.001, and HR per SD 1.95 (95% CI: 1.39-2.73), p 〈 0.001] and NRM [HR per SD 2.10 (95% CI: 1.11-3.97), p 〈 0.024, and HR per SD 2.57 (95% CI: 1.92-3.44), p 〈 0.001] even in the normal heart function group. Conclusion: Plasma BNP and NT-proBNP levels are easy to perform and cost-effective; thus, these could be useful independent biomarkers for predicting allo-HCT prognosis than echocardiography. They enable clinical decision regarding allo-HCT. Disclosures Okamura: NIPPON SHINYAKU CO.,LTD: Honoraria. Nakane:Pfizer Japan Inc.: Research Funding; Janssen Pharmaceutical K.K.: Research Funding; Bayer Yakuhin, Ltd: Research Funding; Novartis: Honoraria, Research Funding; DAIICHI SANKYO COMPANY, LIMITED: Honoraria; Mundipharma K.K: Honoraria. Nanno:Otsuka Pharmaceutical Co., Ltd: Honoraria. Nishimoto:Bayer Yakuhin, Ltd:: Research Funding; Janssen Pharmaceutical K.K.:: Research Funding. Nakamae:Shire Japan KK: Honoraria; Celgene Corporation: Honoraria; DAIICHI SANKYO COMPANY, LIMITED: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Chugai Pharmaceutical Co., Ltd: Honoraria; Japan Blood Products Organization: Honoraria; NIPPON SHINYAKU CO.,LTD: Honoraria; Novartis: Honoraria; Pfizer Japan Inc.: Honoraria; Bristol-Myers Squibb: Honoraria; Kyowa-Hakko Kirin Co.,Ltd: Honoraria; Amgen Astellas BioPharma K.K: Honoraria; Astellas Pharma Inc.: Honoraria; Otsuka Pharmaceutical Co., Ltd: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria. Nakashima:Amgen Astellas BioPharma K.K: Honoraria; Novartis: Honoraria, Research Funding; Eisai Co., Ltd: Honoraria, Research Funding; Amgen Inc: Honoraria; Kyowa-Hakko Kirin Co.,Ltd: Honoraria; Kyowa Kirin Co., Ltd: Honoraria; JCR Pharmaceuticals Co., Ltd: Honoraria; Pfizer Japan Inc: Honoraria; Astellas Pharma Inc: Research Funding; SymBio Pharmaceuticals Limited: Research Funding; Celgene Corporation: Research Funding; AbbVie GK: Research Funding; M S D K. K: Research Funding. Koh:Takeda Pharmaceutical Company Limited: Honoraria, Research Funding; Sumitomo Dainippon Pharma Co., Ltd: Honoraria; M S D K. K: Honoraria; NIHON PHARMACEUTICAL CO., LTD: Honoraria; Chugai Pharmaceutical Co., Ltd: Research Funding; Asahi Kasei Corporation: Research Funding; Amgen Astellas BioPharma K.K: Research Funding; IQVIA Services Japan K.K.: Research Funding; Takeda Science Foundation: Research Funding. Hino:Kyowa-Kirin: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Astellas: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Taiho: Research Funding; Teijin: Research Funding; MSD: Honoraria, Research Funding; Sumitomo Dainippon: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Daiichisankyo: Honoraria, Research Funding; Eisai: Research Funding; Jansenn: Honoraria; Celgene: Honoraria; Mochida: Honoraria; Ono: Honoraria; Sanofi: Honoraria; Japan Blood Products Organization: Research Funding; Nippon Shinyaku: Honoraria; Nihon Pharmaceutical: Research Funding; Mundi Pharma: Honoraria; Alexion: Honoraria. Nakamae:Pfizer Japan Inc: Honoraria, Research Funding; Astellas Pharma Inc: Honoraria, Research Funding; Otsuka Pharmaceutical Co., Ltd: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Amgen Astellas BioPharma K.K: Honoraria; ONO PHARMACEUTICAL CO., LTD: Honoraria; Kyowa-Hakko Kirin Co.,Ltd: Honoraria; Shire Japan KK: Honoraria; Celgene Corporation: Honoraria; DAIICHI SANKYO COMPANY, LIMITED: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Chugai Pharmaceutical Co., Ltd: Honoraria; Japan Blood Products Organization: Honoraria; NIPPON SHINYAKU CO.,LTD: Honoraria; Novartis: Honoraria; PPD-SNBL K.K: Research Funding.