ALBERT

Beschreibung: Abstract 4707 Reduced-intensity stem cell transplantation (RIST) has come to be generally accepted as a method of allogeneic stem cell transplantation (SCT) for patients considered ineligible for myeloablative preparative regimens because of advanced age or comorbidities. We have recently reported unmanipulated nonmyeloablative HLA-haploidentical SCT using a conditioning treatment consisting of fludarabine, busulfan and anti-T-lymphocyte globulin and graft-versus-host disease (GVHD) prophylaxis consisting of tacrolimus and methylprednisolone (1 mg/kg) (Biol Blood Marrow Transplant 2006; 12:1073). In that study, the incidence of severe GVHD was only 10%. One of the mechanisms for such a low incidence of GVHD may have been caused by a reduced intensity of conditioning. Less intensive regimens should be associated with lower toxicity, a lower release of inflammatory cytokines, and potentially less GVHD; however, the mechanisms remain to be determined. Thus, using a murine MHC-haploidentical BMT model, BDF1(H-2b/d)®B6C3F1 (H-2b/k), that we established, we examined the influence of an intensity of conditioning treatment on GVHD. Recipient mice received T-cell-depleted bone marrow (5×106) and spleen cells (2×107) after total body irradiation (TBI) 13 Gy (myeloablative group) or 5 Gy (RIST group). Both groups of mice rapidly achieved donor engraftment. Recipients in the RIST group showed significantly fewer GVHD signs than those in the myeloablatve group. Histopathological examination of the myeloablative group on day 14 revealed various pathological changes in intestine (in particular large intestine) compatible to GVHD. In contrast, intestine samples from the RIST group showed few pathological changes with much less infiltration of donor T cells. Consequently, all recipients in the myeloablative group had died of GVHD by day 60, while all recipients survived for more than 3 months. These results clearly showed that the intensity of conditioning treatment influenced on the severity of GVHD and survival of recipients. Next, we investigated the mechanisms by which reduced intensity of conditioning ameliorated GVHD. Transplantation was performed using spleen cells that were labeled with the fluorescent cytoplasmic dye, carboxyfluorescein diacetate succinimidyl ester (CFSE), and cells in secondary lymphoid organs were analyzed by flow cytometry. The number of donor T cells in mesenteric lymph nodes on day 7 of the RIST group was significantly lower than that of the myeloablative group. In addition, a significantly increased number of host CD4+ T cells were recruited to secondary lymphoid organs on day 4 in the RIST group compared with the myeloablative group. An increased number of donor or host regulatory (Foxp3+CD4+) T cells were also observed in the RIST group. The levels of IFN gamma or IL-4 in lymphoid organs of the RIST group were higher than those of the myeloablative group. These results strongly suggest that host immune cells that survived conditioning treatment or cytokine milieu in secondary lymphoid organs contributed to the suppression of donor T cells during the initiation of GVHD. In addition, the expression of Th1 chemokine receptor, CXCR3, on donor T cells in secondary lymphoid organs and the expression levels of CXCL9, CXCL10, and CXCL11, ligands for CXCR3, in the large intestines were relatively lower in the RIST group, suggesting that the migration ability of donor T cells into GVHD target organs was negatively influenced by the intensity of conditioning. In conclusion, we showed that reduced intensity of conditioning improved the severity of GVHD, and that recipient immune cells, including regulatory T cells, together with reduced expression of inflammatory cytokines or chemokines, contributed to the improvement of GVHD in RIST. Disclosures: No relevant conflicts of interest to declare.

Beschreibung: Abstract 3648 Background: Radioimmunotherapy (RIT) with 90Y-ibritumomab tiuxetan has been used for the treatment of relapsed or refractory indolent B-cell lymphoma. Early prediction of response to the therapy may offer the potential to identify patients who will benefit this therapy. We evaluated the efficacy of fluorine 18 fluorodeoxyglucose (FDG) combined positron emission tomographic-computed tomographic (FDG-PET/CT) imaging for assessment of therapy and predicting outcome in 90Y-ibritumomab tiuxetan radioimmunotherapy. Methods: Radioimmunotherapy with 90Y-ibritumomab tiuxetan was preformed in 52 patients with relapsed or refractory indolent B cell lymphoma (follicular lymphoma, 45; mucosa-associated lymphoid tissue lymphoma, 5; lymphoplasmacytic lymphoma, 2) at Hyogo College of Medicine Hospital from June 2009 through August 2012. FDG-PET/CT scanning was performed at two weeks and the later after 90Y-ibritumomab tiuxetan therapy. Results: In FDG-PET at 2 weeks after 90Y-ibritumomab therapy, 26 (50%) showed complete response (defined as early CR), 20 (38%) showed partial response (PR-2W) and 6 (12%) showed non response (NR-2W). Further follow-up revealed 10 later CR (8 CR out of 20 PR-2W and 2 CR out of 6 NR-2W), showing 69 %(36) of overall CR rate. Relapse was occurred in 4(17%) of 26 early CR and in 6 (60%) of 10 later CR, indicating significantly low relapse late in early CR (P= 0.0074, by Chi-square test). Patients with early CR (CR in 2 weeks after the RIT) showed significantly better progression free survival than those with later CR (P=0.0046, by Logrank test). In contrast, analysis at six weeks after the RIT showed 36 CR patients (10 of which eventually relapse), but failed to discriminate patients who had high risk of relapse. Conclusion: Our results suggest that CR assessed by FDG-PET/CT at 2 weeks after 90Y-ibritumomab tiuxetan therapy discriminates good responder to the RIT and predicts better progression free survival in relapsed or refractory indolent B cell lymphoma. Disclosures: No relevant conflicts of interest to declare.

Beschreibung: Abstract 4117 Related haploidentical donors, as cord blood, can be alternative donor sources in stem cell transplantation (SCT). Severe GVHD, however, has interfered the progress of haploidentical SCT (haploSCT). To deal with this strong GVHD, T cell depletion has usually been used in US and European countries. In order to pursue the controllable GVL effect by T cells, we have performed unmanipulated haploSCT using myeloablative or reduced intensity preconditioning regimen accompanied with intensified GVHD prophylaxis, including steroids. In this meeting, we will summarize our experience of haploSCT for more than ten years. From August 1998 to September 2010, we have performed 351 cases of haploSCT (all cases were HLA 2–3 antigen mismatched in GVH direction). Patients' characteristics are sex: male 186, female 168, age: 16–65 years old (median 39), disease: AML/MDS 149, ALL 81, ML 67, others 54. Eighty-three percent of cases underwent SCT in non-complete remission (non-CR) status. Patients under 45 years old underwent myeloablative preconditioning regimen consisting of FLU/CA/CY/TBI 8Gy (haplo-full, n=100), and patients over 45 years old or with comorbidities or repetitive SCT (including second to fifth SCT) underwent reduced intensity preconditioning regimen consisting of FLU/(CA)/BU/ATG or FLU/(CA)/MEL/ATG (haplo-mini, n=251). High dose Ara-C (CA) was optional to reduce tumor burden. As ATG, ATG (Fresenius) 8mg/kg, or thymoglubulin (genzyme) 2–4mg/kg were integrated into conditioning treatments mainly for reduced-intensity transplantation. GVHD prophylaxis consisted of taclolimus (TAC), methylprednisolone (mPSL) 2mg/kg/day, short term MTX, and mycophenolate mofetil (MMF) 15mg/kg/day in haplo-full, and TAC, and mPSL 1mg/kg/day in haplo-mini, respectively. For elderly patients over 50 years old in haplo-mini, MMF was added. Hematopoietic engraftment in haploSCT was as rapid as that in HLA-identical SCT, except 10 cases of graft rejection. The median time to reach a neutrophil account of 〉0.5 × 109/l was 10 days for haplo-mini and 13 days for haplo-full. Platelet recovery was achieved in 66 % and 60% of patients undergoing haplo-mini and haplo-full, respectively. The median time to reach a nontransfused platelet count of 3 20 × 109/l was 22 days for haplo-mini and 33 days for haplo-full. Sixty percent of haplo-mini patients and 54 % of haplo-full patients did not develop acute GVHD. Acute GVHD (grade II-IV) was observed in 20% for haplo-mini and 36 % for haplo-full. Overall survival at five years was 30% for haplo-full and 40% for haplo-mini, respectively. If limited to CR cases, overall survival reached over 60% in haplo-mini. There is no difference in survival rate among patients' diseases. In multivariate analysis on survival using variables, including disease status before transplantation, haplo-full vs haplo-mini, mismatches in GVH direction, mismatches in HVG direction, patients' age, and the number of transplantation times, the disease status (CR) was found to be only a significantly favorable factor (P= 0.0026). Unmanipulated haploSCT is feasible and effective for refractory diseases. ATG dose used in haplo-mini is critical, and rather low compared with that of European cases reported so far. Although it should be too early to refer long term outcome, unmanipulated haploSCT could be considered as an option to control refractory diseases. Disclosures: No relevant conflicts of interest to declare.

Beschreibung: The origin of macrophage in HPS after SCT was also very interesting to be examined. Material and Method The characteristics of the patients and the information of infections were summarized in Table 1. 1. IL6, MCP|1, VCAM-1, TNF-a, RANTES, sE-selectin and HMGB1were measured by immunosorbent assay of cryopreserved blood samples. 2. In situ hybridization was performed to paraffin sections of aspirated bone marrow cells whose sex chromosome were dyed in different colors to detect the Y chromosome in macrophages. Result yperferritinemia and high levels of serum soluble interleukin-2 receptor were recognized. On day14, initial neutrophil engraftment and complete chimerism were successfully achieved. High dose mPSL 1000mg/day was administered several times but phagocytosis was little better and finally peripheral bloods were completely deprived (secondary graft failure). About sex chromosome, mononuclear cells had XX (donor type) but the phagocytes held original chromosome XY (recipient type). MCP-1 and VCAM-1 were rising up steadily but another adhesion molecule E-selectin or cytokines were not elevated (Fig1.). The same movement of MCP-1 and VCAM-1 was recognized in the case of patient#4 EBV-associated HPS who had immunological dysfunction with Bechet disease. The following two cases, patient #2 and #3 who received haplo-mini-SCT showed completely different cytokine movement. Patient #3 who was 75y.o.female with AM/MDS was infected with multiple candida species after haplo-mini-transplantation. MPC-1 inversely decreased less than 400 pg/ml. Patient#2 who was 60y.o. female with AML(M1) de Montréal (CHUM) between June 1, 2012 and May 31, 2013. Date was collected through medical and pharmaceutical patient records. Our local ethics board approved this study. Results A total of 45 patients received bortezomib for MM or amyloidosis with a median age of 68 years (SD ± 9.3) and 53.3 % were male. Patients received bortezomib in various protocols including Vel-Dex (42.2%), VMP (44.4%) and CyBorD (13.3%). The median starting dose of bortezomib was 1.3 mg/m2 (SD ± 0.13). Patients received SC only bortezomib injections (71.1%) or IV only (15.6%) or were switched from IV to SC (13.3%) for a total of 157 cycles (786 doses). A total of 444 BP values before and 425 BP values after SC bortezomib were analysed. No significant difference was detected between the average systolic BP (125 vs 125; p=0.76), diastolic BP (70 vs 71; p=0.77) or heart rate (79 vs 78; p=0.89) between the 2 measurements. Hypotension, defined as a drop of 20 mmHg of systolic BP, occurred 18 times (4.2%) but systolic BP was never below 90 mmHg. One patient had a severe dysautomia, possibly related to bortezomib that required the discontinuation of the treatment. At our center, CBC are performed prior to each bortezomib dose. Neutropenia occurred in 10 % of the total doses received. Risk factors influencing neutropenia were the use of oral alkylating agent (melphalan and cyclophosphamide) in the regimen and baseline neutrophil count less than 2.0 x 109. Many patients also received bortezomib for a relapsed / refractory disease and were previously exposed to many lines of therapy. Thrombocytopenia occurred in 7,2% of doses received. Cutaneous toxicity occurred mostly with the first patients treated with the SC technique. With time, nursing changed their technique and further skin reactions were less reported. Neuropathy occurred in 21 patients (13 SC, 4 IV, 4 IV to SC), caused dose reductions in 7 patients (2 SC, 2 IV, 3 IV to SC) and treatment discontinuation in 2 patients (SC). Conclusion Our results demonstrate SC bortezomib was well tolerated. The rates of hypotension was quite low. Also rates and intensity of neutropenia and thrombocytopenia varied among different bortezomib containing regimens. Because of the low rate of profound neutropenia, Vel-Dex and VMP protocols can be modified to decrease the number of CBC to once weekly during the cycle rather than before every injection. More data are needed with CyBorD protocol before drawing any conclusions. Disclosures: Adam: Jansen Ortho: Honoraria. Lemieux-Blanchard: Celgene: Honoraria. Lemieux: Jansen Ortho: Honoraria.

Beschreibung: Abstract 4960 Background: MDS ‘s clinical pathology is heterogeneous such as the intensity of cytopenia and the rate and the timing of AML evolution. The definite algorithm is difficult to be settled. We have several approved agents as the MDS therapy in Japan, Thalidomide, Lenalidomide and 5-Azacytidine (AZA) in addition to the conventional agents such as immunosuppressive agents (predonisolone and cyclospoline-A) and hematopoietic cytokines (G-CSF, Erythropoietin). We retrospectively analyze 36 MDS patients who were treated since 2004 in our hospital. The first current treatment was the conventional agents and transfusion that we call best supportive care (BSC). Since 2006 we could treat by thalidomide in addition to the conventional ones. Lenalidomide is limited to use only for 5q- MDS that is not included in 36 MDS. It was 2011 that we applied stem cell transplantation (SCT) for AML/MDS (AML evoluted from MDS). This conditioning regimen is low dose or non-myeloablative that is feasible to older individuals. The stem cell source of haploidentical donor or cord blood is immediately available at the time of urgent transplantation. The rate of GVHD of these HLA-mismatch transplantations is not so high as generally thought. The optimal SCT timing is very difficult and important. Patients and methods: In the baseline characteristics of consecutive 36 MDS patients, the median age was 70 (range 39 ∼ 90), F/M was 24/12. The 26 of them were treated by thalidomide daily 50mg∼100mg as the first line therapy, whose diagnosis was RCUD n=6, RARS n=2, RCMD n=9, RAEB-1 n=2 RAEB-2 n=4 and AML/MDS n=3. Using IPSS score, there were 9 patients with low, 6 int-1, 7 int-2 and 4 high (including 3 AML/MDS). 8 int-2 and 1 high had complex karyotype that is cytogenetically high risk. The other 8 patients received the best supportive care (BSC) by immunosuppressive agents, cytokines and transfusion. Two another patients were treated by AZA as the first line. Two of three AML/MDS had received stem cell transplantation (62 years male received haplo-mini SCT and 75 years female received cord blood SCT). Results: Thalidomide produced hematological improvement in 70% of lower IPSS (low and int-1) simultaneously with transfusion independency. On the contrary, int-2 improved only in 14%, high and AML/MDS in 0% (Fig 1). The improvement by thalidomide of RARS was 100% and RCMD was 67%. The p value about the improvement about WHO classification was 0. 182 because of the insufficiency of the number of patients. When the over all survival of thalidomide treated patients is compared with BSC patients, there was no statistically difference between them in lower risk MDS. In higher risk MDS, two int-2 patients who had failed with the single use of thalidomide achieved the hematological improvement by the combination of thalidomide and AZA. One of them was cytogenetically high risk. Their AZA cycles were 14 and 12. They were still receiving AZA. After the long-term follow-up, it will be clear that this combination makes statistical predominant in OS. This combination was completely ineffective against AML/MDS who received stem cell transplantation as second-line therapy. After the transplantation they received AZA maintenance that is expected to suppress minimal residual disease while monitoring WT1 expression. They are alive now for 1. 41 and 1. 01 years since they were diagnosed as AML/MDS. Conclusion: Thalidomide makes good hematological response of lower risk MDS and bring the free of transfusion that elevates and maintains the QOL of the patients. About the higher risk of MDS, thalidomide single therapy has no works but its' combination with AZA is very effective and bring not only the hematological improvement but also the possibility of longer overall survival. For AML/MDS, stem cell transplantation is the only potential curative treatment. Disclosures: No relevant conflicts of interest to declare.

Beschreibung: Abstract 4203 The major drawback of HLA-haploidentical stem cell transplantation is graft-versus-host disease (GVHD): however, the GVHD can be overcome using substantial T cell depletion method (Perugia), the use of a high dose ATG (Beijing), or the posttransplantation cyclophophamide method (Johns Hopkins). These transplant procedures are found to be effective for the achievement of donor engraftment and immunological tolerance: however, graft-versus-leukemia (GVL) effects are not enough strong to prevent disease relapse. To harness GVL effect of HLA-haploidentical grafts, our regimen for unmanipulated haploidentical myeloablative transplantation is designed for GVH reaction to remain to some extent in the short time after transplantation using a small dose of ATG 2 mg/kg, coupled with GVHD prophylaxis containing a low dose of steroid (methylprednisolone 1 mg/kg). We hypothesize that allogeneic immunological response by donor T cells under low cytokine milieu exerts potent GVL effect without GVHD. This regimen was applied to patients with hematologic disease in an extremely high risk. From August 2008 to June 2012, 23 patients with high-risk or refractory hematologic diseases underwent unmanipulated peripheral blood stem cells using a graft from HLA-haploidentical related donor (11 cases were HLA 2 antigen-mismatched and 12 HLA 3 antigen-mismatched in the GVH direction). Patients' characteristics are sex: male 11, female 12, age: 17–46 years old (median 34), disease: AML/MDS 7, ALL 10, ML 5, others 1. All patients except for 5 underwent transplantation in non-complete remission (non-CR) status, including 5 patients in induction failure, and 10 in resistant relapse. Eleven patients with leukemia who underwent in non-CR state had a median of 66% blasts in the bone marrow (range, 10.6 – 97.0 %). Patients received a conditioning treatment consisting of fuludarabine, cytarabine, cyclophsphamide, TBI 8Gy and ATG (thymoglobuline) 2 mg/kg. GVHD prophylaxis consisted of tacrolimus and methylprednisolone (1 mg/kg). One patient dies of pneumonia on day 3. Among 22 patients that could be evaluated, the engraftment rate was 95.5% (one patient had graft rejection because of donor-specific HLA antibody). Neutrophil (〉0.5×109/l) and platelet (〉20×109/l) engraftment was achieved on day 11 and on day 32, respectively. All patients who underwent transplantation in non-CR achieved CR after transplantation. Eleven patients (52.4%) had no GVHD. Nine patients (42.9%) developed grade II-III acute GVHD. One patient died of cardiac failure on day 46, 1 VOD on day 74, and 1 GVHD on day 235. Two patients died of relapse on days 70 and 548. Four of the 8 patients with leukemia who had more than 50% blasts in the bone marrow at the time of transplantation survive in CR. The overall survival is 60% at 3 years (Figure 1). Our regimen for HLA-haploidentical transplantation using a small dose of ATG coupled with low dose of steroid exerts a strong GVL effect even for patients who had chemorefractory disease, and transplantation-related toxicities, including GVHD, are acceptable. As a result, patients, of whom the majority had a high tumor burden, achieved a high rate of long-term survival. Thus, our strategy for haploidentical stem cell transplantation is promising, although our results will have to be confirmed in a large-scale study. Disclosures: No relevant conflicts of interest to declare.

Beschreibung: [Background] A marker chromosome (MAR) is a structurally abnormal chromosome that cannot be unambiguously identified or characterized by conventional chromosome analysis. MAR is considered to reflect genomic instability and is observed in 5% of acute myeloid leukemia (AML) patients. Although AML with MAR (AML/MAR+) was previously reported as refractory to chemotherapy, MAR is currently not considered associated with any specific cytogenetic risk category. Furthermore, the influence of MAR on the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is unclear. Thus, to understand the characteristics of AML/MAR+ and the influence on prognosis in patients with AML, we reviewed national survey data from Japan. [Patients and Methods] This retrospective study included 14,099 adult patients with AML evaluable for cytogenetic risk who received their first allo-HSCT between January 1986 and December 2017. All data were sourced from the registry of the Japanese Society for Hematopoietic Cell Transplantation. The median age at allo-HSCT was 48 y (range, 16-85 y). The median follow-up period was 1.4 y (range, 0-30 y). The definition of chromosomal abnormalities adhered to the International System for Human Cytogenetic Nomenclature guidelines; chromosomal gains and structural abnormalities had to be detected in at least two metaphases, and chromosomal losses in at least three metaphases to be acknowledged as clonal. Three or more chromosomal abnormalities were defined as "complex karyotype" (CK). Cytogenetic risk was classified as favorable (n = 2,246), intermediate (n = 9,236), or poor (n = 2,617) in accordance with the criteria provided by the National Comprehensive Cancer Network Guidelines (Version 1, 2016). We defined 1st/2nd/3rd remission (n = 8,039) as "remission" and underlying disease or primary induction failure (n = 5,960) as "non-remission". Some patients (n = 100) lacked disease stage data of pre-transplantation. For MAR evaluation, clinical phenotypes were compared, and overall survival (OS) and cumulated incidence of relapse (CIR) were calculated. These variables were validated using multivariate analysis. [Results] MAR was detected in 668 (4.6%) of the 14,099 patients. The median age of patients with AML/MAR+ was 55 y (range, 16-77 y), and so these patients were older than AML/MAR- patients (n = 13,431; age, 48 y; range, 16-85 y; P 〈 0.001). AML/MAR+ included more secondary AML than AML/MAR- (10.9% vs. 6.5%, P 〈 0.001). The frequency of MAR in poor-risk AML patients (n = 580, 22.2%) was significantly higher than in favorable- (n = 13, 0.6%) and intermediate-risk (n = 75, 0.8%) AML patients (P 〈 0.001). When the analysis was limited to poor-risk AML patients with CK (CK+AML, n = 1,368), the frequency of MAR was 42.1% (n = 576). Most cases of AML/MAR+ (n = 580, 86.8%) were categorized as poor-risk cases (vs. AML/MAR-, n = 2,037, 15.2%; P 〈 0.001). Moreover, almost all cases of poor-risk MAR (n = 576/580, 99.3%) reflected adjuncts of CK. Since AML/MAR+ has usually been considered poor-risk AML, especially CK+AML, we performed an evaluation focusing on these patients. First, among poor-risk AML patients, MAR was an independent risk factor of OS (hazard ratio [HR], 1.37; 95% confidence interval [CI], 1.20-1.56; P 〈 0.001) and CIR (HR, 1.41; 95% CI, 1.15-1.72; P 〈 0.001), based on the multivariable analysis adjusting for age, time of transplantation, performance status, disease stage, graft source, conditioning regimen, type of AML, and with/without CK. Next, in CK+AML, the 2-y-OS of CK+AML/MAR+ patients (n = 576) was 20.0% and thereby worse than that of CK+AML/ MAR- patients (n = 792, 33.2%; P 〈 0.001). The 2-y-CIR of CK+AML/MAR+ patients was 61.4% (vs. 48.2% in CK+AML/MAR- patients, P 〈 0.001). Furthermore, CK+AML/MAR+ patients who underwent transplant even in remission (n = 160) showed worse 2-y-OS (39.2%) and CIR (55.8%), than CK+AML/MAR- patients (n = 286, 54.5% [P = 0.004] and 37.8% [P=0.0011], respectively). In multivariable analysis adjusted for other prognosis factors, MAR was an independent risk factor of OS in CK+AML patients (HR, 1.40; 95% CI, 1.23-1.61; P 〈 0.001) and for CIR (HR, 1.44; 95% CI, 1.17-1.77; P 〈 0.001). [Conclusion] Cases of MAR almost exclusively reflected adjuncts of CK. MAR can be used to further stratify AML with CK after allo-HSCT. Disclosures Uchida: Sumitomo Dainippon Pharma: Honoraria; Astellas Pharma Inc.: Honoraria; Otsuka: Honoraria; Chugai Pharma: Honoraria; Novartis Pharma KK: Honoraria. Ozawa:Novartis Co., Ltd.: Honoraria. Kanda:Shionogi: Research Funding; Meiji Seika Kaisha: Honoraria; Sanofi: Honoraria, Research Funding; Mundipharma: Honoraria; Mochida Pharmaceutical: Honoraria; Nippon Shinyaku: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria; Daiichi Sankyo: Honoraria; Shire: Honoraria; Alexion Pharmaceuticals: Honoraria; Takeda Pharmaceuticals: Honoraria; Bristol-Myers Squibb: Honoraria; Kyowa Kirin: Honoraria, Research Funding; Novartis: Honoraria; Eisai: Honoraria, Research Funding; Sumitomo Dainippon Pharma: Honoraria; Celgene: Honoraria; Otsuka: Honoraria, Research Funding; Chugai Pharma: Honoraria, Research Funding; Janssen: Honoraria; Astellas Pharma: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Merck Sharp & Dohme: Honoraria. Ichinohe:Chugai Pharmaceutical Co., Ltd.: Research Funding; Zenyaku Kogyo Company, Limited: Research Funding; Bristol-Myers Squibb: Honoraria; Celgene Corporation: Honoraria; Repertoire Genesis: Research Funding; FUJIFILM Wako Pure Chemical Corporation: Research Funding; Takara Bio Inc.: Research Funding; Takeda Pharmaceutical Company Limited: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; ONO PHARMACEUTICAL CO., LTD.: Research Funding; Kyowa Kirin: Honoraria, Research Funding; Janssen: Honoraria; Pfizer: Research Funding.