Academic literature on the topic 'Meiji Seika Kabushiki Kaisha'

Abstract Background: More than 65% of patients (pts) with extranodal natural killer/T-cell lymphoma, nasal type (ENKL) have localized disease at diagnosis, and sites of ENKL involvement are confined to the nasal cavity and paranasal sinuses in most pts. Chemoradiotherapy with non-anthracycline-containing chemotherapy (eg, radiotherapy with dexamethasone, etoposide, ifosfamide, and carboplatin; RT-DeVIC) has improved the prognosis of pts with localized nasal ENKL and is regarded as the current standard approach. It is known that pts in the NK/T-cell lymphoma prognostic index (NK-PI) Group 3/4 is at a high risk of central nervous system (CNS) relapse in the CHOP era; however, the incidence and risk factors for CNS relapse with localized ENKL in the non-anthracycline era are not well known. In particular, it is unclear whether CNS relapse is more frequent in the pts with involvement adjacent to the skull base. Methods: A dataset of our recent study (NKEA Part A, UMIN000015491) was used for analysis. We retrospectively analyzed data from pts with newly diagnosed localized nasal ENKL who were diagnosed at 31 institutes in Japan between 2000 and 2013. Pts with extranasal ENKL, those having distant lymph node involvement and/or CNS involvement at diagnosis, and those who received anthracycline chemotherapy were excluded. The incidence and risk factors for CNS relapse in the following two cohorts were analyzed: pts who received non-anthracycline therapy (n = 189) and pts treated with RT-(2/3)DeVIC (n = 165). The time to CNS relapse in this study was defined as the time from the diagnosis to disease progression with CNS involvement and treatment failure with CNS relapse after complete response. Univariate and multivariate analyses included the following parameters: male sex, age at diagnosis > 60 years, B symptoms, ECOG PS >1, high-risk NK-PI (Group 3/4), the high-risk group of the prognostic index of NK lymphoma (PINK), C-reactive protein > upper limit of normal (ULN), serum soluble IL-2 receptor (sIL-2R) > ULN, detectable EBV-DNA in peripheral blood, lymphocyte count < 1,000 /mL, hemoglobin < 11 g/dL, platelet count < 150 x 103 /mL, lactate dehydrogenase > ULN, albumin > ULN, the presence of each site of lymphomatous involvement (paranasal sinuses, palate, orbit, gingiva, facial skin, Waldeyer's ring, and regional lymph nodes), CNS prophylaxis (intrathecal administration of methotrexate and/or cytarabine), and the use of RT-DeVIC. In 84 pts, pretreatment CT, MR, or PET-CT was centrally reviewed and evaluated the primary tumor invasion by two radiation oncologists. Subsequently, the relationship between the involvement of paranasal sinus and CNS relapse was analyzed. Results: Of the 189 pts with localized nasal ENKL who received non-anthracycline therapy, the median age was 55 years (range: 16-83 years) and 34% were > 60 years old. The baseline clinical features were as follows: male, 71%; stage II, 28%; lymph node involvement, 21%; elevated LDH, 27%; ECOG PS > 1, 8%; B symptom present, 34%; elevated serum sIL-2R, 39%; and NK-PI high-risk, 22%. The most common site of involvement was the nasal cavity (93%) followed by the paranasal sinuses (27%), palate (6%), orbit (6%), and gingiva (2%). Fifteen pts received CNS prophylaxis. With a median follow-up of 5.8 years, the 5-year OS and PFS were 74% and 64%, respectively. The 2-year and 5-year CNS relapse rates were 5.1% and 7.2%, respectively. During the follow-up, 12 pts experienced CNS relapse. The NK-PI group 3/4 and elevated serum sIL-2R were not associated with CNS relapse in a univariate analysis. A multivariate analysis identified the involvement of the gingiva (HR, 16.74; 95% CI, 3.49-80.23) and that of the palate (HR, 6.27; 95% CI, 1.66-23.77) as independent risk factors for CNS relapse. In pts treated with RT-(2/3)DeVIC, multivariate analysis identified the involvement of the gingiva (HR, 40.28; 95% CI, 7.25-223.77) and the paranasal sinuses (HR, 5.00; 95% CI, 1.37-18.25) as independent risk factors. In the cohort of pts evaluated by central imaging review, involvement of the paranasal sinus was not significantly associated with CNS relapse. Conclusion: The involvement to adjacent sites/organs was risk of CNS relapse in pts with localized nasal ENKL who received non-anthracycline therapy. Our findings suggest that the pts with the involvement of the gingiva and/or palate need more effective treatment approaches to reduce CNS relapse. Disclosures Miyazaki: Teijin Pharma: Research Funding; Ono Pharmaceutical: Research Funding; Sumitomo Group: Research Funding; Novartis: Research Funding; Eisai: Research Funding; Astellas Pharma: Research Funding; Nippon Shinyaku: Research Funding; Shionogi Pharmaceutical: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Novo Nordisk: Research Funding; Mochida Pharmaceutical Co. Ltd.: Research Funding; Daiichi Sankyo: Research Funding; Toyama Chemical Co: Research Funding; Celgene: Honoraria; Kyowa Hakko Kirin,: Honoraria, Research Funding; Chugai Pharma,: Honoraria, Research Funding. Suzuki:Kyowa-Hakko Kirin: Honoraria; Chugai Pharmaceutical: Honoraria; Mochida Pharmaceutical: Honoraria; Novartis: Honoraria; Shionogi: Honoraria; Takeda Pharmaceuticals: Honoraria; Meiji Seika Pharma: Honoraria; MSD: Research Funding; Ohtsuka: Honoraria; Sawai Pharmaceutical: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Gilead Sciences: Consultancy; MundiPharma: Consultancy; Jazz Pharmaceuticals: Consultancy. Asano:Chugai Pharma: Honoraria; Celgene: Honoraria; Takeda: Honoraria. Terui:Novartis pharma: Honoraria; Janssen Pharmaceutical KK: Honoraria; Takeda pharmaceutical: Honoraria; Celgene: Honoraria; Bristol myers Squib: Honoraria. Kobayashi:Pfizer: Research Funding; Ohtuka: Research Funding; Astellas: Research Funding. Yamaguchi:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Meiji Seika Kaisha: Honoraria; Teijin Pharma: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Chugai Pharma: Honoraria, Research Funding; ERYTECH Pharma: Consultancy; Sumitomo Group: Research Funding; Astellas Pharma: Research Funding; Shionogi Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Ono Pharmaceutical: Research Funding; Toyama Chemical Co: Research Funding; Mochida Pharmaceutical Co. Ltd.: Research Funding; Novo Nordisk: Research Funding. Katayama:Bristol-Myers Squibb: Honoraria; Teijin Pharma: Research Funding; Mochida Pharmaceutical Co. Ltd.,: Research Funding; Toyama Chemical Co: Research Funding; Ono Pharmaceutical: Research Funding; Takeda: Honoraria, Research Funding; Janssen: Research Funding; Astellas Pharma: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Shire: Honoraria; Shionogi Pharmaceutical: Honoraria, Research Funding; Novo Nordisk: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; Eisai: Research Funding; Taisho Toyama Pharma: Honoraria; Sysmex: Honoraria; Celgene: Honoraria; Pfizer: Honoraria, Research Funding; Alexion Pharmaceuticals: Honoraria; Kyowa Hakko Kirin: Honoraria, Research Funding; Chugai Pharma: Honoraria, Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Sumitomo Group: Honoraria, Research Funding.

Introduction: Intravascular large B-cell lymphoma (IVLBCL) is a rare disease entity characterized by selective growth of lymphoma cells in the lumina of small vessels. IVLBCL has been listed in the WHO classification, which improves recognition of the disease. However, no standard therapy has been established based on the results of prospective studies. We previously reported promising efficacy of rituximab (R)-containing chemotherapy for IVLBCL (JCO 2008) and a high incidence of central nervous system (CNS) recurrence (25% at 3 y) after R-chemotherapy (Lancet Oncol 2009, Cancer Sci 2010). To explore a more effective first-line treatment, we conducted a phase 2 trial of R-CHOP combined with CNS prophylaxis including R-high-dose methotrexate (R-HDMTX) and intrathecal chemotherapy with MTX, cytarabine (Ara-C), and prednisolone (PSL) (IT). Methods: Major inclusion criteria were untreated, histologically confirmed IVLBCL, age 20-79 y, ECOG PS 0-3, and no apparent CNS involvement at diagnosis. Patients received 3 cycles of R-CHOP followed by 2 cycles of R-HDMTX (3.5 g/m2; 2 g/m2 for ≥70 y) every 2 weeks, and 3 additional cycles of R-CHOP. IT (MTX 15 mg, Ara-C 40 mg, PSL 10 mg) was performed twice during the first 3 cycles of R-CHOP and twice during the final 3 cycles of R-CHOP (4 times in total). If patients achieved complete response (CR), they were observed without any therapy until relapse or disease progression. The primary endpoint was 2-y progression-free survival (PFS), and secondary endpoints included 2-y overall survival (OS), CR rate, cumulative incidence of CNS recurrence at 2 y, patterns of progression, and adverse events. The threshold 2-y PFS was estimated to be 35%, with expected 2-y PFS estimated to be 60%. With a statistical power of 90% and a one-sided, type I error of 5%, a projected sample size of 37 was calculated in anticipation of 10% ineligible patients. The trial was registered in the UMIN Clinical Trials Registry (UMIN000005707). Results: 38 IVLBCL patients were enrolled between June 2011 and July 2016. One patient was found to be ineligible after completion of the protocol treatment due to a past history of lymphoma. The protocol treatment was completed in 34 (89%) of 38 patients. The diagnosis of IVLBCL was histologically confirmed by central pathological review in all enrolled patients. The baseline characteristics of the 37 eligible patients were: male sex, 16 (43%); median age, 66 (range 38-78) y; ECOG PS &gt;1, 15 (41%); stage IV, 37 (100%); serum LDH &gt;ULN, 36 (97%); WBC &lt;4,000/μL, 11 (30%); Hgb &lt;11g/dL, 30 (81%); PLT &lt;105/μL, 17 (46%); and IPI HI/H, 33 (89%) patients. The following clinical symptoms were observed before treatment initiation: B symptoms, 30 (81%); hypoxemia, 10 (27%); neurological symptoms, 3 (8%);exanthema, 4 (11%); hepatomegaly, 15 (40%); splenomegaly, 28 (76%); and hemophagocytosis, 8 (22%) patients. In the 37 eligible patients, the CR rate was 84% (95%CI: 68-94%). With a median follow-up of 3.9 (range, 2.0-6.6) y, 2-y PFS was 76% (95%CI: 59-87%), 2-y OS was 92% (95%CI: 77-97%), and the cumulative incidence of CNS recurrence at 2 y was 2.7% (95%CI: 0.2-12%) (Fig. 1). Only one patient had CNS relapse during follow-up. Of all 38 enrolled pts, there were no treatment-related deaths. G4 non-hematological adverse events were febrile neutropenia, hypokalemia, and low blood pressure in one patient each. Major G3 non-hematological toxicities were febrile neutropenia (32%) and hypokalemia (26%). G3 and G4 lymphocytopenia were observed in 95% and 50% and thrombocytopenia in 40% and 24% of patients, respectively. All toxicities were manageable. Conclusion: This phase 2 trial met its primary endpoint and showed favorable outcomes with a low cumulative incidence of CNS recurrence and acceptable toxicity profiles. These results indicate that R-CHOP combined with CNS prophylaxis including R-HDMTX and IT could be a reasonable treatment option for untreated IVLBCL without apparent CNS involvement at diagnosis. Disclosures Shimada: Takeda Pharmaceutical: Honoraria; MSD: Research Funding; Otsuka Pharmaceutical: Research Funding; Janssen Pharmaceutical: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Eisai: Honoraria, Research Funding; Chugai Pharmaceutical: Consultancy, Honoraria; Kyowa Kirin: Honoraria, Research Funding; AstraZeneca: Honoraria. Yamaguchi:Ono Pharmaceutical: Research Funding; Teijin Pharma: Honoraria; MSD: Honoraria; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Sumitomo Dainippon Pharma: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Astellas Pharma: Research Funding; Sorrento: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Meiji Seika Kaisha: Honoraria; Kyowa Hakko Kirin: Honoraria, Research Funding; Eisai: Honoraria; Chugai: Honoraria, Research Funding. Atsuta:Chugai Pharmaceutical Co., Ltd.: Honoraria; Kyowa Kirin Co., Ltd: Honoraria; Mochida Pharmaceutical Co. Ltd: Honoraria; Janssen Paharmaceutical K.K.: Honoraria. Matsue:Celgene: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Ono Pharmaceutical: Honoraria; Novartis Pharma K.K: Honoraria; Janssen Pharmaceutical K.K.: Honoraria. Kusumoto:Chugai Pharmaceutical Co., Ltd.: Consultancy, Honoraria, Research Funding; Kyowa Kirin Co., Ltd.: Honoraria, Research Funding. Nagai:Eisai: Honoraria, Research Funding; HUYA Bioscience International: Research Funding; AstraZeneca: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen Pharmaceutical: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria, Research Funding; Sanofi: Honoraria; Otsuka Pharmaceutical: Research Funding; SymBio Pharmaceuticals Limited: Honoraria, Research Funding; Solasia Pharma K.K.: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; IQVIA: Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; MSD: Honoraria; Novartis Pharma: Honoraria; Mundi Pharma: Honoraria, Research Funding; Bayer Pharma: Honoraria, Research Funding; AbbVie: Research Funding. Fukuhara:Mundi: Honoraria; Celgene Corporation: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria; Eisai: Honoraria, Research Funding; Janssen Pharma: Honoraria; Kyowa-Hakko Kirin: Honoraria; Mochida: Honoraria; Nippon Shinkyaku: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Zenyaku: Honoraria; AbbVie: Research Funding; Bayer: Research Funding; Gilead: Research Funding; Solasia Pharma: Research Funding. Miyazaki:Eisai: Honoraria; Chugai: Honoraria; Kyowa Hakko Kirin: Honoraria, Research Funding; Celgene: Honoraria; Ono Pharmaceutical: Research Funding; Astellas Pharma: Research Funding; Takeda: Honoraria; SymBio Pharmaceuticals: Honoraria; Nippon Shinyaku: Honoraria; Janssen Pharmaceutical: Honoraria. Okamoto:Kyowa Kirin Co., Ltd.: Other: Scholarship donation; Chugai Pharmaceutical Co., Ltd.: Other: Scholarship donation; Takeda Pharmaceutical Co., Ltd.: Other: Scholarship donation; Taiho Pharmaceutical Co., Ltd.: Other: Scholarship donation. Uchida:Eisai: Honoraria. Tsukasaki:Daiichi Sankyo: Consultancy; Kyowa Kirin: Honoraria; Huya: Consultancy, Honoraria, Research Funding; Byer: Research Funding; Mundi Pharma: Honoraria; Ono Pharmaceutical: Consultancy; Eisai: Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Masaki:Tanabe Mitsubishi: Research Funding; Taiho: Research Funding; Kyowa Kirin: Research Funding; Astellas Pharma: Research Funding; Chugai Pharmaceutical: Research Funding; Ono Pharmaceutical: Research Funding; Pfizer: Research Funding; Eisai: Research Funding; Taisho Toyama: Research Funding; Daiichi Sankyo: Research Funding; Teijin: Research Funding; Takeda Pharmaceutical: Research Funding. Kiyoi:Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Bristol-Myers Squibb: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Astellas Pharma Inc.: Honoraria, Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co.,Ltd.: Research Funding; FUJIFILM Corporation: Research Funding; Eisai Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Pfizer Japan Inc.: Honoraria; Perseus Proteomics Inc.: Research Funding; Daiichi Sankyo Co., Ltd: Research Funding. Suzuki:Chugai Pharmaceutical Co.,Ltd.: Honoraria; Meiji Seika: Honoraria; Merck Sharp & Dohme: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria; Bristol-Myers Squibb: Honoraria; Kyowa Hakko Kirin: Honoraria; Celgene: Honoraria; Eisai: Honoraria; ONO Pharmaceutical Co., Ltd.: Honoraria; Janssen: Honoraria; AbbVie: Honoraria; Novartis: Honoraria.

Background Dimethyl fumarate (DMF), a fumaric acid derivative, is currently used worldwide as a therapeutic agent for autoimmune diseases, such as multiple sclerosis and psoriasis. As an activator of Nrf-2, DMF protects cells from oxidative stress by inducing anti-oxidant enzymes. In addition, a recent report in Science has shown that DMF catalytically inactivates GAPDH, thereby reduces glycolytic activity, and results in immune modulation in activated CD4+ T-cells. We have previously shown that DMF and its metabolite monomethyl fumarate (MMF) significantly inhibit 3H-thymidine uptake in activated T-cells. DMF also decreased the expression of proliferation marker Ki-67 and intracellular IFN-γ of activated T-cells in a dose dependent manner. These findings prompted us to investigate whether DMF can be used for the treatment of graft-versus host disease (GVHD) after hematopoietic stem cell transplantation. In the current study, we investigated whether, and if so, how DMF inhibits human T-cell immune response and suppress acute GVHD in vivo using a xenogeneic GVHD mouse model. Methods To induce acute GVHD, human peripheral blood mononuclear cells (hPBMCs) were intravenously injected into sublethally irradiated (250 cGy) NOG mice. We allocated the mice into two groups; DMF treatment and non-treatment (control mice). Mice in the DMF group were administered DMF orally (100 mg/kg) for consecutive 7 days (day -3 to +3), and compared with the control mice treated with the same volume of vehicle. Results First, we observed that DMF treatment prolonged the survival of mice (Figure 1). Supporting the result, histopathological analysis showed that the number of hPBMCs infiltrated in the lungs and liver was decreased in the DMF group. Next, to identify the alteration of donor human cell populations after DMF treatment, hPBMCs were retrieved from the lungs on day 9 after transplantation and were analyzed by flow cytometry. Consistent with the histological findings, the absolute number of hPBMCs (hCD45+), and also T-cells (hCD45+hCD3+), in the lungs was significantly lower in the DMF group compared with the control (p &lt; 0.01) (Figure 2). Notably, the number of CD4+ T-cells, but not CD8+ T-cells, was decreased by the DMF treatment. The proportion of regulatory T-cells (Tregs) (hCD45+CD4+CD25+Foxp3+) was elevated in the DMF group, and this finding is consistent with existing reports that DMF may increase the proportion of Tregs. Furthermore, the expression level of PD-1 on hCD4+ T-cells was significantly lower in the DMF group. These results suggest that DMF treatment mainly regulates cell proliferation and functional differentiation of donor human CD4+ T-cells, leading to reduced severity of GVHD. Given that GAPDH and aerobic glycolysis have been shown as potential targets of DMF, we then measured glycolytic activity in human T-cells obtained from mice during GVHD. Extracellular acidification rate, an indicator of glycolytic activity, was monitored under basal conditions followed by sequential treatment with glucose, oligomycin, and 2-deoxy-D-glucose (a competitive inhibitor of glucose). Glycolytic activity after the addition of glucose was significantly lower in the T-cells of DMF group than in those of the control group (Figure 3). DMF treatment also led to a significant reduction in glycolytic capacity and glycolytic reserve. Furthermore, the oxygen consumption rate, an indicator of oxidative phosphorylation, was decreased in the DMF group, indicating that DMF disrupts mitochondrial energy production in T-cells, either directly or indirectly. Similar results were obtained from CD4+ T-cells. These results suggest that DMF treatment can negatively regulate aerobic glycolysis in alloreactive T-cells, leading to the mitigation of GVHD. Conclusion Oral administration of DMF ameliorates GVHD and prolongs the survival of mice by reducing donor CD4+ T-cell proliferation, while the number of Tregs is maintained. Our data suggests that DMF treatment drives donor T-cells into a metabolically inactive state by inhibiting aerobic glycolysis. This investigation provides pre-clinical data to use oral DMF as a prophylactic agent for acute GVHD. Disclosures Kanda: Daiichi Sankyo: Honoraria; Shire: Honoraria; Alexion Pharmaceuticals: Honoraria; Takeda Pharmaceuticals: Honoraria; Novartis: Honoraria; Kyowa Kirin: Honoraria, Research Funding; 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; Mochida Pharmaceutical: Honoraria; Mundipharma: Honoraria; Sanofi: Honoraria, Research Funding; Meiji Seika Kaisha: Honoraria; Bristol-Myers Squibb: Honoraria; Shionogi: Research Funding; Ono Pharmaceutical: Honoraria; Nippon Shinyaku: Honoraria, Research Funding.

DDX41 was identified as a causative gene for late-onset familial myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). While DDX41 is thought to be one of the most frequent targets of germline mutations responsible for sporadic cases with AML/MDS and other myeloid neoplasms, the entire spectrum of pathogenic DDX41 variants and their effect size therein are still to be elucidated, and so was the clinical picture of DDX41-mutated myeloid neoplasms. In this study, through an international collaboration, we investigated DDX41 variants in a total of 5,609 sporadic cases with different myeloid neoplasms from different ethnicities, using next generation sequencing. Mutations in the major driver genes commonly mutated in AML/MDS were also examined. Frequencies of germline DDX41 variants were compared between sporadic cases with myeloid neoplasms and healthy individuals (n=13,906). We also characterized genetic/clinical features of DDX41-mutated myeloid neoplasms. We identified a total of 208 (3.6%) patients with DDX41 variants, of whom approximately 50% had both germline and somatic mutations, whereas 37% and 13% had either germline or somatic mutations alone, respectively. Somatic mutations were found in 58% of patients with germline mutation, which was significantly higher than those without (0.21%) (P&lt;0.0001). No somatic mutation was identified in healthy individuals. Among 174 germline variants, truncating and missense mutations were found in 93 and 81 cases, respectively, whereas only 1.9% of somatic mutations were truncating (P&lt;0.0001). Among 21 cases with somatic mutations alone, 4 had multiple somatic mutations and an additional 4 had loss-of-heterozygosity of the DDX41 locus (5q35.3), including 3 with uniparental disomy and 1 with deletion. Thus, 8 out of 21 cases with somatic mutation alone were suspected to have biallelic DDX41 mutations. Germline DDX41 variants showed a conspicuous ethnic diversity; the most frequent germline variants were A500fs in Japan, D140fs in USA, Q41* in Germany, G218D in Italy, M1I in Sweden, S21fs in Thailand. The M1I variant was also seen in other European countries, but not in Japan or Thailand, while no A500fs mutation was found in Europe. Among the Japanese population, significant enrichment in myeloid neoplasms was observed not only for truncating variants, such as A500fs (odds ratio (OR)=12.1) and E7X (OR=11.0) but also for missense variants, including Y259C (OR 14.3) and E256K (OR 7.81), frequently accompanied by a somatic DDX41 mutation (Figure 1). Patients with germline and/or somatic DDX41 variants were significantly older than those without (P=0.00076) and more prevalent in male than female (OR=3.14; P&lt;0.0001). DDX41 variants were significantly more frequent in MDS (4.7%) and AML (2.9%), compared with other myeloid neoplasms (0.58%). Among AML, mutations were more frequent in AML with myelodysplasia-related changes (P&lt;0.00001). Patients with MDS having both germline and somatic mutations were more likely to classified in refractory anemia with excess blasts (RAEB), compared with those with germline or somatic alone (P=0.029). DDX41 variants were significantly associated with lower WBC and granulocyte counts. Most frequently co-occurring mutations included those in ASXL1, SRSF2, TET2, CUX1, and DNMT3A, of which only CUX1 mutations were statistically significant. Overall, no difference was observed in overall survival (OS) between DDX41-mutated and unmutated cases. However, among RAEB cases, DDX41 variants were associated with a significantly longer OS (P=0.0039). In summary, the majority of DDX41-mutated cases had a germline variant, although a minority had somatic mutations alone. Pathogenic DDX41 alleles have a large ethnic diversity, where not only truncating variants but also missense variants are associated with an increased risk of the development of myeloid neoplasms. Disclosures Kanda: Chugai Pharma: Honoraria, Research Funding; Merck Sharp & Dohme: Honoraria; Mundipharma: Honoraria; Ono Pharmaceutical: Honoraria; Nippon Shinyaku: Honoraria, Research Funding; Takeda Pharmaceuticals: Honoraria; Alexion Pharmaceuticals: Honoraria; Shire: Honoraria; Mochida Pharmaceutical: Honoraria; Daiichi Sankyo: Honoraria; Shionogi: Research Funding; Meiji Seika Kaisha: Honoraria; Sanofi: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Janssen: Honoraria; Pfizer: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Novartis: Honoraria; Kyowa Kirin: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding. Miyazaki:NIPPON SHINYAKU CO.,LTD.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Kyowa Kirin Co., Ltd.: Honoraria; Novartis Pharma KK: Honoraria; Astellas Pharma Inc.: Honoraria; Otsuka Pharmaceutical: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Celgene: Honoraria. Maciejewski:Alexion, BMS: Speakers Bureau; Novartis, Roche: Consultancy, Honoraria. Ogawa:Otsuka Pharmaceutical Co., Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; KAN Research Institute, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Asahi Genomics Co., Ltd.: Current equity holder in private company; Chordia Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai Co., Ltd.: Research Funding.

Introduction Despite recent developments on various transplantation procedures and supportive therapy, nonrelapse mortality (NRM) after allogeneic stem cell transplantation (allo-SCT) remains an essential issue. In choosing the appropriate regimen for allo-SCT, decision-making information that considers the complexity of different risk factors is vital. The Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI), which was initially derived and validated by investigators at the Fred Hutchinson Cancer Research Center to predict NRM, has become a widely validated tool for predicting outcomes in many transplant settings (Sorror et al. Blood. 2005). It can also stratify patients for the risk of other outcomes, including overall survival and graft versus host disease. Patients with a high HCT-CI score tend to prefer allo-SCT with reduced-intensity conditioning. Conversely, for those who prefer allo-SCT with myeloablative conditioning (MAC) and has a low HCT-CI score, a prognostic indicator is unnecessary. Furthermore, the risk factors for NRM may differ among various conditioning regimens. Therefore, the current study aimed to establish a new prognostic model for patients specific to each MAC regimen before allo-SCT. Methods We performed a retrospective cohort study to develop prognostic models of NRM in patients conditioned with cyclophosphamide/total body irradiation (Cy/TBI) or busulfan/cyclophosphamide (Bu/Cy). We selected patients who had leukemia and lymphoma in remission or had untreated or stable myelodysplastic syndrome and experienced initial allo-SCT relapse between 2007 and 2017 in the Kanto Study of Group for Cell Therapy (KSGCT). The primary outcome measure was 2-year NRM. Furthermore, we evaluated variables such as patient age, albumin, liver function, renal function, respiratory function, ejection fraction (EF), C-reactive protein (CRP), stem cell source, donor type, antithymocyte globulin use, performance status, recipient/donor sexes, time interval from diagnosis to transplant, and HCT-CI score. To identify a set of variables for Cox proportional hazards, we used an Akaike Information Criterion (AIC)-based variable selection procedure. We assigned weights to individual parameters according to their prognostic significance in Cox proportional hazard models. The identified model's discriminative ability was assessed by Harrell's C-statistic calculated using the bootstrap method. Results Among the 555 patients analyzed, 338 received Cy/TBI, and 217 received Bu/Cy. In Cy/TBI and Bu/Cy, the median age was 39 (11-60) and 44 (18-62) years, the HCT-CI score ≤ 2 was observed in 82.1% and 87.6%, and 2-year NRM was found in 13.5% and 16.0% of the patients, respectively. Before transplantation, the most dominant parameters in Cy/TBI were abnormal liver function (AST/ALT or bilirubin &gt;upper limit of normal) and albumin value &lt; 4.5g/dL, whereas those in Bu/Cy were age &gt;40 years, EF &lt; 65 %, and CRP ≥ 0.2 mg/dL. Internal validation with bootstrap resampling showed good discrimination, with C-statistic values of 0.70 (95% CI: 0.69-0.71) in Cy/TBI and 0.68 (95% CI: 0.67-0.69) in Bu/Cy. Each of the abovementioned parameters, including age &gt;40 years, was scored as 1 point. To evaluate the 2-year NRM, we divided the total scores into three risk groups. In the Cy/TBI group, the NRM was 6.9% in low (score 0-1, n = 186), 19.5% in intermediate (score 2, n = 127), and 35.3% in high (score 3, n = 25) scores. In the Bu/Cy group, the NRM was 8.3% in low (score 0-1, n = 93), 21.7% in intermediate (score 2, n = 98), and 29.8% in high (score 3, n = 26) scores (Figure). Higher scores were strongly associated with worse NRM and survival. Conclusions Our prognostic models for NRM estimation can distinguish patients with a high NRM risk. To our knowledge, these models are the first prognostic models used to estimate NRM for standard-risk patients specific to each MAC regimen. This new simple index may help predict NRM and choose an appropriate conditioning regimen before allo-SCT. Figure 1 Disclosures Nakasone: Takeda Pharmaceutical: Honoraria; Otsuka Pharmaceutical: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Janssen Pharmaceutical: Honoraria; Eisai: Honoraria; Chugai Pharmaceutical: Honoraria; Nippon Shinyaku: Honoraria. Fujisawa:Takeda Pharmaceutical Company Limited.: Speakers Bureau; Astellas Pharma Inc.: Research Funding, Speakers Bureau; Otsuka Pharmaceutical: Speakers Bureau; Pfizer Japan Inc.: Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Speakers Bureau; Novartis Pharma KK: Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Janssen Pharmaceutical K.K: Speakers Bureau; NIPPON SHINYAKU CO.,LTD.: Research Funding. Nakaseko:Novartis Pharma KK: Speakers Bureau; Pfizer Japan Inc.: Speakers Bureau. Kanda:Novartis: Honoraria; Kyowa Kirin: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Takeda Pharmaceuticals: Honoraria; Alexion Pharmaceuticals: Honoraria; Shire: Honoraria; Daiichi Sankyo: Honoraria; Ono Pharmaceutical: Honoraria; Nippon Shinyaku: Honoraria, Research Funding; Mochida Pharmaceutical: Honoraria; Mundipharma: Honoraria; Sanofi: Honoraria, Research Funding; Meiji Seika Kaisha: Honoraria; Shionogi: Research Funding; Otsuka: Honoraria, Research Funding; Celgene: Honoraria; Chugai Pharma: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Janssen: Honoraria; Astellas Pharma: Honoraria, Research Funding; Sumitomo Dainippon Pharma: Honoraria; Pfizer: Honoraria, Research Funding; Merck Sharp & Dohme: Honoraria.

[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 &lt; 0.001). AML/MAR+ included more secondary AML than AML/MAR- (10.9% vs. 6.5%, P &lt; 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 &lt; 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 &lt; 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 &lt; 0.001) and CIR (HR, 1.41; 95% CI, 1.15-1.72; P &lt; 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 &lt; 0.001). The 2-y-CIR of CK+AML/MAR+ patients was 61.4% (vs. 48.2% in CK+AML/MAR- patients, P &lt; 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 &lt; 0.001) and for CIR (HR, 1.44; 95% CI, 1.17-1.77; P &lt; 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.

Background: Rituximab with cyclophosphamide, doxorubicin, vincristine (VCR), and prednisone (R-CHOP) chemotherapy is the standard regimen for newly diagnosed diffuse large B-cell lymphoma (DLBCL). VCR has been widely used in the treatment of lymphoid malignancies and is included in R-CHOP. However, VCR causes peripheral neuropathy (PN), which is one of major toxicities that reduce quality of life. VCR-induced PN (VIPN) is associated with the VCR dose, vincristine cumulative dose, age, and comorbidities (e.g., impaired glucose tolerance). During the last decade, more than 10 gene polymorphisms have been reported to be associated with VIPN in studies of children with acute lymphoblastic leukemia (ALL) who were treated with VCR-containing regimens. Among these polymorphisms, CEP72 rs924607 TT, MTNR1B rs12786200, and ETAA1 rs17032980 were associated with VIPN in both children and adult patients (pts) with ALL in a North American cohort. In a few studies of children with ALL outside the US, the CEP72 rs924607 TT genotype was not associated with VIPN, suggesting an ethnic deviation in the association. Recent studies including children with ALL have also reported that CYP3A5 rs776746, rs7963521, and rs1045644 are associated with VIPN. Little is known about the association between these gene polymorphisms and VIPN in adult pts with B-cell lymphoma. The present study aimed to elucidate the relation between VIPN in adult pts with lymphoma and the CEP72 rs924607, MTNR1B rs12786200, ETAA1 rs17032980, CYP3A5rs776746, rs7963521, and rs1045644 polymorphisms. Methods: This study included 36 pts with mature B-cell lymphoma diagnosed according to the 2008 WHO classification between 2003 and 2017 at Mie University Hospital and who received R-CHOP-like chemotherapy as a first-line therapy. VIPN was graded according to the Common Terminology Criteria for Adverse Events ver. 3.0 from 2003 to 2011 and ver. 4.0 from 2012 to 2017. The specimens used in this study were obtained from the oral mucosa or lymphoma tissue of the pts. Mutation analysis was performed by direct sequencing. CEP72 rs924607, MTNR1B rs12786200, ETAA1 rs17032980, CYP3A5rs776746, rs7963521, and rs1045644 were analyzed in this study. Results: The median age of pts was 64 years (range, 30-78). All pts were Japanese. Five pts had impaired glucose tolerance with no compliant of PN before chemotherapy. Twenty-two pts were diagnosed as having DLBCL, 13 had follicular lymphoma, and one had marginal zone B-cell lymphoma. All pts with the exception of one were treated with R-CHOP. In the remaining patient who had atrial fibrillation, pirarubicin was used instead of doxorubicin in R-CHOP. The total number of cycles of chemotherapy was 6 in 16 pts, 7 in one patient, and 8 in 19 pts. The median cumulative dose of VCR was 12 mg/m2 (range, 2-16). In all 36 pts, 24 pts (67%) experienced any grade of VIPN during chemotherapy and 4 (11%) developed grade 2-4 VIPN. Grade 1 VIPN was observed in 20 pts (56%). Age, impaired glucose tolerance, and the VCR cumulative dose were not associated with the incidence of VIPN. The number of cycles of chemotherapy was significantly associated with the incidence of any grade VIPN (P = 0.04). The CEP72 TT genotype was detected in 7 pts (19%). Four (57%) of 7 pts with the CEP72 TT genotype and 20 (69%) of 29 pts with the CEP72 CT or CC genotype experienced any grade VIPN (P = 0.7). Frequencies of the other gene genotype were as follows: MTNR1B rs12786200 CC in 12 (33%), CT in 18 (50%), and TT in 6 (17%); ETAA1 rs17032980 AA in 22 (61%), AG in 12 (33%), and GG in 2 (6%); CYP3A5rs776746 AA in 4 (11%), AG in 15 (42%), and GG in 17 (47%); rs7963521 CC in 3 (8%), CT in 9 (25%), and TT in 24 (67%); and rs1045644 CC in 21 (58%), CG in 15 (42%), and GG in 0 (0%) of 36 pts. There was no significant association between the incidence of VIPN and these five gene polymorphisms. Conclusions: Our results suggest that the CEP72, MTNR1B, ETAA1, CYP3A5, rs7963521, and rs1045644 polymorphisms analyzed in this study are not associated with the incidence of VIPN in adult pts with mature B-cell lymphoma who received R-CHOP-like chemotherapy. To reduce VIPN in pts who receive R-CHOP, a strategy that devises a VCR administration may be more effective than targeting genetic polymorphisms analyzed in this study. Gene polymorphisms associated with VIPN need to be identified in adult pts with lymphoma. Disclosures Sawaki: Kyowa Hakko Kirin: Research Funding; Ono Pharmaceutical: Research Funding; Astellas Pharma: Research Funding; Chugai: Honoraria. Miyazaki:Kyowa Hakko Kirin: Honoraria, Research Funding; Chugai: Honoraria; Ono Pharmaceutical: Research Funding; Celgene: Honoraria; Eisai: Honoraria; SymBio Pharmaceuticals: Honoraria; Takeda: Honoraria; Nippon Shinyaku: Honoraria; Astellas Pharma: Research Funding; Janssen Pharmaceutical: Honoraria. Imai:Chugai: Honoraria. Tawara:Astellas Pharma: Research Funding; Ono Pharmaceutical: Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding. Yamaguchi:Ono Pharmaceutical: Research Funding; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Sorrento: Membership on an entity's Board of Directors or advisory committees; Sumitomo Dainippon Pharma: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Teijin Pharma: Honoraria; MSD: Honoraria; Meiji Seika Kaisha: Honoraria; Janssen: Honoraria; Kyowa Hakko Kirin: Honoraria, Research Funding; Eisai: Honoraria; Chugai: Honoraria, Research Funding; Astellas Pharma: Research Funding. Katayama:Taisho Toyama Pharma: Honoraria; Sysmex: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Alexion Pharmaceuticals: Honoraria; Chugai: Honoraria; Nippon Shinyaku: Honoraria, Research Funding; Sumitomo Dainippon Pharma: Honoraria; Ono Pharmaceutical: Research Funding; Novo Nordisk: Honoraria; Shionogi Pharmaceutical: Honoraria; Shire: Honoraria; Novartis: Honoraria; Astellas Pharma: Honoraria, Research Funding; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria; kyowa hakko kirin: Honoraria, Research Funding.

Background: During chemotherapy for hematological malignancies, febrile neutropenia (FN) is a frequent and serious complication. The causative organisms of FN vary from era to era and depending on bacterial resistance in each country. Therefore, epidemiological data are required for each era and country from prospective large clinical trials. We previously reported a prospective clinical trial indicating the importance of the D-index, a measure of neutropenia severity (CEDMIC trial, J Clin Oncol. 2020 10; 38: 815). We hypothesized that analyzing these data would provide accurate contemporary epidemiological data for hematological malignancies. Furthermore, as encountered in practice, we suspected that gram-negative (GN) bloodstream infections (BSIs) are more common at high body temperatures (BTs) than at low BTs and examined the relationship between causative bacteria and BT. Patients and Methods: Between June 2013 and April 2017, we enrolled patients with hematological malignancies aged 16-79 years post-chemotherapy or -stem cell transplantation (SCT) with expected neutropenia durations &gt;7 days. Neutrophil counts &lt;500/mL reflected neutropenia, and all fevers had axillary temperatures ≥37.5°C. Prophylactic antibiotics (Abx) were drugs administered post-chemotherapy and pre-FN onset. The FN incidence and blood culture (BC) positivity rate were examined in 4 treatment groups: allogeneic SCT (Allo-SCT), autologous SCT (Auto-SCT), induction chemotherapy for acute leukemia, and other treatments. Results: In total, 423 patients were enrolled, and 413 (median age: 56 years) were included in the intention-to-treat analyses (Table 1). The treatments included induction chemotherapy (n=67), Allo-SCT (n=106), Auto-SCT (n=158), and others (n=82). Prophylactic Abx were administered in 281 (68.5%) patients (only quinolone, n=222; with β-lactam, n=59). Prophylaxis rates were significantly higher in the Allo-SCT (n=94, 88.7%, p&lt;0.001) and induction chemotherapy (n=49, 73.1%, p&lt;0.017) groups. FN occurred in 356/413 patients (86.4%, Table 1). The Allo-SCT group had a higher FN incidence than that in the other treatments group (93.4% vs. 72%, p&lt;0.001). D-indices ≥5500 and &lt;5500 were associated with FN incidences of 100% and 81.8%, respectively (p&lt;0.001). Prophylaxis did not reduce the FN incidence. In total, 1272 BC sets were collected from 356 patients with FN. At FN onset, BCs were collected from 346 patients; 72 (20.8%) were positive (Table 2). Among initial BCs, 46 (63.9%) harbored gram-positive (GP) and 28 (38.9%) harbored GN bacteria. Three patients had multiple bacterial infections. The 2 most frequent GP bacteria were coagulase-negative Staphylococcus (n=21, 44.7%) and viridans streptococci (n=14, 29.8%). The 3 most frequent GN bacteria were Escherichia coli (n=13, 44.9%), Klebsiella pneumoniae (n=4, 13.8%), and Pseudomonas aeruginosa (n=4, 13.8%). Among initial BCs, prophylactic Abx use did not reduce BC positivity. However, the GN BSI incidence was significantly lower in the prevention group vs. non-prevention group (23.8% vs. 56.7%, p=0.007). Among patients who received prophylactic β-lactam, GN BSIs did not occur. Maximum BTs (maxBTs) were significantly higher in patients with positive BCs than negative BCs (38.4°C vs. 38.0°C, p&lt;0.001). The BTs associated with GN BSIs were significantly higher than those associated with negative BCs and GP BSIs (38.7°C vs. 38.0°C vs. 38.2°C, p&lt;0.001, Figure 1). The maxBTs and BC positivity rates were strongly related (Table 3). The BC positivity rates were significantly higher in patients with BTs ≥38°C vs. &lt;38°C (26.5% vs. 14.5%, p=0.008), 38.5°C vs. &gt;38.5°C/&lt;38.5°C (39.7% vs. 15.3%, p&lt;0.001), and ≥39°C vs. &lt;39°C (52.6% vs. 16.9%, p&lt;0.001). Among patients who did not receive prophylactic Abx (n=106), the GN BSI positivity rate was significantly lower in patients with maxBTs &lt;38°C vs. ≥38°C (14.3% vs. 76.2%, p=0.007). Conclusion: In FN patients with high-risk hematological malignancies in Japan, the frequency of GP BSIs is high. Prophylactic Abx use reduces the GN BSI risk but not the FN or BSI risk. Fever severity and BC positivity at FN onset are strongly associated. The BTs of patients with GN BSIs are high. Disclosures Kanda: Astellas Pharma: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Meiji Seika Kaisha: Honoraria; Merck Sharp & Dohme: Honoraria; Pfizer: Honoraria, Research Funding; Shionogi: Research Funding; Celgene: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Eisai: Honoraria, Research Funding; Novartis: Honoraria; Kyowa Kirin: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Takeda Pharmaceuticals: Honoraria; Alexion Pharmaceuticals: Honoraria; Shire: Honoraria; Daiichi Sankyo: Honoraria; Ono Pharmaceutical: Honoraria; Nippon Shinyaku: Honoraria, Research Funding; Mochida Pharmaceutical: Honoraria; Otsuka: Honoraria, Research Funding; Chugai Pharma: Honoraria, Research Funding; Janssen: Honoraria; Mundipharma: Honoraria. Kimura:Takeda Pharmaceuticals: Honoraria; Astellas Pharma: Honoraria; Pfizer: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Merck Sharp & Dohme: Honoraria; Nippon Kayaku: Honoraria; Kyowa Hakko Kirin: Honoraria; Ono Pharmaceutical: Honoraria; Celgene: Honoraria; Asahi Kasei: Honoraria. Oyake:Astellas Pharma: Honoraria; Bayer: Research Funding; Chugai Pharma: Honoraria, Research Funding; Celgene: Honoraria; Kyowa Hakko Kirin: Honoraria, Research Funding; Sumitomo Dainippon Pharma: Honoraria; Bristol-Myers Squibb Japan: Honoraria; Pfizer: Honoraria; Sionogi: Research Funding. Tamura:Asahi Kasei: Honoraria; Ono Pharmaceutical: Honoraria; Eisai: Honoraria; Kyowa Hakko Kirin: Honoraria.

Background: Despite widespread interest in pain management and opioid use across the United States, information on pain and opioid utilization in patients with relapsed or refractory acute myeloid leukemia (R/R AML) is lacking. Better understanding of patient-reported outcomes (PROs) specific to pain could be used to identify strategies to improve the quality of life in patients with R/R AML. Aim/Objective: To describe pain and opioid use in patients with FLT3 mutation-positive (FLT3mut+)R/R AML receiving either gilteritinib or salvage chemotherapy (SC) using PRO data collected from the ADMIRAL study (NCT02421939). Methods: ADMIRAL was a phase 3, open-label, multicenter, active-controlled randomized study comparing the efficacy and safety of gilteritinib to SC in patients with FLT3mut+ R/R AML. Pain was assessed using selected items from the Functional Assessment of Cancer Therapy - Leukemia (FACT-Leu; GP4 item: "I have pain") and the EuroQol 5-Dimension 5-Level Questionnaire (EQ-5D-5L; Pain/Discomfort domain). Data for these instruments were collected at baseline (BL), Day 1 of every treatment cycle, and end of treatment (EOT). A modified EOT (mEOT) was defined as the last PRO assessment before patient discontinuation, study data cut-off date, or patient death. Patients on high-intensity chemotherapy (HIC) were treated for up to two cycles depending on treatment response; as such, only changes from BL to Cycle 2 were evaluated. Opioid utilization, including percentage of patients using any opioid medication, specific medications, duration of use, and use by transfusion dependence, was also described. Analyses of the intention-to-treat population using analysis of covariance, including BL score, response to first-line AML therapy, and investigator-preselected SC as covariates, were conducted to estimate least squares mean (LSM) and compare the differences in pain question responses between treatment arms. Descriptive statistics were used to describe opioid utilization. Results: Of 371 eligible patients, 247 were randomized to gilteritinib and 124 to SC. The median age for both groups was 62 years and slightly more patients were female (gilteritinib, 53.0%; SC, 56.5%). Improvements at the mEOT from BL in the Fact-Leu GP4 item were observed in both gilteritinib (LSM -0.3) and SC (LSM -0.1). Scores also changed on the EQ-5D-5L at the mEOT from BL for both groups (gilteritinib, LSM 0.2; SC, LSM 0.3). No treatment differences were observed between gilteritinib vs SC on the change from BL to Cycle 2 or mEOT on the Fact-Leu GP4 item (LSM [95% CI] of -0.1 [-0.65, 0.38]; P=0.6016 and -0.2 [-0.53, 0.21]; P=0.3902, respectively) or on the EQ-5D-5L Pain/Discomfort domain (LSM [95% CI] of 0.2 [-0.21, 0.62]; P=0.3255 and -0.1 [-0.38, 0.23]; P=0.6288, respectively). During Cycles 1 and 2, no differences were identified between gilteritinib or SC on the percentage of patients using opioids (Cycle 1: 49.8% vs 55.6%; Cycle 2: 58.9% vs 62.7%, respectively) or the time-averaged duration of use (Cycle 1: 12.4 days vs 14.1 days; Cycle 2: 15.0 days vs 17.2 days, respectively). Patients on gilteritinib were less likely to use opioids during the first two cycles compared with patients on HIC, when stratified by chemotherapy intensity (Cycle 1: 49.0% vs 72.0%, P&lt;0.05; Cycle 2: 58.2% vs 74.1%, P&lt;0.05). Conversely, patients on gilteritinib were more likely to use opioids compared with patients on low-intensity chemotherapy during the first two cycles (Cycle 1: 51.0% vs 30.6%, P&lt;0.05; cycle 2: 60.0% vs 33.3%, P&lt;0.05). In patients using opioids across the first two cycles (Table), opioids used most frequently were oxycodone (Cycle 1: 45.3%; Cycle 2: 44.6%) and tramadol (Cycle 1: 43.2%; Cycle 2: 42.5%). In patients on gilteritinib, those dependent on transfusions were generally more likely to use opioids, and for more days (time-averaged) during each cycle than patients independent of transfusions. Conclusions: Patients with FLT3mut+ R/R AML receiving gilteritinib or SC demonstrated modest changes in responses to pain-related assessments at EOT compared with BL values. Opioids were used more frequently by patients receiving HIC regimens and transfusion-dependent patients receiving gilteritinib. These data suggest that treatments for FLT3mut+ R/R AML may impact opioid use; further study should be done to determine the relationships between these factors and their potential impact on overall quality of life. Disclosures Cella: DSI: Consultancy, Research Funding; Evidera: Consultancy; Ipsen: Consultancy, Research Funding; Mei Pharma: Consultancy; Oncoquest: Consultancy; ASAHI KASEI PHARMA CORP.: Consultancy; BMS: Consultancy, Research Funding; IDDI: Consultancy; Kiniksa: Consultancy; Novartis: Consultancy; Pfizer: Consultancy, Research Funding; Apellis: Consultancy; Alexion: Research Funding; Clovis: Research Funding; Janssen: Research Funding; Pled Pharma: Research Funding; PROMIS Health Org: Membership on an entity's Board of Directors or advisory committees, Other; BlueNote: Consultancy; Astellas: Consultancy, Honoraria; FACIT.org: Membership on an entity's Board of Directors or advisory committees, Other: President; Abbvie: Consultancy, Research Funding. Ritchie:Abbvie: Honoraria; Sierra Oncology: Honoraria; Novartis: Honoraria; Pfizer: Honoraria, Research Funding; Jazz pharmaceuticals: Honoraria, Research Funding; Incyte: Speakers Bureau. Kanda:Pfizer: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding; Janssen: Honoraria; Shionogi: Research Funding; Chugai Pharma: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Celgene: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Eisai: Honoraria, Research Funding; Novartis: Honoraria; Kyowa Kirin: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Takeda Pharmaceuticals: Honoraria; Alexion Pharmaceuticals: Honoraria; Shire: Honoraria; Daiichi Sankyo: Honoraria; Ono Pharmaceutical: Honoraria; Nippon Shinyaku: Honoraria, Research Funding; Mochida Pharmaceutical: Honoraria; Mundipharma: Honoraria; Sanofi: Honoraria, Research Funding; Meiji Seika Kaisha: Honoraria; Merck Sharp & Dohme: Honoraria. Ivanescu:Astellas: Other: IQVIA employee which is a contracted by Astellas. Pandya:Astellas Pharma, Inc.: Current Employment. Shah:Astellas: Current Employment.