ALBERT

Description: Backgrounds: Monosomy of chromosome 7 (monosomy 7) is observed in about 9% of acute myeloid leukemia (AML) patients and related to resistance to conventional chemotherapy and poor prognosis. It is required to establish an effective treatment strategy based on the specific molecular pathogenesis associated with the chromosomal abnormality. In this study, we aimed to find a novel therapeutic target in AML with monosomy 7. Methods and Results: Chromosome 7 encodes multiple genes regulating histone methylation such as EZH2, KTM2C and KTM2E. Although loss of these genes is considered to contribute to the development of AML with monosomy 7, it may also be required for some leukemia cell functions. We hypothesized that haploinsufficiency of the epigenetic modifiers in the chromosome 7 is compensated by other epigenetic molecules in different chromosomes, and the AML cells with monosomy 7 are vulnerable to inhibition of those molecules. Based on this notion, we performed an RNA-interference (RNAi)-based screening by targeting 53 genes encoding epigenetic enzymes regulating histone methylation by using AML cell lines with monosomy 7: KG-1 and F-36P cells. We found that the siRNA-mediated knockdown of EED, BRD4 or BRDT significantly decreased cell viability in AML cells with monosomy 7 compared to K562 cells as the control without monosomy 7. Stable knockdown of EED expression by retroviral transduction of shRNA markedly attenuated proliferation as well as increased apoptosis specifically in leukemia cells with monosomy 7. Surprisingly, pharmacologic inhibition of EED, which blocks the binding of EED to the polycomb repressive complex 2 (PRC2), was only marginally effective for the monosomy 7 leukemia cells. These results suggest that EED supports survival of the monosomy 7 leukemia cells in a PRC2-independent manner. Recent studies showed that EED is not only a component of PRC2 but also interacts with the polycomb repressive complex 1 (PRC1). In contrast to modest effects of PRC2 inhibition, inhibition of PRC1 activity showed marked efficacy specifically in leukemia cells with monosomy 7. Co-inhibition of PRC1 and PRC2 synergistically suppressed proliferation of the monosomy 7-AML cells. These results collectively suggest that while both PRC1 and PRC2 cooperatively function, the PRC1 rather than PRC2 has a predominant role in the survival of monosomy 7 leukemia cells. In addition to EED, we identified BRD4 as an essential survival factors in AML with monosomy 7. Although inhibition of BET bromodomain proteins have already shown to be effective for a variety of AML, we showed that blockade of bromodomain proteins preferentially affected cellular proliferation of AML cells with monosomy 7. We then explored whether the deletion of specific genes within the chromosome 7 was responsible for increased sensitivity to BET bromodomain protein inhibition. K562 cells were individually treated with the siRNAs against 22 genes in the presence of a BET bromodomain inhibitor JQ1. We found that knockdown of MLL3 or MLL5 resulted in increased apoptosis of the JQ1-treated K562 cells. We also confirmed that pharmacological inhibition of histone methyltransferase activity of MLL3 and MLL5 showed synergistic effects with JQ1 treatment in the leukemia cells. Conclusion: We identified EED and BRD4 as novel promising therapeutic targets in AML with monosomy 7. Disclosures Kagoya: Kyowa Kirin: Speakers Bureau; Nihon Shinyaku: Research Funding. Miyauchi:kyowa Kirin: Research Funding. Kurokawa:Novartis Pharma K.K.: Research Funding; Celgene K.K.: Consultancy, Speakers Bureau; Astellas Pharma Inc.: Research Funding, Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Eisai Co., Ltd.: Research Funding, Speakers Bureau; Sumitomo Dainippon Pharma Co.,Ltd.: Research Funding, Speakers Bureau; Teijin Limited: Research Funding; Boehringer Ingelheim: Speakers Bureau; Yakult Honsha Company: Speakers Bureau; Nippon Shinyaku Co., Ltd.: Research Funding; Shionogi & Co., Ltd: Consultancy, Honoraria; Bioverativ Japan ltd.: Consultancy; Otsuka Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Daiichi Sankyo Conpany: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Chugai Pharmaceutical Company: Consultancy, Research Funding, Speakers Bureau; Pfizer Japan Inc.: Research Funding; MSD K.K.: Consultancy, Research Funding, Speakers Bureau; Takeda Pharmaceutical Company Limited.: Research Funding, Speakers Bureau; ONO PHARMACEUTICAL CO., LTD.: Speakers Bureau; Shire Japan K.K.: Speakers Bureau; Janssen Pharmaceutical K.K.: Speakers Bureau.

Description: Background: In the daily practice, clinical effectiveness of pegfilgrastim compared to that of daily filgrastim in patients with malignant lymphoma is still unclear. This study aimed to clarify the effectiveness of pegfilgrastim versus daily filgrastim, using a national inpatient database in Japan. Study Design and Methods: We retrospectively reviewed 18095 patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) who received the first R-CHOP treatment between July 2007 and March 2017. Patients who received primary G-CSF prophylaxis were divided into pegfilgrastim group and filgrastim group. Outcomes included incidence of febrile neutropenia, all-cause in-hospital death, length of hospital stay, and total costs. To account for measured confounding, patients' characteristics were adjusted using two different propensity score utilizing methods: propensity score matching (PSM) and stabilized inverse probability of treatment weighting (IPTW). Instrumental variable (IV) analysis was also performed to account for unmeasured confounding. Results: We identified 1299 patients in the pegfilgrastim group and 2203 patients in the filgrastim group. FN occurred in 380 of the 3502 (11%) total patients with a median of 9 days (interquartile range [IQR] 7-10) after the initiation of the chemotherapy. All-cause in-hospital death occurred in 94 (2.7%) of 3502 patients. Median of hospital stay was 17 days (IQR 13-22), and total medical costs during hospitalization were 7300 (IQR 5700-9500) in USD. By one-to-one PSM, 1294 patients for both the pegfilgrastim and filgrastim groups were selected. Pegfilgrastim was administered 2 days (median, IQR 1-3) after the chemotherapy. Daily filgrastim administration was initiated 5 days (median, IQR 3-6) after the chemotherapy, and continued for 6 days (median, IQR 2-7). Compared with the filgrastim group, the pegfilgrastim group showed significant lower risk of the FN incidence (risk difference 6.1%, 95% confidence interval [CI] 4.1-8.1) and all-cause in-hospital mortality (risk difference 0.9%, 95% CI 0.05-1.8). In similar, stabilized IPTW showed that pegfilgrastim group was significantly associated with the lower risk of FN (risk difference 7.0%, 95% CI 5.1-8.9) and in-hospital mortality (risk difference 1.8%, 95% CI 0.9-2.7). In PSM, the length of hospital stay and total costs during hospitalization were also significantly decreased in the pegfilgrastim group compared to the filgrastim group (percent reduction 34% [95% CI 31-37], percent reduction 12% [95% CI 9-15], respectively). Stabilized IPTW also showed the significant percent reduction of the pegfilgrastim group to the filgrastim group for length of hospital stay and total costs (31% [95% CI 25-35], 19% [95% CI 13-24], respectively). In the sensitivity analyses, IV methods showed significantly lower FN susceptibility (odds ratio 0.14, 95% CI 0.07-0.26). However, pegfilgrastim was not associated with the reduction in susceptibility of in-hospital mortality (odds ratio 0.93, 95% CI 0.23-3.70). The ratio of the pegfilgrastim group to the filgrastim group for length of hospital stay and total costs were 55% (95% CI 51-60) and 78% (95% CI 73-84), respectively. Conclusion: Pegfilgrastim contributed to lower susceptibility of FN. Total length of hospital stay and medical costs were also decreased in the pegfilgrastim group. Disclosures Jo: Tsumura: Other: Laboratory of joint program, Research Funding. Miyauchi:kyowa Kirin: Research Funding. Toyama:Bristol-Myers Squibb: Speakers Bureau; Nippon Shinyaku Co., Ltd.: Speakers Bureau; Eisai Co., Ltd.: Speakers Bureau; Celgene K.K.: Speakers Bureau; Otsuka Pharmaceutical Co., Ltd.: Speakers Bureau; Chugai Pharmaceutical Company: Speakers Bureau; Takeda Pharmaceutical Company Limited.: Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Speakers Bureau; Daiichi Sankyo Conpany: Speakers Bureau; ONO PHARMACEUTICAL CO., LTD.: Speakers Bureau. Kurokawa:Bristol-Myers Squibb: Speakers Bureau; Otsuka Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Janssen Pharmaceutical K.K.: Speakers Bureau; Novartis Pharma K.K.: Research Funding; Yakult Honsha Company: Speakers Bureau; Daiichi Sankyo Conpany: Speakers Bureau; Eisai Co., Ltd.: Research Funding, Speakers Bureau; Celgene K.K.: Consultancy, Speakers Bureau; Nippon Shinyaku Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire Japan K.K.: Speakers Bureau; Pfizer Japan Inc.: Research Funding; Sumitomo Dainippon Pharma Co.,Ltd.: Research Funding, Speakers Bureau; Shionogi & Co., Ltd: Consultancy, Honoraria; MSD K.K.: Consultancy, Research Funding, Speakers Bureau; Chugai Pharmaceutical Company: Consultancy, Research Funding, Speakers Bureau; Astellas Pharma Inc.: Research Funding, Speakers Bureau; Takeda Pharmaceutical Company Limited.: Research Funding, Speakers Bureau; Teijin Limited: Research Funding; ONO PHARMACEUTICAL CO., LTD.: Speakers Bureau; Boehringer Ingelheim: Speakers Bureau; Bioverativ Japan ltd.: Consultancy.

Description: Background: Real-world data studies showed poorer outcomes in patients with acute promyelocytic leukemia (APL) than randomized controlled trials, because elderly patients were excluded in such trials. Reportedly, the main cause of death was severe bleeding due to disseminated intravascular coagulation (DIC) during induction therapy for APL. The management of DIC was therefore crucially important especially in elderly patients. This study aimed to clarify factors associated with in-hospital death in all patients, and elderly patients with DIC during induction therapy for APL. Study Design and Methods: We retrospectively identified 1,463 patients with newly diagnosed APL who received induction therapy including all-trans retinoic acid (ATRA) between July 2007 and March 2018 from a nationwide inpatient database in Japan. In-hospital death was evaluated with multivariable logistic regression models in all patients, and in ≥60 year-old patients. Anticoagulants included recombinant human soluble thrombomodulin, delteparin (low molecular weight heparin), danaparoid sodium, gabexate mesilate, and nafamostat mesilate which were administered within three days from admission. Patients who died within three days from the admission were excluded from the study to avoid immortal time bias. Results: We identified a total of 1,138 (78%) patients who developed DIC. We excluded 23 patients who died within three days from the admission. The remaining 1,115 patients were analyzed. During hospitalization, 172 (15%) patients died at a median of 13 days (interquartile range: 7-30). Compared with younger patients (20 to 39 years old), elderly patients were significantly associated with higher in-hospital mortality (60 to 79 years old: odds ratio 5.58 [95% confidence interval 3.05-10.22], 80 years or older: 13.51 [6.07-30.08]). Patients who received ATRA monotherapy had significantly higher incidence of in-hospital death (2.48 [1.54-4.01]). Delayed initiation of ATRA was significantly associated with higher mortality (1.60 [1.11-2.30]). A total of 699 patients (63%) received anticoagulant therapies, but none of these were significantly associated with lower mortality. Use of multiple anticoagulants was significantly associated with higher in-hospital mortality (2.47 [1.16-5.26]). Subgroup analyses in patients ≥60 years old were then conducted. During hospitalization, 122 of 416 (29%) patients died at a median of 13 days (interquartile range: 7-29). Both late initiation of conventional chemotherapy and no conventional chemotherapy were significantly associated with higher in-hospital mortality (1.88 [1.01-3.49], 3.25 [1.74-6.06], respectively). Use of recombinant human soluble thrombomodulin and use of multiple anticoagulants were significantly associated with higher mortality (1.91 [1.09-3.35], 2.64 [1.01-6.90], respectively). Conclusions: Elderly patients who developed DIC during induction therapy for APL were significantly associated with higher in-hospital mortality. Immediate initiation of ATRA and early initiation of conventional chemotherapy may have contributed to preferable outcomes. Disclosures Matsuda: Kyowa Kirin: Speakers Bureau. Jo:Tsumura: Other: Belongs to joint program with Tsumura, Research Funding. Toyama:Bristol-Myers Squibb: Speakers Bureau; Eisai: Speakers Bureau; Kyowa Kirin: Speakers Bureau; Celgene: Speakers Bureau; Daiichi Sankyo: Speakers Bureau; Nippon Shinyaku: Speakers Bureau; Chugai Pharmaceutical,: Speakers Bureau; Ono Pharmaceutical: Speakers Bureau; Otsuka Pharmaceutical: Speakers Bureau; Takeda Pharmaceutical: Speakers Bureau. Kurokawa:Ono: Research Funding, Speakers Bureau; Jansen Pharmaceutical: Speakers Bureau; Teijin: Research Funding; Eisai: Research Funding, Speakers Bureau; Shire Plc: Speakers Bureau; Nippon Shinyaku: Research Funding, Speakers Bureau; MSD: Consultancy, Research Funding, Speakers Bureau; Chugai: Consultancy, Research Funding, Speakers Bureau; Sanwa-Kagaku: Consultancy; Pfizer: Research Funding; Otsuka: Research Funding, Speakers Bureau; Astellas: Research Funding, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Bioverativ Japan: Consultancy; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sumitomo Dainippon Pharma: Research Funding, Speakers Bureau; Boehringer Ingelheim: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau.