Takeda Pharmaceutical Company Research Articles

Hikoboshi Study: Remaining Burden and Current Medical Care Status of Patients with Congenital Hemophilia a: A Study Using Two Japanese Medical Information Databases

Introduction:FVIII prophylaxis for hemophilia A (HA) has reduced the bleeding frequency in patients and enabled the prevention of hemophilic arthropathy and severe bleeding. However, the treatment/disease burden remains a concern, as evidenced by requiring intravenous injections two/three times a week; regular hospital visits to receive a prescription for medication, as drug delivery is not a provision in Japan; and frequent hospital visits because of complications, like bleeding. Moreover, there is no national patient registry for hemophilia in Japan, and few studies have examined the state of medical care and patient burden due to symptoms and medical practices. Herein, data from medical information databases (DBs) were assessed to investigate the state of medical care and patient burden for HA patients in Japan.Methods:The DBs of health insurance subscribers provided by JMDC Inc. (JMDC-DB) and of electronic medical care records provided by Real World Data Co., Ltd. (RWD-DB) were reviewed. Two DBs were used because the differences between them, such as data source for HA patients, may lead to intergroup differences in the characteristics and traceability of each patient.The targets of analysis were HA patients (ICD-10 code: D66) prescribed FVIII concentrates, emicizumab, or bypassing agents. The definition of targets in this analysis was deemed appropriate in a separate validation study.The occurrence rates of intracranial hemorrhage, ischemic heart disease, hospitalizations, emergency visits, and outpatient visits were calculated to evaluate patient burden. Further, data on the number of hospitals visited and prescribed amounts of FVIII concentrates per month were tabulated and descriptive statistics, applied. Table 1 shows the outcome measures.Results:The number of patients included, based on the target period and inclusion criteria, was 459 from JMDC-DB (January 2005 to March 2020) and 229 from RWD-DB (January 1985 to March 2020). Both DBs had a large proportion of patients aged 0-9 years (23.09% in JMDC-DB and 47.16% in RWD-DB) and a small proportion of patients aged ≥60 years (2.61% in JMDC-DB and 5.68% in RWD-DB).The mean (standard deviation [SD]) and median values for the monthly prescribed amount of FVIII concentrate were 10526.36 IU (11260.42) and 8594.91 IU in JMDC-DB and 12569.11 IU (54846.02) and 1514.35 IU in RWD-DB, respectively. The yearly trends of monthly prescribed amounts of FVIII concentrate for patients in JMDC-DB were analyzed. The median values for every 3 years since 2007 were as follows: 1916.67 IU (2007), 3375.00 IU (2010), 7229.17 IU (2013), 8614.58 IU (2016), and 10000.00 IU (2019), indicating an increasing trend in recent years.The occurrence rates (95% confidence intervals [CIs]) of intracranial hemorrhage, ischemic heart disease, and hospitalizations were 2.61% (1.36-4.52), 0.00%, and 32.68% (28.40-37.18) in JMDC-DB and 4.42% (2.14-7.99), 0.44% (0.01-2.44), and 57.08% (50.35-63.62) in RWD-DB, respectively. The age-stratified occurrence rates (95% CIs) of intracranial hemorrhage in JMDC-DB and RWD-DB were 9.43% (4.62-16.67) for 0-9 years, 1.67% (0.04-8.94) for 40-49 years, and 4.00% (0.10-20.35) for 50-59 years and 3.70% (1.02-9.21) for 0-9 years, 13.04% (2.78-33.59) for 10-19 years, 9.09% (1.12-29.16) for 30-39 years, and 6.67% (0.17-31.95) for 40-49 years, respectively. The overall occurrence rates of intracranial hemorrhage were similar in the two DBs: 2.61% (JMDC-DB) vs. 4.42% (RWD-DB).Additional results of our analysis will be presented at the conference.Conclusions:The prescription of FVIII concentrates for Japanese patients with HA is increasing, probably because FVIII prophylaxis in the clinical setting has become more common. The widespread use of FVIII has many benefits for HA patients. However, there are still treatment burdens that should be considered, such as the need for several drug prescriptions and severe bleeding, such as intracranial hemorrhage. [Display omitted] DisclosuresNagao: CHUGAI PHARMACEUTICAL CO., LTD.: Consultancy, Honoraria, Speakers Bureau; Takeda Pharmaceutical Company Limited.: Honoraria, Research Funding; Bayer Yakuhin, Ltd.: Honoraria, Research Funding; Sanofi K.K.: Honoraria; Fujimoto Pharmaceutical Corporation: Honoraria; KM Biologics Co., Ltd.: Honoraria; Pfizer Japan Inc.: Honoraria; Japan Blood Products Organization: Honoraria; Novo Nordisk Pharma Ltd.: Honoraria; CSL Behring K.K.: Honoraria. Ioka: Chugai Pharmaceutical, Co., Ltd.: Current Employment. Nakamura: Chugai Pharmaceutical Co., Ltd.: Current Employment. Murakami: Chugai Pharmaceutical Co., Ltd.: Current Employment. Makishima: Chugai Pharmaceutical, Co., Ltd.: Current Employment. Okada: Chugai Pharmaceutical Co., Ltd.: Current Employment. Sakai: Bayer Yakuhin, Ltd.: Consultancy, Speakers Bureau; Novo Nordisk Pharma Ltd.: Consultancy, Speakers Bureau; CSL Behring K.K.: Speakers Bureau; Takeda Pharmaceutical Company Limited.: Speakers Bureau; CHUGAI PHARMACEUTICAL CO., LTD.: Speakers Bureau; Sanofi K.K.: Speakers Bureau.

EIF4B Is a Novel Target of CAMK2G and Promotes Proliferation of Malignant Cells in Myelofibrosis

BackgroundMyelofibrosis (MF) is a myeloproliferative neoplasm which is associated with megakaryocytic atypia, fibrosis in the bone marrow (BM), and extramedullary hematopoiesis, followed by progressive hematopoietic failure and leukemic transformation. JAK1/JAK2 inhibitors are currently available and reduce spleen volume, improve symptoms related to MF and prolong the overall survival (OS). Although the benefits associated with JAK1/JAK2 inhibitors are well established, not all patients respond to these inhibitors, and long-term exposure to these inhibitors results in the emergence of resistant clones based on the reactivation of the JAK-STAT pathway. Therefore, new therapeutic strategies targeting other molecules can provide additional benefits to patients with MF. In the previous study, we identified Calcium/Calmodulin Dependent Protein Kinase II Gamma (CAMK2G) as a new therapeutic target for MF by performing compound screening. Furthermore, CAMK2G inhibition can overcome drug-resistance against JAK2 inhibitors. Therefore, it is important to investigate the mechanisms underlying the therapeutic effect of CAMK2G inhibition. In this study, to explore the mechanism underlying the therapeutic effect of CAMK2G inhibition, we performed the immunoprecipitation mass spectrometry to find out the protein that has the direct interaction with CAMK2G.MethodsQuantitative Proteomic Analysis of the Target Proteins of CAMK2GThe protein complexes with FLAG-tagged CAMK2G (FLAG-CAMK2G) were trapped by anti-FLAG antibody. The eluted assay mixtures were reduced, alkylated and digested into peptides. Each peptide solution and control mixture were labeled with differential stable isotope tags. The samples were quantitatively analyzed using a Q Exactive mass spectrometer (Thermo Fisher Scientific). The spectra were searched against the SWISS-PROT databases using SEQUEST on Proteome Discoverer software 2.2 (Thermo Scientific).ResultsTo reveal the , we conducted the immunoprecipitation assays by FLAG-CAMK2G or FLAG-tag alone, overexpressed in MF model cells. Because CAMK2G has kinase activity, we attempted to reveal the kinase-activity-dependent targets using unhydrolyzable ATP analog, AMP-PNP（5'-adenylyl-imidodiphosphate）that can maintain the strong-binding state of kinase with its target. The protein complexes with FLAG-CAMK2G were trapped by anti-FLAG antibody. After samples were digested into peptides and the candidate proteins were identified and quantitatively analyzed by mass spectrometry. As a result, we identified eukaryotic translation initiation factor 4B (eIF4B) as a protein that has a direct interaction with CAMK2G. eIF4B is a part of the complex involved in the initiation of translation. It has been reported that eIF4B plays a role in the translation of factors involved in anti-apoptosis (Bcl2, Bclxl, Mcl1), cell cycle (Cdc25c), and cell proliferation (c-Myc). We then checked whether knockdown of eIF4B decrease proliferation of MF model cell line. shRNA-mediated silencing of eIF4B decreased cell growth of these cells. Furthermore, the phosphorylation of eIF4B was increased by the ectopic expression of MPL W515L, one of the common mutations found in MF. Also, the phosphorylation of eIF4B was increased by the overexpression of CAMK2G. We then explored the proteins regulated by eIF4B in MF and identified that knockdown of eIF4B decreased the amount of Bcl2 protein.ConclusionIn our study, we performed immunoprecipitation mass spectrometry and identified eIF4B as a partner protein of CAMK2G. Since CAMK2G inhibition was shown to be effective against MF in vitro and in vivo, we focused on eIF4B as a potential effector in MF. We also showed that overexpression of MPL W515L and CAMK2G phosphorylates eIF4B and that knockdown of eIF4B inhibited proliferation of MF cells. Furthermore, Bcl2 can be one of the target proteins regulated by eIF4B. Based on these, eIF4B plays an important role in MF. We further perform ribosome profiling to comprehensively understand the regulation of translation by eIF4B. Our research not only elucidate the pathogenesis of MF but also identify new therapeutic targets for MF. DisclosuresMasamoto: MSD K.K.: Speakers Bureau; Eisai Co., Ltd.: Speakers Bureau; Otsuka Pharmaceutical Co., Ltd.: Speakers Bureau; ONO PHARMACEUTICAL CO., LTD.: Speakers Bureau; Takeda Pharmaceutical Company Limited.: Speakers Bureau; Chugai Pharmaceutical Company: Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Speakers Bureau; Nippon Shinyaku Co., Ltd.: Speakers Bureau; AbbVie GK: Speakers Bureau; Janssen Pharmaceutical K.K.: Speakers Bureau; SymBio Pharmaceuticals: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Kurokawa: Otsuka Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; ONO PHARMACEUTICAL CO., LTD.: Research Funding, Speakers Bureau; Takeda Pharmaceutical Company Limited.: Research Funding, Speakers Bureau; Chugai Pharmaceutical Company: Research Funding, Speakers Bureau; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding, Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Research Funding, Speakers Bureau; Nippon Shinyaku Co., Ltd.: Research Funding, Speakers Bureau; Daiichi Sankyo Company.: Research Funding, Speakers Bureau; AbbVie GK: Research Funding, Speakers Bureau; Teijin Limited: Research Funding, Speakers Bureau; Pfizer Japan Inc.: Research Funding, Speakers Bureau; Eisai Co., Ltd.: Research Funding, Speakers Bureau; MSD K.K.: Research Funding, Speakers Bureau; Astellas Pharma Inc.: Research Funding, Speakers Bureau.

Risk of Febrile Neutropenia in Very Elderly Patients Aged ≥80 Years Who Received R-CHOP Regimen: A Nationwide Analysis in Japan

Background: Despite the aging society, few studies have evaluated risk factors for febrile neutropenia (FN) in the very elderly. This may be due to the difficulty of conducting a prospective study in the presence of comorbidities and a limited number of patients. We retrospectively analyzed risk factors for FN in the first cycle of rituximab-cyclophosphamide-doxorubicin-vincristine-prednisolone (R-CHOP) regimen in the very elderly aged ≥ 80 years using a nationwide inpatient database in Japan.Study Design and Methods: This study was a retrospective cohort study using the Diagnosis Procedure Combination database, a nationwide inpatient database in Japan. The database includes discharge abstracts and administrative claims data from >1200 acute-care hospitals and covers around 90% of all tertiary-care emergency hospitals in Japan. We identified patients aged ≥ 80 years old with newly diagnosed diffuse large B-cell lymphoma (DLBCL) who received the first cycle of R-CHOP regimen between July 2007 and March 2017 from the database. The initial dose intensity (IDI, %) was calculated as the average ratio of the actual dose to the 100% dose of cyclophosphamide and doxorubicin. IDI less than 80% was defined as reduced IDI. Multivariable logistic regression analysis fitted with a generalized estimating equation accounting for within-hospital clustering was performed to identify factors associated with the occurrence of FN. P<0.05 was considered statistically significant.Results: We identified 1,819 patients aged ≥ 80 years old with DLBCL who were newly diagnosed and treated with R-CHOP. The median age was 83 years (interquartile range: 82-85). A total of 73 (4%) patients received antimicrobial prophylaxis, and 270 (15%) received primary prophylaxis with G-CSF. Reduced IDI of R-CHOP regimen was performed in 1,444 (79%) patients, including 697 patients with 60-80% of IDI and 747 patients with 40-60% of IDI. FN occurred in 115 of the 1,819 patients (6.3%) with a median of 10 days (interquartile range: 8-12) after the administration of cyclophosphamide. Antimicrobial prophylaxis, primary prophylaxis with daily G-CSF, and pegfilgrastim were not significantly associated with a lower occurrence of FN in the very elderly patients (odds ratio 0.69 [95% confidence interval 0.30-2.21], 1.39 [0.73-2.64], 1.43 [0.73-2.81], respectively). Reduced IDI was significantly associated with a lower occurrence of FN (40-60%: odds ratio 0.54 [0.32-0.92]). Advanced-stage lymphoma (>stage 2) and placement of central venous catheter was significantly associated with the occurrence of FN (odds ratio 1.59 [1.02-2.49], 3.19 [1.81-5.62], respectively).Conclusion: The present nationwide study showed that IDI was reduced in most of the very elderly patients with DLBCL in a real-world clinical practice. The proportion of the very elderly patients who developed FN tended to be lower than those in previous studies with younger patients, which may be explained by reduced IDI in the very elderly. Whereas, prevention strategies with G-CSF for FN may be less effective in the very elderly. DisclosuresMatsuda: Ono Pharmaceutical: Other: Lecture fee; Kyowa Kirin: Other: Lecture fee. Jo: Tsumura: Other: Lecture fee, Research Funding; AstraZeneca: Other: Lecture fee; Sanofi: Other: Lecture fee; Boehringer Ingelheim: Other: Lecture fee. Shimura: Eisai: Other: Lecture fee. Honda: Otsuka Pharmaceutical: Other: Lecture fee; Ono Pharmaceutical: Other: Lecture fee; Nippon Shinyaku: Other: Lecture fee; Jansen Pharmaceutical: Other: Lecture fee; Chugai Pharmaceutical: Other: Lecture fee; Takeda Pharmaceutical: Other: Lecture fee. Masamoto: MSD K.K.: Speakers Bureau; Eisai Co., Ltd.: Speakers Bureau; Otsuka Pharmaceutical Co., Ltd.: Speakers Bureau; ONO PHARMACEUTICAL CO., LTD.: Speakers Bureau; Takeda Pharmaceutical Company Limited.: Speakers Bureau; Chugai Pharmaceutical Company: Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Speakers Bureau; Nippon Shinyaku Co., Ltd.: Speakers Bureau; AbbVie GK: Speakers Bureau; Janssen Pharmaceutical K.K.: Speakers Bureau; SymBio Pharmaceuticals: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Yasunaga: Pfizer: Consultancy, Other: Lecture fee; Novartis: Consultancy, Other: Lecture fee; Boehringer Ingelheim: Other: Lecture fee; Chugai Pharmaceutical: Other: Lecture fee; Tsumura: Other: Lecture fee. Kurokawa: MSD K.K.: Research Funding, Speakers Bureau; Eisai Co., Ltd.: Research Funding, Speakers Bureau; ONO PHARMACEUTICAL CO., LTD.: Research Funding, Speakers Bureau; Takeda Pharmaceutical Company Limited.: Research Funding, Speakers Bureau; Chugai Pharmaceutical Company: Research Funding, Speakers Bureau; Daiichi Sankyo Company.: Research Funding, Speakers Bureau; Otsuka Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; AbbVie GK: Research Funding, Speakers Bureau; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding, Speakers Bureau; Nippon Shinyaku Co., Ltd.: Research Funding, Speakers Bureau; Astellas Pharma Inc.: Research Funding, Speakers Bureau; Teijin Limited: Research Funding, Speakers Bureau; Pfizer Japan Inc.: Research Funding, Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Research Funding, Speakers Bureau.

A Nationwide Survey of Lower Risk Myelodysplastic Syndromes in Japan

A Nationwide Survey of Lower Risk Myelodysplastic Syndromes in Japan

Single-Strand Breaks at Genome Initiate FLT3-ITD Formation

Single-Strand Breaks at Genome Initiate FLT3-ITD Formation

Pivotal Phase 2 Study of the EZH1 and EZH2 Inhibitor Valemetostat Tosylate (DS-3201b) in Patients with Relapsed or Refractory Adult T-Cell Leukemia/Lymphoma

Pivotal Phase 2 Study of the EZH1 and EZH2 Inhibitor Valemetostat Tosylate (DS-3201b) in Patients with Relapsed or Refractory Adult T-Cell Leukemia/Lymphoma

Outcomes of Haploidentical Salvage Transplantation Using Post-Transplant Cyclophosphamide for Graft Failure Following Allogeneic Hematopoietic Stem Cell Transplantation

Introduction: Graft failure (GF) is a fatal complication after allogeneic stem cell transplantation (SCT). Although salvage SCT is the only curative therapy for GF, optimal donors and strategies for this procedure have not yet been established. Although in the last decade haploidentical donors have emerged as alternative donors, only limited data are available regarding the outcomes after haploidentical salvage SCT using post-transplant cyclophosphamide (PTCy). Therefore, this nationwide retrospective study aimed to evaluate the transplant outcomes and risk factors for survival after haploidentical salvage SCT using PTCy on behalf of the Transplant Complications Working Group of the Japan Society for Transplantation and Cellular Therapy.Methods: Clinical data were provided by the nationwide database of the Japanese Data Center for Hematopoietic Cell Transplantation. Patients who were diagnosed with GF and underwent a second or higher allogeneic SCT from the haploidentical related donor (≥2 antigen-mismatch), using PTCy as graft-versus-host disease (GVHD) prophylaxis, between 2011 and 2019 were included. Organ failure was defined as either ejection fraction ≤50%, serum creatinine ≥2 mg/dL, bilirubin ≥1.5 × upper limit of normal, or aspartate aminotransferase/alanine aminotransferase ≥2.5 × upper limit of normal. Overall survival (OS) probabilities were estimated using the Kaplan-Meier method and differences among groups were analyzed using the log-rank test. The multivariate analysis for OS was performed using the Cox proportional hazard regression model. Factors from the univariate analysis that demonstrated significance with P values < 0.1 were included in the multivariate analysis.Results: A total of 33 patients were included in the study. The median age was 34 years (range, 2-67), while performance status (PS) was 0-1 in 21 patients (64%). At salvage transplantation, 12 (36%) were receiving treatment for active infection, and 5 (15%) had organ failure. The median interval from SCT to salvage SCT was 49 days (range, 26-1,468), and 21 patients (68%) underwent salvage SCT within 100 days after previous SCT. Conditioning regimens consisted of fludarabine (Flu)/ cyclophosphamide (Cy)-based in 10 (31%), Flu/melphalan (Mel)-based in 10 (31%), and Flu/busulfan (Bu)-based in 7 (21%). The total dose of PTCy was 75-100 mg/kg in 26 patients (84%) and 40-50 mg/kg in 5 patients (16%). Most patients (84%) received tacrolimus plus mycophenolate mofetil as GVHD prophylaxis in addition to PTCy. Previous SCT was cord blood transplantation in 22 patients (67%) and haploidentical transplantation in 6 patients (19%), of which 4 patients (13%) received PTCy. The median time for neutrophil engraftment was 18 days, and the cumulative incidence of neutrophil engraftment at 30 days was 82%. Specifically, a patient who had donor-specific human-leukocyte antigen-antibody successfully achieved neutrophil engraftment at 22 days after salvage SCT. The median OS was 359 days, while the OS at 1 year was 47% (Figure A). In the univariate analysis, the OS of patients who received 75-100 mg/kg PTCy was significantly better than those who received 40-50 mg/kg PTCy (61% vs. 0% at 1 year, P = 0.022, Figure B). After adjusting for PS and the presence of active infection and organ failure, 75-100 mg/kg PTCy was significantly associated with better OS (hazard ratio, 0.30; P = 0.036). Although the differences were not significant, patients who received Flu/Mel-based conditioning exhibited numerically better OS than those who received Flu/Cy- or Flu/Bu-based conditioning (80% vs. 40% vs. 57%, P = 0.21).Conclusions: Haploidentical salvage SCT using PTCy offers promising survival outcomes and can be a substantial option for GF after allogeneic SCT. An adequate dose of PTCy (i.e., 75-100 mg/kg) needs to be administered to achieve long-term survival. [Display omitted] DisclosuresNakamae: PPD-SNBL K.K: Research Funding; Bristol-Myers Squibb Company: Honoraria, Research Funding; Alexion: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Simon-Kucher & Partners: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria; Astellas Pharma Inc.: Honoraria; Otsuka Pharmaceutical Co., Ltd: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria; CMIC HOLDINGS Co., Ltd: Research Funding; Novartis: Honoraria, Research Funding; Pfizer Japan Inc.: Honoraria. Ichinohe: Celgene: Honoraria; Novartis Pharma K.K.: Honoraria; Repertoire Genesis Inc.: Honoraria, Research Funding; Takara Bio Inc.: Research Funding; Zenyaku Kogyo Co.: Research Funding; Taiho Pharmaceutical Co.: Research Funding; Sumitomo Dainippon Pharma Co.: Honoraria, Research Funding; Otsuka Pharmaceutical Co.: Research Funding; Nippon Shinyaku Co: Research Funding; Ono Pharmaceutical Co.: Honoraria, Research Funding; Kyowa Kirin Co.: Honoraria, Research Funding; FUJIFILM Wako Chemicals.: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; Eisai Co.: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Chugai Pharmaceutical: Research Funding; Bristol-Myers Squibb: Honoraria; Takeda Pharmaceutical Co.: Honoraria; AbbVie Pharma: Research Funding; Astellas Pharma: Honoraria, Research Funding. Atsuta: Mochida Pharmaceutical Co., Ltd.: Speakers Bureau; Astellas Pharma Inc.: Speakers Bureau; AbbVie GK: Speakers Bureau; Kyowa Kirin Co., Ltd: Honoraria; Meiji Seika Pharma Co, Ltd.: Honoraria. Nakasone: Takeda Pharmaceutical: Honoraria; Otsuka Pharmaceutical: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Eisai: Honoraria; Chugai Pharmaceutical: Honoraria; Nippon Shinyaku: Honoraria.

Very Low-Dose Dasatinib Is a Safe and Effective Therapy for Elderly Patients with Newly-Diagnosed Chronic-Phase Chronic Myeloid Leukemia: Results from the Davlec Study, a Single-Arm, Multicenter, Phase 2 Trial

Very Low-Dose Dasatinib Is a Safe and Effective Therapy for Elderly Patients with Newly-Diagnosed Chronic-Phase Chronic Myeloid Leukemia: Results from the Davlec Study, a Single-Arm, Multicenter, Phase 2 Trial

Genomic Analysis of NPM1 Mutation and KMT2A(MLL)-Rearrangement/Amplification in Japanese Patients with Acute Myeloid Leukemia: Hematologic Malignancies (HM)-Screen-Japan 01

Genomic Analysis of NPM1 Mutation and KMT2A(MLL)-Rearrangement/Amplification in Japanese Patients with Acute Myeloid Leukemia: Hematologic Malignancies (HM)-Screen-Japan 01

The Outcomes of Systemic Chronic Active EBV Infection Treatment By Allogeneic Hematopoietic Stem Cell Transplantation: An Analysis of Japanese Registry Data

The Outcomes of Systemic Chronic Active EBV Infection Treatment By Allogeneic Hematopoietic Stem Cell Transplantation: An Analysis of Japanese Registry Data

Clinical Outcomes of Relapsed/Refractory Multiple Myeloma Patients Following Treatment with Bispecific Antibodies (BiAbs)

Background: Bispecific antibodies (BiAbs) are a novel off-the-shelf class of drugs currently being investigated in clinical trials for patients with relapsed/refractory multiple myeloma (RRMM) with promising efficacy in heavily pretreated patients. BiAbs simultaneously bind two antigens, thereby engaging CD3+ T cells with myeloma cells expressing specific antigens such as BCMA, GPRC5D, FcRH5 or CD38. However, the outcome of myeloma patients after relapse on BiAbs is unknown and effective approaches for salvage therapy are needed.Methods: Demographics, disease characteristics and post-clinical trial outcomes were collected retrospectively on RRMM patients who relapsed after BiAb therapy at the Tisch Cancer Institute (The Mount Sinai Hospital, New York). We identified a total of 116 patients who were enrolled on trials with BiAbs targeting either BCMA or GPRC5D. Of these, 69 patients were no longer enrolled on the trials due to disease progression (including 5 patients who died on the trial). Clinical data was collected up until July of 2021. This retrospective study was approved by the institutional review board (IRB) and follows the Declaration of Helsinki and International Conference on Harmonization Guidelines for Good Clinical Practice (IRB: GCO#: 11-1433). Survival and response duration were calculated by Kaplan-Meier estimation.Results: The 64 RRMM patients had a median age of 58.5 years (range: 46-82) at time of disease progression following BiAbs therapy, and 48% were male. Median time from diagnosis to initiation of BiAbs therapy was 5 years (range: 1.6-16.3) and patients had a median follow-up of 24.9 months from time of relapse from BiAb therapy. Fifty patients (78%) had high-risk cytogenetics, including gain1q21, del17p, t(4;14), t(14;16) and t(14;20). Most patients were highly pretreated with a median of 7 prior lines (range: 3-17) and 54 patients (84%) had received an autologous stem cell transplant (ASCT) prior to receiving BiAbs. Three patients were treated with chimeric antigen receptor (CAR) T cell therapy prior to BiAb and 5 patients were exposed to a BCMA antibody-drug conjugate prior to the BiAb. Furthermore, 89% of patients were triple-class refractory while 44% were penta-refractory.Following treatment with a BiAb, 2 patients were lost to follow up, 1 patient decided to be monitored off treatment and 61 patients received a median of 2 lines of therapy (range: 1-8). Most common therapies included a second BiAb (n=20; 33%), CAR T cells (n=15; 26%) or intensive chemotherapy (n=36; 59%) such as melphalan, carmustine or VDPACE with stem cell rescue (n=13) or DCEP (n=23). Best response to initial treatment following the BiAb varied widely and included 12 complete responses, 5 very good partial responses, 17 partial responses, 2 minimal responses, 10 stable disease and 13 progressed disease for an overall response rate (ORR) of 58%. Encouraging responses were seen in 10 patients who directly transitioned from one BiAb to another and 8 patients who directly transitioned to CAR T cell therapy. The progression-free survival of those 18 patients who directly transitioned to a T cell directed therapy was 28.9 months (95% CI: 21.6-NE) and their median overall survival was not reached. Furthermore, the overall survival for the whole cohort of patients was 17.6 months (95% CI: 12.0-NE).Conclusion: Our data suggests that heavily pretreated, predominantly triple-class refractory, patients relapsing after BiAbs may still have good outcomes when sequentially treating with other immunological/T cell-directed therapeutics such as BiAbs and CAR T cells. Studying the appropriate sequence of these treatments is of paramount importance as BiAbs are expected to become part of the standard of care for RRMM patients. DisclosuresRichard: Karyopharm, Janssen: Honoraria. Richter: Celgene: Speakers Bureau; Adaptive Biotechnologies: Speakers Bureau; Celgene: Consultancy; Janssen: Consultancy; BMS: Consultancy; Karyopharm: Consultancy; Antengene: Consultancy; Sanofi: Consultancy; X4 Pharmaceuticals: Consultancy; Oncopeptides: Consultancy; Adaptive Biotechnologies: Consultancy; Janssen: Speakers Bureau; Secura Bio: Consultancy; Astra Zeneca: Consultancy. Chari: Janssen Pharmaceuticals: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Novartis Pharmaceuticals: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Takeda Pharmaceutical Company: Consultancy, Research Funding; Karyopharm: Consultancy; Sanofi Genzyme: Consultancy; Oncopeptides: Consultancy; Antegene: Consultancy; Glaxosmithkline: Consultancy; Secura Bio: Consultancy. Parekh: Foundation Medicine Inc: Consultancy; Amgen: Research Funding; PFIZER: Research Funding; CELGENE: Research Funding; Karyopharm Inv: Research Funding.

Genomic Analysis Focusing on RUNX1-RUNX1T1 in Japanese Patients with AML: HM-Screen-Japan 01

Genomic Analysis Focusing on RUNX1-RUNX1T1 in Japanese Patients with AML: HM-Screen-Japan 01

Properties and Distribution of IDH-1/2 Mutations in Acute Myeloid Leukemia By the Comprehensive Genomic Analysis

Properties and Distribution of IDH-1/2 Mutations in Acute Myeloid Leukemia By the Comprehensive Genomic Analysis

Pathogenic Germline Variants in Multiple Myeloma

BACKGROUND: There is growing evidence supporting inherited predisposition to multiple myeloma (MM). Epidemiologic studies have shown that 1st-degree relatives of MM patients (pts) have a 2-4 fold increase in risk of developing MGUS or MM. Genome-wide association studies (GWAS) have identified common SNPs as well as rare high-penetrance variants that collectively explain ~16% of the estimated heritability of multiple myeloma (PMID 30213928). Pathogenic/likely-pathogenic germline variants (PGV) in hereditary cancer genes (HCG) are common in adult cancer patients (~8%, PMID 29625052), but prevalence in MM is not known. The aim of our study is to investigate the occurrence of PGV in newly-diagnosed MM (NDMM), and to describe clinical characteristics & outcomes of carriers.METHODS: We analyzed MMRF CoMMpass data (version IA16) and identified 895 NDMM pts for whom whole-exome sequencing of germline DNA was available. We used the clinical annotation pipeline from Sema4, a CLIA/CAP certified genetic testing laboratory, to identify pts with PGV according to ACMG variant classification guidelines. We compared clinical characteristics & disease phenotypes of PGV carriers vs non-carriers. We used Chi-Square and Fisher's Exact tests to assess statistical significance, which we defined as a two-sided p value < 0.05. Logistic regression models were used for multivariate analyses. Kaplan-Meier method and Cox proportional-hazards models were used for uni- and multivariate survival analysis, respectively. Bonferroni method was used to account for multiple testing.RESULTS: We identified 83 PGV in 31 distinct HCG in 79 (8.8%) of 895 NDMM pts (83% European ancestry) [Figure 1A]. Most PGV involved DNA damage repair (DDR) genes (78%), and homologous recombination (HR) genes were the most commonly mutated (34%). PGV in CHEK2 were the most common (n=10, 1.1% of all MM pts). 2 pts carried PGV in TP53 and reported extensive family history of Li-Fraumeni-associated cancers (breast, sarcoma, gastric & melanoma). 6 pts had germline mismatch repair (MMR) gene defects (1:149, considerably higher than the estimated prevalence of Lynch syndrome in Western populations). 4 pts carried PGV in BRCA2 (previously identified in a family study as a potential MM predisposition gene, PMID 11904319). MM pts with a family history of hematologic malignancy (leukemia, lymphoma or MM) in a 1st or 2nd-degree relative were significantly more likely to carry PGV (22 vs 7.6%, OR=3.3, p<0.001), an association that remained significant in MVA (OR=4.1, p<0.001). CHEK2 variants emerged as leading drivers of this correlation (OR 18.2, 95% CI 4.1-75, adjusted p<0.01), & especially protein-truncating founder variant c.1100delC. Likelihood of being diagnosed w/ MM before age 40 was significantly higher in PGV carriers (6.3 vs 1.8%, OR=3.7, p=0.025). 25% of those younger than 40 y/o carried PGV, but none of these were in DDR-HR genes, a notable difference with other age groups (0 vs 41%, p=0.02). 2/6 MMR PGV were detected in pts diagnosed before age 40. In univariate survival analysis, DDR-PGV carriers had a significant PFS1 advantage over non-carriers (median 52 vs 35 months, p=0.008), as well as a non-significant OS advantage (p=0.08). PFS1 difference remained significant in MVA after adjusting for age, ISS stage, high-risk cytogenetics, treatment type & transplant status (OR 0.65, 95% CI 0.44-0.97, p=0.03) [Figure 1B].CONCLUSIONS: PGV in HCG were common (8.8%) in this large cohort of NDMM pts of predominantly European ancestry, especially in those with a family history of hematologic malignancy (1:4, with high prevalence of CHEK2 variants & particularly protein-truncating founder variant c.1100delC), and in those diagnosed before age 40 (1:4). Routine screening in high-prevalence subgroups might be warranted, as carriers may benefit from counseling and enrollment in early cancer detection programs. We observed a clinically and statistically significant PFS1 advantage in carriers of PGV in DDR genes, possibly due to increased sensitivity to MM therapies, a well-described phenomenon in other cancer types (PMID 33158305). Prospective validation of these findings is needed to better understand prognostic & therapeutic implications of PGV in MM. [Display omitted] DisclosuresChari: Karyopharm: Consultancy; Takeda Pharmaceutical Company: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Research Funding; Amgen: Consultancy, Research Funding; Novartis Pharmaceuticals: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy, Research Funding; Sanofi Genzyme: Consultancy; Oncopeptides: Consultancy; Antegene: Consultancy; Glaxosmithkline: Consultancy; Secura Bio: Consultancy. Richard: Karyopharm, Janssen: Honoraria. Richter: Sanofi: Consultancy; Antengene: Consultancy; Karyopharm: Consultancy; BMS: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Adaptive Biotechnologies: Speakers Bureau; Celgene: Speakers Bureau; Janssen: Speakers Bureau; X4 Pharmaceuticals: Consultancy; Oncopeptides: Consultancy; Adaptive Biotechnologies: Consultancy; Secura Bio: Consultancy; Astra Zeneca: Consultancy. Parekh: Foundation Medicine Inc: Consultancy; Amgen: Research Funding; PFIZER: Research Funding; CELGENE: Research Funding; Karyopharm Inv: Research Funding.

Characterization and Management of Oral and Dermatological Toxicities in Patients Receiving the CD3 X GPRC5D Bispecific Antibody Talquetamab (JNJ-64407564) for the Treatment of Relapsed and/or Refractory Multiple Myeloma

Background: Talquetamab (JNJ-64407564) is a humanized IgG4 bispecific antibody that targets the CD3 receptor complex on T cells and G-protein-coupled receptor class 5 member D (GPRC5D) a transmembrane receptor protein overexpressed on malignant plasma cells in Multiple Myeloma. After 6.3 months of follow up in RRMM, talquetemab monotherapy at the recommended phase 2 dose yielded an overall response rate of 70%. Talquetemab was well tolerated and here we describe the presentation and management of dermatologic and oral adverse events (AEs) in 78 patients (pts) treated with talquetemab at a single center that is part of a multi-center, multi-national study.Methods: Eligible pts with RRMM were enrolled to the Phase 1, first in human, open-label dose escalation study (NCT03399799) at our site, and received talquetamab intravenously (IV; range 1.5µg/kg -1200µg/kg biweekly or weekly) or subcutaneously (SC; 5µg/kg to 800µg/kg weekly). AEs were graded using CTCAE v4.03.Results: As of July 2021, 78 pts received talquetamab, 53 (67.9%) by IV and 25 (32%) by SC route. Treatment emergent dermatologic AEs were observed in 20 (25.6%) pts. The most common AEs were palmar/plantar desquamation in 22 pts (28.2%, grade 1/2), nail disorders in 14 pts (17.9%, all grade 1), systemic rash in 11 patients (14%, grades 1-3), and injection site reaction in 7 pts (8.9%, all grade 1). Time of onset for dermatologic toxicities was generally within the first 30 days of therapy.In collaboration with dermatology consultation, the management of palmar/plantar desquamation, nail disorders, and injection site reaction has been ammonium lactate 12% cream, triamcinolone 0.1% cream, along with plain Vaseline and Vanicream products applied twice daily.Of the 11 pts with systemic rash, 10 were at or above a dose of 405 µg /kg. Five pts had grade 3 rash requiring dose hold and systemic steroids in conjunction with topical medications. All pts have resumed dosing without recurrence of grade 3 rash. Four of these pts were at a dose level of 800 µg/kg SC. Grade 1-2 rash did not require dose hold and was managed with early intervention of the 3 topical treatments applied to affected areas twice daily.In addition to the above described dermatologic AEs, treatment emergent oral AEs were observed in 38 (48.7%) pts, all grade 1-2. 42 pts developed dysgeusia (53.8%), 16 developed dry mouth (20.5%), and 17 developed dysphagia (21.8% ).Dysgeusia resulted in 3 pts requiring drug interruption. 1 pt requiring dose reduction, and 1 discontinued treatment. The average time to onset for dysgeusia was 26.5 days. Dry mouth resulted in no drug interruptions, reductions, or discontinuations, and had an average onset of 6.7 days. Dysphagia also ranged from grades 1-2, with 3 pts requiring drug interruption. There were no dose reductions or treatment discontinuation. The average time to onset was 41.5 days. Dry mouth, dysgeusia, and dysphagia were more prevalent with higher doses.Along with GI and nutrition consultation, oral AEs have been successfully managed with saliva substitute sprays and rinses. These supportive interventions are instituted promptly at time of onset of symptoms.The above-described treatments for dermatologic and oral AEs were not protocol mandated procedures.DiscussionThe dermatologic and oral AEs associated with talquetamab have unknown etiologies and are currently under investigation. These AEs are typically low grade, rarely require dose holds or modifications, and have been manageable with early and consistent supportive care. Only one patient to date at our center, has discontinued treatment due to an oral or dermatologic side effect. Talquetamab appears to have a have favorable risk/benefit profile in RRMM with durable responses and manageable toxicities. A standardized regimen of topical and oral supportive care appears to be beneficial in the management of dermatological and oral side effects. DisclosuresFarrell: Regeneron: Current Employment. Florendo: Legend Biotech: Current Employment. Catamero: Celgene: Ended employment in the past 24 months, Honoraria; Legend: Honoraria; Oncopeptides: Speakers Bureau. Parekh: Foundation Medicine Inc: Consultancy; Amgen: Research Funding; PFIZER: Research Funding; CELGENE: Research Funding; Karyopharm Inv: Research Funding. Richter: Janssen: Speakers Bureau; Celgene: Speakers Bureau; Adaptive Biotechnologies: Speakers Bureau; Celgene: Consultancy; Janssen: Consultancy; BMS: Consultancy; Karyopharm: Consultancy; Antengene: Consultancy; Sanofi: Consultancy; X4 Pharmaceuticals: Consultancy; Oncopeptides: Consultancy; Adaptive Biotechnologies: Consultancy; Secura Bio: Consultancy; Astra Zeneca: Consultancy. Chari: Janssen Pharmaceuticals: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Novartis Pharmaceuticals: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Takeda Pharmaceutical Company: Consultancy, Research Funding; Karyopharm: Consultancy; Sanofi Genzyme: Consultancy; Oncopeptides: Consultancy; Antegene: Consultancy; Glaxosmithkline: Consultancy; Secura Bio: Consultancy.

Prognostic Factors of Idiopathic Hypereosinophilic Syndrome: A Nationwide Survey in Japan

Prognostic Factors of Idiopathic Hypereosinophilic Syndrome: A Nationwide Survey in Japan

Clinical Significance of FLT3 Mutations in a Comprehensive NGS Multicenter Study of AML: HM-Screen-Japan 01

Clinical Significance of FLT3 Mutations in a Comprehensive NGS Multicenter Study of AML: HM-Screen-Japan 01

Increase in Antibody Titers Following Sars-Cov-2 Vaccination Remains Limited for More Than 3 Years after Final Dose of Anti-CD20 Antibody

COVID-19, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has become a global pandemic. Patients with hematological disorders are known to be at high risk of morbidity and mortality from COVID-19, and vaccines against SARS-CoV-2 have been rapidly developed. Although mRNA vaccines against SARS-CoV-2 are reported to be effective, efficacy in patients with hematological malignancies who have received anti-CD20 antibody treatment remains unclear. Here, we prospectively evaluated the efficacy of BNT162b2 mRNA COVID-19 vaccine in patients with B-cell malignancies treated with anti-CD20 antibody.We first evaluated antibody titers in 12 healthy volunteers (median age 75.5 years, range 57-82) and three lymphoma patients undergoing R-CHOP therapy (73, 81, and 81 years old) who had received 2 vaccine doses of BNT162b2 at pre-vaccination, 21 days after the first dose and 14 days after the second dose of vaccination. IgG antibody titers for S1 protein were measured in serum samples by ELISA. In healthy control subjects, titers were clearly increased. In contrast, no patient treated with R-CHOP developed antibodies even after the second vaccination (Figure A). To determine the SARS-CoV-2-specific T-cell reactivity in these three patients, we evaluated interferon (IFN)-γ response to the SARS-CoV-2 spike peptide before and after the second vaccination dose, and detected IFN-γ responses after vaccination in all three patients (Figure B).Next, to investigate the duration of the effect of anti-CD20 antibody on antibody production to BNT162b2, we enrolled 36 patients (median age 74 years, range 50-87) who had received the final dose of anti-CD20 antibody 48-1320 (median 571) days before vaccination. S1 antibody titers were measured 14 days after the second dose of vaccination. Diagnoses included diffuse large B-cell lymphoma (n = 21), follicular lymphoma (n = 9), lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia (n = 3), and mantle cell lymphoma (n = 3). Thirty-four patients had received rituximab-based and 2 had received obinutuzumab-based therapy, with a median of 6 (range 3-20) courses. No patient had received any chemotherapy after the last anti-CD20 antibody dose. No patient vaccinated within close to one year or sooner after the last anti-CD20 antibody administration showed an increase in titers. Furthermore, titers in most patients were lower than in healthy volunteers even among those vaccinated more than three years after the last administration (Figure C). Finally, we investigated surrogate markers of antibody production ability. We found no relationship between the percent of B-cells (CD19-positive cells) and S1 antibody titers (Figure D), whereas all patients (n = 9) with total IgG level below lower normal limit (< 870 mg/dl) had low S1 antibody titers (< 0.16), below the lowest optical density (O.D.) value in healthy donors (Figure E).These findings indicate that the antibody-mediated response to vaccination in patients following treatment with anti-CD20 antibody was considerably impaired for an extended time. Alternative protection strategies for these patients are therefore warranted. Although T-cell responses were detected, we recommend that these patients continue to wear a face mask and wash their hands to prevent COVID-19 even after vaccination. [Display omitted] DisclosuresYakushijin: Chugai pharmaceutical Co. Ltd.: Research Funding; Jazz pharmaceuticals: Research Funding; Nippon Shinyaku: Honoraria. Kiyota: Bristol-Myers Squibb: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Astra-Zeneca: Honoraria, Research Funding; Roche Phamaceuticals: Research Funding; Merck Biopharma: Honoraria; Merck Sharp & Dohme: Honoraria; Eisai: Honoraria; Bayer: Honoraria. Matsuoka: Takeda Pharmaceutical Company: Research Funding; Sysmex: Research Funding. Minami: Behring: Research Funding; CSL: Research Funding; Yakult Honsha: Research Funding; Nippon Shinyaku: Research Funding; Astellas Pharma: Research Funding; Asahi-Kasei Pharma: Research Funding; Eli Lilly: Honoraria, Research Funding; Taiho Pharmaceutical: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; MSD: Honoraria, Research Funding; Merck Serono: Honoraria, Research Funding; Kyowa-Kirin: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; DaiichiSankyo: Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria, Research Funding; Bayer Yakuhin: Honoraria, Research Funding; Nippon Kayaku: Research Funding; Celgene: Honoraria; Ohtsuka Pharmaceutical: Honoraria; Shire Japan: Honoraria; Genomic Health: Honoraria; Abbvie: Honoraria.

Hematologic Malignancies (HM)-Screen-Japan 01: A Mutation Profiling Multicenter Study on Patients with Acute Myeloid Leukemia

Hematologic Malignancies (HM)-Screen-Japan 01: A Mutation Profiling Multicenter Study on Patients with Acute Myeloid Leukemia

Global Coagulation Potentials and Breakthrough Bleeds in Emicizumab-Treated Hemophilia a Patients Were Similar to Mild Hemophilia a Patients

Emicizumab prophylaxis dramatically reduces bleeding events in severe patients with hemophilia A (PwHA) with and without FVIII inhibitors. Recently, some real-world experiences on PwHA with emicizumab prophylaxis have been reported. The effectiveness of emicizumab could be attributed to an earlier report that the coagulant potential in emicizumab at clinical dosage appeared to correspond to 10-15 IU/dL of factor VIII activity (FVIII:C) (Muto, JTH 2014), indicating that emicizumab enables to transform severe PwHA to mild PwHA. However, the comparison of coagulation potential and bleeding characteristics in PwHA receiving emicizumab (Emi-PwHA) and mild PwHA (PwMHA) remains to be investigated. Here, we examined the clinical and laboratory characteristics in Emi-PwHA and PwMHA. Clinical data of bleeding episodes and coagulation potentials were collected from 64 Emi-PwHA and 15 PwMHA (median FVIII:C 13 IU/dL [IQR 8.5-17.0]). Comprehensive coagulation function was evaluated using Ca 2+-triggered rotational thromboelastometry (ROTEM) and/or ellagic acid/tissue factor-triggered clot waveform analysis (CWA). Furthermore, we compared the features of breakthrough bleeds in two groups.We first compared with the clinical characteristics and coagulation function between the Emi-PwHA with and without the experience of breakthrough bleeds. The age, treatment period, annual bleeding rates (ABR), the percentage of inhibitor-positive, and prophylaxis regimen were not significantly different between both groups. There was no significant difference in ROTEM and CWA-based coagulation potential between Emi-PwHA with and without breakthrough bleeds (median; CT+CFT 1,703s [IQR 1,547-1,849] and 1,837s [IQR 1,671-2,216], Ad|min1| 4.92 [IQR 4.63-5.27] and 4.78 [IQR 4.4-5.11], respectively).We examined clinical data and ROTEM-based coagulation function between the Emi-PwHA and PwMHA. The age in PwMHA (median 25 years [IQR 20-49]) was older than that in Emi-PwHA (median 13 years [IQR 6-25]; p=0.004). The ABR and coagulation function in Emi-PwHA (median; ABR 0 [IQR 0-0.4], CT+CFT 1,795s [IQR 1,659-2,135]) were not significantly different from that in PwMHA (median; ABR 0.3 [IQR 0-0.49], CT+CFT 2,077s [IQR 1,627-2,449]), suggesting that the global coagulation potential in Emi-PwHA was equivalent to that in PwMHA.We next investigated bleeding features in Emi-PwHA (19 cases) and PwMHA (12 cases). Bleeding patterns of them were similar and divided into 3 groups; spontaneous, early post-traumatic (bleeding associated with trauma within 1-2 days) and late post-traumatic (bleeding involved with trauma within 1-2 weeks). Emi-PwHA experienced spontaneous (5/19), early post-traumatic (14/19) and late post-traumatic (3/19) bleedings, and PwMHA experienced spontaneous (4/12), early post-traumatic (7/12) and late post-traumatic (5/12) bleedings. Some patients of them had both spontaneous and early post-traumatic bleeding or both early and late post-traumatic bleeding. The majority of their bleedings was trauma-induced.Severe bleeding symptoms such as muscle bleeds, hemarthrosis or fracture in Emi-PwHA were required FVIII (total 60-200 IU/kg) and hospitalization for 3-5 days. In contrast, those severe breakthrough bleedings in PwMHA were required higher doses of FVIII (total 140-705 IU/kg) and hospitalization for 1-2 weeks. Although the coagulation potential in Emi-PwHA was similar to that in PwMHA, the treatment period and hospitalization for breakthrough bleeds in PwMHA appeared to be longer than those in Emi-PwHA. We speculated that this discrepancy might be due to the difference of physical activities or preventive managements for bleeding because Emi-PwHA was originally severe PwHA.In conclusion, the coagulation potential and bleeding characteristics in Emi-PwHA appeared to be similar to PwMHA, suggesting that emicizumab-mediated coagulation potential reflected the mild type in clinical severity. DisclosuresNakajima: Chugai Pharmaceutical Co., Ltd.: Research Funding; Takeda Pharmaceutical company: Research Funding. Mizumachi: Chugai Pharmaceutical Co., Ltd.: Research Funding. Shimonishi: CSL Bering: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding. Furukawa: Chugai Pharmaceutical Co., Ltd.: Research Funding. Ogiwara: Chugai Pharmaceutical Co., Ltd.: Research Funding. Takeyama: Chugai Pharmaceutical Co., Ltd.: Research Funding. Shima: Fujimoto Seiyaku: Consultancy, Speakers Bureau; Sanofi S.A.: Speakers Bureau; BioMarin Pharmaceutical Inc.: Membership on an entity's Board of Directors or advisory committees; Bayer AG: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk A/S: Honoraria, Speakers Bureau; Takeda: Research Funding; CSL Behring: Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd.: Membership on an entity's Board of Directors or advisory committees; Chugai Pharmaceutical Co., Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Inventor of patents related to anti-FIXa/FX bispecific antibodies, Research Funding, Speakers Bureau. Nogami: Chugai Pharmaceutical Co., Ltd.: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda Pharmaceutical Co., Ltd.: Honoraria, Research Funding, Speakers Bureau; CSL Behring: Honoraria, Research Funding, Speakers Bureau; Novo Nordisk A/S: Honoraria, Research Funding, Speakers Bureau; Bayer AG: Honoraria, Research Funding, Speakers Bureau; Sanofi S.A.: Honoraria, Research Funding, Speakers Bureau; KM Biologics Co., Ltd.: Honoraria, Research Funding, Speakers Bureau.