Littérature scientifique sur le sujet « Nihon Seikō »

The perception of natural disasters as a manifestation of work of supernatural forces was spread around the world during those periods of history when scientific knowledge was not developed enough to explain the mechanisms of natural phenomena. Japan, due to its geographical features, was regularly prone to all kinds of destructive natural forces, so it was it was touched by these ideas as well. The view on natural disasters as a form of divine retribution from Heaven for “immoral” ruling has been known in Japan since the establishment of the “state based on laws” (ritsuryo kokka), and often appeared in chronical texts. However, with the decomposition of ritsuryo system other views on the causes of catastrophes appeared more frequently in the texts from historical sources. This article is devoted to the consideration of one of these structure-forming conceptions — the idea of occurrence of natural disasters due to “following the principle” (riun), in other words, “the natural course of things”. The concept of “following the principle” is closely related to the onmyodo and “sango years”, when the state was especially exposed to the risk of various calamities. Those terrible years were predicted basing on the movement of astronomical objects and it was said that the catastrophes did not directly depend on the virtue of the ruler or mistakes made by him and his courtiers. The first mention of the “sango years” was in 758, but the idea became widespread only in the IX century, which was connected with the increase of influence of The Bureau of Yin and Yang (Onmyoryo). The study is based on historical sources of various types: chronicles (“Shoku nihongi”, “Nihon sandai jitsuroku”, “Ruiju Kokushi”, “Honcho Seiki”), diaries of court noblemen (“Gonki” by Fujiwara Yukinari) and the tractate on onmyodo (“Gogyo daigi”).

BACKGROUND The first-generation Bruton's tyrosine kinase (BTK) inhibitor ibrutinib is effective in patients with relapsed/refractory (r/r) primary central nervous system lymphoma (PCNSL). Tirabrutinib is a second-generation oral BTK inhibitor with greater selectivity than ibrutinib. We evaluated the safety, tolerability, efficacy, and pharmacokinetics (PK) of tirabrutinib once daily (QD) as monotherapy in patients with PCNSL to investigate BTK targeting as a novel therapeutic strategy. This multicenter clinical trial was sponsored by Ono Pharmaceutical Co., Ltd. and was conducted in Japan. METHODS Patients with r/r PCNSL, at least 1 parenchymal disease, Karnofsky performance status (KPS) ≥70, and normal end-organ function were treated with tirabrutinib 320 and 480 mg QD in the phase 1 portion to evaluate dose-limiting toxicity (DLT) within 28 days using a 3+3 dose escalation design, and with 480 mg QD in a fasted condition in the phase 2 portion to assess the safety, efficacy, and PK of tirabrutinib. The primary objective of the phase 2 portion was to evaluate overall response rate (ORR) as assessed by an independent review committee (IRC) according to International PCNSL Collaborative Group (IPCG) criteria. RESULTS Forty-four patients were enrolled; 20 received tirabrutinib at 320 mg, 7 at 480 mg, and 17 at 480 mg under fasted conditions as of June 13, 2019. The median patient age and KPS were 60 years (range 29-86) and 80, respectively. The median number of prior therapies was 2 (range 1-14); all patients had received methotrexate; and 28 had isolated parenchymal disease, 14 cerebrospinal fluid (CSF) involvement, and 3 intraocular involvement. No DLTs were observed, and the maximum tolerated dose (MTD) was not reached up to 480 mg. Commonly observed events (AEs) at any grade were rash (32%), neutropenia (23%), leukopenia (18%), and lymphopenia (16%). Commonly observed grade ≥3 AEs were neutropenia (9.1%), lymphopenia, leukopenia, and erythema multiforme (6.8% each). Two grade 5 AEs (pneumocystis jirovecii pneumonia and interstitial lung disease) were observed in a patient 33 days after starting tirabrutinib at 480 mg QD. IRC-assessed ORR was 64% (28/44); 60% (12/20) with 5 complete response (CR)/unconfirmed complete response (CRu) at 320 mg, 100% (7/7) with 4 CR/CRu at 480 mg, and 53% (9/17) with 6 CR/CRu at 480 mg under fasted conditions. Median progression-free survival (PFS) was 2.9 months (95% confidence interval [CI]: 1.8-11.1); 2.1 months (95% CI: 1.8-NA) at 320 mg, 11.1 months (95% CI: 1.4-NA) at 480 mg, and 5.8 months (95% CI: 1.0-5.8) at 480 mg under fasted conditions. Median overall survival was not reached (95% CI: NA-NA). ORR was similar among patients harboring the oncogenic mutants CARD11, MYD88, CD79B, and wild type (Table 1). Mean values of maximum observed plasma concentration of tirabrutinib after multiple administration on Day 28 at 320 mg, 480 mg, and 480 mg under fasting conditions were 1360, 2270, and 2690 ng/mL, respectively. The area under the plasma concentration time curve over a dosing interval was 6370, 11800, and 11800 ng*h/mL, respectively. The exposure of tirabrutinib increased with increasing dose, regardless of fasting status. Mean trough concentration of tirabrutinib in CSF/plasma at 320 mg and 480 mg on Day 28 was 2.19/16.3 ng/mL and 14.0/89.3 ng/mL, respectively. This indicated that CSF concentration increased with increasing plasma concentration at trough, while the trough concentration ratios between CSF and plasma at each dose were comparable with the free fraction of tirabrutinib in plasma. CONCLUSION Tirabrutinib had a tolerable safety profile and MTD was not reached in patients with PCNSL. IRC-assessed ORR was 64%, despite the presence of CARD11 mutation. Median PFS was longer with the increasing dose. Further investigation is warranted. Disclosures Nagane: Tsumura: Research Funding; Takeda: Research Funding; Astellas: Research Funding; Pfizer: Research Funding; Otsuka: Research Funding; Bristol-Myers-Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Dainippon-Sumitomo: Honoraria; NovoCure: Honoraria; UCB Japan: Honoraria; Daiichi-Sankyo: Honoraria, Research Funding; Nippon-Kayaku: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; MSD: Honoraria, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ono: Honoraria, Research Funding; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Research Funding; Sanofi: Research Funding. Narita:Ono: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Dainippon-Sumitomo: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Stella-pharma: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Meiji-seika: Honoraria, Research Funding; SBI pharma: Honoraria, Research Funding. Mishima:Ono: Research Funding; Chugai: Research Funding; MSD: Research Funding; Eisai: Research Funding; Teijin Pharma: Research Funding; Medical U and A: Research Funding; AbbVie: Research Funding; Otsuka: Research Funding; Daiichi-Sankyo: Research Funding; Nihon-Medi-Physics: Research Funding. Terui:Bristol-Myers Squibb, Celgene, Janssen, Takeda, MSD, Eisai, Ono, and Chugai-Roche Pharmaceuticals Co.,Ltd.: Honoraria; Bristol-Myers Squibb K.K.: Research Funding. Arakawa:UCB: Honoraria; Otsuka: Honoraria; AbbVie: Honoraria; NovoCure: Honoraria; CSL Behring: Honoraria; Nippon-Kayaku: Honoraria; Pfizer: Research Funding; Takeda: Research Funding; CLS: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Meiji Seika: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Merck: Honoraria, Research Funding; TanabeMitsubishi: Research Funding; Zeiss: Research Funding; Brainlab: Honoraria, Research Funding; Nihon Medi-Physics: Research Funding; Sanofi: Research Funding; Philips: Research Funding; Siemens: Research Funding; Ono: Research Funding. Yonezawa:Ono: Research Funding. Asai:Ono: Research Funding. Fukuhara:Mundi: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Nippon Shinkyaku: Honoraria; Kyowa-Hakko Kirin: Honoraria; Mochida: Honoraria; Bayer: Research Funding; Gilead: Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Eisai: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Janssen Pharma: Honoraria; Zenyaku: Honoraria; AbbVie: Research Funding; Solasia Pharma: Research Funding. Sugiyama:Ono: Research Funding; Taiho: Research Funding; Daiichi-Sankyo: Research Funding; Bristol-Myers-Squibb: Research Funding; Chugai: Research Funding; Meiji Seika: Research Funding; Yakult: Research Funding. Shinojima:Ono: Research Funding. Kitagawa:Ono: Employment. Aoi:Ono: Employment. Nishikawa:Ono: Honoraria, Research Funding; MSD: Research Funding; AbbVie: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; NovoCure: Honoraria; Daiichi-Sankyo: Honoraria. OffLabel Disclosure: Tirabrutinib. Clinical trial for PCNSL.

Abstract Background: Based on the results of a phase I/II study in Japan (Trial registration: JapicCTI-173646), tirabrutinib (TIR), a second-generation inhibitor of Bruton's tyrosine kinase, was approved in March 2020 for the treatment of relapsed or refractory primary central nervous system lymphoma (r/r PCNSL). We have previously reported overall response rate of 63.6% and manageable safety profile results of this study (Narita et al. Neuro Oncol. 2021;23(1):122-133). Further, one-year follow-up data after the last patient had enrolled showed that the effects of TIR persisted in r/r PCNSL patients (Mishima et al. Poster presented at the Society for Neuro-Oncology virtual conference; November 19-21, 2020). Here, based on this one-year follow-up data, we describe the Quality of Life (QoL) and Karnofsky Performance Status (KPS) in r/r PCNSL patients treated with TIR. Methods: Patients with r/r PCNSL, age ≥20 years, and KPS ≥70 were treated with TIR once daily (QD) at a dose of 320 mg, 480 mg, or 480 mg upon fasting (480 mg fasted QD). TIR was administered in 28-day cycles, and treatment was continued until disease progression or clinically unacceptable toxicity was observed. QoL was assessed using questionnaires issued by the European Organization for Research and Treatment of Cancer (EORTC), namely QLQ-C30 (EORTC QLQ-C30), EORTC QLQ-BN20, and EuroQol 5 dimensions 3-level (EQ-5D-3L). The QoL survey was conducted during the screening period, on Day 28 of Cycle 1, after every 2 cycles (i.e., after Day 1 of Cycle 3), after every 4 cycles (i.e., after Day 1 of Cycle 25), and at the end of treatment. KPS was measured during the screening period, on days 1, 8, 15, and 28 of Cycle 1, on day 1 of every cycle after Cycle 3, and at the end of treatment. Results: Forty-four patients were prospectively enrolled, and 20, 7, and 17 patients were treated with TIR at 320 mg QD, 480 mg QD, and 480 mg fasted QD, respectively. Median patient age was 60 years (range 29-86). Median follow-up period was 14.9 months (range, 1.4-27.7) for the entire cohort but was 19.1 months, 23.5 months, and 12.0 months for the 320 mg QD, 480 mg QD, and 480 mg fasted QD groups, respectively. At the time of data cutoff (February 25, 2020), 11 patients (25%) remained on treatment. Mean (SD) score for the global health status/QoL section of the EORTC QLQ-C30 was 50.9 (23.7) at baseline and remained relatively constant during treatment (Figure 1). This trend was also observed for emotional function, cognitive function, and fatigue sections of the EORTC QLQ-C30, for motor dysfunction, communication deficit, weakness of legs, and bladder control sections of the EORTC QLQ-BN20, and in items pertaining to self-care, usual activities, and anxiety/depression in the EQ-5D-3L. Median KPS was 80.0 (range, 70-100) at baseline, which remained unchanged during TIR treatment (Figure 2). Conclusion: QoL and KPS scores in r/r PCNSL patients were maintained during TIR administration, a new treatment option for r/r PCNSL, which does not lead to the deterioration of QoL and KPS. Figure 1 Figure 1. Disclosures Terui: Ono Pharmaceutical: Speakers Bureau; MSD: Speakers Bureau; Janssen: Speakers Bureau; Esai: Speakers Bureau; Chugai Pharmaceutical: Speakers Bureau; Celgene: Speakers Bureau; AbbVie: Speakers Bureau; Takeda Pharmaceutical: Speakers Bureau. Narita: Ono Pharmaceutical co.: Honoraria, Research Funding; Dainippon-Sumitomo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Honoraria, Research Funding; Stella-pharma: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Bayer: Research Funding; Ohara: Research Funding; Chugai Pharmaceutical co.: Honoraria; Novocure: Honoraria. Nagane: AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Honoraria, Research Funding; Pfizer: Research Funding; MSD: Research Funding; Astellas: Research Funding; Nippon-Kayaku: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; Shionogi: Research Funding; Otsuka: Research Funding; Ono Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novocure: Honoraria; Sumitomo Dainippon Pharma: Honoraria; RIEMSER: Membership on an entity's Board of Directors or advisory committees. Mishima: Ono Pharmaceutical Co: Research Funding; Astellas: Research Funding; HOYA Technosurgical Co.: Research Funding; Daiichi-Sankyo: Research Funding; AbbVie: Research Funding; Medical U and A: Research Funding; Teijin Pharma: Research Funding; Eisai: Research Funding; MSD: Research Funding; Chugai: Research Funding. Arakawa: Sanofi: Research Funding; Carl Zeiss: Honoraria, Research Funding; Brainlab: Honoraria, Research Funding; Nihon Medi-Physics: Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Philips: Research Funding; Siemens: Research Funding; Tanabe Mitsubishi: Research Funding; Chugai: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Meiji Seika: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Stryker: Research Funding; Astellas Pharma: Research Funding; Taiho Pharma: Research Funding; Nippon Kayaku: Honoraria; Novocure: Honoraria; UCB Japan: Honoraria; Integra Japan: Honoraria; Otsuka: Honoraria; Abbvie: Honoraria. Yonezawa: Eisai: Speakers Bureau; Ono Pharmaceutical co.: Speakers Bureau; Chugai Pharmaceutical co.: Speakers Bureau. Fukuhara: Celgene: Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Eisai: Honoraria; HUYA Bioscience International: Honoraria; Incyte: Research Funding; Janssen: Honoraria; Kyowa Kirin: Honoraria; Nippon Shinyaku: Honoraria; Novartis: Honoraria; Ono Pharmaceutical: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria; Zenyaku Kogyo: Honoraria; Bayer: Research Funding; AbbVie: Honoraria. Sugiyama: Daichi Sankyo Inc.: Consultancy; Ono Pharmaceutical Inc: Honoraria. Aoi: Ono Pharma USA, Inc.: Current Employment. Nishikawa: Novocure: Consultancy; Chugai: Honoraria, Research Funding; MSD: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Ono: Honoraria; Nihon-Kayaku: Honoraria. OffLabel Disclosure: Tirabrutinib. Clinical trial for PCNSL.

Abstract <Introduction> Hepatitis B virus (HBV) surface antigen (HBsAg)-positive patients treated with anti-B-cell lymphoma therapy are at high risk of HBV reactivation; indeed, the incidence is as high as 60-80% without antiviral prophylaxis. Hepatitis caused by HBV reactivation usually leads to discontinuation of chemotherapy, which in itself may be fatal. Therefore, several guidelines recommend antiviral prophylaxis for HBsAg-positive patients treated with chemotherapy. However, there is limited evidence regarding the clinical impact of antiviral prophylaxis on HBV reactivation and subsequent hepatitis and long-term outcome, particularly in patients treated with rituximab (R)-containing regimens. To answer these questions, we conducted a nationwide multicenter retrospective analysis for HBsAg-positive patients with diffuse large B-cell lymphoma (DLBCL) treated with R-chemotherapy. <Methods> Data were collected from HBsAg-positive patients with DLBCL who received R-CHOP or R-THP-COP regimens as an initial chemotherapy (regardless of steroid use) at 29 participating institutions between January 2004 and December 2014. Key exclusion criteria were as follows: seropositive for HCV or HIV; alanine transaminase (ALT) levels ≥ 100 U/L at the time of diagnosis; and a history of decompensated cirrhosis or hepatocellular carcinoma. Medical data were also obtained for HBsAg-negative DLBCL patients (controls), regardless of anti-HBc or anti-HBs seropositivity; these patients were diagnosed within 2 month (before and after 1 month) of the diagnosis date of each HBsAg-positive patient. Hepatitis was defined as an absolute serum ALT level of ≥ 100 U/L. HBV reactivation-related hepatitis was defined as hepatitis accompanied by an absolute serum HBV DNA level of ≥ 3.3 Log IU/mL or an absolute increase of ≥ 2 Log compared with the baseline value. Statistical analysis was performed at the Japanese Data Center for Hematopoietic Cell Transplantation using Stata software Version 13.1 and EZR 1.35. The study was registered at UMIN (ID: 000025574). <Results> A total of 394 patients were eligible: 116 (29.4%) were HBsAg-positive and 278 (70.6%) were HBsAg-negative. The baseline characteristics of the two cohorts were similar; exceptions was HBV status (Table). R-CHOP was the most common regimen (n=337, 85.5%), followed by R-THP-COP (n=57, 14.5%). For HBsAg-positive patients with detectable and quantifiable HBV DNA (n=65, 56.0%), the median baseline HBV DNA level was 2.9 Log IU/mL (interquartile range, 2.0-3.7). HBsAg-positive patients were divided into three groups based on prophylactic nucleoside analogue (NA) therapy: no prophylactic therapy (non-NA, n=9), prophylactic therapy with lamivudine (LAM, n=20), and prophylactic therapy with entecavir (ETV, n=87). Of the HBsAg-negative patients, 64 (23.0%) were seropositive for anti-HBc or anti-HBs. The median follow-up time for HBsAg-positive and HBsAg-negative patients was 4.3 years and 4.5 years, respectively. The 4-year cumulative incidence of hepatitis in HBsAg-positive and HBsAg-negative patients was 21.1% (95% confidence interval (CI): 14.1-28.9%) and 14.6% (95% CI: 10.7-19.2%), respectively (p=0.081). Importantly, the 4-year cumulative incidence of HBV reactivation-related hepatitis was higher in HBsAg-positive patients than in HBsAg-negative patients (8.0% (95% CI: 3.9-14.0%) vs. 0.4% (95% CI: 0.0-2.0%, respectively; p<0.001; Figure, panel A). Among HBsAg-positive patients, the 4-year cumulative incidence of HBV reactivation-related hepatitis was highest in the non-NA group (33.3%, 95% CI: 7.8-62.3%), followed by the LAM (15.0%, 95% CI: 3.7-33.5%) and ETV (3.8%, 95% CI: 1.0-9.8%) groups (p<0.001) (Figure, panel B). Remarkably, the 4-year cumulative incidence of HBV reactivation-related fulminant hepatitis was 11.1% in the non-NA group; this was higher than in the LAM (5.0%) and ETV (0.0%) groups (p=0.025). Finally, three non-NA patients (33%) and one LAM patient (5%) (but no ETV patient) died due to HBV reactivation-related hepatitis. <Conclusions> Prophylactic use of entecavir reduced the incidence of HBV reactivation-related hepatitis and reduced mortality associated with HBV reactivation-related hepatitis in HBsAg-positive patients with DLBCL treated with R-chemotherapy. Disclosures Maruyama: Abbvie: Research Funding; Nippon Boehringer Ingelheim: Research Funding; Pfizer: Research Funding; Amgen Astellas BioPharma: Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Fujifilm: Honoraria, Research Funding; MSD: Honoraria, Research Funding; Novartis: Research Funding; GlaxoSmithKline: Research Funding; Chugai Pharma: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Biomedis International: Honoraria, Research Funding; Solasia Pharma: Research Funding; AstraZeneca: Research Funding; Asahi Kasei Pharma: Honoraria; Dai-Nippon-Sumitomo: Honoraria; Zenyaku Kogyo: Honoraria, Research Funding; Mundipharma International: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Astellas Pharma: Research Funding; Otsuka: Research Funding; Dai-ichi-Sankyo: Honoraria. Yamamoto:Bristol-Myers Squibb: Honoraria. Igarashi:Eisai Co Ltd.: Research Funding; Celltrion Inc.: Research Funding; Zenyaku-Kogyo Co.Ltd.: Research Funding; Sanofi K.K.: Research Funding. Izutsu:Takeda: Honoraria, Research Funding; Zenyaku: Research Funding; Amgen: Research Funding; Gilead Sciences: Honoraria; Solasia: Research Funding; Sanofi: Research Funding; Otsuka: Honoraria; Mundhi: Honoraria; Kyowa Hakko Kirin: Honoraria; Abbvie: Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Symbio: Research Funding; Celltrion: Research Funding; Chugai: Honoraria, Research Funding; Nihon Medi-Physics: Honoraria; MSD: Honoraria; Celgene: Consultancy, Research Funding; Bristol- Myers Squibb: Honoraria; Daiichi Sankyo: Honoraria, Research Funding; Astellas: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; HUYA Bioscience International: Research Funding; Eisai: Honoraria, Research Funding; Novartis: Honoraria; Ono: Honoraria, Research Funding; Meiji Seika: Honoraria; Shionogi: Honoraria; Asahi Kasei: Honoraria. Uchida:Nippon Shinyaku: Honoraria; Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Meiji Seika Pharma: Honoraria; Mundipharma: Honoraria; Celgene: Honoraria; Teijin: Honoraria; Novartis: Honoraria; Janssen Pharma: Honoraria; Takeda Pharmaceutical: Honoraria; Otsuka Pharmaceutical: Honoraria; Eisai: Honoraria; Kyowa Hakko Kirin: Honoraria; Chugai Pharmaceutical: Honoraria. Tsukamoto:Chugai: Research Funding; Eisai: Research Funding; Pfizer: Research Funding; Kyowa-Kirin: Research Funding. Nosaka:Celgene Co. LTD.,: Honoraria; Chugai Pharmaceutical Co.LTD.,: Honoraria; Kyowa Kirin Pharmaceutical Development, Inc.,: Honoraria; Eisai Co. Ltd.,: Honoraria; Ono Pharmaceutical Co.LTD.: Honoraria; Bristol-Myers Squibb: Honoraria. Ueda:Rikaken Co. Ltd.: Research Funding; Medical and Biological laboratories Co. Ltd.: Research Funding; Chugai Pharmaceutical Co. Ltd.: Research Funding; Kyowa Hakko Kirin Co. Ltd.: Honoraria, Research Funding; Terumo Co.: Consultancy; Ono Pharmaceutical Co.: Consultancy, Honoraria, Research Funding; Mundipharma K.K.: Consultancy. Mizokami:Sysmex Corporation: Honoraria; Gilead Sciences: Honoraria. Kusumoto:Bristol-Myers Squibb: Honoraria, Research Funding; Chugai Pharmaceutical Co. Ltd: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding.

Abstract Background: CHOP plus rituximab (R-CHOP) is the standard of care for previously untreated DLBCL. R-CHOP comprises CHOP and one-dose rituximab in each 21-day cycle; however, the schedule of rituximab administration has not been fully optimized. Dose-dense rituximab was expected to increase its peak concentration to enhance the synergistic effect with chemotherapy at early phase of treatment. To compare weekly administration of rituximab combined with CHOP (RW-CHOP) with standard R-CHOP in patients with previously untreated DLBCL, we conducted a multicenter, randomized phase II/III study (JCOG0601, UMIN000000929). Methods: Previously untreated patients with CD20+ DLBCL were eligible. Other major inclusion criteria were as follows: aged 20-79 years; ECOG performance status 0-2, at least 1 measurable lesion and preserved organ functions. At the beginning of the study, patients with advanced stage disease and the low or low-intermediate risk group by the International Prognostic Index (IPI) were eligible. These criteria were amended in September 2010 to allow enrollment of the patients with any IPI risk and any clinical stage because of slow accrual. Patients were randomly assigned to standard R-CHOP (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 [max 2 mg], all IV on day 1, and prednisone 100 mg/day PO [40mg/m2 for aged >65] on days 1-5, every 3 weeks) or RW-CHOP (standard CHOP with eight doses of weekly rituximab [375mg/m2 IV on days1, 8, 15, 22, 29, 36, 43 and 50]). Six cycles of CHOP were given in stage I non-bulky patients, 8 cycles were given in stage I bulky and II-IV patients, and rituximab was given 8 times regardless of cycles of CHOP. Randomization was stratified by institution, presence or absence of bulky mass and patient age. The primary endpoint of phase III part was progression-free survival (PFS). Secondary endpoints included overall survival (OS) and adverse events (AE). Assuming 3-year PFS in the R-CHOP arm to be 77% and expecting a 7% increase in 3-year PFS of the RW-CHOP arm, required sample size was 211 per arm with a one-sided alpha of 5%, power of 80%, an accrual period of 7 years, and a follow-up period of 3 years. Results: Between December 2007 and December 2014, a total of 422 patients were randomized to study treatments but primary analysis was performed in 421 patients: 213 to the R-CHOP arm and 208 to the RW-CHOP arm, because of one consent withdrawal. Baseline characteristics of 421 eligible patients were as follows (R-CHOP vs. RW-CHOP): median age, 61 vs. 62 years; male sex, 54.5% vs. 55.8%; Ann Arbor stage I/II/III/IV, 14.6/32.9/26.8/25.8% vs. 16.3/42.8/20.2/20.7%; and IPI score ≤2, 77.0% vs. 87.5%. With a median follow-up of 63.4 months (range: 3.2-119.2) among all patients, there was no significant difference in PFS between the arms (hazard ratio [HR], 0.95; 90.6% confidence interval [CI], 0.68 to 1.31; one-sided log-rank P = 0.39). The 3-year PFS and OS were 79.2% and 88.7% with the R-CHOP arm and 80.3% and 90.4% with the RW-CHOP arm, respectively. The complete response rate and overall response rate were 77.0% and 93.0% in the R-CHOP arm and 82.2% and 91.8% in the RW-CHOP arm, respectively. Major AEs were hematological toxicities and infections. Grade (G) 3/4 neutropenia and G 3/4 thrombocytopenia were observed in 97.7% and 8.0% in the R-CHOP arm and 97.1% and 5.3% in the RW-CHOP arm, respectively. G3 febrile neutropenia was occurred in 33.8% in the R-CHOP arm and in 22.1% in the RW-CHOP arm. The frequency of severe AE was 2.3% in the R-CHOP arm and 3.8% in the RW-CHOP arm. Safety profile was comparable. No unexpected AEs were experienced. Conclusion: In combination of standard CHOP and rituximab, dose-dense weekly rituximab at early phase of treatment did not improve the PFS in patients with untreated DLBCL. Figure. Figure. Disclosures Ohmachi: Celgene: Honoraria; Takeda Pharmaceutical Co., Ltd,: Honoraria; Pfizer: Honoraria; Chugai Pharma: Honoraria; Kyowa Hakko Kirin: Honoraria; Eisai: Honoraria; Janssen: Honoraria; Meiji Pharma: Honoraria. Kinoshita:Takeda: Honoraria; Takeda: Research Funding; Ono: Research Funding; MSD: Research Funding; Solasia: Research Funding; Janssen: Honoraria; Ono: Honoraria; Zenyaku: Research Funding; Eisai: Research Funding; Gilead: Research Funding. Tobinai:Kyowa Hakko Kirin: Honoraria, Research Funding; Zenyaku Kogyo: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Chugai Pharma: Honoraria, Research Funding; HUYA Bioscience International: Consultancy, Honoraria; SERVIER: Research Funding; Abbvie: Research Funding. Fukuhara:Sumitomo Dainippon: Research Funding; Solasia: Research Funding; Symbio: Research Funding; Sanofi: Research Funding; Pfizer: Research Funding; Otsuka Pharmaceutical: Research Funding; Ono: Honoraria, Research Funding; Novartis pharma: Research Funding; Nippon-shinyaku: Research Funding; MSD: Research Funding; Mundipharma: Honoraria, Research Funding; Mitsubishi Tanabe: Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Japan Blood Products Organization: Research Funding; Janssen: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Eisai: Honoraria, Research Funding; Boehringer Ingelheim: Research Funding; Daiichi-Sankyo: Research Funding; Chugai: Research Funding; Celgene: Research Funding; Baxalta: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Bayer Yakuhin: Research Funding; Alexionpharma: Research Funding; AbbVie: Research Funding; Astellas: Research Funding; Nihon Ultmarc: Research Funding; Taiho: Research Funding; Teijin Pharma: Research Funding; Zenyaku Kogyo: Honoraria, Research Funding; Takeda: Honoraria. Uchida:Takeda Pharmaceutical: Honoraria; Chugai Pharmaceutical: Honoraria; Kyowa Hakko Kirin: Honoraria; Meiji Seika Pharma: Honoraria; Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Nippon Shinyaku: Honoraria; Novartis: Honoraria; Teijin: Honoraria; Celgene: Honoraria; Mundipharma: Honoraria; Janssen Pharma: Honoraria; Otsuka Pharmaceutical: Honoraria; Eisai: Honoraria. Yamamoto:Solasia Pharma: Research Funding; Bristol-Myers Squibb: Honoraria; Novartis: Honoraria, Research Funding; ARIAD Pharmaceuticals: Research Funding; Bayer: Research Funding; Celgene: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; AbbVie: Research Funding; Boehringer Ingelheim: Consultancy; Chugai: Consultancy, Honoraria, Research Funding; Meiji Seika Pharma: Consultancy; MSD: Research Funding; Takeda: Honoraria, Research Funding; Zenyaku: Research Funding; Kyowa Hakko Kirin: Honoraria; Otsuka: Honoraria; Pfizer: Honoraria; Sumitomo Dainippon: Honoraria; Mundipharma: Consultancy, Honoraria; HUYA: Honoraria; SymBio: Research Funding; Gilead Sciences: Research Funding. Miyazaki:Kyowa Hakko Kirin,: Honoraria, Research Funding; Celgene: Honoraria; Chugai Pharma,: Honoraria, Research Funding; Sumitomo Group: Research Funding; Nippon Shinyaku: Research Funding; Takeda: Research Funding; Astellas Pharma: Research Funding; Shionogi Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Eisai: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Teijin Pharma: Research Funding; Ono Pharmaceutical: Research Funding; Toyama Chemical Co: Research Funding; Mochida Pharmaceutical Co. Ltd.: Research Funding; Novo Nordisk: Research Funding. Tsukamoto:Kyowa-Kirin: Research Funding; Pfizer: Research Funding; Chugai: Research Funding; Eisai: Research Funding. Iida:Teijin Pharma: Research Funding; Toyama Chemical: Research Funding; Ono: Consultancy, Honoraria, Research Funding; Kyowa-Hakko Kirin: Research Funding; Chugai: Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Astellas: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Gilead: Research Funding; MSD: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Sanofi: Consultancy. Yoshida:Taiho Pharma: Honoraria; Takeda Pharma: Honoraria; Celegene: Honoraria; Chugai Pharma: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding. Masaki:Ono: Research Funding; Kyowa Hakko Kirin: Research Funding; Phizer: Research Funding; Astellas: Research Funding; Eisai: Research Funding. Yakushijin:Mundipharma Co.,: Research Funding; Chugai Co.,: Research Funding; Kyowa-kirin Co.,: Research Funding; Merch Sharp & Dohme Corp.,,: Research Funding; Daiichi-Sankyo Inc.,: Research Funding; Eisai Co.: Research Funding. Suehiro:Kyowa Hakko Kirin: Research Funding; Ono Pharmaceutical: Research Funding; Chugai Pharmaceutical: Research Funding; Takeda Pharmaceutical: Research Funding. Nosaka:Bristol-Myers Squibb: Honoraria; Ono Pharmaceutical Co.LTD.: Honoraria; Eisai Co. Ltd.,: Honoraria; Kyowa Kirin Pharmaceutical Development, Inc.,: Honoraria; Chugai Pharmaceutical Co.LTD.,: Honoraria; Celgene Co. LTD.,: Honoraria. Dobashi:Celgene Co.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co. Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Pfizer Inc.: Research Funding; Sysmex Co.: Research Funding. Kuroda:Chugai Pharma: Honoraria, Research Funding. Takamatsu:Taisho Toyama Pharmaceutical: Research Funding; TAIHO Pharmaceutical: Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Research Funding; Ono Pharmaceutical: Research Funding; Astellas Pharma: Research Funding; Kyowa Hakko Kirin: Research Funding; Chugai Pharma: Research Funding; Takeda Pharmaceutical: Research Funding; Celgene: Honoraria. Maruyama:Ono Pharmaceutical: Honoraria, Research Funding; Fujifilm: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Asahi Kasei Pharma: Honoraria; AstraZeneca: Research Funding; Solasia Pharma: Research Funding; Pfizer: Research Funding; Nippon Boehringer Ingelheim: Research Funding; Dai-Nippon-Sumitomo: Honoraria; Dai-ichi-Sankyo: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Biomedis International: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Chugai Pharma: Honoraria, Research Funding; MSD: Honoraria, Research Funding; Novartis: Research Funding; Otsuka: Research Funding; Amgen Astellas BioPharma: Research Funding; Zenyaku Kogyo: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Abbvie: Research Funding; Astellas Pharma: Research Funding; Mundipharma International: Honoraria, Research Funding. Ando:Eisai: Research Funding; Meiji Seika Pharma: Research Funding; Takeda Pharmaceutical: Research Funding; Kyowa Hakko Kirin: Research Funding; Japan Blood Products Organization: Research Funding. Ishizawa:Eisai: Honoraria; Janssen: Honoraria; Chugai: Honoraria; Celgene: Honoraria; Otsuka: Research Funding; Sanofi: Research Funding; Phizer: Research Funding. Ogura:Celltrion: Consultancy, Research Funding; Mundi Pharma: Consultancy; SymBio: Research Funding; Takeda: Honoraria; Cellgene: Honoraria; MeijiSeika Pharma: Consultancy. Hotta:SymBio: Consultancy; CellSeed Inc.: Membership on an entity's Board of Directors or advisory committees. Tsukasaki:Celgene: Honoraria; Eisai: Research Funding; Chugai Pharma: Honoraria, Research Funding; HUYA: Consultancy, Research Funding; Ono Pharma: Consultancy; Daiich-Sankyo: Consultancy; Mundy Pharma: Honoraria; Kyowa-hakko/Kirin: Honoraria; Seattle Genetics: Research Funding. Nagai:HUYA Bioscience International: Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Ono Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Gilead Sciences Inc.: Honoraria, Research Funding; Bayer Yakuhin Ltd.: Research Funding; Sanofi K. K.: Honoraria; Zenyaku Kogyo Co., Ltd.: Honoraria, Research Funding; Solasia Pharma K.K.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Roche Ltd.: Honoraria; Esai Co., Ltd.: Honoraria, Research Funding; Takeda Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; SymBio Pharmaceuticals Limited: Research Funding; Janssen Pharmaceutical K.K.: Honoraria, Research Funding; Kyowa Hakko Kirin Co., Ltd.: Honoraria, Research Funding; Mundipharma K.K.: Honoraria, Research Funding; AstraZeneca plc.: Research Funding; Abbvie G. K.: Research Funding.

Introduction Aggressive natural killer cell leukemia (ANKL) is a rare leukemic form of mature natural killer cell neoplasms that is closely associated with Epstein-Barr virus. ANKL presents a fulminant clinical course, resulting in a poor prognosis with a median overall survival of approximately 2 months. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently the only curative treatment, but the long-term outcomes after allo-HSCT remain unclear. Methods Using the national Japanese transplant registry database, the outcomes of 59 ANKL patients who underwent first allo-HSCT between 1997 and 2016 were analyzed. Correlation between groups was examined by the c2 test, Mann-Whitney U test, and Kruskal-Wallis test. Patient survival data were analyzed using the Kaplan-Meier method and compared by the log-lank test. The cumulative incidence of relapse and non-relapse mortality were calculated considering competing risks. Results The median patient age was 37 years (range, 9 to 66), and males accounted for 68%. The median time from diagnosis to allo-HSCT was 3.7 months (range, 1.1 to 13.9). Twenty-nine patients received stem cells from cord blood (CB), 18 received them from peripheral blood (PB), and 12 received them from bone marrow (BM). Two patients had a prior history of autologous HSCT. Twenty-one patients (36%) had a complete response (CR) and 7 (12%) had a partial response (PR), but 31 (52%) were not responding at the time of allo-HSCT. Forty-four patients received myeloablative conditioning and 15 received non-myeloablative conditioning. Thirty-two patients received tacrolimus-based GVHD prophylaxis, including 1 with additional post-transplant cyclophosphamide as part of haploidentical HSCT, whereas 26 received cyclosporin-based GVHD prophylaxis. The median follow-up of survivors was 62 months (range, 0.9 to 193). The median OS and relapse-free survival were 3.9 months and 2.6 months, respectively. The probability of OS and relapse-free survival, and cumulative incidence of relapse and non-relapse mortality 1 year after HSCT were 33.9%, 32.4%, 55.5%, and 12.1%, respectively. The probability of OS was significantly higher for patients with CR or PR at allo-HSCT than for those without a response (40.6% vs 16.1% at 5 years; P = 0.046). Among the 24 patients with primary induction failure (PIF) at allo-HSCT, 15 achieved CR after allo-HSCT. The prognosis of these 15 patients was almost equivalent to that of those who received allo-HSCT in CR or PR, as shown in the Figure (P = 0.95). Regarding the stem cell source, the probability of OS was significantly higher for patients who received stem cells from CB than for those who received them from PB or BM (CB 37.3% vs PB 15.8% and BM 16.7% at 5 years; P = 0.04). Seventeen patients (59%) of those who received stem cells from CB were CR at HSCT, whereas only 4 patients (13%) of those who received stem cells from PB or BM were CR at HSCT. In addition, 5 (83%) of 6 patients who received stem CB transplantation in PIF achieved CR after allo-SCT, whereas 10 (56%) of 18 patients who received PB stem cell transplantation or BM transplantation in PIF achieved CR. The age and year at HSCT were not different between the groups. The time from diagnosis to allo-HSCT did not differ among stem cell sources (median CB 3.3 months, PB 3.7 months and BM 4.1 months; P = 0.31). Regarding the conditioning regimen, the probability of OS was not different between myeloablative and non-myeloablative conditioning regimens (P = 0.58). Patients who developed acute GVHD grade 1/2 had a significantly better prognosis than those with grade 3/4 or without GVHD (P < 0.001). In contrast, chronic GVHD development did not affect the prognosis (P = 0.60). At the last follow-up, 42 patients (71%) had died. The most common cause of death was primary disease (62%), followed by infection (14%) and organ dysfunction (7%). Conclusion Allo-HSCT can lead to long-term survival even for patients with PIF at HSCT. CB is useful as a stem cell source, providing good outcomes and timely allo-HSCT for this rapidly progressive disease. To confirm our findings and evaluate the outcome of allo-SCT in more detail, further studies including patients who did not receive allo-SCT for ANKL are warranted. Figure Disclosures Ishida: Bristol-Meyers Squibb: Research Funding; Pfizer: Research Funding; Astellas Pharma: Research Funding; Eli Lily and Company: Research Funding; Celgene: Honoraria; Chugai Pharmaceutical: Consultancy, Research Funding. Izutsu:Celgene: Consultancy, Research Funding; Chugai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Astra Zeneca: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Symbio: Research Funding; Ono: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; Solasia: Research Funding; Zenyaku: Research Funding; Incyte: Research Funding; Novartis: Honoraria, Research Funding; Sanofi: Research Funding; HUYA Bioscience: Honoraria, Research Funding; MSD: Honoraria, Research Funding; Astellas Amgen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; ARIAD: Research Funding; Takeda: Honoraria, Research Funding; Pfizer: Research Funding; Kyowa Kirin: Honoraria; Nihon Medi-physics: Honoraria; Janssen: Honoraria; Dainihon Sumitomo: Honoraria; Bristol-Byers Squibb: Honoraria; Mundi: Honoraria; Otsuka: Honoraria; Asahi Kasei: Honoraria. Suzumiya:Celgene, Kyowa Kirin, Chugai-Roche, Eisai, Takeda, Celltrion, SymBio, Astellas, Ono, AstraZeneca, Ootsuka, Taiho, Mundi, Dainihon-Sumitomo: Research Funding. Mitsui:MSD pharmaceutical: Research Funding; Maruho pharmaceutical: Research Funding; JCR pharmaceutical: Research Funding; Teijin pharmaceutical: Research Funding; Chugai pharmaceutical: Research Funding; Daiichi Sankyo pharmaceutical: Research Funding; Astellas pharmaceutica: Research Funding; Shionogi pharmaceutical: Research Funding. Kanda:Kyowa Hakko Kirin: Honoraria; Otsuka: Honoraria; Daiichi Sankyo Company: Honoraria; MSD: Honoraria; Chugai: Honoraria; Bristol-Meyers Squib: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Astellas: Honoraria; JCR Pharmaceuticals: Honoraria; Takeda: Honoraria; NextGeM Incorporation: Patents & Royalties: 2019-011392. Atsuta:CHUGAI PHARMACEUTICAL CO., LTD.: Honoraria; Kyowa Kirin Co., Ltd: Honoraria. Suzuki:Celgene: Honoraria; Novartis: Honoraria; AbbVie: Honoraria; Kyowa Hakko Kirin: Honoraria; Chugai Pharmaceutical Co.,Ltd.: Honoraria; Meiji Seika: Honoraria; Bristol-Myers Squibb: Honoraria; Merck Sharp & Dohme: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria; Eisai: Honoraria; ONO Pharmaceutical Co., Ltd.: Honoraria; Janssen: Honoraria.