Articles de revues 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.

Abstract Introduction: Tyrosine kinase inhibitor (TKI) has dramatically improved the prognosis of chronic myeloid leukemia (CML) patients. Recently, many trials of TKI discontinuation revealed that approximately 40% to 60% of CML patients who received long time TKI therapy reached the treatment-free remission (TFR), thus now TFR is proposed as one of the goals in CML treatment. Achieving deep molecular response (DMR) by TKI therapy is a minimum requirement of a challenge to TKI discontinuation in CML patient, actually CML patients with molecular residual disease (MRD) showed worse consequence than undetectable MRD (IJH, 2017). On the other hand, it has been known that some patients sustain a molecular response for a long time despite BCR-ABL fusion gene positivity in their peripheral blood. We hypothesized that the residual malignant cells were eliminated by host immune systems in the patients with continuous TFR. Practically, we obtained the data that the immune responses of the patients with continuous TFR were more activated than relapsed patients in the discontinuation trial of imatinib (ASH, 2019). Here, we reported immune effects before and after TFR phase in two Japanese discontinuation trials of second-generation TKIs (JALSG N-STOP216 and D-STOP216). Methods: Japanese patients with CML-CP treated with nilotinib or dasatinib as the first line for at least three years and confirmed in DMR for at least two years were eligible. Patients who received other TKI or stem cell transplantations were excluded. Patients were re-confirmed in MR4.5 before discontinuing TKI and they were sampled peripheral blood at pre- and 1, 3 months after stopping TKIs and after retreatment (figure 1). Peripheral blood mononuclear cells (PBMCs) were subjected to staining with immune markers and analyzed by flow cytometry. Results: 51 patients treated with nilotinib and 49 patients treated with dasatinib were assessed clinical outcomes. At 12 months, 39/51 patients (76.5%) and 27/49 patients (55.1%) remained TFR in N-STOP216 and D-STOP216 respectively (EHA, 2021). For immunological analysis, 48 patients and 43 patients were analyzed by flowcytometry. We classified the patient of each trial into two groups (TFR group and Retreatment (RET) group) (figure 1). The frequency of CD4 + T cells and CD8 + T cells in CD3 + T cells was not different between both groups in each trial. The frequency of FoxP3 +CD4 + regulatory T (Treg) cells were not different between both groups in each trial. However, the kinetics of Treg cells, especially effector Treg (eTreg; FoxP3 hiCD45RA -) cells from Pre-stopping dasatinib to 1 month after stopping dasatinib, significantly increased in TFR groups but not in RET group (figure 2). This difference in kinetics of eTreg cells was not observed in nilotinib discontinuation trial (figure 2). In N-STOP216 trial, there were no differences between TFR and RET groups in the immuno-phenotype of CD8 + T cells, NK cells, or B cells, while granulocytic myeloid-derived suppressor cells (G-MDSCs) increased at 1 month after stopping nilotinib in RET group (0.27% in RET group vs. 0.08% in TFR group, P=0.011) (figure 3). On the other hand, in D-STOP216, CD8 + T cells from the patients with continuous TFR showed less exhausted phenotype (PD-1 +CD8 +T cells 37.4% in RET group vs. 49.8% in TFR group, p=0.018) and more proliferative activity (Ki67+CD8 cells 5.03% in RET group vs. 8.91% in TFR group, p=0.043) compared with RET group at 1 month after stopping dasatinib (figure 4). There were no differences in NK cells, B cells, and MDSCs between TFR and RET groups in D-STOP216. Conclusion: We found that each TKI evoked different immune responses after stopping TKI. Nilotinib has been developed as higher specific for BCR-ABL, therefore immune cells were not affected because of its narrower off-target effect. MDSCs developed by hematopoietic stem cells with BCR-ABL were decreased by the direct effect of nilotinib in the patients with continuous TFR. Antitumor immune responses might be diminished by residual MDSCs in RET group consequently it would be a molecular relapse. On the other hand, dasatinib has different immune effects probably due to its broad-spectrum kinase inhibitory effects. T cell immune responses might be exhausted by long term exposure to dasatinib in RET group. This study showed the possibility of different mechanisms of relapse caused by distinct immune effects. Figure 1 Figure 1. Disclosures Takahashi: Kyowahakko-Kirin: Research Funding; Ono: Research Funding; Asahikasei: Research Funding; Toyamakagaku: Research Funding; Eizai: Research Funding; Chugai: Research Funding; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Atsuta: Astellas Pharma Inc.: Speakers Bureau; Mochida Pharmaceutical Co., Ltd.: Speakers Bureau; Meiji Seika Pharma Co, Ltd.: Honoraria; AbbVie GK: Speakers Bureau; Kyowa Kirin Co., Ltd: Honoraria. Minami: Bristol-Myers Squibb Company: Honoraria; Novartis Pharma KK: Honoraria; Pfizer Japan Inc.: Honoraria; Takeda: Honoraria; Astellas: Honoraria; Ono: Research Funding; CMIC: Research Funding. Iriyama: Bristol Myers Squibb: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Otsuka: Honoraria, Speakers Bureau. Kiyoi: Kyowa Kirin: Honoraria; Fijifilm: Honoraria; Eisai: Honoraria; Dainippon Sumitomo: Honoraria; Daiichi Sankyo: Honoraria; celgene: Honoraria; Astellas: Honoraria; Otsuka: Honoraria; Perseus Proteomics: Honoraria; Pfizer: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Zenyaku Kogyo: Honoraria. Miyazaki: Novartis: Honoraria; Abbvie: Honoraria; Kyowa-Kirin: Honoraria; Nippon-Shinyaku: Honoraria; Chugai: Honoraria; Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Sumitomo-Dainippon: Honoraria, Research Funding; Janssen: Honoraria; Eisai: Honoraria; Daiichi-Sankyo: Honoraria; Astellas: Honoraria; Takeda: Honoraria; Sanofi: Honoraria. Matsumura: Ono: Research Funding; Otsuka: Consultancy, Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Shionogi: Research Funding; Taiho: Research Funding; Takeda: Research Funding; Sumitomo Dainippon: Research Funding; Nihon Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding, Speakers Bureau; Japan Blood Products Organization: Research Funding; Mundipharma: Research Funding; AYUMI Pharmaceutical: Research Funding; Eli Lilly Japan: Research Funding; Novartis: Research Funding, Speakers Bureau; Nippon Shinyaku: Research Funding; MSD: Research Funding; Mitsubishi Tanabe: Research Funding; Amgen: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Janssen: Speakers Bureau; Kyowa Kirin: Research Funding; Eisai: Research Funding; Chugai: Research Funding; Astellas: Speakers Bureau; Asahi Kasei: Research Funding; Addvie: Research Funding.

Abstract Background: Sinusoidal obstruction syndrome (SOS) remains a significant, potentially lethal complication after allogeneic hematopoietic cell transplantation (allo-HCT). Although a liver biopsy is required to diagnose SOS accurately, it is not considered a mandatory evaluation due to its invasiveness. Therefore, the Seattle and Baltimore criteria with minor revisions have been widely used. However, the diagnostic accuracy of those criteria is insufficient. A noninvasive and more accurate diagnostic strategy is necessary. A number of studies have reported several candidate blood biomarkers for the diagnosis and prediction of SOS. However, which biomarkers or combination thereof are most useful for the diagnosis and prediction of SOS is unclear. We explored the best diagnostic and predictive biomarkers/combination among previously reported biomarkers for SOS using a stringent definition based on a liver biopsy. Methods: We performed this single-center prospective observational study in patients who received allo-HCT from April 2014 to February 2019. Seven biomarkers (PAI-1, P3P, ferritin, total bilirubin [T-bil], direct bilirubin [D-bil], brain natriuretic peptide [BNP], and protein C activity) were examined at pre-conditioning, at days 5 and 30, and at the onset of CTCAE grade ≥2 liver disorder after allo-HCT. We described how to diagnose definitive SOS (Fig. 1). A logistic regression (LR) model and the area under the receiver operating characteristic curves (AUC) were used to compare the seven biomarkers in the diagnosis and prediction of definitive SOS. The sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio for the SOS diagnosis and prediction were also calculated by the best cut-off values, using the Youden index. Results of statistical tests with a p &lt; 0.05 were considered significant. Results: A total of 180 patients were included. The median age was 48 (range: 16-68) years old. Forty-eight patients developed CTCAE grade ≥2 liver disorders. Of these, 10 were diagnosed with definitive SOS. The results of LR and AUC analyses of the SOS diagnosis and prediction are shown in the Table. PAI-1, P3P, ferritin, T-bil, and D-bil were found to be significant diagnostic markers for SOS. Among these, PAI-1 showed the highest AUC (0.85; 95% confidence interval [CI], 0.67-1.00). Furthermore, PAI-1, P3P, ferritin, T-bil, D-bil, and BNP were significant predictors for SOS. Among these biomarkers, P3P showed the highest AUC (0.82; 95% CI, 0.67-0.97). To perform further comparisons using multivariable models in SOS prediction, we first constructed a base model including the times of allo-HCT, disease status, and conditioning intensity. The AUC of the base model was 0.66 (95% CI, 0.48-0.84). After adding P3P to the base model, the AUC significantly improved to 0.88 (95% CI, 0.76-1.00) (p = 0.049). In the kinetics analysis of biomarkers, notably, PAI-1 and P3P increased over the peri-transplant period only in patients with definitive SOS (Fig. 2). In contrast, those values in patients with liver disorders other than SOS or without liver disorders did not show significant kinetic characteristics in the allo-HCT period. Discussion: SOS is attributed to toxic injury of the sinusoidal endothelial cells. PAI-1 is a known endothelial factor, released when the endothelial cells are damaged. This could be why PAI-1 was considered useful for the SOS diagnosis. P3P has been shown to be a sensitive biomarker for liver fibrosis. Furthermore, fibrous alterations in the hepatic remodeling process are well-known significant features for patients with SOS. Thus, liver fibrosis may pathophysiologically be a risk factor for SOS, and P3P may allow clinicians to detect SOS-high-risk patients with high accuracy, even at the time of allo-HCT when preclinical liver fibrosis can exist. Conclusion: We demonstrated that PAI-1 and P3P were the most useful biomarkers for the diagnosis and prediction of SOS, respectively. Figure 1 Figure 1. Disclosures Okamura: NIPPON SHINYAKU CO.,LTD.: Honoraria. Koh: AstraZeneca: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; MSD: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria, Research Funding; Novartis: Honoraria; NIHON PHARMACEUTICAL CO., LTD: Honoraria; Asahi Kasei Corporation:: Research Funding; IQVIA Services Japan K.K.:: Research Funding. Takakuwa: Takeda Pharmaceutical Company Limited.: Honoraria; Bristol-Myers Squibb Comapany: Honoraria; Sanofi K.K.: Honoraria; Celgene Corporation: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Novartis: Honoraria; AbbVie GK: Research Funding; Celgene Corporation: Research Funding. Nakamae: Novartis: Honoraria. Nishimoto: Otsuka Pharmaceutical Co., Ltd.: Honoraria; CSL Behring: Honoraria; Kyowa Kirin Co., Ltd: Honoraria; "Bayer Yakuhin, Ltd ": Research Funding; Janssen Pharmaceutical K.K.: Research Funding. Nakashima: Amgen Astellas BioPharma K.K.: Honoraria; Amgen Inc: Honoraria; Novartis: Honoraria, Research Funding; JCR Pharmaceuticals Co., Ltd.: Honoraria; Pfizer Japan Inc.: Honoraria; Eisai Co., Ltd: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; SymBio Pharmaceuticals Limited.: Honoraria, Research Funding; Astellas Pharma Inc.: Research Funding; Celgene Corporation: Research Funding; AbbVie GK: Research Funding. Nakamae: Astellas Pharma Inc.: Honoraria; Otsuka Pharmaceutical Co., Ltd: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria; Simon-Kucher & Partners: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria; Novartis: Honoraria, Research Funding; Pfizer Japan Inc.: Honoraria; Bristol-Myers Squibb Company: Honoraria, Research Funding; Alexion: Research Funding; PPD-SNBL K.K: Research Funding; CMIC HOLDINGS Co., Ltd: Research Funding. Hino: Novartis: Honoraria, Research Funding; NIPPON SHINYAKU CO.,LTD.: Honoraria; Japan Blood Products Organization: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Sanofi: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria, Research Funding; AstraZeneca: Honoraria; Astellas Pharma Inc.: Honoraria; MSD: Honoraria, Research Funding; CSL Behring: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria, Research Funding; Meiji Seika Pharma Co., Ltd.: Honoraria; Eisai Co., Ltd: Honoraria, Research Funding; Kyowa Kirin Co., Ltd: Honoraria, Research Funding; Pfizer Japan Inc.: Honoraria, Research Funding; Bristol-Myers Squibb Comapany: Honoraria; Janssen Pharmaceutical: Honoraria; JCR Pharmaceuticals Co., Ltd.: Research Funding; ARKRAY: Research Funding; Asahi Kasei Corporation:: Research Funding; Abbott: Research Funding; TEIJIN PHARMA LIMITED.: Research Funding; SEKISUI MEDICAL CO., LTD.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; TAIHO PHARMACEUTICAL CO., LTD.: Research Funding; DAIICHI SANKYO COMPANY, LIMITED.: Research Funding; TOSOH CORPORATION: Research Funding.

Abstract Introduction: In limited-stage diffuse large B-cell lymphoma (DLBCL), a continued risk of relapse has been reported (Stephens et al. J Clin Oncol 2016). Another report highlighted that initial limited-stage DLBCL, a favorable International Prognostic Index and extranodal involvement seemed to be risk factors for late relapse (LR; Larouche et al. J Clin Oncol 2010). However, even if a subgroup of patients (pts) with LR shows distinct clinical characteristics, the underlying biology is largely unknown. Methods: Nineteen consecutive pts who developed LR were identified among 337 pts with de novo DLBCL of Ann Arbor stage I/II who were treated with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone), with/without rituximab, between 1997 and 2012. LR was defined as the first relapse of B-cell lymphoma (BCL; including indolent BCL) occurring more than 5 years after a primary diagnosis. The 19 pts underwent clinical, pathological (cell of origin according to the Hans algorithm) and genetic analyses. Genomic DNA (gDNA) was extracted from formalin-fixed, paraffin-embedded sections of tumor specimens at primary diagnosis and relapse, and from bone marrow (BM) specimens without tumor invasion as controls. Genomic DNA samples from paired primary and relapsed tumors were analyzed using BIOMED-2 multiplex PCR for immunoglobulin heavy chain (IGH) rearrangements (Invivoscribe Technologies, San Diego, CA, USA) to determine whether the paired tumors shared the same clonal IGH rearrangements. Target sequencing of 2709 regions across 69 lymphoma-related genes was performed on gDNA samples. Mutational calls were made in comparisons with individual control BM gDNA samples according to the criteria outlined in Table 1. All functional mutations detected in paired tumors per pt were compared, and shared and non-shared mutations were identified. Results: Baseline characteristics of the 19 pts were as follows: median age of 60 years (range, 32-77); 13 (68%) had stage I disease, and 11 (58%) had extranodal disease. At primary diagnosis, 14 of 19 pts (74%) had a non-germinal center B-cell-like (non-GCB) type DLBCL. As an initial treatment, CHOP therapy (median 4 cycles; range, 3-8), with (n=17) or without (n=2) radiation therapy, was performed in all 19 pts. Seven pts were treated with CHOP and rituximab. The median duration from initial diagnosis to LR was 8 years (range, 5-18). At LR, the median age was 71 years (range, 45-84). One pt relapsed as a composite of DLBCL and indolent BCL, and two pts relapsed as indolent BCL. Seven of the 19 pts were excluded from gene analysis because their paired gDNAs were of poor quality. The results of target sequencing combined with clinicopathological information and the results of IGH-PCR analysis are described in Table 2. Shared mutations between individual pairs of primary and relapsed tumors were detected in nine of the 12 pts analyzed. The most frequent shared mutation was a CD79B missense mutation of a single base substitution in positions 196 (n=5) or 199 (n=2). The second most frequent mutation was a MYD88 (L265P) missense mutation (n=5). Co-mutation of CD79B and MYD88 was found in four pts, who were considered to have a MCD (MyD88,CD79b) type DLBCL (Schmitz et al. N Engl J Med 2018). All eight pts with a CD79B and/or MYD88 mutation had a non-GCB type DLBCL. The same clonal IGH rearrangements between paired tumors were found in six of the eight pts. Seven of the eight pts presented with primarily extranodal disease originating from the testis (n=3), nasal/paranasal cavity (n=2) or gingiva (n=2). One pt (#9 in Table 2) with a GCB type DLBCL had shared mutations in MLL2, CREBBP, MEF2B and PIM1. However, different clonal IGH rearrangements were detected between paired tumors, implying these mutations may be the basis for lymphomagenesis; an on-going IGH rearrangement may occur. In the other three pts (#10-12), shared mutations were not detected. Mutations in TP53 were not detected in any pts. We did not identify any specific mutations considered to be associated with LR. Conclusions: Common characteristics shared in a subgroup of pts with limited-stage DLBCL who developed LR were as follows: non-GCB type, CD79B and/or MYD88 mutations, and extranodal disease at primary manifestation. The mechanisms of LR from the viewpoint of gene alterations were considered heterogeneous. Disclosures Maruyama: Asahi Kasei Pharma: Honoraria; Takeda: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Dai-ichi-Sankyo: Honoraria; Dai-Nippon-Sumitomo: Honoraria; MSD: Honoraria, Research Funding; Chugai Pharma: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Fujifilm: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria, Research Funding; AstraZeneca: Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Abbvie: Research Funding; Astellas Pharma: Research Funding; Amgen Astellas BioPharma: Research Funding; Otsuka: Research Funding; Novartis: Research Funding; Nippon Boehringer Ingelheim: Research Funding; Pfizer: Research Funding; Solasia Pharma: Research Funding; Celgene: Honoraria, Research Funding; Biomedis International: Honoraria, Research Funding; Mundipharma International: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Izutsu:Amgen: Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria; Bayer: Consultancy, Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; MSD: Honoraria; HUYA Bioscience International: Research Funding; Celgene: Consultancy, Research Funding; Celltrion: Research Funding; Zenyaku: Research Funding; Sanofi: Research Funding; Gilead Sciences: Honoraria; Eisai: Honoraria, Research Funding; Novartis: Honoraria; Ono: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Nihon Medi-Physics: Honoraria; Symbio: Research Funding; Solasia: Research Funding; Mundhi: Honoraria; Otsuka: Honoraria; Bristol- Myers Squibb: Honoraria; Janssen: Honoraria, Research Funding; Astellas: Honoraria, Research Funding; Meiji Seika: Honoraria; Shionogi: Honoraria; Asahi Kasei: Honoraria. Tobinai:Takeda: Honoraria, Research Funding; SERVIER: Research Funding; Abbvie: Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; HUYA Bioscience International: Consultancy, Honoraria; Zenyaku Kogyo: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Chugai Pharma: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Eisai: Honoraria, Research Funding. Kobayashi:Pfizer: Research Funding; Ohtuka: Research Funding; Astellas: Research Funding.

Introduction: Enhancer of zeste homolog 2 (EZH2) and EZH1 are alternative subunits of polycomb repressive complex 2 that catalyze the tri-methylation of lysine 27 residue of histone H3. This histone modification epigenetically regulates gene expression and may play an important role in tumor progression. Valemetostat (DS-3201) is a potent and highly specific orally bioavailable dual inhibitor of EZH2 and EZH1 demonstrating anti-tumor activity against various hematological malignancies in preclinical studies (Honma D, et al. Cancer Sci 2017; Fujita S, et al. Leukemia 2018). Valemetostat demonstrated clinical activity as a novel oral therapeutic option for both B-cell and T-cell NHLs in the interim analysis of a phase I study (Maruyama D, et al. ASH 2017). Here we report the updated results of this phase I study focusing on ATL patients. ATL is a peripheral T-cell malignancy caused by human T-cell leukemia virus type I (HTLV-1), and is divided into aggressive and indolent subtypes. Aggressive ATL has an extremely poor prognosis, with a median survival time of only 8 to 10 months (Katsuya H, et al. Blood 2015). Although conventional chemotherapeutic agents, anti-CCR4 antibody mogamulizmab, and oral immunomodulator lenalidomide have been used for treatment of aggressive ATL patients, most patients eventually become resistant to treatment. In addition, allogenic hematopoietic stem cell transplantation is not available for elderly patients. Therefore, new therapeutic options are urgently needed. Methods: This ongoing open-label, single-arm phase I study consists of the dose escalation part (NHLs including ATL and peripheral T-cell lymphoma [PTCL]) and the expansion part (ATL and PTCL). The drug was administered orally once daily (QD) continuously over 28-days (1 cycle) until disease progression or intolerance. Results: Thirty-eight patients (15 females) with a median age of 69 (44-88) were enrolled in this study as of the data cut-off of 24 January 2019. Of 38 patients, 25 patients were enrolled in the dose-escalation part, and additional 13 patients (7 ATLs and 6 PTCLs) were treated in the expansion part with 200 mg of valemetostat. In all patients, adverse events (≥30%) on treatment with all grades included; platelet count decreased (73.7%), dysgeusia (52.6%), anemia (42.1%), lymphocyte count decreased (39.5%), neutrophil count decreased (39.5%), and white blood cell count decreased (39.5%). Preliminary efficacy was based on investigator's assessment with an objective response rate (ORR) of 47.2%. Fifteen patients were able to stay on valemetostat for more than 24 weeks with tumor shrinkage. Of the 9 ATL patients in the study (2 in dose escalation and 7 in dose expansion), baseline characteristics are as follows: age, median age 74 (range 61-78 yrs); sex, 7 males and 2 females; ATL subtype, 6 acute- and 3 lymphoma-subtypes; median number of prior therapies, 2 (range 1-8). Adverse events (≥30%) on treatment with all grades in the 9 ATL patients included; platelet count decreased (77.8%), dysgeusia (66.7%), neutrophil count decreased (44.4%), white blood cell count decreased (44.4%), anemia (33.3%), alopecia (33.3%), and dry skin (33.3%). No grade 4 and 5 adverse events were detected. Grade 3 adverse events included; white blood cell count decreased (33.3%), platelet count decreased (22.2%), neutrophil count decreased (22.2%), lymphocyte count decreased (11.1%), and anemia (11.1%), which are consistent with those in all population. Responses for the 9 ATL patients included; 1 unconfirmed complete remission (CRu), 3 partial remission (PR), and 3 stable disease (SD) (ORR = 44.4%; 4/9). Of the 6 prior mogamulizumab treated patients, 3 patients demonstrated a response (ORR = 50%; 3/6). Five of 9 ATL patients continued on valemetostat treatment for more than 12 weeks with tumor shrinkage (Figure). Four ATL patients continue on treatment. The latest study results will be presented. Conclusion: The updated results of this ongoing phase I study showed that the oral EZH1/2 dual inhibitor valemetostat has demonstrated acceptable safety and promising preliminary efficacy in NHL. In addition, the results of ATL patients, including mogamulizumab pretreated patients, showed promising clinical activity. A subsequent pivotal phase II study for ATL will soon be initiated. Clinical trial information: NCT02732275 Disclosures Ishitsuka: Novartis: Honoraria, Research Funding; sanofi: Honoraria; Celgene: Honoraria; Astellas Pharma: Honoraria, Research Funding; Pfizer: Honoraria; Takeda Pharmaceutical: Honoraria, Research Funding; Janssen Pharmaceutical: Honoraria; Janssen Pharmaceutical: Honoraria; Shire: Honoraria; Eisai: Honoraria, Research Funding; Otsuka Pharmaceutical: Honoraria; Mochida: Honoraria, Research Funding; Shire: Honoraria; Teijin Pharma: Research Funding; Sumitomo Dainippon Pharma: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding; Sumitomo Dainippon Pharma: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Genzyme: Honoraria; Genzyme: Honoraria; Eisai: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Teijin Pharma: Research Funding; MSD: Research Funding; Yakult: Research Funding; Asahi kasei: Research Funding; MSD: Research Funding; Asahi kasei: Research Funding; Eli Lilly: Research Funding; Eli Lilly: Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Kyowa Hakko Kirin: Honoraria, Research Funding; mundiharma: Honoraria; Taiho Pharmaceutical: Honoraria, Research Funding; Alexion: Honoraria; Mochida: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria, Research Funding; mundiharma: Honoraria; Taiho Pharmaceutical: Honoraria, Research Funding; Otsuka Pharmaceutical: Honoraria; Ono Pharmaceutical: Honoraria, Research Funding; Yakult: Research Funding; Bristol-Myers Squibb: Honoraria; Chugai Pharmaceutical: Honoraria, Research Funding; Pfizer: Honoraria; Alexion: Honoraria; sanofi: Honoraria. Izutsu:Eisai, Chugai, Zenyaku: Honoraria; Chugai, Celgene, Daiichi Sankyo, Astra Zeneca, Eisai, Symbio, Ono, Bayer, Solasia, Zenyaku, Incyte, Novartis, Sanofi, HUYA Bioscience, MSD, Astellas Amgen, Abbvie, ARIAD, Takeda, Pfizer: Research Funding; Celgene: Consultancy; Eisai, Symbio, Chugai, Zenyaku: Research Funding; Kyowa Kirin, Eisai, Takeda, MSD, Chugai, Nihon Medi-physics, Janssen, Ono, Abbvie, Dainihon Sumitomo, Bayer, Astra Zeneca, HUYA Japan, Novartis, Bristol-Byers Squibb, Mundi, Otsuka, Daiichi Sankyo, Astellas, Asahi Kasei: Honoraria. Kusumoto:Chugai Pharmaceutical Co., Ltd.: Consultancy, Honoraria, Research Funding; Kyowa Kirin Co., Ltd.: Honoraria, Research Funding. Araki:Daiichi Sankyo: Employment. Adachi:Daiichi Sankyo: Employment. Yamashita:Daiichi Sankyo: Employment. Atsumi:Daiichi Sankyo: Employment. Tsukasaki:Eisai: Research Funding; Mundi Pharma: Honoraria; Chugai Pharmaceutical: Honoraria, Research Funding; Huya: Consultancy, Honoraria, Research Funding; Byer: Research Funding; Kyowa Kirin: Honoraria; Ono Pharmaceutical: Consultancy; Celgene: Honoraria, Research Funding; Daiichi Sankyo: Consultancy. Tobinai:Eisai: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Takeda Pharmaceutical: Consultancy, Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Zenyaku Kogyo: Consultancy, Honoraria; Meiji Seika: Honoraria; Verastem: Honoraria; Solasia: Honoraria; Janssen Pharmaceutical: Honoraria, Research Funding; Yakult: Honoraria; AbbVie: Research Funding; Ono Pharmaceutical: Consultancy, Honoraria, Research Funding; Mundi Pharma: Consultancy, Honoraria, Research Funding; HUYA Bioscience: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria.

Abstract Introduction : Bosutinib is approved in Japan for patients with newly diagnosed Philadelphia chromosome-positive (Ph+) chronic phase (CP) chronic myeloid leukemia (CML) and Ph+ CML resistant/intolerant to prior therapy. In the primary report of a phase 2 study of first-line bosutinib in Japanese patients with CP CML (NCT03128411), the major molecular response (MMR) rate at 12 months was 55.0% and adverse events (AEs) were manageable and consistent with the known safety profile of bosutinib. Here we report the final 3-year efficacy and safety results of this phase 2 study. Methods : Japanese patients with newly diagnosed CP CML received bosutinib 400 mg once daily (QD). Dose escalation to a maximum of bosutinib 600 mg QD was permitted for unsatisfactory response. The bosutinib dose could be reduced to 300 mg QD for toxicity; following sponsor approval, dose reduction to bosutinib 200 mg QD was permitted for 4 weeks maximum. Long-term secondary endpoints of the study included duration of response, event-free survival, and overall survival (OS). This final analysis was based on ≥3 years of follow-up. Results: A total of 60 patients were treated with bosutinib. Median age was 55 years (range 20-83), 60.0% of patients were male, and 46.7%, 41.7%, and 11.7% had low-, intermediate-, and high-risk Sokal scores, respectively. Median duration of follow-up was 39.2 months (range 13.2-45.1), and median duration of treatment was 35.9 months (range 0.3-44.2). At study completion, 36 (60.0%) patients were still on treatment. The most common reason for treatment discontinuation was AEs (35.0%). Median dose intensity was 357.4 mg/day (range 95.3-548.1), with 400 mg QD being the most commonly utilized dose (&gt;50% of ongoing patients across the treatment period). Dose reductions or interruptions due to AEs occurred in 36 (60.0%) and 50 (83.3%) patients, respectively; dose escalations due to insufficient response occurred in 10 (16.7%) patients. Cumulative rates of MMR, MR 4, and MR 4.5 at any time were 70.0%, 53.3%, and 48.3%, respectively (Table 1). Among patients who achieved MMR or MR 4, none had a confirmed loss of response. Cumulative rates of MMR at any time in patients with low-, intermediate-, and high-risk Sokal scores were 57.1%, 88.0%, and 57.1%, respectively. In patients with dose reductions to 300 (n=36) and 200 (n=9) mg QD, 63.9% (n=23) and 33.3% (n=3) newly achieved MMR or maintained a previously attained MMR after dose reduction. No patient progressed to accelerated/blast phase while on treatment. The cumulative incidence of progression or death adjusting for competing risk of treatment discontinuation at 3 years (90% CI) was 1.7% (0.2-6.4). Two (3.3%) patients died on study, 1 due to disease progression and 1 due to an AE considered unrelated to treatment. The 3-year Kaplan-Meier OS estimate (90% CI) was 96.7% (89.7-98.9). No evaluable patient had an emergent mutation while on treatment or at treatment completion. Any grade treatment-emergent AEs (TEAEs) occurred in 100% of patients and grade ≥3 TEAEs in 81.7% of patients. The most common TEAEs are shown in Table 2. There were no deaths on treatment. The most common (≥10%) TEAEs leading to dose reduction were alanine aminotransferase (ALT) increased (21.7%) and aspartate aminotransferase (AST) increased (13.3%), and the most common (≥10%) TEAEs leading to dose interruption were ALT increased (28.3%), AST increased (16.7%), diarrhea (11.7%), and liver disorder (10.0%). TEAEs leading to treatment discontinuation in ≥2% of patients were ALT increased (10.0%), AST increased (8.3%), lipase increased (3.3%), drug eruption (3.3%), and erythema multiforme (3.3%). Conclusions: After ≥3 years of follow-up, bosutinib continued to show clinical benefit, with approximately half of patients achieving deep molecular responses. The overall efficacy results were consistent with the global BFORE trial of first-line bosutinib. No new safety signals emerged with this longer follow-up. Bosutinib continues to demonstrate a favorable risk/benefit profile and is an important treatment option in Japanese patients with newly diagnosed CP CML. Figure 1 Figure 1. Disclosures Ono: Celgene: Honoraria, Research Funding; Kyowa Kirin Co., Ltd.: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Novartis Pharma KK: Honoraria; Bristol-Myers Squibb Company: Honoraria; Pfizer Japan Inc.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria, Research Funding; Takeda Pharmaceutical Company Limited.: Honoraria; Astellas Pharma Inc.: Honoraria; Eisai Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K: Honoraria; DAIICHI SANKYO COMPANY, LIMITED.: Honoraria; Mundipharma K.K.: Honoraria; TAIHO PHARMACEUTICAL CO., LTD.: Research Funding; Merck Sharp & Dohme: Honoraria, Research Funding. Hino: TEIJIN PHARMA LIMITED.: Research Funding; SEKISUI MEDICAL CO., LTD.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Abbott: Research Funding; Asahi Kasei Corporation:: Research Funding; ARKRAY: Research Funding; JCR Pharmaceuticals Co., Ltd.: Research Funding; Janssen Pharmaceutical: Honoraria; Bristol-Myers Squibb Comapany: Honoraria; Pfizer Japan Inc.: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; NIPPON SHINYAKU CO.,LTD.: Honoraria; Japan Blood Products Organization: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Sanofi: Honoraria; Kyowa Kirin Co., Ltd: Honoraria, Research Funding; ONO PHARMACEUTICAL CO., LTD.: Honoraria, Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Eisai Co., Ltd: Honoraria, Research Funding; AstraZeneca: Honoraria; Astellas Pharma Inc.: Honoraria; MSD: Honoraria, Research Funding; Meiji Seika Pharma Co., Ltd.: Honoraria; CSL Behring: Honoraria; TAIHO PHARMACEUTICAL CO., LTD.: Research Funding; DAIICHI SANKYO COMPANY, LIMITED.: Research Funding; TOSOH CORPORATION: Research Funding. Matsumura: MSD: Research Funding; Nippon Shinyaku: Research Funding; Novartis: Research Funding, Speakers Bureau; Ono: Research Funding; Otsuka: Consultancy, Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Shionogi: Research Funding; Taiho: Research Funding; Takeda: Research Funding; Sumitomo Dainippon: Research Funding; Nihon Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding, Speakers Bureau; Japan Blood Products Organization: Research Funding; Mundipharma: Research Funding; AYUMI Pharmaceutical: Research Funding; Mitsubishi Tanabe: Research Funding; Kyowa Kirin: Research Funding; Eisai: Research Funding; Chugai: Research Funding; Addvie: Research Funding; Eli Lilly Japan: Research Funding; Amgen: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Janssen: Speakers Bureau; Astellas: Speakers Bureau; Asahi Kasei: Research Funding. Fujisawa: Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding. Ishizawa: Otsuka: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Sanofi: Research Funding; SymBio: Honoraria, Research Funding; Kyowa Kirin: Consultancy; Pfizer: Research Funding; Bristol Myers Squibb: Speakers Bureau; IQVIA: Research Funding; Eisai: Honoraria; Chugai: Honoraria; Ono: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Bayer: Research Funding; AbbVie: Research Funding. Sakaida: Kyowa Kirin: Research Funding; Ono: Research Funding; Chugai: Research Funding; Bristol Myers Squibb: Research Funding. Sekiguchi: Ono: Research Funding; A2 Healthcare: Research Funding; Astellas: Research Funding; Janssen: Research Funding; Merck Sharp & Dohme: Research Funding; Otsuka: Research Funding; Pfizer: Research Funding; PPD-SNBL: Research Funding; Sumitomo Dainippon: Research Funding; Daiichi Sankyo: Research Funding; Bristol Myers Squibb: Research Funding. Ono: Pfizer: Current Employment, Current equity holder in publicly-traded company. Aizawa: Pfizer: Current Employment. Tanetsugu: Pfizer: Current Employment. Koide: Pfizer: Current Employment. Takahashi: Chugai: Research Funding; Eizai: Research Funding; Asahikasei: Research Funding; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ono: Research Funding; Kyowahakko-Kirin: Research Funding; Toyamakagaku: Research Funding.

Abstract Background: Indolent non-Hodgkin lymphoma (iNHL), including follicular lymphoma (FL) and marginal zone lymphoma (MZL), is typically responsive to initial chemoimmunotherapy, but relapse is expected. Single-agent rituximab is FDA approved and frequently administered for patients with relapsed/refractory (R/R) low-grade or follicular CD20-positive B-cell NHL. Lenalidomide is an immunomodulatory agent with preclinical and clinical antilymphoma activity alone and in combination with rituximab. We compared the efficacy and safety of lenalidomide plus rituximab (R2) to rituximab (plus placebo) in patients with R/R iNHL. Methods: AUGMENT (NCT01938001) is a multicenter, double-blind, randomized phase III study of R2 vs rituximab/placebo (control) in patients with FL grade 1-3a or MZL who were previously treated with ≥ 1 prior systemic therapy with documented relapsed or refractory disease but not refractory to rituximab (refractory was defined as < partial response to rituximab or rituximab-chemotherapy OR disease progression < 6 months after last rituximab dose). Patients were stratified by prior rituximab treatment (yes vs no), time since last antilymphoma therapy (≤ 2 vs > 2 years), and histology (FL vs MZL), and then randomized 1:1 to R2 or control for up to 1 year. R2 patients received oral lenalidomide 20 mg/day (d), d1-21/28 for 12 cycles plus rituximab IV 375 mg/m2 weekly in cycle 1 and d1 of cycles 2-5. Control patients received rituximab and placebo on the same schedule. Dose modifications were pre-specified in the protocol to manage toxicities. The primary endpoint was progression-free survival (PFS) per 2007 IWG criteria without PET as assessed by Independent Review Committee (IRC; central review). Secondary endpoints included overall response rate (ORR), complete response (CR), duration of response (DOR), time-to-next antilymphoma treatment (TTNLT), overall survival (OS), and safety. Results: A total of 358 patients were randomized (n = 178 R2; n = 180 control), median age was 63 years (range, 26 - 88), 34% FLIPI score ≥ 3, and histologies of 82% FL/18% MZL. Median number of prior systemic treatments was 1 (range, 1 - 12); 84% received prior rituximab and 51% had prior antilymphoma therapy within 2 years of enrollment. At median follow-up of 28.3 months, the study met its primary endpoint of PFS with HR = 0.46 (95% CI, 0.34 - 0.62; P < 0.0001) (Figure 1). Median PFS was 39.4 months for R2 vs 14.1 months for control. IRC-assessed ORR for R2 was 78% vs 53% for control (P < 0.0001). CR was 34% for R2 vs 18% for control (P = 0.001). Median DOR was 36.6 and 21.7 months for R2 and control arms, respectively. TTNLT was improved for R2 vs control with HR = 0.54 (95% CI, 0.38 - 0.78; P = 0.0007). OS data were not mature with 16 deaths reported in the R2 arm vs 26 deaths in control (HR = 0.61 [95% CI, 0.33 - 1.13]). Selected all-grade treatment-emergent adverse events (TEAEs) of interest more common in the R2 vs control arm (≥ 10% difference) were infections (63% vs 49%), cutaneous reactions (32% vs 12%), constipation (26% vs 14%), thrombocytopenia (15% vs 4%), and tumor flare reaction (11% vs 1%). Grade 3/4 TEAEs were reported in 69% R2 and 32% control patients. More frequent grade 3/4 TEAEs in the R2 vs control arm were primarily attributable to increased neutropenia (50% vs 13%) and leukopenia (7% vs 2%). Grade 5 TEAEs were reported in 2 patients in each arm. TEAEs leading to discontinuation of lenalidomide occurred in 9% of patients vs 5% for rituximab + placebo. Neutropenia was the only TEAE leading to discontinuation of lenalidomide in > 1 patient (n = 5). Seventy-one percent of R2 patients completed all 12 cycles of planned treatment vs 61% of control. Disease progression was the leading reason for discontinuation of lenalidomide/placebo (n = 21 R2, n = 54 control). Conclusions: R2 demonstrated superior efficacy over rituximab monotherapy (plus placebo) as measured by the primary endpoint of progression-free survival as well as secondary endpoints of ORR, CR, DOR, and TTNLT in patients with R/R FL grade 1-3a and MZL. At this early analysis, fewer deaths have been observed in the R2 arm. Despite additional hematologic toxicity, greater efficacy of the R2 regimen (and fewer early progressions) allowed more patients to complete the planned therapy and delayed the need for subsequent treatment. R2 represents an important new treatment option in patients with previously treated FL/MZL, with meaningful advantages over single-agent rituximab. Disclosures Leonard: Celgene: Consultancy; Karyopharm: Consultancy; ADC Therapeutics: Consultancy; MEI Pharma: Consultancy; Juno: Consultancy; Bayer: Consultancy; AstraZeneca: Consultancy; Sutro: Consultancy; Biotest: Consultancy; United Therapeutics: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Genentech/Roche: Consultancy; Gilead: Consultancy; BMS: Consultancy. Trněný:F. Hoffman-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Abbvie: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Morphosys: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Sandoz: Honoraria. Izutsu:Otsuka: Honoraria; Bristol- Myers Squibb: Honoraria; Nihon Medi-Physics: Honoraria; Novartis: Honoraria; Mundhi: Honoraria; HUYA Bioscience International: Research Funding; Kyowa Hakko Kirin: Honoraria; Takeda: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Amgen: Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Gilead Sciences: Honoraria; Eisai: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Astellas: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Zenyaku: Research Funding; Celltrion: Research Funding; MSD: Honoraria; Ono: Honoraria, Research Funding; Symbio: Research Funding; Celgene: Consultancy, Research Funding; Solasia: Research Funding; Sanofi: Research Funding; Meiji Seika: Honoraria; Shionogi: Honoraria; Asahi Kasei: Honoraria. Fowler:Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Zhu:Beijing Cancer Hospital (Peking University Cancer Hospital): Employment. Scheliga:INCA - Instituto Nacional Do Cancer, Brazil: Employment. Pinto:Servier: Consultancy; BMS: Honoraria, Research Funding; MSD: Honoraria; Roche: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Gilead: Honoraria. Scheinberg:Novartis: Consultancy, Speakers Bureau; Janssen: Honoraria, Research Funding; Pfizer: Speakers Bureau. Flinn:Trillium: Research Funding; Takeda: Research Funding; Calithera: Research Funding; Incyte: Research Funding; Verastem: Research Funding; ArQule: Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Forty Seven: Research Funding; Agios: Research Funding; BeiGene: Research Funding; Kite: Research Funding; Portola: Research Funding; Verastem: Consultancy, Research Funding; Celgene: Research Funding; Pfizer: Research Funding; Forma: Research Funding; Merck: Research Funding; Novartis: Research Funding; Constellation: Research Funding; Curis: Research Funding; Infinity: Research Funding; TG Therapeutics: Research Funding; Genentech: Research Funding; Gilead: Research Funding. Moreira:Instituto Português de Oncologia do Porto FG, EPE, Porto, Portugal: Employment. Liu:Celgene: Employment, Equity Ownership. Kalambakas:Celgene: Employment, Equity Ownership. Fustier:Celgene: Employment, Equity Ownership. Wu:Celgene: Employment, Equity Ownership. Gribben:Cancer Research UK: Research Funding; Unum: Equity Ownership; Novartis: Honoraria; Abbvie: Honoraria; Wellcome Trust: Research Funding; Acerta Pharma: Honoraria, Research Funding; Kite: Honoraria; NIH: Research Funding; Roche: Honoraria; Janssen: Honoraria, Research Funding; Medical Research Council: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; TG Therapeutics: Honoraria; Pharmacyclics: Honoraria.

Karube Tadashi: Toward the Meiji revolution. The Search for „Civilization” in Nineteenth-Century Japan. JPIC Tokyo, 2019. Japan Publishing Industry Foundation for Culture. transl. by David Noble, from „Ishin kakumei” e no michi: „Bunmei” o motomeru jūkyū seiki Nihon Shinchosha Publishing Co., Ltd. 2017