Abstract: Background: Darinaparsin is a novel organic arsenic compound composed of dimethylated arsenic linked to glutathione. In two phase I studies including Japanese and Korean patients with relapsed or refractory peripheral T-cell lymphoma (PTCL), darinaparsin was well tolerated and demonstrated potential efficacy (ASH2015 Abstract #2714 and Jpn J Clin Oncol. 2021, 51:218). The efficacy, safety and pharmacokinetics of darinaparsin in Asian patients with relapsed or refractory PTCL were evaluated in a multinational phase II study. Methods: Eligible patients had histologically confirmed PTCL not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL) or anaplastic large cell lymphoma (ALCL), which had relapsed from or were refractory to one or more prior regimen with systemic chemotherapy. Darinaparsin was intravenously administered for 5 consecutive days at 300 mg/m 2/day every 3 weeks. The primary endpoint was the overall response rate (ORR) within 6 cycles of treatment. Tumor response was assessed based on computed tomography (CT) and fluorodeoxyglucose-positron emission tomography (FDG-PET) evaluation by central review according to the Revised Response Criteria for Malignant Lymphoma (J Clin Oncol. 2007, 25:579). Secondary endpoints included progression-free survival (PFS), overall survival (OS), toxicity, and pharmacokinetic parameter. This study was conducted in 25 sites in East Asia (13 in Japan, 6 in Korea, 5 in Taiwan, and 1 in Hong Kong). Results: A total of 65 patients (37, 19, 8 and 1 from Japan, Korea, Taiwan and Hong Kong, respectively) including 43 PTCL-NOS, 17 AITL and 3 ALK-negative ALCL; 45 males and 20 females, with a median age of 68 (range 28-85) years received darinaparsin. The median number of prior systemic chemotherapy regimens was 2 (range 1-11). Approximately 30% of patients did not have evidence of response to the most recent prior systemic therapy. The median number of cycles received darinaparsin was 3 (range 1-39). In 57 evaluable patients, the ORR as assessed by an independent efficacy assessment committee was 19% (11 of 57; 90% Confidence Interval (CI) 11.2-29.9), and the lower limit of the 90% CI exceeded the predefined 10% threshold (p=0.024, binomial test). The ORR was 16.2% (6 of 37) in the subjects with PTCL-NOS and 29.4% (5 of 17) in the subjects with AITL. None of the subjects with ALCL, ALK-negative responded. Of the 11 responders, 5 achieved a Complete Response (CR) (8.8%), and 6 had a Partial Response (PR) (10.5%). Eight of the 11 responders showed response by Cycle 3. The disease control rate defined as the proportion of patients who achieved CR, PR or Stable Disease (SD) was 46% (26 of 57, 90% CI 34.3-57.3), and more than half of the patients achieved tumor shrinkage (Figure 1). Median duration of response (DOR) was 3.8 months (90% CI 2.7-5.7). Four patients who had achieved SD or better continued the treatment with darinaparsin for more than 1 year, and median duration of treatment in these subjects was 28.6 months (range 14-41). Median PFS and OS were 3.3 months (90% CI 1.9-4.2) and 13.7 months (90% CI 9.9-18.6), respectively. Among all 65 treated patients, the incidence of adverse events (AEs) was 97%, and that of drug-related AEs was 68%. AEs with an incidence of ≥ 20% were pyrexia (42%), anemia (25%), thrombocytopenia (20%) and decreased appetite (20%). The incidence of ≥ Grade 3 AEs was 62%, and that of ≥ Grade 3 drug-related AEs was 29%. The common ≥ Grade 3 AEs were anemia (15%), thrombocytopenia (12%), neutropenia (12%), lymphopenia (9%) and leukopenia (9%). While electrocardiogram (ECG) QT prolongation at 3% was reported as drug-related AEs associated with cardiac toxicity, there were no substantial changes from baseline in the descriptive statistics of ECG parameters associated with darinaparsin treatment. There was no apparent ethnic difference in pharmacokinetic profiles of patients studied. Conclusions: Darinaparsin had clinical efficacy and was well tolerated in patients with relapsed or refractory PTCL. AEs were clinically acceptable and manageable. Darinaparsin is a potential option for the treatment of relapsed or refractory PTCL. Updated results of DOR PFS, OS, and long-term safety are being analyzed for presentation at the conference. Figure 1 Figure 1. Disclosures Fukuhara: Ono Pharmaceutical: Honoraria, Research Funding; Novartis: Honoraria; Nippon Shinyaku: Honoraria; Kyowa Kirin: Honoraria; Janssen: Honoraria; Incyte: Research Funding; HUYA Bioscience International: Honoraria; Eisai: Honoraria; Chugai Pharmaceutical: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Bayer: Research Funding; AbbVie: Honoraria; Takeda Pharmaceutical: Honoraria; Zenyaku Kogyo: Honoraria. Kim: Celltrion: Research Funding; Dong-A Pharmaceutical: Research Funding; Eisai: Research Funding; Johnson & Johnson: Research Funding; Kyowa Kirin: Research Funding; Roche: Research Funding; IGM Biosciences: Research Funding; Sanofi: Research Funding. Yamamoto: Nippon Shinyaku: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Sanofi: Honoraria; Solasia Pharma: Research Funding; SymBio: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Yakult: Honoraria, Research Funding; Zenyaku: Honoraria, Research Funding; Micron: Honoraria; IQIVA/Genmab: Research Funding; ADC Therapeutics: Honoraria; Chugai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Eisai: Honoraria, Research Funding; IQIVA/Incyte: Research Funding; IQIVA/HUYA: Honoraria; HUYA: Consultancy; Janssen: Honoraria; Kyowa Kirin: Honoraria; Meiji Seika Pharma: Consultancy, Honoraria, Research Funding; MSD: Honoraria; Mundipharma: Research Funding; Bristol-Myers Squibb/Celgene: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Izutsu: Novartis: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Pfizer: Research Funding; Symbio: Honoraria, Research Funding; Allergan Japan: Honoraria; FUJI FILM Toyama Chemical: Honoraria; MSD: Research Funding; Janssen: Honoraria, Research Funding; Incyte: Research Funding; Genmab: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Beigene: Research Funding; Bayer: Research Funding; AstraZeneca: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Yakult: Research Funding; Takeda Pharmaceutical: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; HUYA Bioscience International: Research Funding; Eisai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. 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. Ando: Astellas Pharma: Honoraria; Celgene: Honoraria; Chugai Pharmaceutical: Research Funding; Kyowa Kirin: Research Funding; Novartis: Honoraria; Takeda Pharmaceutical: Research Funding. Suehiro: Otsuka Pharmaceutical: Research Funding; Ono Pharmaceutical: Research Funding; Novartis: Research Funding; Nippon Shinyaku: Honoraria; Kyowa Kirin: Honoraria, Research Funding; Incyte: Research Funding; Eisai: Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Celgene: Research Funding; Bristol-Myers Squibb: Honoraria; Bayer: Research Funding; Amgen BioPharma: Research Funding; Pfizer: Research Funding. Nagahama: Solasia Pharma: Current Employment, Current equity holder in publicly-traded company. Sonehara: Solasia Pharma: Current Employment, Current equity holder in publicly-traded company. Nagai: Ono Pharmaceutical: Honoraria; Sanofi: Honoraria; Sumitomo Dainippon Pharma: Honoraria; SymBio Pharmaceuticals: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria, Research Funding; Zenyaku Kogyo: Research Funding; Novartis: Honoraria; Nippon Shinyaku: Research Funding; Mundipharma: Honoraria, Research Funding; Kyowa Kirin: Research Funding; Janssen: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Chordia Therapeutics: Honoraria; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Bayer: Research Funding; AstraZeneca: Honoraria, Research Funding; AbbVie: Research Funding. Tien: Novartis: Honoraria; Celgene: Honoraria, Research Funding; AbbVie: Honoraria. Tobinai: Ono Pharmaceutical: Consultancy, Honoraria; Solasia Pharma: Honoraria; Mundipharma: Consultancy, Honoraria; Kyowa Kirin: Honoraria; HUYA Bioscience International: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Eisai: Honoraria; Chugai Pharmaceutical: Honoraria; Celgene: Consultancy, Honoraria; Takeda Pharmaceutical: Consultancy, Honoraria; Zenyaku Kogyo: Consultancy, Honoraria; Yakult: Honoraria. OffLabel Disclosure: Darinaparsin is an investigational product that is not approved in any country/region in the world.

Abstract: Previous studies have shown that the cyclin-dependent kinase inhibitor (CDKI) genes p15INK4B and p16INK4A are frequently inactivated by genetic alterations in many malignant tumors and that they are candidate tumor-suppressor genes. Although genetic alterations in these genes may be limited to lymphoid malignancies, it has been reported that their inactivation by aberrant methylation of 5′ CpG islands may be involved in various hematologic malignancies. In this study, we investigated the p15INK4B and p16INK4A genes to clarify their roles in the pathogenesis of myelodysplastic syndrome (MDS). Southern blotting analysis showed no gross genetic alterations in either of these genes. However, hypermethylation of the 5′ CpG island of the p15INK4B gene occurred frequently in patients with MDS (16/32 [50%]). Interestingly, the p15INK4B gene was frequently methylated in patients with high-risk MDS (refractory anemia with excess blasts [RAEB] , RAEB in transformation [RAEB-t], and overt leukemia evolved from MDS; 14/18 [78%] ) compared with patients with low-risk MDS (refractory anemia [RA] and refractory anemia with ring sideroblast [RARS] ; 1/12 [8%]). Furthermore, methylation status of the p15INK4B gene was progressed with the development of MDS in most patients examined. In contrast, none of the MDS patients showed apparent hypermethylation of the p16INK4A gene. These results suggest that hypermethylation of the p15INK4B gene is involved in the pathogenesis of MDS and is one of the important late events during the development of MDS.

Abstract: Mantle cell lymphoma ( MCL ) is essentially incurable with conventional chemotherapy. The MCL International Prognostic Index ( MIPI ) is a validated specific prognostic index, but was derived from patients with advanced‐stage disease primarily in the pre‐rituximab era. We analysed 501 MCL patients (median age, 67 years; range 22–90) treated with rituximab‐containing chemotherapy, and evaluated the prognostic factors adjusted by the treatment. Five‐year overall survival ( OS ) in the low, intermediate and high MIPI groups was 74%, 70% and 35%, respectively. Additional to MIPI risk factors, multivariate analysis revealed that low serum albumin and bone‐marrow involvement were also significantly associated with a poor outcome. The revised‐ MIPI (R‐ MIPI ) was constructed using six factors, namely age, performance status, white blood cell count, serum lactate dehydrogenase, bone‐marrow involvement and serum albumin, which is divided into four prognostic groups. Five‐year OS in low, low‐intermediate (L‐I), high‐intermediate (H‐I) and high R‐ MIPI groups was 92%, 75%, 61% and 19%, respectively. Hazard ratio for OS of L‐I, H‐I and high risk to low risk patients were 5·4, 8·3 and 33·0, respectively. R‐ MIPI , a new prognostic index with easy application to the general patient population, shows promise for identifying low‐ and high‐risk MCL patients in the rituximab era.

Abstract: Abstract 3694 Poster Board III-630 [Background and Purpose] Bendamustine hydrochloride is a bifunctional alkylating agent with novel mechanisms of action. Although bendamustine is known to have anti-tumor activity against indolent B-NHL as a single agent, efficacy in MCL with bendamustine monotherapy has not been reported. To assess the efficacy and toxicity of bendamustine in patients with relapsed indolent B-NHL and MCL, we conducted a multicenter phase II study. [Patients and Methods] Patients diagnosed with relapsed or refractory indolent B-NHL or MCL, 75= or 〉 age= or 〉 20, and PS 0-1 (ECOG) were enrolled in the study. Bendamustine was administered intravenously at a dose of 120 mg/m2 infused over 60 minutes on days 1 and 2 of each 21-day treatment cycle for up to 6 cycles (minimum of 3 cycles). The primary endpoint was the overall response rate (ORR). Tumor response was assessed by a central radiological review committee according to the International Workshop Criteria for NHL (1999). [Results] A total of 69 patients were enrolled and treated, including 52 (75%) cases of follicular lymphoma (FL) and 11 (16%) cases of MCL, ages 33 to 75 years, with predominantly stage III/IV indolent B-NHL (86%) or MCL (64%). The median number of unique prior therapies was two (range, 1 to 16), and sixty-six patients (96%) had received rituximab as a prior therapy. Twenty-nine patients (42%) completed the planned six cycles of chemotherapy, with fifty patients (72%) receiving 3 or more cycles. Dose reduction of bendamustine was required in 11 patients (16%). The ORR was 91% (63 of 69 patients; 95% CI, 82% to 97%) with a complete response (CR) rate of 67% (%CR), including %CRu (46 of 69 patients; 95% CI, 54% to 78%). The ORR in FL and MCL was 90% and 100%, respectively. The %CR in FL and MCL was 66% and 73%, respectively. Median progression-free survival (PFS) for all 69 patients was not reached at the median follow-up duration of 248 days (39-359 days). Median PFS for indolent B-NHL (58) and MCL (11) patients was not reached at the median follow-up duration of 254 days and 226 days, respectively. Hematologic toxicities, including grade 4 lymphopenia (72%) and neutropenia (48%), were the most frequently reported toxicities in patients. Non-hematologic toxicities were mild, with no grade 4 non-hematologic toxicity recorded. The most frequently reported grade 3 non-hematologic toxicities were GI toxicities (9%) including grade 3 vomiting (4%) and anorexia (3%), and infections (7%) which included one case of grade 3 febrile neutropenia, pneumonia, herpes infection, and viral pharyngitis. [Conclusion] Bendamustine monotherapy is a highly effective and less toxic treatment in patients with relapsed or refractory indolent B-NHL and MCL who have been pretreated (96%) with rituximab. It is noteworthy that a very high complete response rate (73%) was achieved in relapsed or refractory MCL patients although the number of patients was relatively small. Disclosures: No relevant conflicts of interest to declare.

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

Abstract: Introduction The prognosis of classic Hodgkin lymphoma (cHL) in young adults has improved following advances in current therapeutics. However, evidence of elderly patients with cHL has limited due to its rarer. To analyze clinical outcomes and risk factors in elderly patients with advanced-stage cHL who received a doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) regimen, we conducted a nationwide multi-center retrospective study in Japan (UMIN000033264). Methods The key eligibility criteria of the current study were as follows: 1) patients with histologically diagnosed cHL between 2007 and 2016 in each institution; 2) advanced-stage cHL (stage III, IV or IIB with bulky or extranodal lesion); 3) age at diagnosis & gt; 60 years; and 4) had received at least one cycle of an ABVD regimen as initial treatment including a modified ABVD regimen (dacarbazine dose reduced to 250 mg/m 2 at first cycle). Patients with human immunodeficiency virus infection or methotrexate-associated cHL were excluded. The primary endpoint was 5-year overall survival (OS). Secondary endpoints included progression-free survival (PFS) and event-free survival (EFS), the latter defined as the time from a diagnosis of cHL to disease progression or relapse, subsequent systemic chemotherapy for cHL, or death due to any cause in this study. The average relative dose intensity (ARDI) of ABVD was calculated as the sum of the relative dose intensity of each drug divided by four. Results A total of 171 patients from 45 institutions were included in this study. The central pathological review could be performed in 140 cases (82%), in which histological subtypes of cHL were determined as follows: mixed cellularity, 89 (64%); nodular sclerosis, 33 (24%); lymphocyte-deleted, 4 (3%); lymphocyte-rich, 2 (1%); not otherwise specified, 12 (9%). The median age was 71 years (interquartile range [IQR] 65-76). The number of patients in each 10-year age group was 79 (46%) for 61-70 years, 78 (46%) for 71-80 years, and 14 (8%) for & gt; 81 years. The numbers of patients with ECOG performance status (PS) ≥2 and B symptoms were 33 (19%) and 85 (50%), respectively. Bulky mediastinal diseases were found in four patients (2%). The risk factors used for the International Prognostic Score (IPS), including male sex, stage IV, hypoalbuminemia, anemia, leukocytosis, and lymphopenia, were not significantly different among these age groups. The median number of cycles of ABVD was 6 (IQR:5-7), and 66% of patients completed at least 6 cycles. The median ARDI was 77%. The median ARDI in each 10-year age group was 88% for 61-70 years, 71% for 71-80 years, and 54% for & gt; 81 years. With a median follow-up time of 52 months (IQR:31-76), the estimated OS, PFS, and EFS at 5 years were 72%, 59%, and 54%, respectively. Among 131 patients whose Epstein-Barr virus (EBV) status was analyzed using EBV-encoded small RNA1 (EBER1) in situ hybridization, 61 (46%) were positive for EBER1. The OS was not significantly different between EBV-positive and EBV-negative patients (75% and 76% at 5 years, respectively). Univariate analysis for OS revealed that age, PS ≥ 2, hypoalbuminemia, anemia, lymphopenia, and the presence of B symptoms were significantly associated with short OS. In multivariate analysis, age (hazard ratio [HR] 1.568 per 10-year increase, 95% confidence interval [CI] 1.020-2.411) was only an independent risk factor for OS, whereas lymphopenia (HR 1.967, 95% CI 1.196-3.235) was an independent risk factor for EFS. Higher ARDI was significantly associated with improved OS and EFS. Bleomycin-induced lung toxicity (BLT), observed in 41 (24%) patients, was not associated with OS. In this study, we found that 55 patients died: 23 within two years after diagnosis mainly due to cHL progression (n = 10, 43%) and treatment-related toxicity (infection [n = 4, 17%] and BLT [n = 4, 17%] ). The remaining 32 patients died more than two years after diagnosis mainly due to second primary malignancies (n = 14, 44%), including solid tumors (n = 6), other types of lymphoma (n = 4), and myelodysplastic syndrome/acute myeloid leukemias (n = 4). Conclusions The HORIZON study showed relatively good prognosis for elderly patients with advanced-stage cHL who received an ABVD regimen (estimated five-year OS rates was 72%). Age and lymphopenia were an independent risk factors for OS and EFS, respectively. The development of novel therapies is warranted to improve the outcomes of such patients. Disclosures Makita: SymBio: Honoraria; Novartis: Honoraria; Eisai: Honoraria; Daiichi-Sankyo: Consultancy; CSL Behring: Honoraria; Chugai: Honoraria; BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Kusumoto: Kyowa Kirin: Honoraria; Chugai: Honoraria, Research Funding; Daiichi Sankyo: Research Funding. Tsujimura: Takeda: Honoraria; Chugai: Honoraria; Kyowa Kirin: Honoraria; Eisai: Honoraria; Janssen: Honoraria. Takayama: Chugai: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding. Kuroda: Otsuka Pharmaceutical: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; MSD: Research Funding; Abbvie: Consultancy, Honoraria; Ono Pharmaceutical: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Sysmex: Research Funding; Pfizer: Honoraria, Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Shionogi: Research Funding; Asahi Kasei: Research Funding; Taiho Pharmaceutical: Research Funding; Fujimoto Pharmaceutical: Current Employment, Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Dainippon Sumitomo Pharma: Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Bristol-MyersSquibb: Consultancy, Honoraria, Research Funding; Janssen Pharmaceutical K.K: Consultancy. Shimada: BMS: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Janssen: Honoraria; Chugai: Consultancy, Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; AstraZeneca: Honoraria; Otsuka: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; SymBio: Honoraria. Okamoto: Chugai: Research Funding; Kyowa Kirin: Research Funding; Ono: Research Funding; Taiho: Research Funding; Takeda: Research Funding. Asano: Takeda: Honoraria. Maruyama: Janssen: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Novartis: Research Funding; MSD: Honoraria, Research Funding; Otsuka: Research Funding; Ono: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Astellas Pharma,: Research Funding; Celgene: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Amgen: Research Funding; BMS: Honoraria, Research Funding; Mundipharma: Honoraria; Kyowa Kirin: Honoraria; Zenyaku: Honoraria; AstraZeneca: Honoraria; Nippon: Honoraria; SymBio: Honoraria. Yamaguchi: Chugai: Honoraria, Research Funding; Genmab: Research Funding; MSD: Honoraria; Kyowa Kirin: Honoraria, Research Funding; Takeda: Honoraria; Ono: Honoraria; Celgene: Honoraria; Otsuka: Honoraria; Sumitomo Dainippon: Honoraria; Eisai: Honoraria; AstraZeneca: Consultancy. Nagai: AbbVie: Research Funding; AstraZeneca: Honoraria, Research Funding; Bayer: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Chordia Therapeutics: Honoraria; Chugai Pharmaceutical: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Kyowa Kirin: Research Funding; Mundipharma: Honoraria, Research Funding; Nippon Shinyaku: Research Funding; Novartis: Honoraria; Ono Pharmaceutical: Honoraria; Sanofi: Honoraria; Sumitomo Dainippon Pharma: Honoraria; SymBio Pharmaceuticals: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria, Research Funding; Zenyaku Kogyo: Research Funding.

Abstract: Abstract 4884 Background: Bendamustine is an alkylating agent with a unique mechanism of action and has demonstrated efficacy as a single agent for the treatment of relapsed or refractory indolent B-NHL or MCL. We conducted a multicenter, phase II study of bendamustine in Japanese patients with indolent B-cell NHL or MCL, reporting an overall response rate of 91% (90% in indolent B-NHL and 100% in MCL) according to International Workshop Response Criteria after a median follow-up of 12.6 months (Ohmachi et al. Cancer Sci 2010 [Epub ahead of print]). Here we report the updated progression-free survival (PFS) data, including median PFS, which had not been reached at the time of previous reports. Patients and Methods: Eligible patients (aged 20–75 years; Eastern Cooperative Oncology Group performance status of 0 or 1) with measurable, pathologically confirmed indolent B-NHL or MCL that failed to respond to, or relapsed after, prior therapy were enrolled. Bendamustine 120 mg/m2 was administered intravenously over 60 minutes on days 1 and 2 every 21 days for up to 6 cycles. PFS was assessed 3 months after completion of the last cycle, and then at 3-month intervals. Results: A total of 69 patients, aged 33–75 years, were enrolled: 58 with indolent B-NHL, mainly follicular lymphoma (n = 52), and 11 with MCL. Patients had primarily stage III or IV disease. The median number of prior regimens was 2 (range, 1–9) for patients with indolent B-NHL and 4 (range, 1–16) for those with MCL. A median of 5 (range, 1–6) bendamustine cycles were administered, with 72% of patients completing 3 or more cycles. The median follow-up time for all patients is 20.6 months (range, 2.5–27.2 months). The median PFS was 21.1 months (95% CI, 15.8-NA; NA = not available due to short period of observation): 20.0 months (95% CI, 12.3-NA) in indolent B-NHL, and 21.7 months (95% CI, 16.5-NA) in MCL. Estimated 2-year PFS rates were 45.2% and 34.1% in indolent B-NHL and MCL, respectively. Conclusions: Bendamustine monotherapy is highly effective in patients with relapsed or refractory indolent B-NHL and MCL. The durable responses observed in this study strongly support the use of bendamustine in these patients and are particularly encouraging in the relapsed or refractory MCL population. Disclosures: Off Label Use: Bendamustine is a novel alkylator that has shown efficacy and safety in patients with indolent lymphomas, and particularly encouraging is the activity in patients with mantle cell lymphoma, which is difficult to treat. Although bendamustine is currently investigational in Japan, approval for relapsed/refractory indolent NHL and mantle cell lymphoma is anticipated in October 2010.

Abstract: Background: Darinaparsin is a novel organic arsenic compound composed of dimethylated arsenic linked to glutathione, and has similar structure to one of the intermediates of the arsenic detoxification pathway. The mechanism of action includes induction of apoptosis in tumor cells, primarily through disruption of mitochondrial functions and increase in reactive oxygen species production. Two phase I studies of darinaparsin for injection were conducted in patients with relapsed or refractory (r/r) PTCL to evaluate its safety, efficacy and pharmacokinetics in Japan and Korea, respectively. Methods: Patients with histologically confirmed PTCL not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), anaplastic lymphoma kinase (ALK) -positive anaplastic large cell lymphoma (ALCL) or ALK-negative ALCL who failed or were refractory to 1 or more prior systemic therapy were eligible. Darinaparsin was administered for 5 consecutive days at 200 mg/m2/day or 300 mg/m2/day every 4 weeks, or at 300 mg/m2/day every 3 weeks in the Japanese phase I study, and at 300 mg/m2/day every 4 weeks or every 3 weeks in the Korean phase I study. Darinaparsin was given intravenously over 1 hour, and the treatment was continued until disease progression or unacceptable toxicity. As one of the secondary endpoints, tumor response was explanatorily assessed by using the Revised Response Criteria for Malignant Lymphoma (Cheson BD et al, J Clin Oncol 2007) in patients who completed at least 2 cycles of treatment and who had evaluable data of FDG-PET and CT scan. Since use of an inorganic arsenic compound is limited by cardiotoxicity, the potential of darinaparsin to prolong QTcF and any possible relationship between darinaparsin plasma concentration and change in QTcF were assessed. Results: In these 2 studies, 17 Japanese patients and 6 Korean patients; a total of 23 patients, included 16 PTCL-NOS, 6 AITL and 1 ALK-negative ALCL; 14 males and 9 females, with a median age of 63 (range 22-83) years were enrolled. Dose-limiting toxicities occurred in 1 Japanese patient who received 300 mg/m2/day (grade [G] 3 hepatic dysfunction). Drug-related adverse events 〉 = G3 were reported in 4 Japanese patients who received 300 mg/m2/day. Occurrence of diffuse large B-cell lymphoma was reported in 1 patient, anemia in 1, leukopenia in 1, neutropenia in 2, febrile neutropenia in 1, lymphopenia in 2, thrombocytopenia in 2, hepatic dysfunction in 1, nausea in 1 and activated partial thromboplastin time (APTT) prolonged in 1. No drug-related adverse event 〉 = G3 was reported in Korean patients. No patient showed QTcF 〉 500 msec or delta QTcF 〉 60 msec throughout the study period. Concentration-dependent or treatment-duration-independent effect on the QTcF was not identified. There was no significant relationship between the plasma concentration of darinaparsin and a change in QTcF interval (r=0.003). Tumor response was assessed in 14 patients who completed at least 2 cycles of treatment, and objective response was observed in 4 patients (1 complete response and 3 partial responses). Five of 6 patients with stable disease showed tumor shrinkage to some extent. In Japanese and Korean patients who received 300 mg/m2/day, the mean (± SD) values of Cmax were 838 ± 181 and 708 ± 81 ng/mL, AUC0-24 were 12759 ± 3419 and 11282 ± 905 ng•h/mL, and t1/2 were 20 ± 6.3 and 20.6 ± 2.8 h, respectively. The systemic arsenic exposures were similar between Japanese and Korean patients. There was no apparent difference in the mean plasma concentration-time profiles between Japanese and Korean patients at the doses studied. Conclusion: The results from integrated data analysis of these 2 phase I studies revealed that darinaparsin was well tolerated at all doses and dosing schedules studied, and demonstrated its potential efficacy against r/r PTCL. Furthermore, it was suggested that 300 mg/m2/day for 5-consecutive days every 3 weeks would be the recommendable dosing schedule of darinaparsin for subsequent studies. Based on the promising results of these phase I studies, we are planning to conduct an Asian multicenter phase II study for r/r PTCL. Disclosures Kim: Kyowa-Kirin: Research Funding; Takeda: Research Funding; Novartis: Research Funding; Roche: Research Funding; Donga: Research Funding; Merck: Research Funding. Ogura:Eisai Co., Ltd.: Research Funding; Kyowa Hakko Kirin co., Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Phizer Japan Inc.: Research Funding; Janssen Pharmaceutical K.K.: Research Funding; GlaxoSmithKline K.K.: Research Funding; MSD K.K.: Research Funding; AstraZeneca K.K.: Research Funding; Takeda Pharmaceutical Company Limited: Research Funding; Symbio Pharmaceuticals Limited: Research Funding; Solasia Phama K.K.: Research Funding; Mundipharma K.K.: Research Funding; Celgene K.K.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding. Uchida:Eisai Co., Ltd.: Research Funding. Ishizawa:Takeda: Speakers Bureau; Janssen: Research Funding; Takeda: Research Funding; Kyowa Kirin: Speakers Bureau; GSK: Research Funding; Kyowa Kirin: Research Funding; Celgin: Research Funding; Pfizer: Speakers Bureau; Celgin: Speakers Bureau. Tobinai:Gilead Sciences: Research Funding. Nagahama:Solasia Pharma K.K.: Employment. Sonehara:Solasia Pharma K.K.: Employment. Nagai:Servier: Research Funding; Mundipharma: Research Funding; Otsuka: Research Funding; Takeda: Research Funding; CMIC: Research Funding; Janssen: Research Funding; Gilead Sciences: Research Funding.