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: The efficiency of upfront consolidation with high‐dose chemotherapy/autologous stem‐cell transplantation (HDCT/ASCT) for newly diagnosed high‐risk diffuse large B‐cell lymphoma (DLBCL) may be influenced by induction chemotherapy. To select better induction chemotherapy regimens for HDCT/ASCT, a randomized phase II study was conducted in high‐risk DLBCL patients having an age‐adjusted International Prognostic Index (aaIPI) score of 2 or 3. As induction chemotherapy, 6 cycles of R‐CHOP‐14 (arm A) or 3 cycles of R‐CHOP‐14 followed by 3 cycles of CHASER (arm B) were planned, and patients who responded proceeded to HDCT with LEED and ASCT. The primary endpoint was 2‐y progression‐free survival (PFS), and the main secondary endpoints included overall survival, overall response rate, and adverse events (AEs). In total, 71 patients were enrolled. With a median follow‐up of 40.3 mo, 2‐y PFS in arms A and B were 68.6% (95% confidence interval [CI], 50.5%‐81.2%) and 66.7% (95% CI: 48.8%‐79.5%), respectively. Overall survival at 2 y in arms A and B was 74.3% (95% CI: 56.4%‐85.7%) and 83.3% (95% CI: 66.6%‐92.1%). Overall response rates were 82.9% in arm A and 69.4% in arm B. During induction chemotherapy, 45.7% and 75.0% of patients in arms A and B, respectively, had grade ≥ 3 non‐hematologic toxicities. One patient in arm A and 6 in arm B discontinued induction chemotherapy due to AEs. In conclusion, R‐CHOP‐14 showed higher 2‐y PFS and less toxicity compared with R‐CHOP‐14/CHASER in patients with high‐risk DLBCL, suggesting the former to be a more promising induction regimen for further investigations (UMIN‐CTR, UMIN000003823).

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: The safety, efficacy, and pharmacokinetics of copanlisib were evaluated in this phase Ib/II study in Japanese patients with relapsed/refractory indolent non-Hodgkin lymphoma (NHL). The primary endpoint was safety at the recommended dose; efficacy endpoints included objective response rate (ORR), progression-free survival (PFS), and overall survival. In phase Ib, patients received copanlisib 45 mg intravenously on days 1, 8, and 15 of a 28-day cycle, and when tolerated, consecutive patients received copanlisib 60 mg. As no dose-limiting toxicities occurred at the 45 mg ( n  = 3) or 60 mg ( n  = 7) dose in phase Ib, the recommended dose for Japanese patients was determined to be 60 mg, and this dose was used in phase II ( n  = 15). Although all patients experienced at least one treatment-emergent adverse event (TEAE), with hyperglycemia being the most common AE, no AE-related deaths were reported. The ORR was 68.0% (17/25 patients), median PFS was 302 (95% CI 231–484) days, and the duration of response was 330 (range 65–659) days. The pharmacokinetic properties of copanlisib were similar between Japanese and non-Japanese patients. Overall, copanlisib 60 mg had an acceptable safety profile and showed promising antitumor activity in Japanese patients with relapsed/refractory indolent NHL.