ALBERT

Description: Background Although the proteasome inhibitor bortezomib (Btz) shows excellent efficacy in multiple myeloma (MM), some patients exhibit sub-optimal or no response to this agent. In addition, Btz-induced toxicity, such as peripheral neuropathy (PN) and skin disorders, limits its use in some patients. A comprehensive analysis of metabolites (metabolomics) in biofluids can be a potential novel strategy to predict the efficacy or adverse events of Btz treatment. With respect to the metabolic pathways in MM cells, a few studies have applied metabolomics using serum/plasma samples to elucidate MM pathogenesis or the mechanisms underlying the malignant transformation of MM cells. In addition, no metabolomic profile has been examined in terms of efficacy or toxicity of the specific MM treatment. In this study, we performed lipid metabolomics analysis using plasma samples from patients with newly diagnosed MM (NDMM) prior to the initial Btz therapy, and have attempted to identify the association between the level of specific biomarkers in plasma lipid metabolites and the efficacy or severity of Btz-related toxicity. Materials & Methods Fifty-four plasma samples were analyzed from transplant-ineligible patients with NDMM enrolled in a randomized phase II study comparing two less intensive regimens of melphalan, prednisolone, and Btz (MPB) (JCOG1105; UMIN000011180). Informed consent to participate in the JCOG-BioBank, Japan Biorepository project, was obtained from the patients prior to sample acquisition. Frozen plasma samples obtained prior to MPB therapy were subjected to lipid metabolomics analysis, and the levels of phospholipids, sphingolipids, neutral lipids, and fatty acids (FAs) were measured using Liquid Chromatography/Mass spectrometry. The levels of lipid metabolites were relatively quantified as the ion peak ratio of each metabolite to the internal standard. We then evaluated whether the level of each lipid metabolite associated with the depth of response to MPB therapy and the grade of Btz-induced toxicity, such as peripheral neuropathy (PN) and skin disorders. Statistical analysis was performed by a multivariate permutation test using the Welch's t-statistic for multiple comparisons of the metabolite levels between the two groups categorized based on their response to MPB therapy or the grade of toxicity, ie. responder vs non-responder to the therapy, and grade 0-1 vs grade 2 or higher in the toxicities. Results and Discussion Lipid metabolomics analysis detected approximately 485 lipid metabolites in 54 plasma samples. We then evaluated the association between the level of each lipid metabolite and the grade of Btz-induced PN (BiPN) or skin disorders. As shown in Figure 1, high levels of seven phospholipids, including four lysophosphatidylcholine (LPC) and three phosphatidylcholine (PC), were associated with BiPN of grade 2 or higher (n=11). LPC species were reported to facilitate neuropathic pain and nerve demyelination of the dorsal root ganglion and cuneate nucleus in the experimental model of PN. Therefore, high level of plasma LPC might worsen BiPN. Moreover, low levels of three fatty acids-FA (18:2), FA (18:1), and FA (22:6)-were observed in patients who developed severe skin disorders of grade 2 or higher (n=10). Low level of FA (18:2), also called linoleic acid, has been reported to impair the anti-inflammatory response and repair skin barrier during the healing process. Therefore, low level of plasma FA (18:2) might associate with the aggravation of Btz-induced skin disorders. No metabolite was significantly associated with tumor response, such as CR (n=9), in 53 samples evaluated for the best response to MPB therapy. Conclusion To our knowledge, this is the first plasma lipid metabolomics study to demonstrate that plasma lipid metabolite levels are associated with the severity of BiPN and skin disorders in patients with MM. These metabolites may serve as candidate biomarkers to predict Btz-induced toxicity in patients with MM before initiating Btz therapy. Our exploratory results need to be confirmed in further validation studies. Disclosures Ri: Janssen Pharmaceutical: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Kyowa Kirin: Research Funding; Chugai Pharmaceutical: Research Funding; Sanofi: Honoraria, Research Funding; Abbvie: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; MSD: Research Funding; Novartis Pharma: Research Funding; Gilead Sciences: Research Funding; Astellas Pharma: Research Funding; Teijin Pharma: Research Funding. Iida:Celgene: Honoraria, Research Funding; Chugai: Research Funding; Kyowa Kirin: Research Funding; Abbvie: Research Funding; MSD: Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Teijin Pharma: Research Funding; Janssen: Honoraria, Research Funding; Daichi Sankyo: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Astellas: Research Funding; Gilead: Research Funding; Sanofi: Research Funding. Maruyama:Eisai: Honoraria, Research Funding. Tohkin:Towa Pharmaceutical: Research Funding. Tobinai:Kyowa Kirin: Honoraria, Research Funding; Meiji Seika: Honoraria; Zenyaku Kogyo: Consultancy, Honoraria; Takeda Pharmaceutical: Consultancy, Honoraria, Research Funding; Verastem: Honoraria; Ono Pharmaceutical: Consultancy, Honoraria, Research Funding; HUYA Bioscience: Consultancy, Honoraria; Janssen Pharmaceutical: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Solasia: Honoraria; Chugai Pharmaceutical: Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Eisai: Honoraria, Research Funding; Yakult: Honoraria; Mundi Pharma: Consultancy, Honoraria, Research Funding; AbbVie: Research Funding. Fukuhara:Chugai Pharmaceutical Co., Ltd.: Honoraria; Zenyaku: Honoraria; Eisai: Honoraria, Research Funding; Janssen Pharma: Honoraria; Mochida: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Mundi: Honoraria; Kyowa-Hakko Kirin: Honoraria; AbbVie: Research Funding; Celgene Corporation: Honoraria, Research Funding; Nippon Shinkyaku: Honoraria; Bayer: Research Funding; Gilead: Research Funding; Solasia Pharma: Research Funding. Miyazaki:Ono Pharmaceutical: Research Funding; Astellas Pharma: Research Funding; Eisai: Honoraria; SymBio Pharmaceuticals: Honoraria; Takeda: Honoraria; Nippon Shinyaku: Honoraria; Celgene: Honoraria; Kyowa Hakko Kirin: Honoraria, Research Funding; Chugai: Honoraria; Janssen Pharmaceutical: Honoraria. Tsujimura:Chugai Pharmaceutical: Honoraria; Eisai: Honoraria; Kyowa Kirin: Honoraria; Takeda Pharmaceutical: Honoraria. Yoshimitsu:Novartis: Speakers Bureau; Bristol-Myer-Squibb,: Speakers Bureau; Shire: Speakers Bureau; Takeda: Speakers Bureau; Chugai: Speakers Bureau; Sanofi: Speakers Bureau. Tsukasaki:Byer: Research Funding; Kyowa Kirin: Honoraria; Mundi Pharma: Honoraria; Ono Pharmaceutical: Consultancy; Daiichi Sankyo: Consultancy; Eisai: Research Funding; Celgene: Honoraria, Research Funding; Huya: Consultancy, Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding. Nagai:SymBio Pharmaceuticals Limited: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; HUYA Bioscience International: Research Funding; Solasia Pharma K.K.: Research Funding; Zenyaku Kogyo: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria, Research Funding; AbbVie: Research Funding; Bayer Pharma: Honoraria, Research Funding; Mundi Pharma: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen Pharmaceutical: Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; MSD: Honoraria; IQVIA: Research Funding; Otsuka Pharmaceutical: Research Funding; Sanofi: Honoraria; Novartis Pharma: Honoraria.

Description: Introductions Diffuse large B-cell lymphoma (DLBCL) is one of the aggressive type of non-Hodgkin lymphoma (NHL) and is known to have a good drug-sensitivity and prognosis. More than 40% of patients with DLBCL are older than 70 years old at diagnosis, and age is known as a poor prognostic factor. However, dose modification is frequently necessary due to their comorbidities and organ function decline, and this leads to poor outcome of their treatment. Therefore, it is important to optimize treatment strategy and chemotherapy for the elderly with DLBCL to improve their outcome. Aims The aim of this study is to unveil underlying problems in the treatment against elderly patients with DLBCL and develop a new therapeutic approach to overcome them. Methods The medical records of all new elderly patients (70 years old〈 ) with DLBCL between 2003 April and 2011 October at Nagoya Medical Center were reviewed for a retrospective analysis , to identify characteristics and treatment response of those patients. Survival of patients intensively treated (82 pts) was evaluated using Kaplan-Meier method, and analyzed using Log-rank test. Results We experienced new 93 patients aged over 70 years (41.9 % of all DLBCL cases). Median observation period of was 52.7 months. R-CHOP and R-CHOP-like regimes were administrated into 78 and 4 patients respectively. Four patients treated without rituximab due to patients’ decision. CR was obtained in 70 patients (CR rate 85.3%), and 3-yr OS and PFS were 72.2% and 72.1% respectively. Eleven patients died during induction chemotherapy or didn’t obtain CR and eventually died. The median doses of ADR, CPM, and VCR were 69.51±15.2%, 70.23±20.0% and 59.1±28.1% of original regimen, respectively.% of VCR to original CHOP regimen was significant different between age 70-79 and age more than 80 (p

Description: 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.

Description: 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.

Description: 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.

Description: Background Rituximab has dramatically improved the clinical outcomes of mature B cell lymphoma. It has been reported that women show more favorable survival than men with rituximab-containing treatment. A multicenter, retrospective study was conducted to assess the role of sex in survival with rituximab treatment. Patients and Methods Patients with newly diagnosed mature B cell lymphoma treated at 20 National Hospital Organization hospitals in Japan from January 2000 to December 2004 were consecutively registered. Rituximab was approved in September 2002 for indolent B cell lymphoma and in September 2003 for aggressive B cell lymphoma in Japan. The patients were divided into two groups depending on whether they received induction therapy containing rituximab. The target population of this study was all mature B cell lymphoma patients who received first remission induction therapy containing rituximab. The patients treated without rituximab were used as controls. The endpoint was to compare 2-year progression-free survival (PFS) and overall survival (OS) between men and women. Survivals were assessed using the Kaplan-Meier method, and the groups were compared using the log-rank test. Results A total of 1126 patients received systemic chemotherapies during this study period. Of these, 348 (men 185, women 163), including 184 diffuse large B cell lymphomas (DLBCLs) and 111 follicular lymphomas (FLs), were treated by rituximab-containing regimens as front-line therapy. The 2-year PFS was better in women than in men (75.8% vs. 64.2%, p=0.048). This difference was not seen in the control group (men 396, women 382), which was treated by chemotherapeutic regimens without rituximab (48.7% vs. 50.6%, p=0.994). The 2-year OS was not statistically different between men and women (81.9% vs. 88.6%, p=0.115). When this population was broken down into DLBCL and FL, the women’s benefit in 2 year PFS was not statistically significant in both subtypes. Multivariate analysis both with forced entry and stepwise method could not show that sex was an independent prognostic factor in mature B cell lymphoma treated by rituximab containing induction regimen. Conclusions In mature B cell lymphoma, women would have better PFS than men when treated with rituximab containing therapy. These data suggest that the sex-based rituximab dose modification might be considered. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction:Pralatrexate (PDX) is a dihydrofolate reductase inhibitor with high affinity for reduced folate carrier 1 and folylpolyglutamate synthetase, resulting in extensive internalization and accumulation in tumor cells. In the previous phase 2 study for relapsed or refractory (R/R) PTCL in western countries, the overall response rate (ORR) was 29% (32 of 109 evaluable patients [pts]), as assessed by an independent central review (O'Connor et al. JCO 2011). We conducted this phase 1/2 study to evaluate the tolerability, safety, efficacy and pharmacokinetics of PDX in Japanese pts with R/R PTCL. Methods: Eligibility criteria included age ≥20, histologically confirmed PTCL according to the 2008 WHO classification, disease progression after ≥1 prior systemic therapy, ≥1 measurable disease and Eastern Cooperative Oncology Group performance status ≤2. PDX was administered intravenously weekly for 6 weeks in 7-week cycles with concurrent vitamin B12 and folic acid. There were 2 cohorts in phase 1: Cohort 1 was at 30 mg/m2 of the US-approved dose and Cohort 2 would start at 20 mg/m2 if 30 mg/m2 was not tolerated. The primary endpoint was ORR in phase 2 and secondary endpoints included duration of response (DoR), progression-free survival (PFS) and overall survival (OS). Response was evaluated by the independent central imaging review using the International Workshop Criteria (Cheson et al. JCO 1999). Cryotherapy and professional oral care (e.g. dental cleaning and oral hygiene instruction) by dentists before and during PDX treatment were recommended to reduce the severity of mucositis. An educational handbook was offered to all pts to learn symptoms, prevention and self-care of oral mucositis. Results:A total of 25 pts received ≥1 dose of PDX and were included in the safety analysis (median age 71 years; 68% male; median of 3 prior therapies; 32% refractory to the most recent therapy; 16% low risk, 48% low-intermediate risk, 24% high-intermediate risk and 12% high risk by International Prognostic Index). Of these, 3 pts were enrolled in phase 1 and 22 pts in phase 2. Two pts in phase 2 were excluded from the efficacy analysis due to lack of a confirmed diagnosis of PTCL by the central pathology review. In phase 1, no dose-limiting toxicity was observed in 3 pts for Cohort 1. In phase 2, using 30 mg/m2 as the recommended dose, the ORR was 45% (9 of 20 evaluable pts in phase 2; 90% CI, 26% to 65%) with 2 complete responses and 7 partial responses achieved in Cycle 1. At the time of data cut-off, median DoR of 9 responders was not reached (range, 1 to 358 days) and 4 responders were still on PDX treatment. The median PFS of all 20 evaluable pts was 150 days (95% CI, 43 to 183). Among 23 evaluable pts for efficacy in phase 1/2, 5 pts had died and median OS was not reached (range, 41 to 570 days) after a median follow-up of 183 days for censored cases. In contrast to the results from the previous phase 2 study in western countries showing the ORR of 8% (1 of 13) in pts with angioimmunoblastic T-cell lymphoma (AITL), the ORR in AITL pts was 44% (4 of 9), which was similar to the ORR in pts with PTCL not otherwise specified (50%; 6 of 12) or pts with anaplastic lymphoma kinase-negative anaplastic large cell lymphoma (50%; 1 of 2) in this study. The plasma PDX concentration peaked immediately after intravenous injection over 3 to 5 minutes and the elimination half-life was about 10 to 20 minutes. The most common grade (G) 3 or 4 adverse events were lymphopenia (52%; 13 pts), thrombocytopenia (40%; 10 pts), leukopenia (28%; 7 pts), neutropenia (24%; 6 pts), anemia (20%; 5 pts). Mucositis was observed in 21 pts (84%) including G1 (20%; 5 pts), G2 (44%; 11 pts) and G3 (20%; 5 pts). G4 mucositis did not occur in any pts. Median duration of G2 mucositis was 8 days (range, 3 to 15) and that of G3 was 12 days (range, 8 to 17). According to the criteria for dose modification, the dose of PDX was reduced to 20 mg/m2 due to mucositis in 6 pts. One pt discontinued the treatment due to G2 mucositis recurrence after dose reduction. All 25 treated pts received ≥1 time cryotherapy at PDX administration and 20 of them continued it throughout the study. Thirteen pts received ≥1 time dental scaling or dental cleaning. Conclusion: PDX at 30 mg/m2 weekly for 6 of 7 weeks was effective and well-tolerated in Japanese pts with R/R PTCL. Early oral or dental care potentially ameliorates mucositis and it may be useful for continuing PDX treatment more safely. This study was sponsored by Mundipharma KK. Disclosures Maeda: Mundipharma KK: Research Funding. Tobinai:Ono Pharmaceutical: Research Funding; Takeda: Honoraria, Research Funding; HUYA Bioscience: Honoraria; Daiichi Sankyo Co., Ltd.: Consultancy; Zenyaku Kogyo: Honoraria; SERVIER: Research Funding; GlaxoSmithKline: Research Funding; Kyowa Hakko Kirin: Research Funding; Janssen Pharmaceuticals: Honoraria, Research Funding; Chugai Pharma: Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Eisai: Honoraria, Research Funding; Mundipharma KK: Honoraria, Research Funding. Nagai:Mundipharma KK: Research Funding; Takeda: Honoraria, Research Funding; Janssen: Research Funding. Nakane:Mundipharma KK: Research Funding. Shimoyama:Mundipharma KK: Research Funding. Nakazato:Mundipharma KK: Research Funding. Sakai:Mundipharma KK: Research Funding. Ishikawa:Mundipharma KK: Research Funding. Izutsu:Eisai: Honoraria; Chugai Pharmaceutical: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria; Takeda Pharmaceutical: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Celgene: Research Funding; Gilead: Research Funding; Abbvie: Research Funding; Mundipharma KK: Research Funding. Ueda:Kyowa Hakko Kirin: Research Funding; Mundipharma KK: Consultancy.

Description: Background: Lenalidomide, one of the immunomodulatory drugs, is an important component of treatment for multiple myeloma. Lenalidomide inhibits the proliferation of tumor cells via antiangiogenesis, induces apoptosis and acts directly on the immune system and tumor microenvironment. Immunomodulatory effects of lenalidomide notably stimulate the production of cytokines and activation of T-cells and natural killer cells. Skin rash is a frequent adverse event of lenalidomide. Some studies have shown a correlation between the efficacy of anti-cancer agents such as tyrosine kinase inhibitors and the development of skin rash. However, the relationship between the development of lenalidomide-associated skin rash and its efficacy is unclear. We conducted a retrospective survey to clarify whether development of skin rash correlates with the efficacy of lenalidomide. Materials and Methods: All patients with multiple myeloma who received lenalidomide at 9 hospitals in Japan from July 2009 to December 2015 were serially registered. The chart review was performed for all identified patients to obtain the following information; age, sex, performance status at the initiation of lenalidomide, International Staging System (ISS) classification, prior chemotherapy regimen, tumor response, development of skin rash and clinical outcomes. A log-rank test was used to assess the relationship between the presence of skin rash and survival. A two-sided p 〈 0.05 was considered statistically significant. This study received approval from the appropriate ethics committees. Results: We identified 215 patients (92 women and 123 men), with a median age was 69 years (range, 39-86 years). Types of myeloma were as follows: 139 patients of IgG, 43 of IgA, and 29 of Bence-Jones protein. ISS was available for 204 patients, and of these, 63, 73, and 68 patients were classified as ISS stage I, II, and III, respectively. The median number of prior therapies was 2 (range, 0-6); 161 (74.9%) and 46 patients (21.4%) had previously received bortezomib and thalidomide, respectively. Fifty patients (23.3%) had undergone previous autologous stem cell transplantation. Sixty-five patients (30.2%) developed a skin rash after lenalidomide initiation, and the median time to onset of skin rash was 12 days. The patients with and without skin rash were similar with respect to age, type of myeloma, and ISS. The median follow-up of survivors was 28.9 months (range, 1.7-80.3 months). The progression-free survival and overall survival were better in patients who had skin rash than in those who did not (p = 0.009 and p = 0.033, respectively) (Figures A and B). Conclusions: In this study, the progression-free survival and overall survival among patients with skin rash during lenalidomide therapy was significantly superior to the patients without skin rash. Lenalidomide-associeated skin rash in patients with multiple myeloma may be a predictive factor of their clinical outcome. Figure Figure. Disclosures Nagai: Takeda: Honoraria, Research Funding; Janssen: Research Funding; Mundipharma KK: Research Funding.