Interim analysis of an ongoing phase II trial assessing safety and efficacy of R-IDEA as salvage therapy in patients with relapsed/refractory DLBCL： An intergroup study of the society of lymphoma treatment in Japan (SoLT-J) and the west japan hematology/oncology group (WestJHOG) Eisei Kondo1, Kazuhiko Yamamoto2, Taro Masunari3, Katsuhiro Miura4, Jun Takizawa5, Yasufumi Masaki6, Tadashi Matsumura7, Yasushi Hiramatsu8, Jun Murakami9, Hideki Tsujimura10, Naoto Tomita11, Yoshinobu Maeda1, Masatoshi Kanno12 1Okayama university hospital, Okayama, 2Okayama Citizens' Hospital, Okayama, 3Chugoku central hospital, Fukuyama, 4Nihon University School of Medicine, Tokyo, 5Niigata University Faculty of Medicine, Niigata, 6Kanazawa Medical University, Ishikawa, 7Himeji St.Mary's Hospital, Himeji, 8Himeji Red-corss Hospital, Himeji, 9Toyama university hospital, Toyama, 10Chiba Cancer Center, 11Chiba, Yokohama City University Graduate School of Medicine, Yokohama, 12Nara Medical University School of Medicine, Kashihara, Japan Results　20 pts were enrolled (median age 59.5, range 42-65; M:F ratio 11:9). 17 pts were enrolled after first relapse and three were primary refactory. 5 pts relapsed within 1 year from initial diagnosis. The most frequent grade 3/4 adverse events were neutropenia (55/56 cycles), thrombocytopenia (46/56 cycles), anemia (24/56 cycles), and febrile neutropenia (26/56 cycles). No other grade 5 adverse event occurred. After completion of R-IDEA, 7 pts (35%) achieved CR, 5 (25%) PR, one had SD, and 7 had PD. The median CD34+ count was 2.64 million/kg (range: 0.17-43.7). 3 pts failed to mobilize >2 million of CD34+ cells/kg, for a MARR of 45% (9/20). No patient of primary refractory or relapsed within 1 year after initial diagnosis and 9 pts relapsed >1 year from diagnosis achieved mobilization adjusted response (p=0.001) The nine pts proceeded to HDT/ASCT. Conclusions 0.00 0.25 0.50 0.75 1.00 Probability 1 2 3 4 Years after relapse Overall survival Progression free survival Aim Table 1. R-IDEA regimen Figure 1. Consort flow diagram   Dose 1 2 3 4 5 Rituximab 375 mg/m2 div ↓ Ifosfamide 1300 mg/m2 Dexamethazone 40 mg/body Etoposide 150mg/m2 Ara-C 750mg/m2　x2 ↓↓ High dose chemotherapy (HDT) with autologous stem cell support (ASCT) has been proven effective in relapsed(rel)/refractory(ref) Diffuse large B cell lymphoma (DLBCL), but the benefit is limited to the patients (pts) who are sensitive to salvage chemotherapy (CTx) and are able to mobilize sufficient peripheral blood stem cells (PBSCs). The salvage CTx regimen IDEA was previously reported as effective (ORR; 67.6%) and feasible to mobilize PBSCs (77.8%). (Nishimori et al. Antican Res 2009) Accordingly, we designed a multicenter phase II trial addressing safety and efficacy of IDEA plus Rituximab(R) in rel/ref DLBCL pts (UMIN000004892). Herein, we report the interim analysis on the first 20 enrolled pts. This study includes pts aged 18-65 years with primary refractory or first relapse CD20＋ DLBCL after anthracycline-containing CTx.　The R-IDEA regimen consisits of R 375mg/m2 on day 1, IFO 1.3g/m2, ETP 150mg/m2 on days 2-4, Dex 33mg IV on days 2-5 and Ara-C 750mg/m2 twice daily on days 3-4. R-IDEA was administered every 21 days for a total of 3 cycles. PBSCs were harvested after cycle 3. Pts in a CR/PR after R-IDEA and who got successful mobilization (>2 million of CD34+ cells/kg) received HDT/ASCT. Primary endpoint was mobilization adjusted response rate (MARR; [CR] + [PR] - mobilization failure). R-IDEA is feasible and well tolerated in pts with rel/ref DLBCL. Primary refractory and early relapsed DLBCL pts had a poorer prognosis. New treatment strategy seems to be warranted for the high risk pts. R-IDEA PBSC harvest Evaluation (PET-CT) CR/PR (n=12) relapsed/refractory DLBCL (n=20) SD/PD (n=3) PD n=1 PD n=2 Poor mobilization HDT/ASCT (n=9) Table 2. Patient characteristics Age Median (range) 59.5 (42-65) Sex Male Female 11 9 Firstline chemotherapy R-CHOP R-CHOP like 18 2 ECOG PS 1 3 4 10 5 serum LDH > ULN 13 Stage I-II III-IV 8 12 secondary age-adjusted IPI 6 Disease status Primary refractory Relapse 5 (< 1y from Dx) 12(> 1y from Dx) Methods Mobilization adjusted response rate (MARR) 9/20 (45%) 1.00 0.00 0.25 0.50 0.75 1 2 3 4 1.00 Sensitive relapse (CR/PR after R-IDEA: n=12) Relapsed from > 1 year after initial diagnosis 0.75 Figure 2. Adverse events during R-IDEA Refractory or Relapsed from < 1 year after initial diagnosis P=0.085 0.50 Overall survival Overall survival 0.00 0.25 0.50 0.75 1.00 1 2 3 4 P=0.044 saaIPI = 0 0.25 Non-sensitive relapse (n=8) saaIPI = 1 P=0.0003 0.00 1 2 3 saaIPI = 2 Years after relapse Cycles 0.00 0.25 0.50 0.75 1.00 1 2 3 4 1.00 Relapsed from > 1 year after initial diagnosis Conclusions Sensitive relapse (CR/PR after R-IDEA: n=12) 0.75 Refractory or Relapsed from < 1 year after initial diagnosis 0.50 P=0.023 Progression free survival Table 3. Results of CD34+ cell harvests Days of apheresis 2 (1-6) Total CD34+ cells (x106/kg) 2.64 (0.17-43.7) No. <2.0x106 /kg 3 (15%) Progression free survival 0.00 0.25 0.50 0.75 1.00 1 2 3 4 0.25 saaIPI = 0 Non-sensitive relapse (n=8) P=0.002 0.00 Eisei Kondo : eisei-k@okayama-u.ac.jp Deparment of General medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences saaIPI = 1 1 2 3 4 saaIPI = 2 P=0.13 Years after relapse

dose 1 2 3 4 5 ・・・・ 21 Rituximab 375 mg/m2 div ↓ Ifosfamide (I) 適格規準 ・組織学的に確認されたCD20陽性びまん性大細胞型B細胞リンパ腫の初回再発または初回難治性例 ・測定可能な病変を有すること。 ・年齢18歳以上65歳以下 ・Performance Status（ECOG）：0～2の症例 ・重篤な臓器障害のない症例 ・初回治療にてアントラサイクリン系薬剤を含む化学療法を受けている症例 ・自己末梢血幹細胞移植併用大量化学療法の適格症例である症例 ・本研究への参加について患者本人の同意が得られている。ただし、未成年の場合は代諾者及び本人から文書による同意が得られていること。 主要評価項目（Primary Endpoint） 末梢血幹細胞採取成功率を補正した R-IDEA第3コース終了時の全奏効率(Mobilization-adjusted overall response rate; MARR) 副次的評価項目（Secondary Endpoints） ２年無増悪生存割合 progression-free survival (PFS) 2年全生存割合overall survival (OS)、治療全体の奏効率（CR,PR）、導入化学療法（R-IDEA）の奏効率（CR,PR） 移植適格割合、移植施行割合、末梢血幹細胞採取効率 有害事象発生頻度、二次がん発生割合 登録患者数の設定根拠・登録期間・観察期間 予定登録患者数：40人 患者数設定根拠：　本試験のprimary endpointはMARRであり、R-IDEA療法によるMARRが他の救援化学療法のそれを上回ると仮説した。CORAL study において、R-ICE群のMARR 52.3%(奏効率63%、採取不良10％)、R-DHAP群MARR 54.5% (奏効率64%、採取不良8％)であることから、 R-IDEA療法の閾値MARRを50%、期待MARRを70%とし、α=0.05（片側）、β=0.2のもとで必要症例数を算出すると37例となり、脱落例を10％と仮定して40 症例を最終必要症例数とした。中間解析として20例において安全性とMARRを検討し、R-IDEA療法の安全性と効果を確認する。MARRが45%（20例中9例）に達しない場合にはプロトコールは中止される。なお、安全性が確認され、かつ第一段階の20例の評価をおこなった時点で9例以上のMARRが確認されれば最終段階まで症例を集積する。   dose 1 2 3 4 5 ・・・・ 21 Rituximab 375 mg/m2 div ↓ Ifosfamide (I) 1300 mg/m2 Dexamethazone (D) 40 mg/body Etoposide (E) 150mg/m2 Ara-C (A) 750mg/m2　x2 ↓↓ Eisei Kondo1, Kazuhiko Yamamoto2, Taro Masunari3, Katsuhiro Miura4, Jun Takizawa5, Yasufumi Masaki6, Tadashi Matsumura7, Yasushi Hiramatsu8, Jun Murakami9, Hideki Tsujimura10, Naoto Tomita11, Yoshinobu Maeda1, Masatoshi Kanno12 1Okayama university hospital, Okayama, 2Okayama Citizens' Hospital, Okayama, 3Chugoku central hospital, Fukuyama, 4Nihon University School of Medicine, Tokyo, 5Niigata University Faculty of Medicine, Niigata, 6Kanazawa Medical University, Ishikawa, 7Himeji St.Mary's Hospital, Himeji, 8Himeji Red-corss Hospital, Himeji, 9Toyama university hospital, Toyama, 10Chiba Cancer Center, 11Chiba, Yokohama City University Graduate School of Medicine, Yokohama, 12Nara Medical University School of Medicine, Kashihara, Japan