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E7777 is a recombinant cytotoxic fusion protein composed of the diphtheria toxin fragments A and B and human interleukin‐2. It shares an amino acid sequence with denileukin diftitox, but has improved purity and an increased percentage of active monomer. We undertook a multicenter, single‐arm phase II study of E7777 in patients with relapsed or refractory peripheral T‐cell lymphoma (PTCL) and cutaneous T‐cell lymphoma (CTCL) to evaluate its efficacy, safety, pharmacokinetics, and immunogenicity. A total of 37 patients were enrolled, of which 17 and 19 patients had PTCL and CTCL, respectively, and one patient with another type of lymphoma (extranodal natural killer/T‐cell lymphoma, nasal type), diagnosed by the Central Pathological Diagnosis Committee. Among the 36 patients with PTCL and CTCL, objective response rate based on the independent review was 36% (41% and 31%, respectively). The median progression‐free survival was 3.1 months (2.1 months in PTCL and 4.2 months in CTCL). The common adverse events (AEs) observed were increased aspartate aminotransferase (AST) / alanine aminotransferase (ALT), hypoalbuminemia, lymphopenia, and pyrexia. Our results indicated that a 9 µg/kg/d dose of E7777 shows efficacy and a manageable safety profile in Japanese patients with relapsed or refractory PTCL and CTCL, with clinical activity observed across the range of CD25 expression. The common AEs were manageable, but increase in ALT / AST, hypoalbuminemia, and capillary leak syndrome should be carefully managed during the treatment., Among 36 patients with refractory peripheral T‐cell lymphoma (PTCL) and cutaneous T‐cell lymphoma (CTCL), objective response rate based on the independent review was 36% (41% in PTCL and 31% in CTCL). Our results indicated that a 9 µg/kg/d dose of E7777 shows efficacy and a manageable safety profile in Japanese patients with relapsed or refractory PTCL and CTCL, with clinical activity observed across the range of CD25 expression. The common adverse events were manageable, but increase in alanine aminotransferase / aspartate aminotransferase, hypoalbuminemia, and capillary leak syndrome should be carefully managed during the treatment.

We conducted a nationwide retrospective analysis of 116 hepatitis B virus (HBV) surface antigen (HBsAg)‐positive patients with diffuse large B‐cell lymphoma (DLBCL) and 278 HBsAg‐negative patients with DLBCL, as a control cohort, who received rituximab‐containing regimens as an induction chemotherapy at 30 Japanese medical centers between January 2004 and December 2014. Hepatitis was defined as an absolute serum alanine aminotransferase (ALT) level of ≥100 U/L. HBV reactivation‐related hepatitis was defined as hepatitis with an absolute serum HBV DNA level of ≥3.3 log IU/mL or an absolute increase of ≥2 log compared with the baseline value. HBsAg‐positive patients were divided into three groups based on anti–HBV prophylactic therapy: no nucleos(t)ide analogue (non–NA, n = 9), lamivudine (LAM, n = 20), and entecavir (ETV, n = 87). The 4‐year cumulative incidence (CI) of hepatitis in HBsAg‐positive and HBsAg‐negative patients was 21.1% and 14.6% (P = .081), respectively. The 4‐year CI of HBV reactivation‐related hepatitis was higher in HBsAg‐positive patients than in HBsAg‐negative patients (8.0% vs 0.4%; P, Prophylactic use of entecavir reduced HBV‐related hepatitis and mortality in HBsAg‐positive DLBCL treated with R‐chemotherapy. The 4‐year overall survival rate in HBsAg‐positive DLBCL patients receiving prophylactic entecavir was similar to that in HBsAg‐negative DLBCL.

CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is characterized by poor prognosis and a high frequency of central nervous system relapse after standard immunochemotherapy. We conducted a phase II study to investigate the efficacy and safety of dose-adjusted (DA)- EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) combined with high-dose methotrexate (HD-MTX) in newly diagnosed patients with CD5+ DLBCL. Previously untreated patients with stage II to IV CD5+ DLBCL according to the 2008 World Health Organization classification were eligible. Four cycles of DA-EPOCH-R followed by two cycles of HD-MTX and four additional cycles of DAEPOCH- R (DA-EPOCH-R/HD-MTX) were planned as the protocol treatment. The primary end point was 2-year progression-free survival (PFS). Between September 25, 2012, and November 11, 2015, we enrolled 47 evaluable patients. Forty-five (96%) patients completed the protocol treatment. There were no deviations or violations in the DA-EPOCH-R dose levels. The complete response rate was 91%, and the overall response rate was 94%. At a median follow up of 3.1 years (range, 2.0-4.9 years), the 2- year PFS was 79% [95% confidence interval (CI): 64-88]. The 2-year overall survival was 89% (95%CI: 76-95). Toxicity included grade 4 neutropenia in 46 (98%) patients, grade 4 thrombocytopenia 12 (26%) patients, and febrile neutropenia in 31 (66%) patients. No treatment-related death was noted during the study. DA-EPOCH-R/HD-MTX might be a first-line therapy option for stage II-IV CD5+ DLBCL and warrants further investigation. (Trial registered at: UMIN-CTR: UMIN000008507.)

The aim of this randomized phase II study was to improve the treatment delays and discontinuations associated with bendamustine use by comparing the effect of Benda-14 (intravenous bendamustine, 120 mg/m

Dasatinib is one of the key treatment options for chronic myeloid leukemia (CML) patients. Increase in lymphocyte counts has been known to be predictive of a good treatment response under dasatinib treatment as a second line therapy. However, clinical significance of lymphocyte dynamics in the upfront setting has yet to be clarified. To investigate the significance of lymphocyte dynamics in newly diagnosed chronic phase (CP)-CML, patient data of D-First study (ClinicalTrials.gov NCT01464411) were analyzed. Fifty-two CML-CP patients enrolled to this study were treated with dasatinib (100 mg day(-1) ) and all were followed-up for 18 months. The incidence of lymphocyosis was observed in 14 (27%), but it was not associated with deep molecular response achievement. However, natural killer (NK) cell or cytotoxic T lymphocyte (CTL) counts at 1 month were significantly higher in patients with deep molecular response (DMR) by 18 months compared to those without DMR. When the patients were divided into two groups according to those calculated thresholds by receiver operating characteristic curve (407/μL for NK cells and 347/μL for CTLs), the cumulative DMR rates by 18 months were significantly better in higher value group compared to lower value group. In contrast, regulatory T cell counts were significantly lower at 12 and 15 months in patients achieved DMR. These results suggest the presence of dual effects of dasatinib on immune system through the cytotoxic lymphocytes activation and Treg deregulation in different periods in newly diagnosed CML-CP.

The prognosis of patients with primary mediastinal large B-cell lymphoma has improved over recent years. However, the optimal treatment strategy including the role of radiotherapy remains unknown. We retrospectively analyzed the clinical outcomes of 345 patients with newly diagnosed primary mediastinal large B-cell lymphoma in Japan. With a median follow up of 48 months, the overall survival at four years for patients treated with R-CHOP (n=187), CHOP (n=44), DA-EPOCH-R (n=9), 2(nd)- or 3(rd)-generation regimens, and chemotherapy followed by autologous stem cell transplantation were 90%, 67%, 100%, 91% and 92%, respectively. Focusing on patients treated with R-CHOP, a higher International Prognostic Index score and the presence of pleural or pericardial effusion were identified as adverse prognostic factors for overall survival in patients treated with R-CHOP without consolidative radiotherapy (IPI: hazard ratio 4.23, 95% confidence interval 1.48-12.13, P=0.007; effusion: hazard ratio 4.93, 95% confidence interval 1.37-17.69, P=0.015). Combined with the International Prognostic Index score and the presence of pleural or pericardial effusion for the stratification of patients treated with R-CHOP without radiotherapy, patients with lower International Prognostic Index score and the absence of effusion comprised approximately one-half of these patients and could be identified as curable patients (95% overall survival at 4 years). The DA-EPOCH-R regimen might overcome the effect of these adverse prognostic factors. Our simple indicators of International Prognostic Index score and the presence of pleural or pericardial effusion could stratify patients with primary mediastinal large B-cell lymphoma and help guide selection of treatment.

Hepatitis B virus (HBV) surface antigen (HBsAg)-positive patients treated with anti-B-cell lymphoma therapy are at high risk of HBV reactivation; indeed, the incidence is as high as 60-80% without antiviral prophylaxis. Hepatitis caused by HBV reactivation usually leads to discontinuation of chemotherapy, which in itself may be fatal. Therefore, several guidelines recommend antiviral prophylaxis for HBsAg-positive patients treated with chemotherapy. However, there is limited evidence regarding the clinical impact of antiviral prophylaxis on HBV reactivation and subsequent hepatitis and long-term outcome, particularly in patients treated with rituximab (R)-containing regimens. To answer these questions, we conducted a nationwide multicenter retrospective analysis for HBsAg-positive patients with diffuse large B-cell lymphoma (DLBCL) treated with R-chemotherapy. Data were collected from HBsAg-positive patients with DLBCL who received R-CHOP or R-THP-COP regimens as an initial chemotherapy (regardless of steroid use) at 29 participating institutions between January 2004 and December 2014. Key exclusion criteria were as follows: seropositive for HCV or HIV; alanine transaminase (ALT) levels ≥ 100 U/L at the time of diagnosis; and a history of decompensated cirrhosis or hepatocellular carcinoma. Medical data were also obtained for HBsAg-negative DLBCL patients (controls), regardless of anti-HBc or anti-HBs seropositivity; these patients were diagnosed within 2 month (before and after 1 month) of the diagnosis date of each HBsAg-positive patient. Hepatitis was defined as an absolute serum ALT level of ≥ 100 U/L. HBV reactivation-related hepatitis was defined as hepatitis accompanied by an absolute serum HBV DNA level of ≥ 3.3 Log IU/mL or an absolute increase of ≥ 2 Log compared with the baseline value. Statistical analysis was performed at the Japanese Data Center for Hematopoietic Cell Transplantation using Stata software Version 13.1 and EZR 1.35. The study was registered at UMIN (ID: 000025574). A total of 394 patients were eligible: 116 (29.4%) were HBsAg-positive and 278 (70.6%) were HBsAg-negative. The baseline characteristics of the two cohorts were similar; exceptions was HBV status (Table). R-CHOP was the most common regimen (n=337, 85.5%), followed by R-THP-COP (n=57, 14.5%). For HBsAg-positive patients with detectable and quantifiable HBV DNA (n=65, 56.0%), the median baseline HBV DNA level was 2.9 Log IU/mL (interquartile range, 2.0-3.7). HBsAg-positive patients were divided into three groups based on prophylactic nucleoside analogue (NA) therapy: no prophylactic therapy (non-NA, n=9), prophylactic therapy with lamivudine (LAM, n=20), and prophylactic therapy with entecavir (ETV, n=87). Of the HBsAg-negative patients, 64 (23.0%) were seropositive for anti-HBc or anti-HBs. The median follow-up time for HBsAg-positive and HBsAg-negative patients was 4.3 years and 4.5 years, respectively. The 4-year cumulative incidence of hepatitis in HBsAg-positive and HBsAg-negative patients was 21.1% (95% confidence interval (CI): 14.1-28.9%) and 14.6% (95% CI: 10.7-19.2%), respectively (p=0.081). Importantly, the 4-year cumulative incidence of HBV reactivation-related hepatitis was higher in HBsAg-positive patients than in HBsAg-negative patients (8.0% (95% CI: 3.9-14.0%) vs. 0.4% (95% CI: 0.0-2.0%, respectively; p Prophylactic use of entecavir reduced the incidence of HBV reactivation-related hepatitis and reduced mortality associated with HBV reactivation-related hepatitis in HBsAg-positive patients with DLBCL treated with R-chemotherapy. Disclosures Maruyama: Abbvie: Research Funding; Nippon Boehringer Ingelheim: Research Funding; Pfizer: Research Funding; Amgen Astellas BioPharma: Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Fujifilm: Honoraria, Research Funding; MSD: Honoraria, Research Funding; Novartis: Research Funding; GlaxoSmithKline: Research Funding; Chugai Pharma: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Biomedis International: Honoraria, Research Funding; Solasia Pharma: Research Funding; AstraZeneca: Research Funding; Asahi Kasei Pharma: Honoraria; Dai-Nippon-Sumitomo: Honoraria; Zenyaku Kogyo: Honoraria, Research Funding; Mundipharma International: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Astellas Pharma: Research Funding; Otsuka: Research Funding; Dai-ichi-Sankyo: Honoraria. Yamamoto:Bristol-Myers Squibb: Honoraria. Igarashi:Eisai Co Ltd.: Research Funding; Celltrion Inc.: Research Funding; Zenyaku-Kogyo Co.Ltd.: Research Funding; Sanofi K.K.: Research Funding. Izutsu:Takeda: Honoraria, Research Funding; Zenyaku: Research Funding; Amgen: Research Funding; Gilead Sciences: Honoraria; Solasia: Research Funding; Sanofi: Research Funding; Otsuka: Honoraria; Mundhi: Honoraria; Kyowa Hakko Kirin: Honoraria; Abbvie: Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Symbio: Research Funding; Celltrion: Research Funding; Chugai: Honoraria, Research Funding; Nihon Medi-Physics: Honoraria; MSD: Honoraria; Celgene: Consultancy, Research Funding; Bristol- Myers Squibb: Honoraria; Daiichi Sankyo: Honoraria, Research Funding; Astellas: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; HUYA Bioscience International: Research Funding; Eisai: Honoraria, Research Funding; Novartis: Honoraria; Ono: Honoraria, Research Funding; Meiji Seika: Honoraria; Shionogi: Honoraria; Asahi Kasei: Honoraria. Uchida:Nippon Shinyaku: Honoraria; Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Meiji Seika Pharma: Honoraria; Mundipharma: Honoraria; Celgene: Honoraria; Teijin: Honoraria; Novartis: Honoraria; Janssen Pharma: Honoraria; Takeda Pharmaceutical: Honoraria; Otsuka Pharmaceutical: Honoraria; Eisai: Honoraria; Kyowa Hakko Kirin: Honoraria; Chugai Pharmaceutical: Honoraria. Tsukamoto:Chugai: Research Funding; Eisai: Research Funding; Pfizer: Research Funding; Kyowa-Kirin: Research Funding. Nosaka:Celgene Co. LTD.,: Honoraria; Chugai Pharmaceutical Co.LTD.,: Honoraria; Kyowa Kirin Pharmaceutical Development, Inc.,: Honoraria; Eisai Co. Ltd.,: Honoraria; Ono Pharmaceutical Co.LTD.: Honoraria; Bristol-Myers Squibb: Honoraria. Ueda:Rikaken Co. Ltd.: Research Funding; Medical and Biological laboratories Co. Ltd.: Research Funding; Chugai Pharmaceutical Co. Ltd.: Research Funding; Kyowa Hakko Kirin Co. Ltd.: Honoraria, Research Funding; Terumo Co.: Consultancy; Ono Pharmaceutical Co.: Consultancy, Honoraria, Research Funding; Mundipharma K.K.: Consultancy. Mizokami:Sysmex Corporation: Honoraria; Gilead Sciences: Honoraria. Kusumoto:Bristol-Myers Squibb: Honoraria, Research Funding; Chugai Pharmaceutical Co. Ltd: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding.

Recent large-scale randomized clinical trials in Europe and the US demonstrated that maintenance therapy with rituximab significantly improved the progression-free survival (PFS) in indolent B-cell non-Hodgkin lymphoma (B-NHL) patients, especially those with follicular lymphoma (FL). However, rituximab maintenance has not been approved in Japan, because there are no clinical data supporting the benefit of rituximab maintenance in Japanese patients. Therefore, we conducted a single-arm, multicenter bridging study in previously untreated indolent B-NHL patients with high tumor burden. The primary endpoint was 4-year PFS and was expected to be 70 % based on previous studies. Sixty-two patients, including 55 FL patients, were enrolled and received induction therapy with CHOP combined with rituximab (R-CHOP). Fifty-eight patients responding to R-CHOP induction received rituximab at 375 mg/m2 every 8 weeks for 2 years as for the rituximab maintenance arm in the PRIMA study. A 4-year PFS of 69.8 % was obtained (95 % confidence interval 55.9–80.0 %). Rituximab maintenance was well tolerated and common adverse events were infections, neutropenia, and/or leukopenia that were manageable with conventional supportive care. No patients died. These data were compatible with the PRIMA data. R-CHOP induction followed by rituximab is useful in Japanese patients with untreated indolent B-NHL having high tumor burden. Clinical trial number UMIN000001191

Progressive transformation of germinal center (PTGC) usually affects the peripheral lymph nodes. Little is known about the extranodal PTGC. To clarify the clinicopathological and molecular findings of extranodal PTGC, we studied 14 such cases. Using formalin-fixed, paraffin-embedded sections, we carried out histological and immunohistochemical examinations, as well as in situ hybridization (ISH) and polymerase chain reaction (PCR). Eleven patients were female, and three were male. They were between 44 and 77 years old, with a mean age of 62 years. The large intestine (n=7) was the most frequently involved tissue, followed by skin (n=2) and subcutaneous soft tissue (n=2). Oral cavity, Waldeyer ring, and orbit were affected in one case each. Histologically, 13 cases contained both early stage PTGC and late stage PTGC. The remaining 14th case contained only late stage PTGC. Expansion of the marginal zone was identified in three cases. Immunohistochemical study demonstrated the reactive nature of the B-cells in all 14 lesions. However, PCR study revealed immunoglobulin heavy chain (IgH) gene rearrangement in one of our 14 cases. There was no development of B-cell lymphoma in one lesion with IgH rearrangement. ISH study demonstrated Epstein-Barr virus-encoded small RNA+ cells in three lesions. Compared with PTGC of the peripheral lymph node, PTGC of extranodal sites was characterized by a female predominance, an older age group, and the presence of numerous PTGC at the affected sites. However, the histological findings of extranodal PTG were similar to those of lymph node PTGC. The clinicopathological findings of the extranodal PTGCs appeared to be different from those of lymph node PTGC.

Atypical lymphoplasmacytic immunoblastic proliferation (ALPIB) is a rare lymphoproliferative disorder (LPD) associated with autoimmune disease (AID). To further clarify the clinicopathologic, immunohistological, and genotypic findings of ALPIB in lymph nodes associated with well-documented AIDs, 9 cases are presented. These 9 patients consisted of 4 patients with systemic lupus erythematosus, 3 patients with rheumatoid arthritis, and one case each with Sjögren's syndrome and dermatomyositis. All 9 patients were females aged from 25 to 71 years with a median age of 49 years. Four cases presented with lymphadenopathy as the initial manifestation. In 4 patients, immunosuppressive drugs were administered before the onset of lymph node lesion. However, none of the 9 patients received methotrexate therapy. The present 9 cases were characterized by : (i) prominent lymphoplasmacytic and B-immunoblastic infiltration ; (ii) absence of pronounced arborizing vascular proliferation ; (iii) absence of CD10(+) "clear cells" ; (iv) presence of hyperplastic germinal center in 7 cases ; (v) immunohistochemistry, flow cytometry, and polymerase chain reaction demonstrated a reactive nature of the T- and B-lymphocytes ; and (vi) on in situ hybridization, there were no Epstein-Barr virus -infected lymphoid cells in any of the 9 cases. Overall 5-year survival of our patients was 83%. The combination of clinical, immunophenotypic, and genotypic findings indicated that the present 9 cases can be regarded as having an essentially benign reactive process. Finally, we emphasized that ALPIB should be added to the differential diagnostic problems of atypical LPDs, particularly lymph node lesions of IgG4-related diseases.

To clarify the presence or absence of cyclin D1 overexpression in extramedullary plasmacytomas (EMPs) , we examined 11 cases using an immunohistochemical study. None of the 11 cases showed evidence of underlying multiple myeloma at the diagnosis of EMP. The main clinicopathological findings of the 11 cases are summarized in Table I. Four (Nos. 14) of the 11 cases demonstrated greater than 30% Cyclin D1 tumor cells (Fig. 1a), whereas there were no cyclin D1 tumor cells in the remaining seven cases (Nos. 511). According to WHO classification standards, two of the four cyclin D1 cases were poorly differentiated EMP and the other two samples comprised cases of well differentiated EMP and moderately differentiated EMP. Five of the seven cyclin D1 cases were well differentiated EMP and two were moderately differentiated EMP. Two cases (Nos. 6 and 11) showed prominent amyloid deposition. Immunohistochemistry was performed on paraffin sections using a Ventana automated (BenchMarkTM) stainer. There were no CD5 or CD20 tumor cells in any of the 11 cases. All 11 cases showed monotypic intracytoplasmic immunoglobulins and expressed CD38 and CD138 antigens. The plasma cells exhibited monotypic intracytoplasmic k light chain in five patients (Nos. 1, 2, 4, 8, and 9) and l light chain in six (Nos. 3, 57, 10, and 11). Intracytoplasmic immunoglobulin heavy chains were positive in nine (Nos. 24, and 611) of the 10 lesions tested (Nos. 14, and 611) : of these, four (Nos. 3, 6, 7, and 10) stained positive for IgG, three (Nos. 4, 8, and 9) staind for IgG and IgA, and two (Nos. 2 and 11) stained for IgA alone. IgM were not detected in any of the lesions. There were no CD56 or human-herpes virus type8 tumor cells in any of the 11 cases. A two-color fluoresence in situ hybridization (FISH) assay using commercially available 14q32 and 11q13 probes (Vysis Inc, Downers Grove, IL, USA) disclosed separate BCL1 and IgH signals in the nuclei of tumor cells, which is a pattern seen in non-rearranged cells (Fig. 1b). However, two (Nos. 2 and 3) of the three cases (Nos. 13) were scored as having an 11q13 trisomy or polysomy (Fig. 1c). In the remaining one case (No. 4), there were insufficient materials available for FISH analysis. Among the four cyclin D1 cases, one case (No. 1) showed only partial remission and bone marrow involvement was found 13 months after the onset of disease. Complete remission was obtained in the remaining three cases (Nos. 24). However, all of the three cases were relapsed (bone marrow = 2, duodenum = 1). Three (Nos. 13) of the four cyclin D1 cases died of disease. Complete remission was achieved in all seven cyclin D1 cases. Three cases (Nos. 6, 9, and 11) relapsed. The remaining one (No. 11) died due to ovarian cancer. EMPs are rare, typically solitary tumors lacking any signs of systemic spread, and represent approximately 4% of all

CHOP combined with rituximab (R-CHOP) is regarded as one of the most effective treatments for indolent B-cell non-Hodgkin lymphoma (B-NHL), however, its optimal combination schedule remains unknown. We performed a randomized phase II study to explore a more promising schedule in untreated, advanced indolent B-NHL. Patients were randomized to receive either six courses of CHOP concurrently with rituximab (Arm C), or six courses of CHOP followed by six courses of weekly rituximab (Arm S). A total of 69 patients received the concurrent (n=34) or sequential (n=35) regimen. Overall response rate (ORR) in Arm C was 94% (95% confidence interval [CI], 79 to 99), including a 66% complete response (CR) compared with 97% (95% CI, 85-100), including a 68% CR in Arm S. Patients in Arm C experienced more grade 4 neutropenia (85%versus 70%) and experienced more grade 3 or greater non-hematological toxicities (21%versus 12%). Both arms were tolerated well. With a median follow-up of 28.2 months, the median progression-free survival (PFS) time was 34.2 months in Arm C, and was not reached in Arm S. R-CHOP is highly effective in untreated indolent B-NHL, either concurrent or in a sequential combination. Both combination schedules deserve further investigation.

To investigate the factors that affect molecular responses on dasatinib treatment in patients with chronic-phase chronic myeloid leukemia (CML-CP), we performed a clinical trial named the "D-First study." Fifty-two patients with newly diagnosed CML-CP were enrolled in this study and received 100 mg dasatinib once daily. A deep molecular response (DMR) was defined as

We conducted a phase I study to evaluate the safety and efficacy of radioimmunotherapy with yttrium-90-ibritumomab tiuxetan (Y2B8) in Japanese patients with relapsed or refractory indolent B-cell lymphoma. Indium-111-labeled ibritumomab tiuxetan (In2B8; 3.5 or 5 mCi [129.5 or 185 MBq]) was administered on day 1, followed by serial gamma-camera imaging to investigate the distribution of In2B8 in the whole body of patients and to judge the feasibility of Y2B8 administration. Y2B8 with a dose of 0.3 mCi/kg (11.1 MBq/kg) or 0.4 mCi/kg (14.8 MBq/kg) was administered on day 8. Grade 4 neutropenia and grade 3 thrombocytopenia were observed in three of nine of the patients evaluated for safety. Critical toxicities (prolonged thrombocytopenia or severe non-hematological toxicities) were observed in two of six patients in the 0.4 mCi/kg (14.8 MBq/kg) dose group but were not seen in any of the three patients in the 0.3 mCi/kg (11.1 MBq/kg) dose group. The non-hematological toxicities of the nine patients were of grade 2 or less, except in two patients who had been heavily treated previously. They experienced critical toxicities such as infection, diarrhea, hyponatremia and prolonged thrombocytopenia, as well as other frequent grade 2 non-hematological toxicities. Although the pharmacokinetic profiles were similar to those in the US study, one of the two patients was clarified retrospectively as showing abnormal biodistribution of In2B8 in the bone marrow, as judged by an independent third party panel of radiologists. Five of the 10 participants achieved complete responses or unconfirmed complete responses and two partial responses. In conclusion, the recommended dose of Y2B8 for the subsequent phase II study for Japanese patients is 0.4 mCi/kg (14.8 MBq/kg). This dose of radioimmunotherapy was feasible when patients with altered biodistribution of In2B8 were excluded, and it was highly effective. (Cancer Sci 2005; 96: 903-910).

Background: The aim of the study was to determine factors affecting the toxicity and efficacy of rituximab monotherapy in relapsed patients with indolent B-cell lymphoma and mantle cell lymphoma (MCL). Patients and methods: A total of 90 patients were enrolled and treated with rituximab infusions at 375 mg/m 2 once weekly for 4 weeks. Central pathology review revealed that histologically, 81 patients had indolent B-cell lymphoma or MCL: 59 with follicular lymphoma, 17 with MCL, four with marginal zone lymphoma and one with lymphoplasmacytoid lymphoma. Of these, four were ineligible due to violation of other eligibility criteria. Pre-treatment variables affecting toxicities were analyzed for all 90 patients, and those affecting response and progression-free survival (PFS) were analyzed for 77 eligible patients with confirmed indolent B-cell lymphoma or MCL. The relationship between serum rituximab levels and efficacy was also analyzed for 66 eligible patients. Results: Hematological toxicities (grade ≥3) occurred more frequently in females (P

We report here a case of light-chain-restricted monocytoid B-cell (MBC) cluster in reactive lymphadenitis associated with Sjogren syndrome (SS).A 55-year-old Japanese man presented with a 2-month h...

Previous phase II trials in Japan suggested that irinotecan was a promising agent for advanced or metastatic breast cancer pretreated with anthracycline. However, irinotecan has not yet been evaluated in the salvage setting for breast cancer pretreated with both anthracycline and taxane, which are two active agents for breast cancer.The efficacy and safety of irinotecan were retrospectively evaluated in patients with breast cancer who had previously been treated with both doxorubicin and docetaxel. From 1996 to 1999, irinotecan was administered to 20 patients, all with a performance status of2. Irinotecan treatment was repeated in approximately 6 week cycles consisting of the administration of irinotecan once weekly for 4 weeks followed by a 2 week rest. The median dose of irinotecan administered was 100 mg/m(2) weekly. The median number of irinotecan cycles given was 1 (range: 1-8 cycles). The median total dose was 388 mg/m(2) (range: 50-2400 mg/m(2)).Performance status declined to3 after treatment with irinotecan in four patients. Two patients had grade 3 leukopenia; three had grade 3 anemia and one had a creatinine elevation of grade 4. The objective response rate for all patients was 5.0% (95% CI: 0-15.5%). The median time to progression and overall survival were 35 days (range: 17-285 days) and 124 days (range: 17-667 days), respectively, since the start of the administration of irinotecan.Salvage chemotherapy with irinotecan may be inactive against advanced and metastatic breast cancer pretreated with doxorubicin and docetaxel. We will evaluate irinotecan for advanced and metastatic breast cancer patients as first- or second-line chemotherapy combined with anthracycline or taxane.

Introduction Achievement of deep molecular response (DMR) has become an important treatment goal for patients with chronic phase chronic myeloid leukemia (CP-CML) since it is considered to be necessary for the challenge of stopping tyrosine kinase inhibitor (TKI) treatment. However, prognostic marker for prediction of DMR has not been established. We have previously reported the results of D-First study that shorter having time of BCR-ABL1 transcripts and early cytotoxic lymphocyte expansion were associated with achievement of DMR in newly diagnosed CP-CML patients treated with dasatinib. Here, the long-term follow-up results of the study were analyzed after a minimum 36 months follow-up. In this analysis, we mainly focus on dynamics of regulatory T cells (Treg) influencing patients' clinical course, as well as immunoprofiles during dasatinib treatment. Methods: A total of 52 patients with newly diagnosed CP-CML who were enrolled between June 2011 and June 2012 and treated with dasatinib 100 mg once daily on an open-label, multicenter, prospective phase II clinical trial (NCT01464411). All patients were followed-up for minimum of 36 months. Patients were assessed for molecular response before and 1, 3, 6, 9, 12, 15, 18, 24, and 36 months after starting dasatinib by real-time quantitative polymerase chain reaction analysis of BCR-ABL1 transcripts standardized on an international scale (BCR-ABL1 IS). A DMR was defined as less than 0.01% BCR-ABL1IS (MR4). The analysis of immunophenotyping of lymphocyte fractions in the peripheral blood samples was performed by flow cytometry before and 1, 2, 3, 6, 9, 12, 15, 18, 24, and 36 months after starting dasatinib treatment at a centralized laboratory (BML). Results: Patients' characteristic at diagnosis has been reported previously. Briefly, the median age was 52 years. High Sokal risk score was seen in 12% patients. With a minimum follow-up of 36 months, 12 (23%) patients have discontinued therapy. Reasons for treatment discontinuation includes: pleural effusion (N=3), pericardial effusion (1), proteinurea and systemic edema (1), pulmonary hypertension (1), malaise (1), elevation of intraocular pressure (1), interstitial pneumonia (1), and patient's requests (3). A cumulative rate of MMR was 75% by 12 months, 80% by 18 months, 86% by 24 months and 88% by 36 months. A cumulative rate of DMR was 49% by 12 months, 59% by 18 months, 59% by 24 months, and 65% by 36 months. Two patients died because of reasons unrelated to CML. No patients progressed to accelerated or blastic phase. Three-year overall survival was 96%. Flow cytometric analysis of peripheral blood revealed that average number of CD4+ T lymphocytes did not change over the course of 36 months. In contrast, ratio of CD4+CD25+CD127low Treg among CD4+ T cells decreased in a time-dependent manner during the follow-up. The ratio of Treg at 12 months of dasatinib treatment was associated with achievement of DMR, which was especially significant at 18 months (p Conclusion: The long term results from this study of dasatinib as frontline treatment of newly diagnosed CP-CML showed the excellent results of achieving DMR. Inhibition of Treg in peripheral blood, possibly induced by dasatinib, was associated with the achievement of DMR, which could be one of the prognostic markers for predicting the important treatment goal. Disclosures Yoshida: Pfizer: Honoraria, Speakers Bureau; Otsuka Pharmaceutical: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau. Iriyama:Bristol-Myers Squibb: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Okamoto:Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Shionogi & Co., Ltd.: Research Funding; Teijin Pharma Limited: Research Funding; Alexion Pharmaceuticals, Inc.: Research Funding; Eisai Co., Ltd.: Research Funding; Asahi Kasei Pharma Corp.: Research Funding; Bristol-Myers Squibb K.K.: Honoraria, Research Funding; Astellas Pharma Inc.: Research Funding; Toyama Chemical Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Pfizer Inc.: Honoraria, Research Funding; JCR Pharmaceuticals Co., Ltd.: Research Funding. Kumagai:Pfizer: Speakers Bureau; Novartis: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau. Ohyashiki:Bristol-Myers Squibb: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Ariad: Consultancy. Morita:Bristol-Myers Squibb: Speakers Bureau. Sakamoto:Takeda Pharmaceutical: Consultancy; Yakult: Other: Remuneration. Inokuchi:Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria; Celgene: Honoraria; Pfizer: Honoraria.

Introduction: CD5+ DLBCL comprises 5-10% of DLBCL and is an immunohistochemical subgroup of DLBCL, not otherwise specified. CD5+ DLBCL shows a significantly worse survival than CD5-negative DLBCL with rituximab (R)-CHOP. Of note, central nervous system (CNS) relapse, particularly brain parenchymal relapse, frequently occurs even in the R-era (Miyazaki K, et al. Ann Oncol 2011). Most CD5+ DLBCL is classified as non-germinal center B-cell-like (non-GCB)/activated B-cell-like DLBCL. DA-EPOCH-R is reported to show promising outcomes in patients with newly diagnosed non-GCB DLBCL (Wilson WH, et al. J Clin Oncol 2008). High-dose methotrexate (HD-MTX) therapy has a greater potential than intrathecal administration of MTX to prevent brain parenchymal relapse. To explore a more effective treatment for newly diagnosed CD5+ DLBCL, we conducted a multicenter phase II study of DA-EPOCH-R combined with HD-MTX (PEARL5 study; UMIN000008507). Methods: Patients with newly diagnosed stage II-IV disease from 20 to 75 years of age with ECOG performance status (PS) of 0 to 3 were eligible for enrollment. CD5 expression in tumor cells was examined by immunohistochemistry and/or flow cytometry in participating institutes. Four cycles of DA-EPOCH-R followed by 2 cycles of HD-MTX (3.5 g/m2) and additional 4 cycles of DA-EPOCH-R were planned as the protocol treatment. The primary endpoint was 2-year progression-free survival. Secondary endpoints were complete response (CR) rate, overall response rate, 2-year overall survival, 2-year CNS recurrence, and toxicity. Response was assessed at each participating institute using the revised International Workshop Criteria. Toxicity was graded according to the Common Terminology Criteria for Adverse Events v4.0. This planned interim analysis included response and toxicity by the protocol treatment. Results: Forty-seven patients were enrolled between Aug 2012 and Nov 2015. The diagnosis of CD5+ DLBCL in all patients was confirmed by the central pathology review. Cyclin D1 and EBER were negative in all cases examined (n = 47 and n = 46, respectively). According to the Hans' criteria, 72% (33/46) of the patients had non-GCB DLBCL and 28% (13/46) had germinal center B-cell-like DLBCL. The median age was 62 years (range: 37-74 years), and 60% were > 60 years. The baseline clinical features were as follows: female sex, 62%; ECOG PS >1, 4%; stage III/IV, 53%; elevated LDH, 66%; extranodal involvement > 1 site, 34%; bone marrow involvement, 11%; and high-intermediate-risk or high-risk groups of the International Prognostic Index, 47%. Skin/subcutaneous tissue was the most frequent site of extranodal involvement (15%). One patient had primary testicular DLBCL. Forty-six (99%) patients completed the protocol treatment. In the remaining patient, the protocol treatment was discontinued due to grade 3 stomatitis during the sixth cycle of DA-EPOCH-R. The median dose level of DA-EPOCH-R was 2 (range: 1-4). There was no deviation or violation in determining the dose levels of DA-EPOCH-R. At the time of this interim analysis, 46 patients were assessed for response. The CR rate was 91% (42/46; 95% confidence interval [CI], 79 - 98%) and the ORR was 93% (43/46; 95% CI, 82 - 99%). Two patients experienced disease progression during the treatment. Toxicity was assessed in 357 cycles of DA-EPOCH-R/HD-MTX in all 47 patients. There was no treatment-related death. Grade 4 non-hematologic toxicity was observed in only one patient who experienced tumor lysis syndrome with hyperkalemia soon after the first administration of R. The most common grade 3 non-hematologic toxicity was elevated alanine transaminase, which occurred in 6% of cycles. Two patients experienced grade 3 infection (cellulitis and endocarditis). Grade 3 neuropathy occurred in only 1% of cycles. There was no grade 3 cardiac toxicity. The targeted absolute neutrophil count (> 500/mm3) occurred in 77% of cycles. Thrombocytopenia of < 25,000/mm3 occurred in 8% of cycles. Febrile neutropenia (FN), which occurred in 23% of cycles, was manageable. Conclusion: These interim results demonstrate that DA-EPOCH-R/HD-MTX provides a high CR rate in patients with newly diagnosed stage II-IV CD5+ DLBCL. This therapeutic approach was feasible, although most patients experienced FN during the protocol treatment. Disclosures Miyazaki: Eisai: Honoraria; Kyowa Kirin: Honoraria; Chugai: Honoraria. Asano:Jannsen: Honoraria; Chugai: Honoraria. Nishikori:Janssen Pharmaceutical: Honoraria; Eisai: Honoraria, Research Funding; Kyowa Kirin: Honoraria. Sunami:Daiichi Sankyo: Research Funding; Novartis: Research Funding; Celgene: Honoraria, Research Funding; Janssen Pharmaceutical: Research Funding; Sanofi: Research Funding; Bristol-Myers Squibb K.K.: Research Funding; Takeda: Research Funding; Ono Pharmaceutical: Research Funding. Yoshida:Kyowa Kirin: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Celgene: Honoraria; Mundipharma: Membership on an entity's Board of Directors or advisory committees. Tamaru:Kyowa Kirin: Honoraria. Izutsu:Abbvie: Research Funding; Gilead: Research Funding; Celgene: Research Funding; Janssen Pharmaceutical K.K.: Honoraria; Eisai: Honoraria; Kyowa Hakko Kirin: Honoraria; Chugai Pharmaceutical: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria; Mundipharma KK: Research Funding. Kinoshita:Kyowa Kirin: Honoraria; Janssen: Honoraria; Solasia: Research Funding; Gilead: Research Funding; Takeda: Research Funding; Ono: Research Funding; Chugai: Honoraria, Research Funding; Zenyaku: Honoraria, Research Funding; Eisai: Honoraria, Research Funding. Suzumiya:Toyama Chemical: Research Funding; Takeda: Honoraria; Eisai: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Kyowa Hakko kirin: Research Funding; Astellas: Research Funding. Nishikawa:Daiichi Sankyo: Honoraria, Research Funding; Sanofi: Honoraria. Katayama:Takeda: Honoraria; Pfizer: Honoraria; Bristol-Myers Squibb Japan: Honoraria; Alexion Pharmaceuticals: Honoraria; Celgene: Honoraria; Chugai: Honoraria, Research Funding; Astellas: Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Kyowa Hakko Kirin: Honoraria, Research Funding; Taisho Toyama Pharma: Honoraria; Shire: Honoraria; Nippon Shinyaku: Honoraria; Eisai: Honoraria; Dainippon Sumitomo Pharma: Honoraria; Shionogi: Honoraria. Yamaguchi:Zenyaku: Honoraria; Chugai: Honoraria; Kyowa Kirin: Honoraria; Takeda: Honoraria; Eisai: Honoraria.

Background : Nilotinib is a potent and selective inhibitor of BCR-ABL. In the Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients (ENESTnd) trial, frontline nilotinib therapy at 300 mg twice daily (BID) resulted in a higher rate of deep molecular response (DMR) compared to imatinib therapy in patients with chronic myelogenous leukemia in the chronic phase (CML-CP). Furthermore, in the ENESTxtend study, many patients with suboptimal response or treatment failure achieved a major molecular response (MMR) after the nilotinib dose was increased to 400 mg BID from 300 mg BID. The present study was aimed at investigating a strategy of intra-patient nilotinib dose escalation for patients with newly diagnosed CML-CP in order to achieve MR4.5early. Methods : N-Road is a multicenter phase II clinical study for patients with newly diagnosed CML-CP, in which nilotinib was administered at 300 mg BID for 24 months. In this study, increasing the nilotinib dose to 400 mg BID was allowed if patients satisfied the criteria for no optimal response at any time points. The criteria for no optimal response were defined as follows: BCR-ABL1 > 10% on the International Scale [IS] after 3 months, BCR-ABL1 > 1% on the IS after 6 months, BCR-ABL1 > 0.1% on the IS after 12 months, BCR-ABL1 > 0.0032% on the IS after 18 months, two consecutive losses of MMR, and two consecutive losses of MR4.5 (BCR-ABL1 ≤ 0.0032% on the IS). The primary endpoint was the cumulative MR4.5rate by 24 months after the initiation of nilotinib treatment. Results: Between August 2012 and July 2015, 53 Japanese patients were enrolled, of whom 51 were evaluated in the study. The median patient age was 50 years. The ratio of men to women was 33:18. The numbers of patients with low, intermediate, high Sokal risk scores was 21 (41.2%), 21 (41.2%), and 6 (11.8%), respectively, and 3 (5.9%) had an unknown risk. The median duration of nilotinib treatment was 23.8 months (range, 4.1-26.3 months). Of the patients, 33 (64.7%) completed 24 months of treatment, 7 (13.7%) had ongoing treatment, and 11 (21.6%) discontinued treatment because of adverse events (AEs; n=4), protocol deviation (n=1), loss to follow-up (n=3), death (n=1), insufficient effect (n=1), or consent withdrawal (n=1). The cumulative MR4.5 rate (95% confidence interval [CI]) in the 46 evaluable patients was 52.0% (36.9-69.0%) by 24 months (Figure). The cumulative MR4.0 and MMR rates were 60.9% (46.1-76.0%) and 83.5% (69.6-93.5%) by 24 months, respectively. Among the 46 evaluable patients, 26 satisfied the criteria for no optimal response. The dose was increased in 6 of the 26 patients but not in the remaining 20 patients for the following reasons,: hematological AEs (n=3), non-hematological AEs (n=9), achievement of MR4 at 18 months (n=2), patient refusal (n=4), and unknown (n=2). Although 4 patients with no optimal response achieved MR4.5, all of them did not receive an increased treatment dose. The actual mean dose intensities in the patients with or without optimal response were 570 and 560 mg/day, respectively. None of the patients had disease progression, and 1 patient died of an unknown cause during the study. The estimated rates (95% CI) of progression free survival and overall survival at 24 months were 98% (84-100%) and 98% (84-100%), respectively. The most common (≥20%) non-hematological AEs of any grade were rashes (47%), headache (34.2%), fatigue (21.6%) and nausea (23.5%). The most common (≥5%) grade 3/4 laboratory abnormalities were increased lipase (10.6%), decreased phosphate (12.2%) and increased alanine aminotransferase (7.8%). Cardiovascular events were observed to be ischemic heart disease in 2 patients (3.9%). Conclusion: In this study, it was difficult to evaluate the efficacy of nilotinib dose escalation to achieve MR4.5 early because the dose could not be increased to 400 mg BID in many patients who did not show optimal response. However, as we were unable to increase the dose to 400 mg BID in many patients because of AEs and as nilotinib therapy demonstrated superior MR4.5, these results might support continuous nilotinib therapy using a dosage of at least 300 mg BID for newly diagnosed CML. Disclosures Nishiwaki: Novartis PHARMA: Research Funding.

[Background] Bendamustine has demonstrated high response rates in non-Hodgkin lymphomas (NHL). However, standard administration schedule frequently shows delayed hematological recovery resulting in the discontinuation of treatment. Here we designed a novel treatment schedule that could be more tolerable and conducted randomized phase II study (UMIN000008702). [Methods] Patients (pts) with relapsed/refractory(R/R) indolent B-cell NHL and mantle cell lymphoma were randomly assigned to standard arm (120mg/m2 on day1 and 2, every 3 weeks) or Benda-14 arm (120 mg/m2 on day1 and 15, every 4 weeks) of bendamustine monotherapy. Each arm was repeated to 6 cycles and the accomplishment rate (AR) of all scheduled treatment was analyzed as primary end point. [Results] A total of 46 pts were enrolled into the study. Baseline characteristics were: median age 64 years (range 46-78); 48% male; 76% follicular lymphoma; 33% ECOG PS ≥1; 50% having one previous regimen. 65% stage III/IV. 24% bone marrow positive. 33% with bulky mass (>6cm). Using random allocation, twenty two and 24 pts were assigned to standard and Benda-14 arm and the AR of 6 cycles in each arm was 41 and 38%, respectively. The median number of cycles was 4.5 in both arms. Eleven (50%) in standard and 10 (42%) in Benda-14 arm withdrew from protocol due to mainly prolonged hematological toxicities. Three withdrew due to disease progression. Two withdrew due to adverse events (AE). Grade 4 non-hematological AE was observed in one. Overall response rate (ORR) in the standard arm was 77% (95% confidence interval [CI], 59 to 95), including a 50% complete response (CR) compared with 83% (95% CI, 68-99), including a 46% CR in Benda-14 arm. After a median follow-up time of 16 months, the median event-free survival (EFS) in the standard arm and Benda-14 arm was 14.6 months (95% CI, 8-26) and 15 months (95% CI, 11 - not reached), respectively. There was no significant difference between two arms in AR and in EFS (p=0.431). The overall survival (OS) in both arms was the same of 89% at 15 months. [Conclusions] Although this study did not confirm the superiority of Benda-14 to complete 6 cycles of treatment, Benda-14 arm appears to be equally tolerable and active as the present standard therapy. Benda-14 could be a study arm of next trial that determines better practical strategy for this disease population. Disclosures Igarashi: Zenyaku-Kogyo Inc.: Research Funding. Tsukasaki:Daiichi Sankyo Co., Ltd.: Consultancy; Takeda: Research Funding.

The purpose of this study was to investigate the toxicity and the efficacy of re-treatment with rituximab, a chimeric mouse human anti-CD20 monoclonal antibody, in relapsed patients with indolent B-cell non-Hodgkin's lymphoma (NHL) who responded to rituximab in the previous phase I or phase II study. Thirteen patients with relapsed B-cell NHL, each of whom was confirmed to have Revised European-American Lymphoma Classification type II, 1-6 histology (indolent B-NHL), enrolled in this re-treatment study. All were re-treated with rituximab at 375 mg/m2 weekly for 4 consecutive weeks. Rituximab re-treatment was well tolerated with no grade 3/4 nonhematological toxicities, similar to that of the initial treatment. No patients developed detectable human anti-chimeric antibody. Partial responses were observed in 5 of 13 patients (38%; 95% confidence interval [CI], 14% to 68%); 6 patients showed stable disease and 2 showed progressive disease. Overall survival rate was 93% at 19 months of median follow-up after rituximab re-treatment. Median progression-free survival (PFS) after the re-treatment was 5.1 months (95% CI, 4.1 to 5.6 months), and the median PFS after the initial treatment was 8.2 months (95%CI, 5.9 to 11.3 months). Although rituximab re-treatment induced prolonged depletion of normal peripheral blood B cells in all patients, no significant decrease in serum immunoglobulin or complement level was observed. In conclusion, rituximab re-treatment was well tolerated, and it may produce a prolonged PFS in some patients with indolent B-cell NHL who showed initial response to rituximab.

Summary Background CHOP is accepted as the gold standard for first line chemotherapy of aggressive non-Hodgkin's lymphoma (NHL). A dose-escalation study of CHOP was conducted to determine the maximal tolerated dose (MTD) and toxicity profile of CHOP at three-week intervals with or without prophylactic recombinant human granulocyte colony-stimulating factor (rHuG-CSF) in patients with aggressive NHL. Patients and methods The doses of drugs were escalated from 50 mg/m2 to 70 mg/m2 for doxorubicin and from 750 mg/m2 to 2250 mg/m2 for cyclophosphamide, with conventional doses of vincristine and oral prednisolone. After the MTD was determined without rHuG-CSF, dose escalation was conducted with prophylactic rHuG-CSF. Results Thirty-three patients with NHL were enrolled into the study. The MTD without prophylactic rHuG-CSF was 70 mg/m2 of doxorubicin and 1250 mg/m2 of cyclophosphamide, with neutropenia as a dose-limiting toxicity. The MTD with prophylactic rHuG-CSF was 70 mg/m2 of doxorubicin and 2250 mg/m2 of cyclophosphamide. The overall response rate was 100% (76% complete response and 24% partial response). Progression-free survival and overall survival at five years were 45% and 66%, respectively. Conclusions Significant dose escalation of doxorubicin and cyclophosphamide was feasible with prophylactic rHuG-CSF. The efficacy of dose-escalated CHOP should be compared with that of standard CHOP.

Background The optimum dose of granulocyte colony-stimulating factor (G-CSF) for peripheral blood stem cell (PBSC) mobilization after disease-oriented, conventional-dose chemotherapy remains unknown. Methods A multicenter dose-finding study of glycosylated G-CSF (lenograstim) for the mobilization of PBSCs following adjuvant CAF chemotherapy (cyclophosphamide, doxorubicin and 5-fluorouracil) was performed in 38 patients with postoperative breast cancer. Each 10, ten and eight patients were sequentially allocated to one of the three dose groups (2, 5 and 10 micrograms/kg, respectively) of lenograstim. Lenograstim was administered subcutaneously (s.c.) daily from day 8 to the day of the last apheresis and CD34+ cells and colony-forming units-granulocyte macrophage (CFU-GMs) in peripheral blood were measured serially. Additionally, 10 patients who received adjuvant CAF chemotherapy alone also participated in the study, as a control. Results Lenograstim was well tolerated up to 10 micrograms/kg, except for one patient given 10 micrograms/kg who developed transient grade 3 hepatic enzyme elevation. The peak levels of CD34+ cells and CFU-GMs in peripheral blood showed dose-response relationships. The median peak CD34+ cells for the 0, 2, 5 and 10 micrograms/kg dose groups were 5.4, 34.3, 55.0 and 127.6 cells/microliter, respectively, and those of CFU-GMs for the 0, 2, 5 and 10 micrograms/kg dose groups were 0.01, 0.33, 1.32 and 3.30 CFU-GMs/microliter, respectively. Conclusions Considering the previous reports suggesting that a pre-apheresis number of 40-50 CD34+ cells/microliter in peripheral blood is highly predictive for achievement of more than 2.5 x 10(6) CD34+ cells/kg in a standard apheresis procedure of 10 litres, the optimum dose of lenograstim for PBSC mobilization following CAF chemotherapy in patients with postoperative breast cancer is 5 micrograms/kg/day s.c.

A 42-year-old female with a mediastinal tumor and massive pleural effusion ws admitted to our hospital in June 1993. Biopsy revealed lymphoblastic lymphoma. She had no evidence of distant metastasis except pleural effusion. Bone marrow examination revealed a normal karyotype (46, XY). The patient had been progression-free for more than 1 year after achieving complete remission by induction, consolidation and maintenance therapy according to the standard chemotherapy and involved-field radiation for lymphoblastic lymphoma. From May 1996 progressive leukopenia and thrombocytopenia developed. The diagnosis of refractory anemia with excess of blasts (RAEB) was made. Subsequently, in November 1996, she developed acute myelogenous leukemia (AML), M4 type by FAB classification. The karyotype of MDS and AML clones involved inversion (3) (q21q26) and monosomy 7. The EVI 1 gene was examined and was proved to be rearranged and activated. This may be the first case among the therapy-related cases of MDS/AML reported whose karyotypes were followed and in which the mRNA expression of EVI 1 gene involved was directly proved in the leukemogenesis process of chemotherapy-induced secondary MDS and AML.

To determine the maximum-tolerated doses (MTDs), the dose-limiting toxicities (DLTs) and the recommended doses for further trials of docetaxel in combination with a 5-day continuous infusion of 5-fluorouracil (5-FU) in advanced or recurrent breast cancer patients who had been treated previously with at least one chemotherapeutic regimen, patients were treated with docetaxel as a 1-h infusion on day 1 followed by 5-FU as a continuous infusion on days 1 through 5 every 3-4 weeks. Three or six patients were assessed at the following escalating dose levels of docetaxel/5-FU per day: 40/150, 40/300, 50/300, 50/500 and 60/500 mg m(-2). Nineteen patients entered this trial, of whom 18 could be assessed for adverse event and therapeutic efficacy. The DLTs were neutropenia and diarrhoea. The MTDs were 60 mg m(-2) of docetaxel on day 1 and 500 mg m(-2) per day of 5-day continuous infusion of 5-FU. One of 18 patients achieved a complete response and eight achieved partial response (over all response rate: 50%). The recommended doses of docetaxel and 5-day continuous infusion of 5-FU for a phase II trial are 50 mg m(-2) and 500 mg m(-2) per day every 3 or 4 weeks.

We report the successful treatment with nedaplatin of two cases of ovarian cancer that recurred after platinum-containing chemotherapy. A 52-year-old woman presented in June 1994 with massive accumulation of ascitic fluid. Pathological diagnosis of the specimen obtained at surgery in July 1994 was serous papillary adenocarcinoma of the ovary. In September 1995, approximately seven months after the completion of six cycles of CAP chemotherapy (cyclophosphamide, adriamycin and cisplatinum), she was referred to our hospital because of massive accumulation of ascitic fluid. The carbohydrate antigen 125 (CA-125) value was 485 U/ml. Cytologic study of her ascitic fluid was positive for adenocarcinoma cells. She did not respond to intravenous irinotecan and two cycles of intraperitoneal cisplatin. Nedaplatin 100 mg/m2 was administered. Complete response was achieved in September 1996 and continued for four months with a total of seven cycles of nedaplatin. The second case was a 60-year-old woman who was admitted to our hospital in December 1994 because of ascitic fluid. Diagnosis of ovarian cancer was based on an elevated level of CA-125 (1380 U/ml). Treatment with CAP and CC (cyclophosphamide and carboplatin) maintained a partial response for seven months. In August 1996, her disease progressed, although she was receiving CC therapy. Nedaplatin 100 mg/m2 was administered. Partial response was achieved again in November 1996 and continued for four months, with a total of five cycles of nedaplatin. In the light of our experience, treatment with nedaplatin in a patient with recurrent ovarian cancer might be worthwhile as palliative chemotherapy.

Summary Background In clinical trials in the USA, IDEC-C2B8 (a mouse-human chimeric anti-CD20 monoclonal antibody) has demonstrated high response rates with only mild toxic effects in relapsed B-cell lymphoma at a dose of four weekly 375 mg/m2 infusions. The aim of the present trial was to determine whether or not this dose is practically applicable to Japanese patients with relapsed B-cell lymphoma with respect to safety, pharmacokinetics and efficacy. Patients and methods Patients with relapsed CD20 + B-cell lymphoma received intravenous infusions of IDEC-C2B8 once a week for four weeks. A total of 12 patients (four at 250 mg/m2 and eight at 375 mg/m2) were enrolled. Results All 11 eligible patients treated with either dose level tolerated IDEC-C2B8 well. Commonly observed adverse drug reactions were grades 1 or 2 non-hematologic toxicities during the infusion, consisting mostly of flu-like symptoms and skin reactions. All of the observed hematologic toxicities were of grade 3 or less, and transient. A rapid and sustained B-cell decrease in peripheral blood was observed, but no infectious episodes were encountered. Human anti-mouse and anti-chimeric antibodies were not detected. Of the 11 eligible patients (eight with follicular, two with diffuse large-cell and one with mantle cell lymphoma), two showed a complete response and five showed a partial response, and all of the seven responders had lymphoma with follicular histology. A pharmacokinetic analysis showed that the elimination half-life (T1/2) of IDEC-C2B8 was 445 ± 361 hours, and that the serum antibody levels increased in parallel with the course of infusions, and in most patients was still measurable at three months. Conclusions The dose of four weekly 375 mg/m2 infusions of IDEC-C2B8 is safe and effective in Japanese patients with relapsed B-cell lymphoma. Further studies evaluating IDEC-C2B8 are warranted.

We report a case of isolated local recurrence of breast cancer, which was accompanied by idiopathic thrombocytopenic purpura (ITP) and benign monoclonal gammopathy that presented 24 years after the patient underwent mastectomy. A 72-year-old female patient with a chest wall tumor was referred to our hospital in November 1994. Twenty-four years previously she had surgically treated breast cancer, of which the pathology was scirrhous carcinoma. Needle biopsy of the tumor revealed tubular carcinoma, which is compatible with local recurrence of breast cancer. She had no evidence of regional lymph node involvement or distant metastasis. Hematological and serological examination revealed a low platelet count accompanied by M-proteinemia (IgG, kappa-type) and a mild increase in platelet-associated IgG. She was initially treated with extensive-field chest wall radiation (60 Gy), followed by systemic administration of tamoxifen. Complete local control of isolated local recurrence (LR) was achieved after radiation therapy (RT) and the patient has been progression-free for more than 2 years. Platelet count recovered gradually to a normal level after achievement of complete remission induced by radiation and tamoxifen. This may be the first case suggestive of a paraneoplastic syndrome of immune thrombocytopenia accompanied by local recurrence of breast cancer.

We determined cytosol c-erbB-2 protein levels using a sandwich enzyme immunoassay in benign breast disease and primary and recurrent breast cancer and analyzed the relationship between c-erbB-2 protein levels and clinicopathological factors. Overexpression of c-erbB-2 protein, the cut-off value being set at 18 ng/mg protein, was observed in 26 of the 139 cases of stages I-IIIB breast cancer (18.7%), four of the 12 cases of stage IV breast cancer (33.3%) and seven of the 13 recurrent breast cancer cases (53.8%). The levels of c-erbB-2 protein were significantly different between the stages. Overexpression of c-erbB-2 protein in stages I-IIIB breast cancer was associated with histological grade and serum CEA level, but not with other clinicopathological factors. In addition, there was an inverse correlation in the group of stages I-III plus IV breast cancer between c-erbB-2 protein expression and estrogen receptor status. Overexpression of c-erbB-2 protein can be easily determined in the cytosol fraction together with hormonal receptor by this method. The prognostic importance will be evaluated in ongoing adjuvant trials for operable breast cancer patients.

As a different entity of diffuse large B-cell lymphoma (DLBCL) according to the current World Health Organization classification,1 primary mediastinal large B-cell lymphoma (PMBL) is different from DLBCL in terms of clinical, immunohistochemical and genetic features.2 Despite a remarkable advance with first-line treatment of PMBL patients in the rituximab era,3, 4, 5, 6, 7 10–30% of patients still experience progression or relapse. Although patients with relapsed or refractory PMBL are often treated with high-dose therapy followed by autologous stem cell transplantation (HDT/ASCT) after salvage treatment, the progression-free survival (PFS) at 5 years of 27% is unsatisfactory compared with DLBCL in the pre-rituximab era.8, 9, 10 Moreover, information regarding outcomes after HDT/ASCT for relapsed or refractory PMBL is limited in the rituximab era. Therefore, clarifying the current role of HDT/ASCT is vital to establish the optimal treatment strategy.

Information regarding rituximab monotherapy with eight weekly infusions for relapsed or refractory indolent B cell non-Hodgkin lymphoma (B-NHL), in particular for patients pretreated with rituximab, is limited. To evaluate the efficacy and safety of eight doses of rituximab monotherapy, 52 patients with relapsed or refractory indolent B-NHL were enrolled in the present study. Forty of 45 eligible patients (89%) had follicular lymphoma and 24 (53%) were at intermediate or high risk group according to the Follicular Lymphoma International Prognostic Index. The median number of prior chemotherapy regimens was 1 (range 1-7). At the median follow-up of 12.2 months, the overall response rate (ORR), complete response rate (%CR), and median progression-free survival (PFS) were 69% (95% confidence interval [CI] 53%-82%), 47% (95% CI 32%-62%), and 15.6 months (95% CI 10.6- months), respectively. In the 33 patients pretreated with rituximab, the ORR, %CR, and median PFS were inferior compared with values for the 12 patients who had not received rituximab previously (64%vs 83% for ORR; 39%vs 67% for %CR; and 13.8 vs 17.5 months for median PFS, respectively). All mild-to-moderate infusion-related toxicities were reversible. Grade 3/4 non-hematologic adverse events occurred in six of the 52 patients. Two patients developed Grade 4 late-onset neutropenia and a decrease (>50%) in serum immunoglobulin was observed in six patients. In conclusion, rituximab monotherapy with eight weekly infusions is effective in relapsed patients with indolent B-NHL, with acceptable toxicities, including in patients pretreated with rituximab; however, careful monitoring is recommended for infections associated with late-onset neutropenia and hypogammaglobulinemia. (University Hospital Medical Information Network no. UMIN000002974.)

Rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) is one of the most frequently applied initial treatments for indolent B-cell non-Hodgkin lymphoma (B-NHL); however, information on its long-term outcome is limited. Untreated patients in the concurrent arm (Arm C) received six R (375 mg/m(2) ) treatments, 2 days prior to each cycle of CHOP, and patients in the sequential arm (Arm S) received 6 weekly R (375 mg/m(2) ) treatments following six cycles of CHOP. Sixty-nine patients were randomized but two patients were withdrawn before receiving the protocol treatment. Sixty-five patients (94%) had follicular lymphoma, and 37 (55%) were at low risk, 23 (34%) at intermediate risk and seven (10%) at high risk according to the Follicular Lymphoma International Prognostic Index. We previously reported that the overall response rate (ORR) in Arm C and in Arm S was 94% and 97%, respectively. The median progression-free survival (PFS)/7-year PFS rate in Arm C, Arm S and all 67 assessable patients was 2.4 years/23% (95% confidence interval [CI], 9-40%), 3.8 years/41% (95% CI, 23-57%) and 2.8 years/32% (95% CI, 20-45%), respectively. There was no significant difference between the two arms (P = 0.107). The overall survival (OS) of the 67 patients was 95% at 7 years. In conclusion, R-CHOP is a highly effective initial treatment for untreated indolent B-NHL in terms of ORR and OS; however, its long-term PFS is not good enough either in concurrent or sequential combination, warranting further investigations on post-remission therapy.

To investigate the relationship between the degree of liver dysfunction and the pharmacokinetics of docetaxel, a population pharmacokinetic model was developed in an oncology practice without excluding patients with moderate to severe liver dysfunction. Two hundred patients were treated with docetaxel as a single agent or in combination chemotherapy. The plasma concentration-time course data were analyzed using a three-compartment open model with zero-order administration and first-order elimination on the NONMEM program. Sixty-one had elevated transaminase levels, and alkaline phosphatase was elevated in 40. Body surface area, albumin, alpha1-acid glycoprotein, and liver function were found to be significant covariates for the systemic clearance of docetaxel. Compared to patients with normal or minimal impairment of liver function, patients with grade 2 and 3 elevations of transaminases at baseline in conjunction with elevation of alkaline phosphatase had 22 and 38% lower clearances, respectively. Goodness-of-fit plots indicated that the model was fitted well with the observed data, and the bootstrap method guaranteed robustness of the model. We developed a population pharmacokinetic model for docetaxel, which can be used in the setting of an oncology practice. Based on the model, dose reduction by approximately 20 and 40% should be considered for patients with grade 2 and 3 elevations of transaminases at baseline in conjunction with elevation of alkaline phosphatase, respectively.

Regional lymph nodes of Küttner's tumor from 3 patients showed reactive follicular hyperplasia and prominent interfollicular plasmacytosis. The patients were 71-, 57-, and 73-year-old Japanese men. The polytypic nature of plasma cells was demonstrated by immunohistochemistry. There were numerous IgG-positive plasma cells with scattered IgA-positive or IgM-positive plasma cells. IgG4-positive cells comprised 25% to 40% of IgG-positive plasma cells. Prominent polyclonal hyperimmunoglobulinemia was demonstrated on laboratory test in 2 cases examined. An elevated serum IgG4 level (16%) was also demonstrated in 1 patient. The present 3 cases indicated that regional lymph node of Küttner's tumor may show reactive follicular hyperplasia and prominent interfollicular plasmacytosis and should be differentiated from various benign and malignant lymphoproliferative disorders including systemic rheumatic disease, plasma cell type of Castleman disease, and lymph node involvement of marginal B-cell lymphoma of the mucosa-associated lymphoid tissue type showing prominent plasma cell differentiation.

A randomized controlled trial was conducted to evaluate the efficacy of high-dose chemotherapy (HDC) as consolidation of the treatment of high-risk postoperative breast cancer. Patients under 56 years of age with stage I to IIIB breast cancer involving 10 or more axillary lymph nodes were eligible. The primary endpoint was relapse-free survival (RFS). Between May 1993 and March 1999, 97 patients were enrolled, and two patients became ineligible. The median age of the 97 patients was 46 years (range 27-55 years), and 72 (74%) were premenopausal. The median number of involved axillary nodes was 16 (range 10-49). All patients had undergone a radical mastectomy. Major characteristics were well balanced between the treatment arms. Forty-eight patients in the standard-dose (STD) arm received six courses of cyclophosphamide, doxorubicin, and 5-fluorouracil followed by tamoxifen. Forty-nine patients were assigned to undergo HDC with cyclophosphamide and thiotepa after six courses of cyclophosphamide, doxorubicin, and 5-fluorouracil followed by tamoxifen; however, 15 of these patients (31%) did not undergo HDC. HDC was well tolerated without any treatment-related mortality. At a median follow-up of 63 months, the 5-year RFS of 47 eligible patients in the STD arm and 48 eligible patients in the HDC arm was 37% and 52% on an intent-to-treat basis, respectively (P = 0.17). Five-year overall survival of all randomized patients was 62% for the STD arm and 63% for the HDC arm (P = 0.78). Although the prespecified values of the two arms were not so accurate as to allow detection of the observed difference, no advantage of HDC was observed in terms of RFS or overall survival.

Alpha(1)-acid glycoprotein, a plasma protein that binds docetaxel, is a significant determinant of the clearance and activity of docetaxel, but its serum levels in cancer patients are variable. This emphasizes the importance of investigating the pharmacokinetics of unbound drug rather than total drug in the plasma. In the present study, the pharmacokinetics and pharmacodynamics of unbound docetaxel were investigated in cancer patients. Docetaxel was infused over a 1-h period in 69 patients. The concentration of unbound docetaxel was measured in the plasma ultrafiltrate at the end of infusion and the unbound fraction (fu) was calculated. The pharmacokinetics of total docetaxel in the plasma was investigated. The area under the concentration-time curve (AUC) of unbound docetaxel was calculated by multiplying fu by the AUC of total docetaxel. The peak concentration at the end of infusion (Cmax) and AUC of total and unbound drug were compared between patients who did or did not experience grade 4 neutropenia. The median of fu was 4.0%, ranging from 1.2 to 22.6% (5-95% percentile; 1.4-10.5%). Grade 4 neutropenia was observed in 24 patients. Although Cmax and AUC of total drug were not different in patients with or without grade 4 neutropenia, patients who experienced grade 4 neutropenia had significantly greater Cmax (92.3 vs 63.3 ng/mL, P=0.01) and AUC (0.137 vs 0.104 microgxh/mL, P=0.05) of unbound docetaxel. In a logistic regression analysis, the unbound Cmax and alpha1-acid glycoprotein were determinants of grade 4 neutropenia. Pharmacokinetics of unbound drug rather than total drug is a better predictor of neutropenia for docetaxel.

Background: The introduction of the tyrosine kinase inhibitor (TKI) imatinib has dramatically improved the outcomes for patients diagnosed with chronic myeloid leukemia (CML). Furthermore, second-generation TKIs nilotinib and dasatinib, approved as initial treatment agents for patients with chronic myeloid leukemia-chronic phase (CML-CP), are now available clinically. Although the DASISION study demonstrated that in comparison to imatinib treatment dasatinib significantly improves both the major molecular response (MMR) and complete molecular response (CMR) rates; there remains serious concern about the adverse effects associated with it such as pleural effusion (PE). Further, the clinical significance of the mechanism underlying the development of PE is still elusive, especially in the upfront setting. Thus, we analyzed the clinical significance of PE incidence and the association of immunoprofiles based on records derived from the prospective D-First study (ClinicalTrials.gov NCT01464411). The present study sought to investigate the efficacy and safety profile of dasatinib treatment (100 mg QD) among newly diagnosed CML-CP patients in Japan. Patients and Methods: Fifty-two patients with newly diagnosed CML-CP were enrolled in the study. All patients in the present study were followed for at least 18 months. Chest radiographs, and molecular assessments for detecting and quantifying BCR-ABL transcript levels, were performed routinely (at 1, 3, 6, 9, 12, 15, and 18 months) after initiation of dasatinib treatment. An MMR was defined as Results: Of the patients enrolled into the study, 17 (33%) developed PE but all were moderate (Grade 1, 10 and Grade 2, 7). In examining patients at diagnosis with or without PE (PE+ or PE-), a significant difference was observed by patient age (median 63 and 41 years, P = 0.00075); however other characteristics including sex, Sokal risk, BCR-ABL transcript value, body weight, or performance status, did not differ. The MMR rate by 3 months in the PE+ group was significantly higher than that in the PE- group (59% vs 24%, P = 0.013); however, the MMR rates by 12 months and CMR rates by 18 months did not differ by group (MMR rates 82% vs 74%, P = 0.48; CMR rates 71% vs 53%, P = 0.23). Because the incidence of PE was associated with an early response to dasatinib, we investigated the immunoprofiles of patients at 1, 2, and 3 months after treatment with dasatinib according to the presence or absence of PE by 18 months. We found that the lymphocyte value at 1 month significantly affected the incidence of PE by 18 months (area-under-the-curve [AUC] 0.64, 48% vs 21% in lymphocytes ≥1,550/μL and Conclusion: The incidence of PE on dasatinib treatment is associated with advanced patient age, lymphocyte value at 1 month (especially in the CD56-positive fraction), and achievement of an early molecular response. These results suggest that the incidence of PE until 18 months may be due to an immune-mediated mechanism involving NK-cells, with the underlying mechanism contributing to a transient tumor decline that is probably not retained over a long period in patients newly diagnosed with CML-CP. Disclosures Iriyama: Bristol: Honoraria. Yoshida:Bristol: Honoraria. Chiba:Bristol: Honoraria. Ohyashiki:Bristol: Honoraria. Morita:Bristol: Honoraria. Sakamaki:Bristol: Honoraria, Research Funding.

Background: Second generation tyrosine kinase inhibitors (2G-TKIs) are more potent than imatinib against chronic myeloid leukemia in chronic phase (CML-CP) as a first-line therapy, and the majority of patients (pts) on 2G-TKIs could achieve favorable molecular responces over MR3.0 by 24 M (Saglio G, et al. Blood 2011, Kantarjian HM, et al. Blood 2012). It is also likey that molecular response at 3 M will predict outcome for CML-CP pts on imatinib. Furthermore, Mustjoki S, et al. showed that Ph+ stem cell burden at diagnosis is a prognostic marker of molecular responses at 3-9 M on dasatinib or imatinib (Leukemia 2013). Thus, early prognostic marker of outcome is feasible for CML-CP on TKIs. Methods: We are conducting a phase II study (N-road) for newly diagnosed CML-CP pts, in which nilotinib 300mg BID is given for 24 M and is to be escalated to 400mg BID if no optimal response at any check points. The primary endpoint is CMR rate by 24 M, and secondary endpoints include MR3.0/MR4.0 by 12 M and exploring prognostic factors. In this setting, the impact of initial Ph+ stem cell burden on clinical findings and therapeutic responses has been investigated in a sub-study. By July 2014, 48 pts were enrolled and BM CD34+ cell fractions could be evaluated by FACS-FISH analysis at diagnosis in 43 pts, among those 35 pts passed 3 M, 34 pts 6 M and 15 pts 12 M, respectively. Results: MR3.0 rate was 8/35 at 3M, 23/34 at 6M and 10/15 at 12M. When 43 pts were classified into two groups (higher: H, lower: L) according to the mean CD34+ cell counts at diagnosis (5995/mL of BM aspirates), there were significant differences (p The median percentage of Ph+ cells, as measured by FISH (~1000 cells analyzed), in CD34+CD38- fraction at diagnosis was 97.1% (range 2-100%) compared to 98.6% (range 28.2-99.8%) in CD34+CD38+ fraction. The proportion of Ph+ cells in CD34+CD38- fraction correlated with PLT count (r=0.394, p=0.014) but inversely with RBC count (r=-0.474, p=0.003), Hb (r=-0.587, p=0.0001) and Ht (r=-0.475, p=0.003), respectively. Between the two groups divided by the median percentage, there were significant differences in RBC count (406 vs 460 x104/mL, p=0.046), Hb (11.7 vs 14.5 g/dL, p=0.009) and Hct (38.8 vs 44.7%, p=0.040). There were no significant differences in molecular responses at any check points. On the other hand, when divided by the mean percentage (81.1%), there was only a significant difference in PLT count (48.1 vs 27.2 /mL, p=0.028). Absolute Ph+ cell counts in CD34+CD38- fraction were estimated in each patient by combining 3 parameters of CD34 cell counts/mL of BM aspirates, proportion of CD38- fraction and percentage of Ph+ cells. Ph+CD34+CD38- cell counts siginificantly correlated with WBC count (r=0.365, p=0.021) and inversely with RBC count (r=-0.361, p=0.002), Hb (r=-0.409, p=0.009) and percentage of lymphocytes (r=-0.339, p=0.032). Between the 2 groups divided by the median cell counts (256/mL), there were significant differences in RBC (406.5 vs 472.0 x104/mL, p=0.005), Hb (11.8 vs 14.3 g/dL, p=0.004), Hct (39.0 vs 44.6 %, p=0.024). Although we could not find significant difference in molecular responses at any check points, patients with lower number of Ph+CD34+CD38- cells tend to achieve MR3.0 faster than those with higher number of cells (p=0.059) (Figure 1). When divided by the mean cell counts (578/mL), there was a significant difference in WBC count (94.45 vs 22.44 /mL, p=0.016). Conclusion: increased Ph+ stem cell burden apparently affects the level of leukocytosis and anemia at diagnosis, but not MR3.0/MR4.0 rate by 12 M on nilotinib, although it is likely to extend time to achieve MR3.0. Figure1. Time to achieve MR3.0 according to initial Ph+ stem cell burden Figure1. Time to achieve MR3.0 according to initial Ph+ stem cell burden Disclosures Nishiwaki: Novartis: Research Funding. Sugimoto:Novartis: Speakers Bureau. Shimizu:Novartis: Speakers Bureau. Wakita:Novartis: Speakers Bureau. Tojo:Novartis: Research Funding, Speakers Bureau.

Inactivation of the retinoblastoma susceptibility (Rb) gene has been observed in various cancers. Nevertheless, in several cancer cases, including non-Hodgkin's lymphoma, previous investigations showed that the Rb gene product (pRb) was abundantly expressed with varying degree. Here we report the THS-SP1.1 cell line isolated from non-Hodgkin's lymphoma. The THS-SP1.1 cells abundantly expressed pRb and showed resistance against radiation-induced apoptosis. Culture with the antisense phosphorothioate oligonucleotide complementary to the Rb gene augmented the apoptosis of THS-SP1.1 cells after radiation, whereas the control oligonucleotides did not. These data showed that pRb abundantly expressed in the lymphoma cells inhibited radiation-induced apoptosis.

Capecitabine is a three-step prodrug that was rationally designed to be a more effective and safer alternative to its intermediate metabolite, 5'-deoxy-5-fluorouridine (5'-DFUR). We compared the pharmacokinetics/pharmacodynamics of these drugs in metastatic breast cancer patients.Six patients received oral capecitabine at 1657 mg/m2 twice daily and 17 received 5'-DFUR at 400 mg three times daily. Both drugs were administered for 21 days followed by a 7-day rest.Median daily 5'-DFUR AUC was significantly higher for capecitabine than for 5'-DFUR (81.1 vs 32.6 mmol h/l; P = 0.01). Following treatment with 5'-DFUR, the median AUC and Cmax of 5'-DFUR tended to be higher in patients with a partial response (3.83 microg h/ml and 4.88 microg/ml) and stable disease (6.46 microg h/ml and 4.96 microg/ml) than in those with disease progression (2.53 microg h/ml and 1.36 microg/ml). The AUC and Cmax of 5'-DFUR was significantly related to overall survival.These results support the superiority of capecitabine over 5'-DFUR.

To evaluate the efficacy and feasibility of rituximab monotherapy in Japanese patients with relapsed or refractory aggressive B-cell lymphoma.Sixty-eight patients were treated with rituximab at 375 mg/m(2) by eight consecutive weekly infusions. Pretreatment variables affecting overall response rate (ORR) and progression-free survival (PFS) and the relationship between pharmacokinetic parameters and efficacy were analyzed.The ORRs of 68 enrolled patients and 57 eligible patients were 35% [95% confidence interval (CI) 24% to 48%] and 37% (95% CI 25% to 51%), respectively. Median PFS of 53 evaluable patients was 52 days, whereas time to progression of 21 eligible responders was 245 days. Mild to moderate infusion-related toxicities were observed frequently at the first infusion, but all of them were reversible. Elevated lactate dehydrogenase (LDH) and refractoriness to prior chemotherapy were unfavorable factors affecting ORR and PFS (P0.01). Serum trough levels of rituximab and area under the concentration-time curve for responders were higher than for non-responders (P0.05).Eight consecutive weekly infusions of rituximab have significant anti-lymphoma activity for relapsed or refractory aggressive B-cell lymphoma. Several pretreatment variables and serum rituximab levels are useful for predicting its efficacy.

Extragonadal germ cell tumors (EGCT) represent only 2-5% of adult germ cell malignancies. Some publications from Asia have reported inferior treatment outcomes compared to data from an international study group. To ascertain whether this is generally the case, here we analyze treatment outcomes for 30 Japanese patients with EGCT. The medical records of 30 patients (25 nonseminomas and 4 pure seminomas) treated from 1992 to 2002 were reviewed retrospectively. All patients with seminoma achieved long survival except one who died of chemotherapy-related sepsis. Ten and 11 patients with EGCT presented with mediastinal and retroperitoneal primary sites, respectively. The 5-year overall survival (OS) and progression-free survival (PFS) for nonseminoma was 71% and 42%, respectively. The 5-year OS and PFS was 60% and 44%, respectively, for 10 patients with mediastinal nonseminoma, and 91% and 48%, respectively, for patients with retroperitoneal nonseminoma. Tumor marker values on day 7 were available for 19 patients. Among the 19 patients in whom AFP or beta-HCG were measured on day 7, the values had declined in 12 patients and were transiently elevated in 7 patients compared to pretreatment values. The transient elevations of tumor markers were significantly associated with poor OS (P = 0.02) and PFS (P = 0.008). The treatment outcome of Japanese patients with EGCT seemed to be comparable to that reported from international studies, suggesting no difference between ethnic groups. Transient tumor marker elevations on day 7 predict poor survival in EGCT patients and may be a useful parameter for identifying patients requiring more aggressive treatment.

The purpose of this study was to investigate the treatable subsets in cancer of unknown primary origin (CUP). Fifty patients (27 males and 23 females; median age, 53 years) with CUP diagnosed between April 1992 and June 1999 were analyzed retrospectively. Of the 50 patients, 39 received chemotherapy: platinum-based in 31, non-platinum-based in 4, and clinical trials of new agents in 4. Of the 39 patients, 13 (33.3%; 95% confidence interval: 19.1 - 50.2%) showed objective responses, with 4 complete responders. Patients with poorly differentiated carcinomas in whom beta-subunit of human chorionic gonadotropin (beta-HCG) was elevated more than 10 mIU / ml and female patients with peritoneal adenocarcinomatosis achieved high response rates (83.3% and 80%, respectively) with platinum-based chemotherapy, as compared with only a 15.3% response rate in the remaining patients. Platinum-based chemotherapy provided promising results in patients with poorly differentiated carcinomas and in female patients with peritoneal adenocarcinomatosis. Significantly elevated serum levels of beta-HCG in patients with poorly differentiated carcinoma might predict a better response to platinum-based chemotherapy. However, the investigation of novel chemotherapeutic approaches is warranted for other groups of patients with CUP.

Background and Objective Primary mediastinal large B-cell lymphoma (PMBL) accounts for 2 to 4% of non-Hodgkin lymphomas and is characterized by distinct clinical, pathological and genetic features. Although the utility of DA-EPOCH-R without radiotherapy (RT) and a PET-guided RT approach were recently reported, a standard therapy has not yet been established, mostly due to the lack of data from prospective randomized studies. In addition, the prognosis for patients (pts) with relapsed PMBL is not well understood. Therefore, we conducted a multicenter, cooperative retrospective study to evaluate the clinical outcome of pts with PMBL. Patients and Methods We analyzed a total of 345 pts with newly diagnosed PMBL from 65 institutes between May 1986 and September 2012 in Japan. Pts were treated according to each institutional protocol or physicians' decisions. In pts treated with R-CHOP, the role of PET before RT was analyzed. In addition, we analyzed prognostic factors for PMBL pts and constructed a novel prognostic model using data from patients treated with R-CHOP. Results The median age was 32 (range, 17-83) years, and female pts were predominant (58%) among the patient population. Median tumor diameter was 10 cm. Stage I/II, low-risk by IPI, and PS 0/1 were also predominant (68%, 52% and 75%, respectively). The presence of pleural or pericardial effusion, elevated lactate dehydrogenase level and extra-nodal lesions were observed in 46%, 80% and 44% of pts, respectively. With a median follow-up of 48 months in surviving pts, overall survival (OS) and progression-free survival (PFS) at 4 years were 87% and 70%, respectively. The OS and PFS were improved in pts treated with rituximab(R)-containing chemotherapy (n = 267) (4-year OS: 91% vs. 77%, P < 0.001; 4-year PFS: 75% vs. 54%, P < 0.001, respectively). The OS at 4 years for patients treated with CHOP (n = 44), R-CHOP (n = 187), DA-EPOCH-R (n = 9), second- or third-generation regimens (n = 45; 28 with R and 17 without R), and chemotherapy followed by ASCT (n = 57; 43 with R and 14 without R) were 67%, 90%, 100%, 91% and 92%, respectively (P < 0.001). The PFS at 4 years were 40%, 71%, 100%, 83% and 76%, respectively (P < 0.001) (Figure 1). Consolidative RT was given to 42% of the patient population. A total of 119 of 187 pts treated with R-CHOP were assessed by PET/CT after the completion of R-CHOP, and 64 pts received consolidative RT after R-CHOP. In pts with negative PET after R-CHOP (n = 84), the OS (100% vs. 100%, P > 0.99) and PFS (92% vs. 72%, P = 0.36) at 4 years were similar when comparing pts treated with (n =25) or without RT (n =59). However, in pts with positive PET after R-CHOP (n = 28), both OS (100% vs. 60%, P = 0.010) and PFS (80% vs. 17%, P < 0.001) at 4 years were superior in pts who received RT (n = 21) than in pts who did not receive RT (n = 7). A total of 97 pts (28%) relapsed or progressed after first-line therapy. Of these, 67 (19%) and 11 pts (3%) relapsed in the mediastinum and CNS, respectively. Median time from initial diagnosis to relapse or progression was 9 months. Median OS after relapse or progression was 16 months and was higher in patients treated with stem-cell transplantation (SCT) (n = 58; 44 ASCT, 14 allogeneic SCT) than in patients who did not undergo SCT (4-year OS: 67% vs. 31%, P < 0.001). The IPI was predictive for OS (P = 0.002) and PFS (P < 0.001) in pts with PMBL treated with R-CHOP. Moreover, multivariate analysis showed that the presence of pleural or pericardial effusion was a significant and independent prognostic factor for PFS. We constructed a novel prognostic model (PMBL prognostic index; PMBIPI) and classified pts treated with R-CHOP into three different risk groups using these two factors (the presence of pleural or pericardial effusion, and IPI high/intermediate-risk or high-risk). For 93 pts (51%) classified as the low-risk group (0 factor), OS and PFS at 4 years were 97% and 89%, respectively. For 61 pts (34%) classified as the intermediate-risk group (1 factor), OS and PFS at 4 years were 85% and 59%, respectively. For 27 pts (15%) classified as the high-risk group (2 factors), OS and PFS at 4 years were 72% (P = 0.001) and 44% (P < 0.001), respectively (Figure 2). Conclusions The combination of R and chemotherapy improved outcomes for patients with PMBL. In addition, PET could predict the necessity for RT in pts with PMBL treated with R-CHOP. PMBIPI is a promising tool for risk-stratification of pts with PMBL. These findings require further validation in prospective studies. Disclosures: No relevant conflicts of interest to declare.

Cross-resistance is one of the chief obstacles in salvage therapy for refractory breast cancer. Although paclitaxel is one of the most promising drugs, it shows a response rate of 30% at most for patients with breast cancer resistant to doxorubicin, and no effective treatments for tumors refractory to both agents have been reported. We describe a 38-year-old woman with recurrent breast cancer, who was treated successfully with mitomycin-C and vinblastine after doxorubicin-based chemotherapy and paclitaxel failed. The combinations of mitomycin-C and microtubule inhibitors including vinca alkaloids and taxanes may have a potential application to refractory breast cancer.

The current status of breast cancer chemotherapy in Japan was examined and compared with internationally accepted standard therapy, by reviewing the previous treatment of patients with advanced or metastatic breast cancer who had been referred to the National Cancer Center Hospital East. Forty patients were referred mainly from middle-sized or large hospitals between July 1992 and June 1993. The most commonly used regimen for adjuvant therapy was a combination of long-term and oral low-dose fluoropyrimidine compounds (LDFU), which is rarely used in Western countries, and tamoxifen. Some patients had received perioperative intravenous mitomycin C. The adjuvant polychemotherapy most commonly used internationally has been given to only a few patients. The first-line treatment for advanced or metastatic disease in the previous hospitals varied, but myelosuppressive chemotherapy including anthracyclines was given to half of the patients. Oral LDFU was also used for some patients alone or in combination as the first-line chemotherapy. Local therapy for metastasis to soft tissue was performed in 9 patients. Oral LDFU therapy that is frequently used for cancer treatment in Japan should be evaluated in a well designed controlled trial.

Emergence of drug resistance with conventional cytotoxic therapy is a major challenge towards the curability of many cancers, especially in patients undergoing autologous BMT with ex-vivo purged hematopoietic support. We have explored the potential role of photoradiation therapy in purging hematopoietic stem cells of various hematological malignancies. Benzoporphyrin derivative, monoacid ring A (BPD-MA), dihematoporphyrin ether (DHE), and MC-540 were evaluated for the "ex-vivo" purging of residual tumor cells from autologous bone marrow (BM) grafts. BPD-MA and DHE photosensitizing activity was tested against two human large cell lymphoma cell lines and colony forming-unit leukemia (CFU-L) derived from patients with acute myelogenous leukemia (AML). In mixing experiments four log elimination of tumor cell lines was observed after 1 hr of incubation with BPD-MA or DHE followed by white light exposure. By comparison, using the same concentration of BPD-MA or DHE, the mean recovery of normal BM progenitors was 4-5.2% for granulocyte-macrophage colony forming unit (CFU-GM) and 5-9.8% for burst forming unit erythroid (BFU-E). The T lymphoblastic leukemia cell line CEM and its vinblastine (VBL)-resistant subline CEM/VBL100, along with the acute promyelocyte leukemia cell line HL-60 and its vincristine (VCR)-resistant subline HL-60/VCR, were also tested. Our results demonstrated the preferential cytotoxicity of BPD-MA and DHE toward neoplastic cell lines and CFU-L from AML patients. In addition, DHE was slightly more effective in purging tumor cells expressing the p-170 glycoprotein.(ABSTRACT TRUNCATED AT 250 WORDS)

We evaluated the potential role of photoradiation therapy with a benzoporphyrin derivative, monoacid ring A (BPD-MA), and dihematoporphyrin ether (DHE), for the ex vivo purging of residual tumor cells from autologous bone marrow (BM) grafts. BPD-MA and DHE photosensitizing activity was tested against two human large-cell lymphoma cell lines and colony-forming unit-leukemia (CFU-L) derived from patients with acute myelogenous leukemia (AML). In mixing experiments, 4-log elimination of tumor cell lines was observed after 1 hour of incubation with 75 ng/mL of BPD-MA or 30 minutes of treatment with 12.5 micrograms/mL of DHE followed by white light exposure. By comparison, using the same concentration of BPD-MA, the mean recovery of normal BM progenitors was 4% +/- 0.8% (mean +/- SD) for granulocyte- macrophage colony-forming unit (CFU-GM) and 5% +/- 0.8% for burst- forming unit-erythroid (BFU-E). Similarly, DHE treatment resulted in the recovery of 5.2% +/- 2% and 9.8% +/- 3% of CFU-GM and BFU-E, respectively. Furthermore, equivalently cytotoxic concentrations of both DHE and BPD-MA and light were found not to kill normal pluripotent stem cells in BM, as demonstrated by their survival in two-step long- term marrow culture at levels equal to untreated controls. The T- lymphoblastic leukemia cell line CEM and its vinblastine (VBL)- resistant subline CEM/VBL, along with the acute promyelocyte leukemia cell line HL-60 and its vincristine (VCR)-resistant subline HL-60/VCR, were also tested. BPD-MA at 75 ng/mL was able to provide a greater than 4-log elimination of the drug-sensitive cell lines, but only a 34% and 55% decrease of the drug-resistant HL-60/VCR and CEM/VBL cell lines, respectively. On the contrary, 12.5 micrograms/mL of DHE reduced the clonogenic growth of all the cell lines by more than 4 logs. Further experiments demonstrated decreased uptake of both BPD-MA and DHE by the resistant cell lines. However, all the cell lines took up more DHE than BPD-MA under similar experimental conditions. Our results demonstrate the preferential cytotoxicity of BPD-MA and DHE toward neoplastic cell lines and CFU-L from AML patients. In addition, DHE was slightly more effective in purging tumor cells expressing the p-170 glycoprotein. These results suggest that photoradiation with DHE would be useful for in vitro purging of residual drug-resistant leukemia and lymphoma cells.