Background Myelosuppressive chemotherapy-induced febrile neutropenia (FN) is a life-threatening condition. Patients receiving granulocyte colony-stimulating factors (G-CSF) have shorter duration of neutropenia, faster recovery from fever, and shorter duration of antibiotics use. Most strategies for FN prevention using daily G-CSF and pegfilgrastim are based on overseas studies. Data on Japanese patients were lacking; thus, we previously determined the incidence of FN in non-Hodgkin B cell lymphoma (B-NHL) patients at our center. Here, we aimed to gain additional insights into pegfilgrastim use in this population. Methods This single-center, retrospective, observational study (STOP FN in NHL 2) enrolled patients with B-NHL who underwent a regimen comprising rituximab and CHOP therapy over a 2-year period (January 2015-June 2017). The incidence of FN in cycle 1 of chemotherapy, risk factors for FN development, and use of daily G-CSF and pegfilgrastim were evaluated. Results We evaluated 239 patients: 61 patients did not receive G-CSF and 178 received G-CSF. The incidence of FN was 10.5% (95% confidence interval [CI] 6.9-15.1%) in cycle 1 and 13.0% (95% CI 9.0-17.9%) in all cycles. The FN incidence was significantly lower (P = 0.0008) in patients receiving daily G-CSF and pegfilgrastim than patients not receiving G-CSF. Significant risk factors for FN were age ≥ 65 years, albumin < 3.5 g/dL, hemoglobin < 12 g/dL, and no prophylaxis with daily G-CSF/pegfilgrastim during cycle 1. Conclusions The incidence of FN in cycle 1 and in all cycles and the identified risk factors were similar with those we previously reported; thus, our results validate previous findings. Trial registration UMIN000029534.Keywords Febrile neutropenia . Incidence . Japan . Non-Hodgkin B cell lymphoma . R-CHOP . Risk factor Background Myelosuppressive chemotherapy-induced febrile neutropenia (FN) is a life-threatening condition associated with increased morbidity and mortality [1, 2] that often results in extended hospitalization and death [3]. FN may lead to unwanted chemotherapy dose reductions or may halt treatment altogether, which can compromise treatment outcomes [2].According to the current Japanese guidelines [4], all patients who present an FN incidence ≥ 20% should receive prophylaxis granulocyte colony-stimulating factor (G-CSF), regardless of the presence or absence of risk factors, in order to prevent and treat FN induced by chemotherapy [5]. Further, all patients with risk factors for FN and FN incidence of 10 to < 20% should receive prophylaxis with G-CSF [4].Findings from this study were presented as a poster presentation at the

Proteasome inhibitor MG132 was shown to enhance the secretion of interleukin 8 (IL-8) by various cells. The enhancement is regulated by the transcription factor activator protein-1 (AP-1) at the transcriptional level. AP-1 is a dimer formed by AP-1 family proteins. The purpose of the present study was to explore the combinations of the AP-1 family proteins that contribute to MG132-driven IL-8 secretion. Oral squamous cell carcinoma-derived cell lines, Ca9-22 and HSC3, were used to demonstrate their response to MG132. IL-8 secretion was augmented by MG132 in both cell lines. c-Jun expression was detected in both the cell lines, whereas c-Fos expression was detected only in the HSC3. The influence of MG132 stimulation on c-Jun and c-Fos expression was further examined by western blot analysis. c-Jun expression was increased by MG132 stimulation, whereas c-Fos expression was not detected even after MG132 stimulation. As JunB is reported to inhibit the transcriptional activity of the AP-1 complex, we speculated that the c-Jun homodimer should contribute to IL-8 enhancement. Expression vectors encoding wild type and c-Jun mutants, M17 and M22-23, respectively, were constructed and transfected into the Ca9-22 cells. In contrast to our expectations, MG132-induced IL-8 secretion was significantly reduced in all the transfectants suggesting that other c-Jun members might form homodimers with c-Jun and contribute to IL-8 enhancement. Transfection of the cells with c-Jun or JunB small hairpin RNA (shRNA) reduced IL-8 secretion up to 50% and 65% of the control shRNA transfectant. Furthermore, cotransfection of both shRNA almost completely inhibited the IL-8 secretion. These results indicate that JunB not only inhibits but also enhances the transcription of c-Jun targets in combination with c-Jun.

Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy is the standard of care for patients with diffuse large B-cell lymphoma (DLBCL). Typically, the dose of rituximab is 375 mg/m2; data obtained from recent clinical trials about the pharmacokinetics of rituximab showed that elderly women have a better outcome than elderly men and a more favorable pharmacokinetics of rituximab than all other patients with DLBCL. Therefore, optimization of the dose and schedule of rituximab is required for the subpopulation of patients with DLBCL that show a fast clearance of rituximab. The metabolism of rituximab, which is mostly excreted through the kidneys, is not completely understood thus far. Renal function, which is determined using creatinine clearance (CCr), at the time of administration may affect the clearance of rituximab, and thus, the therapeutic outcomes. We examined the association between the rate of CCr and survival outcome in patients with DLBCL treated with R-CHOP. We evaluated 653 patients with newly diagnosed de novo DLBCL, excluding those with transformed DLBCL, at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research from January 2005 to December 2015. All patients were treated with R-CHOP or modified regimens. CCr was calculated using the Cockcroft-Gault formula. Tumour staging and response assessment were performed using the revised response criteria for malignant lymphoma and the International Conference on Malignant Lymphomas Imaging Working Group by using positron emission tomography-computed tomography and bone marrow biopsy. Progression-free survival (PFS) and overall survival (OS) were defined as the time from the date of initiation of R-CHOP to the date of disease progression, relapse, last follow-up, or death from lymphoma. Deaths due to reasons other than lymphoma were censored. PFS and OS were estimated using the Kaplan-Meier method, and the differences were compared using the log-rank test. The Cox proportional hazards regression models were used to identify the prognostic factors to predict the PFS and OS. A total of 653 patients with DLBCL were met the inclusion criteria, and the median follow-up for survival was 64 months. Our results showed that 133 (20.3%) patients had a CCr rate less than 60 mL/min. Patients with a low rate of CCr were older, had an advanced stage of DLBCL, extranodal disease, high levels of lactate dehydrogenase (LDH), and high proportion of non-germinal cell (GC) subtype, which are indicators of a poor prognosis. Therefore, patients with a lower rate of CCr showed poorer PFS (5-year PFS 74.2% vs. 80.8%, p = 0.13) and OS (5-year OS 77.1% vs. 86.9%, p=0.013). Further, we performed subgroup analysis according to CCr using the revised International Prognostic Index (R-IPI), which includes of age >60 years, stage III/IV disease, elevated LDH levels, performance status ≥ 2, more than one extranodal site of disease. Although all prognostic groups did not show a significant difference depending on the CCr, the groups with very good and good prognosis showed superior PFS in a low rate of CCr group than high rate of CCr group (Figure 1). The results of subgroup analysis for OS were similar to those observed for PFS. Thus, patients with very good and good prognosis determined using R-IPI may be affected by the subtle difference in the clearance of rituximab, whereas those with poor prognosis may not be affected by this difference. Results of multivariate analysis for PFS and OS showed that a low rate of CCr was not a significant prognostic factor. Thus, our results showed that although CCr may be a factor for clearance of rituximab, no significant association exists between the rate of CCr and survival. Our findings suggest that modification of the dose of rituximab depending on CCr is not recommended for improving survival. Further studies are required to establish an optimal dose and schedule of rituximab in all subgroups of patients with DLBCL. Disclosures Nishimura: Chugai Pharmaceutical Co., Ltd.: Other: commissioned work. Mishima:Chugai pharmaceutical inc, Roche: Other: commissioned work. Yokoyama:Chugai pharmaceutical inc, Roche: Other: commissioned work. Terui:Bristol myers Squib: Honoraria; Celgene: Honoraria; Janssen Pharmaceutical KK: Honoraria; Takeda pharmaceutical: Honoraria; Novartis pharma: Honoraria.

No abstract

Background: Primary mediastinal B-cell lymphoma (PMBCL) is a unique entity of non-Hodgkin lymphoma with distinct clinical and biological features. Several different chemoimmunotherapy approaches have been studied, mostly in retrospective case series, without reaching a consensus on the optimal upfront treatment. A phase 2 study, published by Dunleavy et. al. (NEJM 368, 1408(NEJM 368, -1416(NEJM 368, , 2013, demonstrated excellent survival outcomes after R-DAEPOCH without consolidative radiotherapy in 51 patients with PMBCL. Based on these promising data we adopted R-DAEPOCH regimen as an upfront therapy in newly diagnosed PMBCL patients. Aims: The aim of the study was to evaluate the outcomes and toxicity of newly diagnosed PMBCL patients treated with R-DAEPOCH vs R-VA-COPB, an ambulatory dose-dense third generation regimen previously used in our center. Methods: We thoroughly reviewed the electronic medical records of newly diagnosed PMBCL patients treated with R-DAEPOCH in our center between 1.2016 and 12.2017 in comparison with prior historical cohort of patients treated with R-VACOPB between 3.2003 and 12.2009. We documented demographics, clinical characteristics and toxicity and analyzed the survival outcomes. Comparison between categorical variables was done using Chi-square test, survival analysis with Kaplan-Meier method and comparison between survivals with Log-Rank test. Results: Forty nine patients were included in the study. Eighteen patients were treated with R-DAEPOCH and thirty one patients were treated with R-VACOPB. Median follow-up was two years (range 0.3-4.4) in the R-DAEPOCH group and 10.2 years (range 0.4-14.4) in the R-VA-COPB group. There were no statistically significant differences between the two groups in terms of gender, stage I/II at diagnosis, B symptoms, ECOG performance status, LDH levels, aaIPI category, bone marrow involvement, disease bulk, SVC syndrome, pericardial effusion, pleural effusion, and extra-nodal involvement. Median age was 32 years (range 23-43) in the R-DAEPOCH and 31 years (range 17-48) in the R-VACOPB group. Neutropenic fever (n = 36) was observed in 56% of the R-DAEPOCH patients compared with 20% in R-VACOPB (p = 0.036). Most neutropenic fever events in the R-DAEPOCH arm occurred after the fifth cycle (range 3-6). Median last escalation was in the third cycle (range 1-5). None of the baseline patient characteristics predicted PFS or OS. No statistically significant differences were found in PFS and OS between the two groups. Median PFS was not reached in both groups (p = 0.31). Two year PFS was 76% in the R-DAEPOCH and 86% in the R-VACOPB group. Median OS was not reached in both groups. Summary/Conclusion:With patient and disease characteristics comparable to historical cohort, outcomes of patients treated with R-DAEPOCH did not differ in terms of PFS and OS from patients treated with R-VA-COPB. R-DAEPOCH was associated with higher toxicity. These data may challenge the concept of routinely using R-DAEPOCH in PMBCL.

Introduction The international prognostic index (IPI) was a most common prognostic score in patients with aggressive non-Hodgkin lymphoma. Therefore, rituximab improved OS in patients with diffuse large B-cell lymphoma (DLBCL), revised IPI (R-IPI) was suggested. Although, the 5-year OS is higher than 50% in patients of high risk R-IPI. National Comprehensive Cancer Network published an enhanced IPI (NCCN-IPI) for improving risk stratification. However, NCCN-IPI didn't enough evaluate clinical and disease characteristics, for example beta-2-microglobulin (B2MG), cell of origin, albumin, soluble interleukin-2 receptor (sIL-2R). Aim of this study is to evaluate clinical and disease prognostic factor in patients with DLBCL. Methods We retrospectively analyzed 647 patients who were newly diagnosed de novo DLBCL and treated with R-CHOP in our hospital from January 2005 to December 2016. We excluded primary central nervous system lymphoma and transformed from low grade B-cell lymphoma. Median follow-up time is 58.5 months (range; 2-160 months.). We collected data of blood and imaging test before chemotherapy. The patient's baseline clinical and disease characteristics included age, Ann Arbor stage, serum albumin, bulky, B symptoms (defined as recurrent fever, night sweats, or >10% weight loss), B2MG, cell of origin, cluster of differentiation (CD) 5 positive, serum C-reactive protein (CRP), ECOG performance status (PS), ferritin, gender, lactate dehydrogenase (LDH), sIL-2R, monocyte, number and site of involvement extranodal. We evaluate over 60-years old, advance stage (Ann Arbor stage Ⅲ-Ⅳ) and more than PS 2. We defined the cut-off value of B2MG, CRP, ferritin, sIL-2R, monocyte and albumin by using receiver operating characteristic curves. LDH was over the upper limit of normal. Cell of origin was classified by Hans' algorithm. CD 5 was evaluated by immunohistochemistry. The univariate analyses of between factors and OS was used in univariate of log-rank test. And the multivariate analysis was used cox proportional hazards regression analysis. Results The patient's median age was 65 years old (range 17-90 years old.). The cut-off value of B2MG is ≧2.23 mg/L, CRP is ≧0.4 mg/dl, ferritin is ≦250 ng/ml, sIL2-R is ≧1000 U/mL, monocyte is ≧608 /μL and serum albumin is ≦3.4 g/dl. In the result of univariate analysis, age, stage, albumin, B symptoms, B2MG, CD5, CRP, PS, ferritin, LDH, sIL-2R, monocyte, nonGCB, the number of extranodal sites (>1) and the involvement of bonemarrow, liver, lung, muscle, skin and pancreas affected OS. In multivariate analysis, the worse prognostic factors were age (Hazard ratio (HR) 2.13, 95% confidence interval (CI) 1.27-3.57, p<0.01), albumin (HR 1.59, 95% CI 1.01-2.51, =0.047), B2MG (HR 1.86, 95% CI 1.18-2.93, p<0.01), PS (HR 2.01, 95% CI 1.22-3.33, p<0.01), sIL-2R (HR 1.75, 95% CI 1.11-2.76, p=0.016), pancreas (HR 4.43, 95% CI 1.75-11.22, p<0.01) and skin (HR 1.94, 95% CI 1.11-3.39, p=0.021). Albumin, B2MG and sIL-2R weren't included prognostic score of IPI, R-IPI and NCCN-IPI. In order to validate we developed prognostic score consisting of 5 factors (age, PS, B2MG, sIL-2R and albumin). And compared with NCCN-IPI in our data. We categorized patients into 4 risk groups: low (0 factor), low-intermediate (1 factor), high-intermediate (2 or 3 factors), high (4 or 5 factors). The low risk of 5-year OS was 91.5%, low-intermediate risk was 86.2%, high-intermediate risk was 72.3% and high risk was 37.4%. The low risk of NCCN-IPI was 95.1%, low-intermediate was 86.2%, high-intermediate was 68.8% and high was 50.6%. The absolute difference in the 5-year OS between low and high risk groups was 54.1% with our study prognostic score compared with 44.5% with NCCN-IPI in our study. Conclusions Our study suggest that B2MG, sIL-2R and serum albumin are significant prognostic factors in patients with DLBCL in the rituximab era. Figure. Figure. Disclosures Yokoyama: Chugai pharmaceutical inc, Roche: Other: commissioned work. Mishima:Chugai pharmaceutical inc, Roche: Other: commissioned work. Nishimura:Chugai pharmaceutical inc, Roche: Other: commissioned work. Terui:Novartis pharma: Honoraria; Takeda pharmaceutical: Honoraria; Janssen Pharmaceutical KK: Honoraria; Celgene: Honoraria; Bristol myers Squib: Honoraria.

Background: We previously reported that low-dose erlotinib has a certain degree of efficacy with lower toxicity in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations (Eur J Cancer 2015). This multicenter phase II study was undertaken to investigate the efficacy and safety of lowdose erlotinib for those patients with frailty. Methods: Chemotherapy-naïve NSCLC patients with EGFR-mt who had frailty were enrolled and received erlotinib 50 mg/d. Dose escalation was allowed to those with stable disease after 4 weeks. Patient's frailty was defined as follows: (Group 1) 20 to 74 years of age with Eastern Cooperative Oncology Group performance status (PS)!2 or Charlson Comorbidity Index (CCI)!6 points; (Group 2) 75 to 80 years of age with PS ! 1 or CCI!6 points; (Group 3)!81 years of age with any PS and CCI. The primary endpoint was independent review committee (IRC)-confirmed objective response rate (ORR) to the low-dose erlotinib, with target ORR of 65% and threshold of 50% (SWOG two-stage design). Results: Eighty patients were enrolled between December 2014 and April 2017: males/ females 26/54; median age 80 (range 49-90); Group 1/2/3 15/28/37; Ad/Sq/Others 76/1/ 3. EGFR-mt types were: exon 19/21 42/38. All 80 patients were included in efficacy and safety analysis. The IRC-confirmed ORR was 60.0% (90%CI: 50.2-69.2%), and the primary endpoint was met. The disease control rate was 86.3% (90%CI: 78.3-92.1%). Median progression-free survival was 9.2 months. Although overall survival data are immature, median survival time and 1-year survival rate were 26.3 months and 68.9%, respectively. Toxicities were generally mild, with a few grade 3 or more toxicities. There was no case of interstitial lung disease or treatment-related death. Conclusion: This is the first prospective study evaluating low-dose erlotinib for frail patients with EGFR-mt NSCLC. Low-dose erlotinib is active and could be a treatment option for those patients. O2 À 11 À 5 Osimertinib for patients with EGFR T790M mutation-positive non-small-cell lung cancer who have poor performance status

Introduction; The prognosis of relapsed and refractory DLBCL (RR-DLBCL) after R-CHOP therapy is poor and the more than half of these cases had no cure. Autologous peripheral blood stem cell transplantation (auto-PBSCT) raises the survival rate about 20%, however many patients cannot reach the transplantation. The poor prognostic factors in RR-DLBCL have not been cleared yet. MYC/IgH translocations induced poor prognosis of DLBCL, especially double hit DLBCL is independent category in WHO 2016 criteria. However, in RR-DLBCL, the impact of MYC/IgH translocation had not been cleared yet. In this study, we studied the expression of MYC/IgH translocation in RR-DLBCL cases and analyzed the relationships with the prognosis by retrospectively. Methods; We studied the translocations of MYC and BCL-2 by FISH analysis RR-DLBCL cases from 2006 to May 2017 in our institute. The cells were obtained from the biopsy samples at the first diagnosis and relapse or refractory status. The cells have been fixed by carnoy solution. After hybridizing with each probe, the 100 cells or more were analyzed by In Cell Analyzer 6000 and the positive levels were determined as 5% or more in both MYC and BCL-2. Additionally pathological review and clinical status were studied among these cases, retrospectively. All cases are treated by R-CHOP at diagnosis and followed by salvage therapy after relapse with or without auto-PBSCT. This study protocol was approved in our institutional ethical review board. Results; Within 46 RR-DLBCL, 24 cases were negative for MYC translocation and 22 were positive. All MYC-positive cases were translocated with IgH except one case and the 9 cases (47.8%) were BCL2-positive. The median age was 62.4 (40-83) in MYC-negative and 62.6 (44-82) in MYC-positive cases. GC type was 11 (45%) and 9 (40.9%), and High IPI cases were 8 (33.3%) and 12 (54.5%) in MYC-negative and positive cases respectively. In these RR-DLBCL, the 5-year Overall survival (OS) was inferior in MYC-positive group (79.4%, 95% CI; 53.5-91.8%) compared to MYC-negative group (56.2%, 95%CI; 32.1-74.7%) (P=0.0414). There was no significant difference in progression free survival (PFS). There were no statistically significant differences in overall response rate (ORR), OS and PFS after second therapy between MYC-positive and negative group. The death cases were 6 (25%) and 11 (50%), respectively (P=0.079). By the pathological analysis, the transformed DLBCL cases from follicular or indolent lymphoma were significantly more in MYC negative group (12; 50%) than in MYC positive group (4; 18.1%) (P=0.024). In the transformed DLBCL, at the first relapse, 2nd biopsy detected heterogeneous pattern, such as the only indolent lymphoma, DLBCL or contamination of both type. In such cases, at the 2nd relapse, the pathological diagnoses had changed again. OS and PFS were significant superior in transformed DLBCL than de-novo DLBCL after second therapy. 2-year OS were 59.0%(95%CI 37.9-75.1%) and 92.9%(59.1-99.0%) (P=0.00474) and PFS were 16.13 and 49.43 moths (95% CI was 10.4 to 20.1 months and 16.1 to 63.7 months; P=0.00063), in transformed FL and de novo-DLBCL, respectively. The multivariate analysis identified transformed DLBCL as independent prognostic factor for both PFS and OS. Also, in MYC positive group, transformed DLBCL cases were superior to de-novo DLBCL for both OS (17.5 months vs. not yet reached, P=0.0353) and PFS (13.3 vs. 63.3moths, P= 0.0353) respectively. Discussion and conclusion; From our results, it was suggested MYC-positive is still poor prognostic factor of overall survival in RR-DLBCL. However, RR-DLBCL contaminated transformed DLBCL especially in the MYC-negative group. After 2nd therapy, the transformed DLBCL were related to good prognoses compared to de-novo-DLBCL, in also MYC-positive group. We can consider that treatment strategy of transformed DLBCL were should be separated from de-novo DLBCL at the relapse, then MYC-positive transformed DLBCL still possesses for indolent character. Disclosures Mishima: Chugai pharmaceutical inc, Roche: Other: commissioned work. Yokoyama:Chugai pharmaceutical inc, Roche: Other: commissioned work. Nishimura:Chugai pharmaceutical inc, Roche: Other: commissioned work. Terui:Celgene: Honoraria; Janssen Pharmaceutical KK: Honoraria; Takeda pharmaceutical: Honoraria; Novartis pharma: Honoraria; Bristol myers Squib: Honoraria.