Ibrutinib is a first-in-class small molecule inhibitor that has shown remarkable efficacy in the treatment of CLL. Current guidelines recommend lifelong administration at a fixed daily dose of 420mg. Data from real-world studies indicate up to 17.5% of patients discontinue ibrutinib due to toxicity. Hypothetically, judicious dose reductions could result in improved tolerance. Our objective was to study the impact of dose reductions on outcomes in CLL patients treated with ibrutinib in a real-world setting. We identified 70CLL patients treated with ibrutinib at Roswell Park Comprehensive Cancer Center between January 2014 and June 2017. Twenty-three (31.3%) patients required dose reductions. There was no statistically significant difference in overall response rate (ORR), clinical benefit rate (CBR), median progression-free survival, and overall survival (OS) between the dose-reduced and standard-dose groups (SDGs). These results extended to all patients, irrespective of whether the modification was made within three months of treatment initiation, or later.

Introduction: Metformin is a frequently prescribed biguanide-class oral hypoglycemic agent. Clinically, it has been demonstrated that metformin improves outcomes when used alone or in combination with chemotherapy in diabetic cancer patients. Metformin derives its therapeutic effects from its intrinsic tumor-suppressor activity, specifically by a direct inhibitory effect in the adenosine monophosphate-activated protein kinase (AMPK) and target of the rapamycin (mTOR) pathways. Both signaling pathways had been targeted pharmacologically in B-cell malignancies. Previously, we demonstrated that the use of metformin during first line chemo-immunotherapy was associated with an improvement in progression free survival (PFS) and overall survival (OS) in patients with diffuse large B-cell lymphoma (DLBCL). The therapeutic effects of metformin in FL have not been studied. Methods: Using the RPCI tumor registry, we performed a retrospective cohort analysis to evaluate the effects of metformin on the clinical outcomes of FL patients who have received bendamustine and rituximab (BR) at our institute either in the front-line setting or in the relapsed/refractory (r/r) setting (N=80). Demographic, clinical, pharmacological and pathological characteristics were recorded. Differences in response rates (complete remission, partial remission and overall response rate), progression free survival (PFS) and overall survival (OS) were evaluated between non-diabetic pts, diabetic pts on metformin, and diabetic pts on other glucose-lowering agents. Results: Based on the use of metformin during chemo-immunotherapy, FL patients were classified as non-diabetic (N=60, 75%), diabetic on metformin (N=12, 15%) or diabetic on other glucose-lowering agents (N=8, 10%). The median age at diagnosis was 66yrs (34-97), 55% were female patients (N=44), 43.8% patients had a FLIPI score of 3 at diagnosis and 51.3% received at least 1 line of therapy. BR was given in the first line setting in 40 patients and in the relapsed/refractory setting in 41 patients (1 patient was treated with BR on two separate occasions during the course of his disease). The median OS for whole cohort of patients was 10 years (0-26y). Response rates to BR in both the first line setting and r/r settings were similar between metformin users and non-users. FL diabetic patients on metformin treated with BR in the first line setting had similar OS and PFS when compared to non-diabetic patients or diabetic patients on other glucose lowering agents (30mo vs 30mo for PFS) (80mo vs. 83 mo for OS). Conclusions: In this cohort analysis, metformin did not appear to provide a meaningful improvement in the response rates, PFS or OS when used during BR therapy for FL in the first line or r/r setting. The sample size and the heterogeneity of the patient population studied could have impacted our findings. Further pre-clinical studies and larger population cohort studies would better define the effect of metformin use in low grade B-cell lymphoma.

Introduction: Ibrutinib is an irreversible Bruton Tyrosine Kinase (BTK) inhibitor that has shown efficacy in the treatment of CLL as a front-line therapy or in patients with relapse/refractory (RR) disease. Anecdotally, accelerated disease progression and refractoriness to subsequent therapies in CLL or other B-cell malignancies patients treated with ibrutinib has been observed. In our present contribution, we studied in a real-world patient population the clinical outcome of CLL patients treated with ibrutinib who discontinued therapy. Methods: We conducted a comprehensive retrospective analysis on CLL patients receiving ibrutinib at our Institute. Demographic characteristics, response to subsequent therapies, and results of FISH analysis were obtained. Correlation between clinical outcomes and status on ibrutinib therapy (responding, progressing, or discontinuing due to toxicity) was performed. Statistical analysis was carried out in SPSS v20. Chi Square, Fisher's exact test were used to compare categorical data, Kaplan Meier and Log rank tests for time to event analysis and Cox regression for univariate analysis. Results: A total of 70 CLL patients treated with ibrutinib were followed for a median period of 19.4 mo [ range 0.3 - 41.3]. Sixty-three patients had RR CLL and 7 received ibrutinib as frontline therapy. Our patients had a median age of 67.9 years (46 - 92), a majority had advanced stage disease (Rai stage 3 - 31.4%, Rai stage 4 - 41.4%). Median number of prior treatments was 2 (range 0-7). Overall response rate (ORR) to ibrutinib was 52.8% (complete response [CR] - 11.4%, partial response [PR] - 41.4%]. Additionally, stable disease [SD] was present in 25.7% leading to a Clinical Benefit Rate (CBR) of 78.5%. A total of 25 (38%) patients discontinued therapy. Reasons for discontinuation included progressive disease (PD) in 13 (52%) (5 with Richter's transformation [RT]), drug toxicity (DT) in 7 (28%), and other reasons in 5 (20%) patients. DTs included atrial fibrillation (n=2), sepsis (n=2), pneumonia (n=1), congestive heart failure (n=1) and fatigue (n=1). Other reasons for discontinuation were other terminal cancer (n=2), patient preference, alcoholism and insurance issues. Univariate analysis showed an increased risk of discontinuation associated with del(13q) (HR 1.56, 95%CI 0.7-3.7, p=0 .32), ATM deletion (HR 1.32, 95%CI 0.5-3.4, p=0 .57), Unmutated IgH (HR 3.5, 0.5-27.3, p=0 .23) though none reached statistical significance. We did not observe an increased risk of discontinuation in patients with del(17p) (HR 0.80, 95%CI 0.3-2.7, p=0 .72). Cytogenetic data after ibrutinib discontinuation was available in 12 patients and showed new onset del(13q) (n= 3), del(17p) (n= 4) and ATM deletion (n= 1) including 1 patient who had complex cytogenetics (≥3 cytogenetic abnormalities). In patients who discontinued therapy, we observed a mortality rate of 72% (18/25) with a median overall survival (OS) of 17.8 mo (95% CI, 7.4-28.2); in comparison, median OS was not reached in patients who remained on therapy (p <0.05). A lower median OS was observed in patients who discontinued due to DT (5.9 mo, 95% CI, 3.9-8), compared to those with RT (11.5 mo, 95% CI 3.1-20), PD (18.2 mo, 95%CI 3.8-32.6) though this was not statistically significant (p= 0.117). Despite trends towards lower median OS in patients who discontinue ibrutinib, univariate analysis did not show a statistically significant association with del(13q) (HR 1.8, 95%CI 0.7-5, p=0 .248), ATM deletion (HR 1.32, 95%CI 0.5-3.9, p=0 .61), Unmutated IGH (HR 1.08, 95%CI 0.13-9, p=0 .94), and ZAP70+ (HR 1.15, 95%CI 0.36-3.64, p=0 .81). Two patients had complex cytogenetics with a median OS of 1.5 mo (HR 4.5, 95%CI 0 .9-22.4, p <0.05). Thirteen patients received subsequent therapy after ibrutinib discontinuation with idelalisib (n=3), lenalidomide (n=3), rituximab with bendamustine (n=2), R-CHOP (n=2), or other treatments (n=3). ORR to post ibrutinib therapy was 23.1% with CR in 3/13 patients (reason for discontinuation- RT - 1, other reasons- 2). Two patients had SD (both discontinued Ibrutinib for PD) leading to a CBR of 38.5%. Eight of 13 patients had PD and died during follow up period. Conclusion: Ibrutinib has good efficacy in the treatment of CLL as front-line therapy and in relapse refractory disease in a real-world setting. However, patients who discontinue therapy have poor survival outcomes and poor response to salvage therapy.

•We compared two PICCs, a standard of care PICC and a PICC manufactured with EndexoTM technology. We followed each line for 60 days and assessed alteplase usage.•We found no statistical difference in alteplase usage between groups, or time to first dose of alteplase.•The increased cost of an EndexoTM PICC does not seem to be offset by a reduction in alteplase usage.•More research is need to assess the efficacy of an EndexoTM PICC at reducing thrombotic complications.

e19023 Background: Adequate cytoreduction with cisplatin-based chemotherapy is commonly used prior to high dose chemotherapy and autologous stem cell support (HDC-ASCS) among R/R aggressive lymphoma patients. However, it is associated with significant cisplatin-related toxicities. Swapping cisplatin with another platinum agent could decrease treatment related toxicities. Methods: To this end, we developed the DHAC regimen and retrospectively studied the clinical outcome of patients receiving this regimen between 06/00 and 07/12 (N = 40). Outcomes included overall response rate (ORR), overall survival (OS) and treatment related toxicities. DHAC consisted of: Dexamethasone at 15mg/m2/dose po q6 hrs x 10 doses, High-dose Cytarabine at 3gr/m2 (1.5gr/m2 if > 50 yrs old) intravenously (IV) q12 hrs for 4 doses and Carboplatin at 200mg/m2 IV q24hrs for 2 doses. When utilized, patients received rituximab at 375mg/m2, 24-48 hrs prior to each DHAC cycle. Growth factor support and anti-microbial prophylaxis was implemented 24 hrs post chemotherapy. The regimen was repeated every 21 days. Responses were assessed after 2 cycles with patients proceeding to HDC-ASCS once optimal cytoreduction was obtained. Results: Median age 61yrs; 58% male; 28% had diffuse large B-cell lymphoma (DLBCL), 27% transformed DLBCL, 7.5% follicular lymphoma (FL); 7.5% Hodgkin lymphoma (HL), 12.5% chronic lymphocytic leukemia (CLL), and 10% mantle cell lymphoma (MCL). Median number of prior therapies was 2 (0-6). Median number of DHAC ± R cycles was 2. The ORR was 52% with a complete response (CR) rate of 38%. HDC-ASCS was performed in 38%. Refractory disease to prior therapy was associated with lower CR rates (P = 0.003) and shorter OS (210 days vs. not reached) (P = 0.049). DHAC ± R was well tolerated with manageable grade 3/4 hematologic toxicities. Conclusions: DHAC ± R is a safe and effective salvage regimen for relapsed/refractory aggressive lymphoma. Refractory disease to prior therapy was associated with poor clinical response to this regimen and shorter OS, stressing the need to develop alternative therapeutic strategies for this subgroup of aggressive lymphoma patients.

e19041 Background: Treatment of locally advanced unresectable (LAU) or metastaticCSCC (mCSCC) is sub-optimal with a paucity of robust data on systemic therapy. Platinum or fluorouracil-based chemotherapy is commonly used. This retrospective study aimed to evaluate the efficacy and outcomes of patients (pts) with LAU or mCSCC treated with systemic therapy. Methods: Records ofpts with CSCC treated with systemic therapy from Jan ‘01 – Jan ‘11 were reviewed. Response was assessed using WHO criteria. Descriptive results were assessed using Wilcoxon Rank Sum test for ordinal responses and Pearson Chi-square test for categorical responses. Survival was calculated by the Kaplan-Meier method. Results: Of 28 pts identified, 25 pts (M:F – 18:7), median age 66 yrs (39, 85) had required data for final analysis. 11 pts (44%) had facial primary tumors (including 7 of the external ear). 19 pts (76%) had LAU and 6 pts had mCSCC. 17 pts (68%) received multi-agent 1st-line chemotherapy (CT). 72%, 76% and 48% pts received platinum, taxane or cetuximab respectively as part of their regimens. 14 pts got 2nd line therapy and 4 pts received concurrent radiation therapy. Partial response (PR) was 44% and 24% pts had stable disease (SD) for a disease control rate of 68%. With a median follow-up of 42.8m, the median progression-free (PFS) and overall survival (OS) were 5.5m (2.3, 13.2) and 10.9m (5.3, 21.3) respectively; 3-yr OS was 22%. Pts with WHO response had improved PFS (20.8m; 4.4, NR; p<.0001) and OS (37.5m; 10.3, NR; p=.0003) compared to pts with SD/PD (PFS 2.7m; OS 5.9m). Use of platinum-based therapy significantly improved PFS and OS, while taxanes and cetuximab had no impact in this small cohort. 91% (n=10) of pts who had a PR received a platinum drug. There was no difference in PFS or OS between face and non-face primary site CSCC and multi-agent versus single agent therapy. Conclusions: Platinum-based therapy remains a standard option in advanced CSCC management. Agents to improve response rates are needed and future trials should address the role of other therapies in CSCC, including novel targeted and CT combinations.

Purpose: The purpose of this review article is to present the current treatment options for castrate resistant prostate cancer in addition to the recently approved agents and their role in treatment. Summary: The biology of prostate cancer and the data supporting the use of traditional chemotherapeutic options in castrate resistant prostate cancer are reviewed. The newly approved agents, sipuleucel-T, cabazitaxel, and abiraterone, are presented as well. The studies that led to the approval of these three agents are discussed in this article as well as their current and potential roles in the treatment of castrate resistant prostate cancer. Conclusion: New mechanisms, drugs, and clinically relevant molecular targets show survival advantage and are new options available for patients after traditional chemotherapy. The roles of these new agents have yet to be further clarified in future studies.

Pneumatosis intestinalis (PI) occurs when inter-luminal air enters the bowel wall of the gastrointestinal tract via a mucosal defect. The condition is caused by numerous disease states, direct trauma, and various drugs. When PI is secondary to drug therapy, discontinuation of the offending agent results in the resolution of PI. We report on the case of a 73-year-old male with a history of refractory gastrointestinal stromal tumor experiencing PI while on sunitinib treatment. PI was noted via computed tomography (CT) scans 68 days after starting sunitinib therapy and showed near complete resolution on a follow up CT performed one month after discontinuing sunitinib. Given that a CT scan performed five months prior to the initiation of sunitinib did not show PI, lack of abdominal symptoms in our patient, and resolution of PI after discontinuing sunitinib, the cause of PI in our patient was likely due to sunitinib treatment.