Central nervous system (CNS)-directed prophylactic intrathecal (IT) therapy is indicated in patients with Burkitt and acute lymphoblastic lymphoma. Its role in diffuse large B cell lymphoma (DLBCL), a heterogeneous subtype, is less well defined. While addition of rituximab to standard cyclophosphamide-hydroxydaunorubicin-oncovin-prednisone (CHOP) chemotherapy (R-CHOP) has improved the outcomes of DLBCL patients, its role in reducing CNS relapse is unclear. We aim to (1) evaluate the clinical risk factors predictive of CNS relapse, (2) the role of rituximab in influencing CNS relapse, and (3) role of intrathecal prophylaxis. Four hundred ninety-nine patients with DLBCL from 2000 to 2008 were included (CHOP 179 vs. R-CHOP 320). IT prophylaxis was administered to 82 patients based on our institution's guidelines. Baseline characteristics between CHOP- and R-CHOP-treated patients were similar. Although R-CHOP significantly increased the complete remission rate from 71% to 81% (P < 0.01), CNS relapse rates remained unchanged (R-CHOP 6% vs. CHOP 5.1%). On multivariate analysis, poor performance status (Eastern Cooperative Oncology Group >1; hazard ratio (HR) = 2.01, 95% confidence interval (CI) 1.29-3.14), failure to attain remission (non-complete response (CR) vs. CR: HR = 2.39, 95% CI = 1.03 to 5.51), testicular (HR = 6.67, 95% CI = 1.62 to 27.53), kidney (HR = 20.14, 95% CI = 5.23 to 77.46), and breast involvement (HR = 6.14, 95% CI = 1.61 to 23.37) were each independently predictive of CNS relapse. Use of IT prophylaxis did not appear to decrease CNS relapse. Median survival after CNS relapse was 3.2 months. CNS relapse, a fatal event, remains a challenge in R-CHOP-treated patients. IT prophylaxis may not be sufficient to reduce CNS relapse, and strategies including systemic agents with high CNS penetration should be evaluated in high-risk patients identified in this study.

Background: Dysregulation of the canonical Wnt signaling pathway has been implicated in colorectal cancer (CRC) development as well as incipient stages of malignant transformation. An important regulator of the Wnt pathway are tankyrases that function in reducing Axin2 levels which is an essential protein in the β-catenin destruction complex. Targeting this pathway with a potent tankyrase inhibitor presents a plausible approach in drug development. In this study, we evaluated the antitumor effects AZ1 (a novel tankyrase 1/2 inhibitor which also carries PARP1 activity) as a single agent and in combination with irinotecan in our patient derived CRC explant xenograft models. Methods: Twenty patient derived CRC explant xenografts were treated with vehicle, AZ1 (50mg/kg/day), irinotecan (30mg/kg/week) or AZ1 (50mg/kg/day) + irinotecan (30mg/kg/week) for 28 days. Pharmacokinetic effect of AZ1 was determined in plasma and tumor over 24h. Both pharmacodynamic effects (Axin2 levels) and changes in biomarkers relevant to the Wnt pathway were determined by Western blotting. Intra-nuclear β-catenin levels were evaluated by immunohistochemistry. A tumor growth index (TGI) was calculated as the ratio in tumour volumes in the treated animals and the control animals (T/C) on the last day of drug treatment to determine efficacy. TGI≤ 50% was considered sensitive and TGI &gt; 50% was resistant. Results: Three out of 20 CRC explants showed some tumour growth inhibition with AZ1. In animals bearing CRC40 xenografts, AZ1 showed a Tmax of 1 hour in plasma and 30 minutes in tumor. In addition, Axin2 stabilization post AZ1 started 15 minutes after drug administration, with the maximum stabilization observed at 8 hours. Treatment with AZ1 + irinotecan resulted in a greater anti-tumor effect (achieving stasis or better) than either agent alone in 4 out of 20 CRC xenografts. A significant association (fisher exact test: p= 0.007) was identified between combinational sensitivity and KRAS wild type. Evaluation of tumors after treatment showed marked stabilization of Tankyrase 1/2 and Axin2; however, active β-catenin levels were not changed. Also, there were no changes to intra-nuclear β-catenin (IHC) levels after treatment. Interestingly, NuMa, a protein involved in maintenance of the mitotic spindle and a target of Tankyrase 1/2 increased following irinotecan in 3 models, 2 showing a combination effect and 1 which did not. Numa levels decreased with the combination of AZ1 and irinotecan compared to irinotecan alone in 2 models showing a significant combination effect. Conclusion: Combination AZ1 and irinotecan achieved greater anti-tumor effect compared to monotherapy in 4 out of 20 CRC xenografts. Activity was limited to CRC xenografts with KRAS WT status. Further studies are warranted to validate these findings in KRAS WT patients and to understanding the specific mechanisms in tumors that responded to combinational therapy. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B30. Citation Format: WM Tai, Kevin Quackenbush, Alicia Purkey, Stacey Bagby, Wells Messersmith, Eun Kee Song, Todd Pitts, John J. Arcaroli. KRAS wild type tumors exhibit increased efficacy to the combination of AZ1 (a tankyrase inhibitor) + irinotecan in a patient-derived CRC explant model. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B30.

Introduction:Whilst the addition of rituximab, a humanized monoclonal antibody to standard CHOP chemotherapy (R-CHOP) has improved the outcomes of DLBCL, the validity of the previously identified prognostic index based on clinical parameters is questioned. It is conceivable that prognostic model may alter with introduction of new therapeutics with differing efficacy and mechanisms of action. Methods:We conducted a retrospective analysis comparing the relevance of International Prognostic Index (IPI), Age-adjusted IPI and Revised International Prognostic Index (R-IPI) in 320 consecutive patients with DLBCL from 2003-2008 treated with R-CHOP chemotherapy with curative intent. We evaluated the prognostic factors determinant of survival in our group of patients. Results:Patients were followed up for a median of 2.70 years. IPI was only able to stratify patients into 3 main risk groups instead of 4. In addition, among patients <60, aa-IPI no longer seem a robust prognostic model. We showed that R-IPI was able to separate patients into 3 different prognostic groups and perhaps most relevant in the era of chemo-immunotherapy. Significant prognostic factors identified in multivariate analysis were performance status (P=0.004) and bone marrow involvement (P=0.026). Conclusion:The most robust prognostic index for patients with DLBCL in the era of rituximab remains uncertain. Incorporation of molecular markers into clinical parameters should be evaluated, a study we are embarking on.

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