Faculty Publications

Purpose A phase I study assessed the safety, tolerability, pharmacokinetics, and preliminary antitumor effect of mapatumumab, a fully-human agonist monoclonal antibody to the tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1, DR4), in combination with paclitaxel and carboplatin. Patients and Methods Patients with advanced solid malignancies received 3, 10, or 20 mg/kg of mapatumumab with standard doses of paclitaxel and carboplatin every 21 days for up to six cycles in the absence of disease progression. Additional cycles of paclitaxel and/or mapatumumab were permissible in selected cases. Results Twenty-seven patients (21 males), with a median age of 54 years, received mapatumumab in the following three cohorts: 3 mg/kg (n = 4), 10 mg/kg (n = 11), and 20 mg/kg (n = 12). The median number of cycles was four. Dose-limiting toxicities (DLTs) were grade 3 hypersensitivity reaction (n = 1) and neutropenic fever (n = 1), both at 10 mg/kg. Non-DLT treatment-related adverse events occurring in more than 10% of administered doses included alopecia, neutropenia, fatigue, nausea, anemia, thrombocytopenia, anorexia, and neuropathy. Paclitaxel and carboplatin exposures were similar in the presence or absence of mapatumumab. Plasma mapatumumab concentrations seemed similar to data from previous phase I monotherapy studies. Five patients (19%) achieved a confirmed radiologic partial response (including one pathologic complete response), and 12 patients (44%) had stable disease as their best response. Conclusion Mapatumumab is well-tolerated up to 20 mg/kg in combination with paclitaxel and carboplatin. There are no apparent pharmacokinetic interactions among the drugs. Preliminary anticancer activity demonstrated clinical benefit for the majority of these patients.

BACKGROUND: Precursor B-cell lymphoblastic lymphoma (B-LBL) is an uncommon high-grade neoplasm of immature B cells. In contrast to the more common lymphoblastic lymphoma of T-cell lineage, B-LBL can be an extranodal disease, with a propensity to involve skin and bone. Most reported cases of B-LBL in the skin, a rarity in adults, are manifestations of existing systemic disease. OBSERVATIONS: We report 2 unusual cases of primary cutaneous B-LBL in adults. Fluorescence in situ hybridization studies, not previously reported in primary cutaneous B-LBL to our knowledge, demonstrated rearrangement of the MLL gene in one patient and possible hyperdiploidy in the other, both reported in precursor acute lymphoblastic leukemia. CONCLUSIONS: Review of the literature identified 13 reported cases of B-LBL occurring primarily in the skin, in addition to our 2 cases. Precursor B-cell lymphoblastic lymphoma is more common in children and in young adults, with a tropism for the head and neck region. Histologically, B-LBL must be differentiated from other high-grade lymphoid tumors and small "blue round cell" tumors. Because of the common absence of mature B-cell markers in immunohistochemical studies and the frequent expression of CD99, B-LBL may present a diagnostic challenge. Although there is a suggestion in a limited number of patients that abbreviated therapy may provide long-term disease control, the risk of relapse remains significant, particularly if a patient's condition is misdiagnosed and the patient is treated as having mature B-cell lymphoma. In the absence of prospective studies for this population, patients with B-LBL are treated currently with intensive acute lymphoblastic leukemia regimens.

Oblimersen sodium plus rituximab was evaluated in relapsed/refractory B-cell non-Hodgkin lymphoma (NHL) patients. Oblimersen was administered as a continuous intravenous infusion at a daily dose of 3 mg/kg/d for 7 d on alternate weeks for 3 weeks. Rituximab was given at a weekly dose of 375 mg/m(2) for six doses. Patients with stable disease or objective response were allowed to receive a second course of treatment. The overall response rate (ORR) was 42% with 10 complete responses (CR) and eight partial responses (PR). Twelve (28%) patients achieved a minimal response or stable disease. Among the 20 patients with follicular lymphoma the ORR was 60% (eight CR, four PR). Three of the responders were refractory to prior treatment with rituximab, and two of the responses occurred in patients who had failed an autologous stem cell transplant. Median duration of response was 12 months. Most toxicities were low grade and reversible. In conclusion, oblimersen sodium can be safely combined with rituximab. The combination appears to be most beneficial in patients with indolent NHL and warrants further investigation in a large randomized trial.

Objectives: Gonadotropin-releasing hormone agonists (GnRHa) are associated with greater risk of coronary heart disease and myocardial infarction in men with prostate cancer, but little is known about their potential effects on cardiovascular mortality. We assessed the relationship between duration of GnRHa therapy and cardiovascular mortality in a large randomized trial of men treated with short-term versus longer-term adjuvant goserelin and radiation therapy (RT) for locally advanced prostate cancer. Methods: From 1992 to 1995, 1554 men with locally advanced prostate cancer (T2c-4, prostate-specific antigen [PSA] < 150 ng/ml) received RT and 4mo of goserelin and then were randomized to no additional therapy (arm 1) or 24 mo adjuvant goserelin (arm 2) in a phase 3 trial (Radiation Therapy Oncology Group [RTOG] 92-02). Cox regression analyses were performed to evaluate the relationship between treatment arm and cardiovascular mortality. Covariates included age, prevalent cardiovascular disease (CVD), hypertension, diabetes (DM), race, PSA, Gleason score, and stage. Results: After median follow-up of 8.1 yr, 185 cardiovascular-related deaths had occurred. No increase in cardiovascular mortality occurred for men receiving a longer duration of goserelin. At 5 yr, cardiovascular mortality for men receiving longer-term adjuvant goserelin was 5.9% versus 4.8% with short-term goserelin (Gray's p = 0.16). In multivariate analyses, treatment arm was not significantly associated with increased risk of cardiovascular mortality (adjusted hazard ratio [HR] = 1.09; 95% confidence interval [CI], 0.81-1.47; p = 0.58; when censoring at time of salvage goserelin, HR = 1.02, 95%CI, 0.73-1.43; p = 0.9). Traditional cardiac risk factors, including age, prevalent CVD, and DM, were significantly associated with greater cardiovascular mortality. Conclusions: Longer duration of adjuvant GnRHa therapy does not appear to increase cardiovascular mortality in men with locally advanced prostate cancer. (C) 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved.

PURPOSE OF REVIEW: Mantle cell lymphoma is characterized by dysregulation of cyclin D1, but this is not sufficient for lymphoma development. It is a difficult disease to treat, being incurable with standard chemotherapy and having a median survival of approximately 5 years. The purpose of this review is to update recent advances in mantle cell lymphoma biology with prognostic and potentially therapeutic implications, and mantle cell lymphoma treatment approaches and new agents. RECENT FINDINGS: Genetic alterations that cooperate with cyclin D1 have been described that alter proliferation, in particular p27Kip and p16INK4, or apoptosis. Biological factors such as high-proliferation signature defined by gene expression profiles, loss of p27 and presence of mutant p53 confer poor prognosis. Proliferative rate also predicts patient outcome. Clinical criteria such as the international prognostic index, follicular lymphoma international prognostic index or a formula using age, performance status, white blood cell count and lactate dehydrogenase, separate prognostic groups. Not all patients require therapy at diagnosis.Although the best reported results have been with rituximab-hyperfractionated cyclophosphamide-vincristine-doxorubicin-dexamethasone-methotrexate/cytara bine, a cooperative group study of this regimen appears not quite as successful. Consolidation of remission after rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone with high-dose therapy/stem-cell support prolongs remission and consolidation with radioimmunotherapy shows promise. Intensifying induction by alternating intensified rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone with rituximab and high-dose cytarabine, followed by high-dose therapy appears quite promising. Novel agents active in relapsed disease include bortezomib, mammalian target of rapamycin inhibitors, immunomodulatory agents, antibodies and cyclin pathway-directed agents such as flavopiridol and cyclin-dependent kinase inhibitors. SUMMARY: New insights into mantle cell lymphoma biology may lead to targeted therapy. Meanwhile, combinations of existing therapeutic approaches seem to have improved outcomes.

The CHEK2-1100delC mutation is recurrent in the population and is a moderate risk factor for breast cancer. To identify additional CHEK2 mutations potentially contributing to breast cancer susceptibility, we sequenced 248 cases with early-onset disease; functionally characterized new variants and conducted a population-based case-control analysis to evaluate their contribution to breast cancer risk. We identified 1 additional null mutation and 5 missense variants in the germline of cancer patients. In vitro, the CHEK2-H143Y variant resulted in gross protein destabilization, while others had variable suppression of in vitro kinase activity using BRCA1 as a substrate. The germline CHEK2-1100delC mutation was present among 8/1,646 (0.5%) sporadic, 2/400 (0.5%) early-onset and 3/302 (1%) familial breast cancer cases, but undetectable amongst 2,105 multiethnic controls, including 633 from the US. CHEK2-positive breast cancer families also carried a deleterious BRCA1 mutation. !