Obatoclax in combination with fludarabine and rituximab is well-tolerated and shows promising clinical activity in relapsed chronic lymphocytic leukemia.

Obatoclax is a small molecule mimetic of the BH3 domain of BCL-2 family proteins. This phase 1 study combining obatoclax with FR was undertaken in chronic lymphocytic leukemia (CLL) patients relapsed after at least one prior therapy. Obatoclax was given as a 3-h infusion on days 1 and 3 and escalated through three dose levels, with standard dose FR days 1-5. Thirteen patients were enrolled, with a median of two prior therapies. One dose-limiting toxicity (DLT) of a 2-week treatment delay for persistent grade 2-3 neutropenia was observed at the highest obatoclax dose (20 mg/m2), but no maximum tolerated dose (MTD) was reached. The overall response rate (ORR) was 85%, with 15% complete responses (CRs) by NCI-96 criteria and 54% by IWCLL 2008 criteria. Median time to progression was 20 months. It is concluded that obatoclax can be safely administered to relapsed CLL patients in combination with FR and shows promising clinical activity.

Prevalence of familial malignancy in a prospectively screened cohort of patients with lymphoproliferative disorders.

Increasing evidence points to a heritable contribution in the development of lymphoma. The goal of this study was to determine the rate of familial lymphoproliferative malignancy among consecutive lymphoma patients presenting to a tertiary care center and to enroll families with multiple affected first-degree relatives on a data and tissue collection study. Beginning in 2004 all new patients presenting to the Dana-Farber Cancer Institute with non-Hodgkin (NHL) or Hodgkin lymphoma (HL) or chronic lymphocytic leukaemia (CLL) were asked to complete a one-page self-administered family history questionnaire. 55.4% of 1948 evaluable patients reported a first-degree relative with a malignancy, with the highest rate among CLL probands. Lymphoid malignancies were particularly common, with 9.4% of all probands reporting a first-degree relative with a related lymphoproliferative disorder (LPD). This frequency was again highest for CLL, at 13.3% of CLL probands, compared to 8.8% of NHL probands and 5.9% of HL probands (P = 0.002). The prevalence of CLL was significantly increased in parents of CLL probands (P < 0.05), and a greater risk of NHL was seen in fathers of NHL probands than in mothers (P = 0.026). We conclude that familial aggregation of LPDs is common among newly diagnosed patients, varies significantly by diagnosis and contributes meaningfully to the population disease burden.

Targeting the follicular lymphoma microenvironment through blockade of TNFalpha with etanercept.

Follicular dendritic cells (FDCs) support the survival of follicular lymphoma (FL). Tumor necrosis factor alpha (TNFalpha) is overexpressed by FL cells and is critical in the development and maintenance of FDCs. We hypothesised that TNFalpha might be an ideal therapeutic target. We treated seven patients with relapsed/refractory FL with 8 weeks of etanercept, 25 mg SC on day 1 and 4 of each week. Patients without progression received 16 additional weeks of etanercept. All patients completed at least 8 weeks of etanercept and two patients completed 24 weeks. At the 8 week evaluation five patients had SD. Of the five with SD, two progressed at 9 and 12 weeks on therapy and the remaining three progressed between 12 and 24 weeks after initiating therapy. Minimal toxicity was observed. FDG-PET imaging demonstrated decreases in standardized uptake value (SUV) following treatment with etanercept in five patients. Further studies in FL targeting the microenvironment in conjunction with standard cytotoxic therapy are warranted.

Ethical issues in cancer genetics: I 1) whose information is it?

This article presents and discusses four clinical cases that exemplify the complexity of ethical dilemmas concerning the provider's obligation to disclose or withhold genetic information from patients. Case 1: What is the responsibility of the cancer genetics provider to ensure that a positive test results is shared with distant relatives? Case 2: To ensure that results go to at-risk relatives, do we have the right to ignore the wishes of the designated next-of-kin? Case 3: Do we have the right to reveal a familial BRCA1 mutation to a patient's relative, who is at 50% risk? Case 4: Do we have an obligation to reveal that a patient is not a blood relative and therefore, not at risk to have inherited a familial mutation? These cases form the basis for discussing the provider's dual obligations to keeping patient confidentiality and informing patients and families about risk (i.e. duty to warn). We also provide a summary of consensus points and additional discussion questions for each case.