Phase I to II multicenter study of oblimersen sodium, a Bcl-2 antisense oligonucleotide, in patients with advanced chronic lymphocytic leukemia.

PURPOSE: To determine the maximum-tolerated dose (MTD), efficacy, safety, and pharmacokinetics of oblimersen sodium in patients with advanced chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: Eligible patients had relapsed or refractory CLL after treatment with fludarabine. Oblimersen was administered at doses ranging from 3 to 7 mg/kg/d as a 5-day continuous intravenous infusion in cycle 1 and as a 7-day continuous intravenous infusion in subsequent cycles every 3 weeks in stable or responding patients. RESULTS: Forty patients were enrolled and treated (14 patients in phase I and 26 patients in phase II). Dose-limiting reactions in phase I included hypotension and fever, and the MTD for phase II dosing was established at 3 mg/kg/d. Two (8%) of 26 assessable patients achieved a partial response. Other evidence of antitumor activity included > or = 50% reduction in splenomegaly (seven of 17 patients; 41%), complete disappearance of hepatomegaly (two of seven patients; 29%), > or = 50% reduction of lymphadenopathy (seven of 22 patients; 32%), and > or = 50% reduction in circulating lymphocyte counts (11 of 22 patients; 50%). Adverse events included transient hypotension, fever, fatigue, night sweats, diarrhea, nausea, vomiting, hypokalemia, and cough. Plasma concentrations of oblimersen (parent drug) and its major metabolites were variable. Renal clearance represented only a small portion of total parent drug clearance. CONCLUSION: Dosing with oblimersen sodium in patients with CLL is limited by development of a cytokine release syndrome that is characterized by fever, hypotension, and back pain. Oblimersen sodium has modest single-agent activity in heavily pretreated patients with advanced CLL, and further evaluation of its activity in combination with cytotoxic drugs is warranted.

Behavioral and socio-emotional functioning in children with selective mutism: a comparison with anxious and typically developing children across multiple informants.

We examined differences among 158 children, 44 with selective mutism (SM; M = 8.2 years, SD = 3.4 years), 65 with mixed anxiety (MA; M = 8.9 years, SD = 3.2 years), and 49 community controls (M = 7.7 years, SD = 2.6 years) on primary caregiver, teacher, and child reports of behavioral and socio-emotional functioning. Children with SM were rated lower than controls on a range of social skills, but the SM and MA groups did not significantly differ on many of the social skills and anxiety measures. However, children with SM were rated higher than children with MA and controls on social anxiety. Findings suggest that SM may be conceptualized as an anxiety disorder, with primary deficits in social functioning and social anxiety. This interpretation supports a more specific classification of SM as an anxiety disorder for future diagnostic manuals than is currently described in the literature. The present findings also have implications for clinical practice, whereby social skills training merits inclusion in intervention for children with anxiety disorders as well as children with SM.