The CALGB studied the feasibility and effect of oblimersen (G3139; Genasense) with imatinib mesylate in patients with primary imatinib resistant CML. We hypothesized that CML cells that are resistant to imatinib mesylate (i.e., less than a complete hematologic remission after 8 weeks of treatment or less than a major cytogenetic remission after 6 months of treatment) are no longer being driven to proliferate by Bcr/Abl tyrosine kinase activity alone. Instead, the anti-apoptotic protein Bcl-2 would regulate one of the pathways controlling growth and/or viability. Thus, blocking both Bcr/Abl and Bcl-2 simultaneously with imatinib mesylate and G3139, respectively, would result in hematologic and cytogenetic improvement. Preclinical data suggested synergy. G3139 was administered via continuous intravenous infusion with an ambulatory pump over 10 days every 21 days, along with daily oral imatinib. Doses of both drugs were escalated in 3 cohorts; the initial dose of imatinib was 600 mg/day. The median age of the 21 enrolled patients (13 females and 8 males) who received any therapy was 54 years (range, 25–74), with 13 Caucasians and 8 African Americans. Twelve patients had primary imatinib resistance and 8 had secondary imatinib resistance (data are not yet available on 1 patient). Five patients had never achieved complete hematologic remission while only two patients had achieved major cytogenetic remission while on a prior imatinib therapy. Nine patients received 4 mg/kg/day G3139 and 600 mg of imatinib, 7 patients received 7 mg/kg/day G3139 and 600 mg of imatinib, and 5 patients received 7 mg/kg/day G3139 and 800 mg of imatinib. Progressive CML after the first (4 patients), second (1 patient), third (2 patients) or fourth course (1 patient) was noted in 8 patients whose imatinib dose had been reduced from 800 mg to 600 mg/day to comply with study entry requirements. Nine patients completed all 4 planned courses. Grade IV thrombocytopenia and fatigue (both at 7 mg/kg G3139 and 600 mg of imatinib) and deep vein thrombosis (at 7 mg/kg G3139 and 800 mg of imatinib) were noted in one patient each. One patient with primary imatinib resistance achieved complete hematologic remission following 2 courses of therapy at 4 mg/kg G3139 and 600 mg of imatinib. No patients had cytogenetic responses. Although the combination of G3139 and imatinib is safe and feasible, we did not detect clinical benefit in these patients with imatinib-resistant CML using these doses and schedule.