Topoisomerase enzymes are critical components of genomic replication and function to minimize torsional stress on DNA. Inhibition of topoisomerase function leads to DNA strand breaks followed by apoptosis. In malignant lymphomas, topo II inhibitors (anthracyclines, epidophyllotoxins) are part of many active regimens, and topo I inhibitors (camptothecins) show modest single agent activity. Supported by preclinical data, we hypothesized that the sequential administration of a topo II inhibitor followed by a topo I inhibitor would be potentially synergistic, with enhanced cytotoxicity of the topo I inhibitor due to increased target enzyme levels following topo II inhibition. The treatment regimen consisted of doxorubicin 25 mg/m2 IV on day 1 and topotecan 1.75 mg/m2/d IV on days 3–5, repeated at 21 day intervals. The primary objective of this phase II study was to determine the overall response rate, time to progression, and toxicity in patients with relapsed/refractory aggressive NHL. Eligible patients had recurrent or refractory aggressive NHL, no prior camptothecins, and limited prior anthracycline exposure (<400 mg/m2 prior doxorubicin; <96 mg/m2 prior mitoxantrone), and an ejection fraction ≥ 45% at baseline. Results: From July 2000 to August 2003, 26 patients were registered. One registered patient did not start protocol treatment and is excluded from analysis. Of 22 patients with a known histologic subtype, 18 had diffuse large B cell lymphoma and there was one case each of Burkitt’s, follicular grade III, anaplastic large cell, and anaplastic large cell, Hodgkin’s like lymphoma. The median age was 58 (range 23–74) years. All patients were heavily pretreated with a median of 2 (range 1–5) prior regimens, including 5 patients who had a prior stem cell transplant (SCT). A median of 2 cycles (range 1–6) were administered. Five patients (20%, 95% CI 0.07, 0.42) responded with 1 (4%) complete remission (CR) and 4 (16%) partial remissions (PR); an additional 3 (12%) patients had stable disease. 12 (48%) patients progressed during or after the first cycle and 5 (20%) progressed after the second cycle. The one patient achieving a CR had Burkitt’s lymphoma, and received a total of 6 cycles; this patient remains in remission 21 months following the end of treatment. Of the PR patients, 2 remain in PR at 1.5 and 12 months following therapy, and 2 patients have progressed at 1.5 and 6 months. Interestingly, 4 of the 5 responders had prior SCT. The main toxicity was hematologic, with 14 (63%) and 9 (41%) patients having grade 3 or 4 neutropenia and thrombocytopenia, respectively. Three patients had febrile neutropenia. There were no treatment-related deaths. Seven patients remain alive and 18 patients have died. The median follow-up time for surviving patients is 14 (range 7–27) months. The median event-free survival is 1.3 months and the median overall survival is 3.6 months. The combination of doxorubicin and topotecan is well-tolerated and has modest activity in relapsed/refractory NHL, with an occasional patient having a prolonged remission.