Activity of topotecan 21-day infusion in patients with previously treated large cell lymphoma: long-term follow-up of an Eastern Cooperative Oncology Group study (E5493)

Abstract

The purpose of this study was to determine the activity of topotecan given by 21-day continuous infusion in patients previously treated with one prior therapy for a diffuse large cell lymphoma or immunoblastic lymphoma. Patients with appropriate histology and measurable disease who had been treated with one prior chemotherapy regimen were eligible for study. Slides of tumor biopsies were submitted for central review of pathology. Patients were required to have ECOG performance status of 0, 1, or 2 and adequate bone marrow function. Patients were treated with continuous infusion topotecan, 0.4 mg/m2/day × 21 days. Therapy could be escalated to 0.5 and then 0.6 mg/m2/day in subsequent cycles if there was no dose limiting toxicity at the initial dose level. Patients were treated with 2 cycles after achieving complete response or until disease progression or unacceptable toxicity occurred. Thirty seven patients were enrolled, however, only 26 cases were eligible due to performance status of > 2 (2), more than one prior chemotherapy (1), and wrong histology on review (8). Due to the unexpectedly high ineligibility rate, two sets of analysis were done for all the 37 patients enrolled and for the 26 eligible patients, respectively. Of the 37 patients (15 males and 22 females), international prognostic index included 11% low risk, 30% low-intermediate risk; 46% high-intermediate risk, and 8% high risk. The median follow up was 77 months. A total of 136 cycles of therapy were given with a median of 3 cycles per patient. Grade 4 toxicities included: 14% grade 4 thrombocytopenia; 14% grade 4 granulocytopenia, 8% leukopenia, 3% each anemia, hemorrhage, infection, vomiting, thrombosis, liver toxicity, and neuromotor toxicity. The response analysis including all 37 patients showed 5 complete remissions (CR) and 4 partial remissions (PR) for a total response rate of 24% (90% two-stage confidence interval 13–39%). Median progression free survival (PFS) was 3.7 months, with one and two year PFS of 21% and 6% respectively (90% confidence interval 11–34% and 2–15%). Median overall survival (OS) was 10.5 months, with one and two year OS 41% and 27% respectively (90% confidence interval 27–53% and 16–39%). Analysis including only eligible patient showed similar response rates and survival outcomes. Single agent topotecan has moderate activity for previously treated high grade lymphoma equivalent to that of several newer agents, and should be considered for incorporation into multi-drug salvage chemotherapy programs.

Paclitaxel, topotecan and rituximab: long term outcomes of an effective salvage programme for relapsed or refractory aggressive B‐cell non‐Hodgkin lymphoma

“…In addition, TTR does not require aggressive hydration and therefore can be easily given in the outpatient setting. TTR produced an ORR of 69% and CR rate of 42%, which compares favourably to our previous experiences with paclitaxel and topotecan, alone and in combination (Table IV) (Preti et al, 1995;Arbuck et al, 1997;Younes et al, 1997Younes et al, , 2001Kewalramani et al, 2004;Mey et al, 2006;Wiernik et al, 2012). The addition of rituximab in the current study also improved the ORR in patients with primary refractory or relapsed disease.…”

Macromolecular Prodrug That Provides the Irinotecan (CPT-11) Active-Metabolite SN-38 with Ultralong Half-Life, Low Cmax , and Low Glucuronide Formation

“…They proposed that a minimum threshold of the drug must be maintained over long periods for optimal antitumor activity; higher dose-intensity did not provide further benefit, but it enhanced toxicity. Several phase 1 clinical trials of low-dose continuous infusions, including 1 to over 9 weeks of CPT-11, yielded steady-state levels of SN-38 of ∼3 to 15 nM, confirming the tolerability and feasibility of low, protracted dosing. − Similar phase 1 trials of continuous infusions of the topo 1 inhibitor topotecan also showed activity in several tumors, − again suggesting that efficacy may be achieved by time-over-target inhibition. Thus, topo 1 inhibitors may display exposure-time-dependent rather than concentration-dependent cytotoxicity: achieving a high inhibitor concentration for a short period does not necessarily produce the same effect as maintaining a low concentration for a prolonged period, even if the total AUC per treatment period are equal.…”

Triggering of Suicidal Erythrocyte Death by Topotecan

“…The camptothecin analogue [1] topotecan is utilized for the treatment of malignancy, such as ovarian cancer [2][3][4][5][6][7], cervical cancer [5,[8][9][10], retinoblastoma [11][12][13], small cell lung cancer [14][15][16][17][18], hematopoietic cell malignancy [19,20] and Wilms' tumor [21]. It is applied at a dosage of 10 mg/kg b.w.…”