A phase I and pharmacodynamic study of fludarabine, carboplatin, and topotecan in patients with relapsed, refractory, or high-risk acute leukemia.

Abstract

PURPOSE:

A novel regimen designed to maximize antileukemia activity of carboplatin through inhibiting repair of platinum-DNA adducts was conducted in poor prognosis, acute leukemia patients.

EXPERIMENTAL DESIGN:

Patients received fludarabine (10 to 15 mg/m(2) x 5 days), carboplatin (area under the curve 10 to 12 by continuous infusion over 5 days), followed by escalated doses of topotecan infused over 72 hours (fludarabine, carboplatin, topotecan regimen). Twenty-eight patients had acute myelogenous leukemia (7 untreated secondary acute myelogenous leukemia, 11 in first relapse, and 10 in second relapse or refractory), 1 patient had refractory/relapsed acute lymphoblastic leukemia, and 2 patients had untreated chronic myelogenous leukemia blast crisis. Six patients had failed an autologous stem cell transplant. Patients ranged from 19 to 76 (median 54) years. Measurement of platinum-DNA adducts were done in serial bone marrow specimens.

RESULTS:

Fifteen of 31 patients achieved bone marrow aplasia. Clinical responses included 2 complete response, 4 complete response with persistent thrombocytopenia, and 2 partial response. Prolonged myelosuppression was observed with median time to blood neutrophils >/=200/microl of 28 (0 to 43) days and time to platelets >/=20,000/microl (untransfused) of 40 (24 to 120) days. Grade 3 or greater infections occurred in all of the patients, and there were 2 infection-related deaths. The nonhematologic toxicity profile was acceptable. Five patients subsequently received allografts without early transplant-related mortality. Maximum tolerated dose of fludarabine, carboplatin, topotecan regimen was fludarabine 15 mg/m(2) x 5, carboplatin area under the curve 12, and topotecan 2.55 mg/m(2) over 72 hours. An increase in bone marrow, platinum-DNA adduct formation between the end of carboplatin infusion and 48 hours after the infusion correlated with bone marrow response.

CONCLUSIONS:

Fludarabine, carboplatin, topotecan regimen is a promising treatment based on potential pharmacodynamic interactions, which merits additional study in poor prognosis, acute leukemia patients.

• Authors: Brenda W Cooper, Gareth J Veal, Tomas Radivoyevitch, Michael J Tilby, Howard J Meyerson, Hillard M Lazarus, Omer N Koc, Richard J Creger, Graham Pearson, Geoff M Nowell, David Gosky, Stephen T Ingalls, Charles L Hoppel, Stanton L Gerson
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 10 Issue 20 Pg. 6830-9 (Oct 15 2004) ISSN: 1078-0432 [Print] United States
• PMID: 15501959 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• DNA Adducts
• Topotecan
• Carboplatin
• Vidarabine
• fludarabine

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, pharmacokinetics, therapeutic use)
• Carboplatin (administration & dosage, adverse effects, pharmacokinetics)
• DNA Adducts
• Drug Resistance, Neoplasm
• Female
• Humans
• Infusions, Intravenous
• Leukemia, Myeloid, Acute (drug therapy, pathology)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, pathology)
• Prognosis
• Recurrence
• Topotecan (administration & dosage, adverse effects, pharmacokinetics)
• Vidarabine (administration & dosage, adverse effects, analogs & derivatives, pharmacokinetics)