SAN DIEGOUp to 80% of newly diagnosed elderly acute myelogenous leukemia (AML) patients overexpress P-glycoprotein (P-gp), leading to multidrug resistance and a poor prognosis, said Dr. P. Sonneveld, University Hospital, Rotterdam, in a presentation at the American Society of Hematology (ASH) annual meeting.
The addition of a P-gp inhibitor to standard chemotherapy regimens may prevent multidrug resistance in these patients and lead to an improved response to treatment.
In their dose-finding study, Dr. Sonneveld and his colleagues determined the optimum daunorubicin(Drug information on daunorubicin) (Cerubidine) dose to be used in conjunction with cytarabine(Drug information on cytarabine) and PSC833, a P-gp inhibitor, in elderly AML patients.
The study included 39 patients over age 60 with newly diagnosed AML, 19 given 35 mg/m2 of daunorubicin on days 1 to 3, and 20 given a 45 mg/m2 dose. PSC833 was given at a daily IV dose of 10 mg/kg on days 1-4, and cytarabine was administered at 200 mg/m2 on days 1 to 7. Steady state PSC833 blood levels exceeded the level required for inhibition of P-gp, Dr. Sonneveld said.
Although the higher daunorubicin dose produced a higher complete response rate (60% vs 42% with the lower dose), it came at the cost of increased toxicity. Seven of the patients on the higher dose died of drug-related complications, all while in complete remission, compared with two on the lower dose. Thus, 35 mg/m2 was established as the daunorubicin dose to be used in a randomized controlled phase III trial of PSC833. This study proves the safety of PSC833 in combination with chemotherapy in elderly patients with AML, Dr. Sonneveld said.
The researchers also analyzed P-gp expression in 33 patients and found that those who were P-gp positive were just as likely to achieve a complete response as those who were P-gp negative. Thus, use of PSC833 appeared to overcome the negative prognostic effect of P-gp overex-pression.
Unlike standard treatment, which is less effective in patients with high levels of P-gp, this regimen combining PSC833 with chemotherapy at a reduced dose was equally effective in patients with and without high P-gp levels, Dr. Sonneveld concluded.