Mitoxantrone, Etoposide and Cyclosporine A Therapy for Relapsed and Refractory Acute Myelogenous Leukemia, A Pediatric Oncology Group Phase II Trial

Abstract

Multidrug resistance remains a major obstacle to effective treatment of patients with Acute Myelogenous Leukemia (AML). A growing body of evidence indicates that over-expression of the MDR1 gene, which encodes the multidrug transporter P-glycoprotein(P-gp), contributes to the resistance of human cancers to many anti-cancer drugs [1,2]. One strategy currently being explored to overcome this resistance is the coadministration of non-cytotoxic drugs that bind to and inhibit the function of P-gp, thereby rendering the cells sensitive to concurrently administered chemotherapy. The Pediatric Oncology Group Phase II clinical trial reported here was designed to test the safety and efficacy of this strategy. Among the agents that are currently approved for clinical trials, Cyclosporine A (CSA) is the most potent inhibitor of P-gp. CSA has been shown to reverse chemotherapeutic resistance due to expression of the MDR1 P-gp both in vitro and in animal models. Phase I trials have demonstrated that blood levels of CSA similar to those required to modulate MDR in vitro can be achieved with acceptable toxicity. Alterations in the pharmacokinetics of MDR related drugs have been reported so that chemotherapy doses need to be chosen carefully to prevent undue toxicity [5].