The principal objective of this proposal is to characterize biologic and pharmacologic variables influencing treatment outcome in a Phase III clinical trial, SWOG-9126, testing the effectiveness of the drug- resistance modulator cyclosporin-A in relapsed refractory acute myeloid leukemia. Resistance to chemotherapy remains the major obstacle limiting the success of conventional treatment for acute myeloid leukemia (AML). Investigations performed by the Principal Investigators and others have shown that multidrug resistance (MDR) due to expression of the MDR1 gene and its P-glycoprotein product is associated with a number of adverse prognostic features in AML and an inferior outcome with conventional therapy. Because MDR may be an important biologic mechanism of resistance in AML, strategies to circumvent MDR may improve treatment outcome. In a Phase I/II trial, sequential treatment with high-dose cytarabine (HDAC) and daunorubicin administered with the MDR-modulator cyclosporin-A (CSA) yielded a high response rate in patients with poor-risk AML and a high prevalence of P-glycoprotein. The contribution of CSA-chemomodulation to treatment outcome will now be tested in a randomized Phase III trial in the Southwest Oncology Group (SWOG-9126) in which patients will be randomized to treatment with HDAC and daunorubicin with or without CSA. Response to treatment, however, may be influenced by a number of clinical and biologic features, including the frequency of detection of the mdr1 gene message in each treatment arm, the presence of non-mdr1 mechanisms of drug resistance, the ability to achieve and sustain blood levels of CSA that are effective in blocking P-glycoprotein, and/or CSA-induced changes in daunorubicin pharmacokinetics. An alternate form of MDR, not associated with MDR1/Pgp expression, was recently characterized by one of the co- investigators. Cell lines expressing this type of resistance exhibit enhanced drug efflux in association with expression of a 120kD cytoplasmic protein that is detected with the monoclonal antibody, LRP56. To characterize the biologic and pharmacologic variables affecting therapeutic response in patients registered to SWOG-9126, we will investigate the following specific aims: 1. Determine if the addition of CSA to daunorubicin plus HDAC is more effective than HDAC plus daunorubicin alone in the elimination of mdr1+ blasts. 2.Evaluate the prevalence of a non-mdr1 mechanism of resistance identified by cellular reactivity with LRP56 and its relationship to clinical outcome and its correlation with other biologic markers. 3. Determine if blood concentrations of CSA achieved in vivo are effective in modulating cellular daunorubicin cytotoxicity ex vivo. 4. Monitor blood levels of CSA and daunorubicin in vivo and their relationship to toxicity and treatment outcome.
