Fludarabine Based Regimen (FLAI) Is an Effective Treatment for Induction of Multidrug Resistant Pgp-Positive Acute Myeloid Leukemia Patients.

Induction treatment of acute myeloid leukemia (AML) is conventionally based on regimens containing cytarabine (Ara-C), one anthracycline and, sometimes, a third drug, such as etoposide. Primary P-glycoprotein (Pgp) overexpression is the most important mechanism of multidrug resistance (MDR) in AML cells and it is almost always associated with less response to treatment. To deal with this problem, in 1997, we started a treatment program with a regimen including Fludarabine (FLUDA) for the induction of newly diagnosed AML patients. FLUDA showed to be toxic against the MDR cells, in vitro, and able to enhance Ara-C cytotoxicity by increasing cell concentration of Ara-C 5′ triphosphate and inhibiting DNA repair. Between 1997 and 2004, 110 newly diagnosed AML patients aged less than 60 years were induced with FLAI (Fludarabine 25 mg/sqm/day days 1–5, Ara-C 2 gr/sqm/day days 1–5, Idarubicine 10 mg/sqm/day days 1, 3, 5) in the context of three consecutive prospective multicentric trials. At diagnosis, all the patients were assessed for the Pgp expression by an indirect immunofluorescence method with the anti-p170 monoclonal antibody MRK-16. The results were expressed as the mean fluorescence index (MFI) and patients with a MFI > 6 were setted as MDR+ve. We correlated the Pgp-expression, with the response to the induction.

Interestingly, the Pgp+ve (MFI > 6) patients treated with FLAI entered CR as well as the Pgp-ve (MFI < 6). Twenty-four out of 39 Pgp+ve patients (61%) and 54 out of 71 Pgp-ve patients (76%) achieved a CR after a single induction course of FLAI (p= 0.1). This observation strongly supported the original hypothesis that fludarabine could play a favourable role against MDR+ve cells. In order to validate this finding we compared the results obtained in an hystorical group of 136 newly diagnosed AML patients younger than 60 years treated with a non-fludarabine containing regimen AI (Ara-C 200 mg/sqm/day c.i. days 1 - 7, Idarubicine 10 mg/sqm/day days 1, 3, 5). In the non-fludarabine group, 22 out of 69 Pgp+ve patients (32%) and 42 out of 67 Pgp-ve patients (63%) achieved a CR after one course of the induction therapy. This difference was stastically significant (p= 0.0006). Based on these observations, we decided to conduct a match pair study to confirm the superiority of FLAI for overcoming the primary multidrug resistance Pgp-mediated in AML.