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

Abstract

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.

Incidence of bacterial and fungal infections in newly diagnosed acute myeloid leukaemia patients younger than 65 yr treated with induction regimens including fludarabine: retrospective analysis of 224 cases

“…Between 1997 and 2002, 224 newly diagnosed AML patients <65 yr were enrolled in three consecutive multicentric clinical trials (AML97, AML99 and AML02) testing the efficacy and toxicity of two fludarabine‐containing induction regimens, FLAI and FLAIE (25–27). All the enrolled patients were included in this analysis.…”

“…The response evaluation, in terms of CR, non-responders (NRs) and death during induction (DDI) was performed according to the previously published criteria (25)(26)(27). Induction death was defined as any death before day +28 from chemotherapy start, with hypocellular marrow (25)(26)(27).…”

“…Addition of a third drug to the standard combination of anthracycline and arabinosyl cytosine (Ara-C) or the use of high-dose Ara-C (HD-AC) are the most common approaches to intensify induction (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). We attempted to improve induction's efficacy with a non-conventional induction regimen of fludarabine in combination with intermediate-dose Ara-C and standard dose idarubicin (FLAI) (23)(24)(25)(26)(27). The rationale of this combination was that fludarabine is slightly myelotoxic (28)(29)(30), it potentiates the anti-leukaemic effects of Ara-C and anthracyclines (31)(32)(33), and it is in vitro insensitive to P-glycoprotein (p. 170), a drug-transporter protein related to multidrug resistance of leukaemic cells (31,33).…”

“…In this study, we retrospectively analysed the incidence of infections in 224 newly diagnosed AML patients consecutively treated with a fludarabine-containing induction regimen in three multicentric trials performed in 11 haematological Italian centres between 1997 and 2002 (25)(26)(27). The data were then compared with historical data reported for patients treated with standard induction regimens not containing fludarabine (2,7,(38)(39)(40)(41).…”

Case–control study of multidrug resistance phenotype and response to induction treatment including or not fludarabine in newly diagnosed acute myeloid leukaemia patients

“…Furthermore, they suggested a probable advantage of Fluda regimens in the treatment of MDR‐Pgp‐positive (MDR‐Pgp‐pos ve ) patients that overexpressed Pgp (MFI ≥ 6 [Michieli et al , 1996a]). Indeed, it was observed that MDR‐Pgp‐negative (MDR‐Pgp‐neg ve , MFI < 6) patients and MDR‐Pgp‐pos ve patients treated with FLAI/FLAIE had a similar probability of achieving a CR, unlike what was observed with conventional regimens (Michelutti et al , 1997; Russo et al , 2005b).…”