MULTIDRUG-RESISTANCE EXPRESSION AND PROLIFERATIVE STUDIES IN POOR-RISK ACUTE MYELOID-LEUKEMIA TREATED WITH THE FLAG (G-CSF PLUS FLUDARABINEAND ARA-C) REGIMEN

Fourteen poor risk acute myeloid leukemia (AML) patients were treated with G-CSF prior (from day 0) and during chemotherapy with fludarabine and Ara-C from day 1 to day 5 (the FLAG regimen). Several biological parameters were monitored on the blast population: multidrug resistanc e (MDR) functional expression by rhodaimine-123 efflux (Rhd-E), cell c ycle changes, induction of apoptosis and leukemic clonogenic cell grow th (CFU-L). The mean basal Rhd-E value was 14.4% (range 0-51.2), and 1 2/14 patients exhibited a dye efflux >4%, efficiently blocked by the M DR-reversal agent cyclosporin A. After 24 h of G-CSF administration, c ell cycle studies showed in bone marrow (BM) samples a significant mea n increase in S phase (p = 0.04) and in RNA content of G(1) cells (p = 0.01), coupled to a significant increase in apoptosis (p = 0.02). Clo nogenic cell growth analysis showed a twofold increase in BM CFU-L in 6 of the 14 cases tested. When G-CSF activity was assessed without the addition of exogenous growth factors (autonomous proliferation), a si gnificant increase (p = 0.02) in CFU-L was found only in patients who achieved a complete remission (CR); these patients were also character ized by lower S-phase values at diagnosis. Eight of the 14 patients tr eated achieved CR, but the median response duration was three months, and only two cases are still in CR. The FLAG regimen can thus induce r emission in poor risk AML patients. The responses, however, are short, suggesting that resistant cells are not efficiently affected by eithe r the use of agents not involved in the MDR-efflux mechanism or by the G-CSF priming strategy. Other post-induction therapies need to be con sidered in further approaches.