MULTIDRUG-RESISTANT CELLS WITH HIGH PROLIFERATIVE CAPACITY DETERMINE RESPONSE TO THERAPY IN ACUTE MYELOID-LEUKEMIA

High spontaneous proliferation of acute myeloid leukemia (AML) in vitr o is an unfavorable, tumor-specific prognostic factor. We investigated the frequency of drug-resistant tumor cells with high proliferating c apacity in de novo AML and analyzed the expression of multiple resista nce parameters in relation to the response to chemotherapy and overall survival. Thirty-eight patients were included in this study. P-glycop rotein (P-gp) expression was found in 28/38 patients and was associate d with lower intracellular accumulation of DNR (P = 0.0001). Thirty-fi ve out of 38 patients were treated with 1-2 regimens of daunorubicin ( DNR)/cytarabine (Ara-C), and 57% attained a complete remission (CR). F ailure to achieve a CR correlated with autonomous growth (P = 0.0064), CD34 and P-gp expression alone (P = 0.0005 and P = 0.048 respectively ), and with simultaneous expression of P-gp and CD34 (P = 0.0001), but not with expression of the non-P-gp drug resistance associated-protei n (p110), the multidrug resistance-associated protein (MRP), Ara-CTP f ormation or Ara-C incorporation, respectively. AML cells with CD34/P-g p double expression were more frequently observed in samples with high autonomous growth (P = 0.003). The median survival was 6 months in CD 34(+)/P-gp(+) patients as compared with 15 months in other AML patient s (P = 0.003). In patients with de novo AML who fail on chemotherapy, a population of autonomously proliferating, immature AML cells with a multidrug resistant phenotype can be recognized. These cells thus show primary resistance to chemotherapy and have the potential for rapid r egrowth, leading to resistant disease.