Reversal of drug-resistance by cyclosporin-A in a patient with acute myelocytic leukaemia.

The emergence of resistant leukaemia in a patient with acute myeloid leukaemia (AML) was evaluated during clinical progression of the disease. At relapse, a decrease of the intracellular accumulation of daunorubicin (DNR) as determined by real time flow cytometry was associated with a relative overexpression of RNA encoding for the multidrug resistance phenotype (MDR1), and by a decreased in vitro sensitivity to DNR of clonogenic AML cells (IC50 0.8-3.4 microM). Intracellular DNR accumulation and in vitro DNR sensitivity could be completely restored by adding cyclosporin-A (3 microM) to the cells. At progressive relapse the patient was treated with re-induction therapy (DNR 30 mg/m2 x 3, cytarabine 200 mg/m2 x 7) to which cyclosporin-A was added (Cy-A 4 mg/kg twice daily for 3 d. 2.5 mg/kg twice daily for 2 d), which resulted in elimination of the MDR1 positive AML cells with restoration of the original DNR accumulation and in vitro sensitivity. After 12 weeks the resistant clone reappeared in the blood and bone marrow.