Prediction of Response to Chemotherapy in Acute Leukemia by in Vitro Drug Sensitivity Testing on Leukemic Stem Cells1

Twenty-two patients with acute myeloid leukemiawere studied for in vitro drug sensitivity of the leukemic clonogenic cells in agar. The cells were preincubated for 1 hr with 1-/3-o-arabinofuranosylcytosine (ara-C; 0.15, 0.3, 0.6, 1.2, and 2.4 ¿tg/ml) or daunorubicin (0.018, 0.037, 0.075, 0.15, and 0.30 jig/ml), washed, and plated in agar, and cluster/colonies were counted after 10 days of incubation. Survival curves were constructed and used for calculation of the surviving fraction of clonogenic cells. In 18 patients treated with thioguanine-daunorubicin-1-/jD-arabinofuranosylcytosine-prednisone,the in vitro drug sensitiv ities could be correlated to the in vivo response to therapy. Patients who entered remission (12 of 18) were significantly more sensitive to ara-C (p < 0.005) and to daunorubicin (p < 0.02) than patients who did not enter remission (six of 18). All patients who entered remission, except two, had normal or increased sensitivity to both drugs, and all patients who did not enter remission, with one exception, had decreased sensitivity to one or both drugs. Comparison of the cytostatic effect of [3H]thymidine and ara-C suggested that, in some cases, ara-C killed more clonogenic cells than those in S phase, and in some cases, the cells seemed to be metabolically resistant to ara-C. We conclude that in vitro drug sensitivity tests on leukemic clonogenic cells reflect the patient's in vivo response to the tested drugs and may be used to study the biological properties of leukemic stem cells that determine their drug sensitivity.