Autonomous Proliferation of Leukemic Cells in Vitro as a Determinant of Prognosis in Adult Acute Myeloid Leukemia

Abstract

Background and Methods: A characteristic of acute myeloid leukemia is the frequent ability of the leukemic cells to sustain their own proliferation in vitro. To determine the clinical importance of this property, we measured the uptake of tritiated thymidine by leukemic cells in serum-free and cytokine-free cultures as a means of determining the rate of spontaneous proliferation in 114 patients with newly diagnosed acute myeloid leukemia. Proliferation was then classified according to three quantitative levels of activity and related to overall survival and to treatment outcome (the response to treatment, the actuarial probability of relapse, and disease-free survival) in 91 patients who were treated with chemotherapy to induce remission. Results: Of the 114 patients, 37 had low, 39 had intermediate, and 38 had high levels of proliferation. The probability of survival at three years was 36 percent among patients with low levels of proliferative activity and 3 percent among those with high levels (P<0.001). Among the patients treated with chemotherapy, those with low rates of proliferative activity had a 68 percent rate of complete remission and a 49 percent probability of remaining free of relapse, whereas those with high rates of proliferative activity had only a 39 percent rate of complete remission (P = 0.04) and an 11 percent probability of remaining in complete remission (P = 0.009). The probability of disease-free survival at three years among the patients in complete remission after chemotherapy was 49 percent among those with low rates of proliferative activity and 9 percent among those with high rates (P = 0.004). Accordingly, patients with low rates of proliferative activity also had a significantly higher rate of overall survival (44 percent vs. 4 percent; P = 0.002). Patients whose cells had intermediate levels of proliferation in vitro had intermediate rates of survival, relapse, and disease-free survival. Conclusions: The capacity of leukemic blasts for autonomous proliferation is associated with highly aggressive acute myeloid leukemia., Acute myeloid leukemia (AML) is a neoplastic disease of malignantly transformed hematopoietic progenitor cells. The malignant clone outgrows the normal hematopoietic cells, resulting in a predominance of immature cells in the hematopoietic tissue that are unable to mature. The transformation to leukemogenesis may require multiple steps, including defects in growth and differentiation. One of these steps could involve the acquisition by the leukemic cells of the capacity to produce self-supporting growth factors. In a substantial proportion of patients with AML, autonomous proliferation has been observed as a characteristic feature of blast-cell proliferation in culture, and spontaneous growth in vitro generally… © 1993, Massachusetts Medical Society. All rights reserved.