Applications of cytometry to study acute leukemia: In vitro determination of drug sensitivity and detection of minimal residual disease

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Abstract
Modern clinical applications of cytometry include the determination of the most powerful antileukemic drugs in each patient at the time of diagnosis and the monitoring of residual disease during and off treatment. The precision of in vitro assays to test the susceptibility of cancer cells to cytotoxic drugs depends on the ability to maintain the cells' viability in culture. We found that bone marrow‐derived allogeneic stromal cells are critical to prevent death by apoptosis of acute lymphoblastic leukemia (ALL) cells. Thus, we devised an in vitro drug sensitivity assay in which ALL cells are seeded onto stromal cells and viable leukemic cells are counted at the end of cultures by flow cytometry. Our preliminary results indicate that this assay is suitable for evaluating the drug sensitivity of leukemic lymphoblasts and testing the antileukemic activity of potentially effective compounds which have not yet been administered to patients with ALL. The identification of immunophenotypes expressed on leukemic cells but absent or extremely rare among normal hematopoietic progenitors allows close monitoring of the effects of drug treatment in vivo. Phenotypes that afford a detection level of 1 leukemic cell among 10,000 normal bone marrow cells have been identified in 90% of cases of T‐ALL, 25% of B‐lineage ALL, and 40% of acute myeloid leukemia (AML). In several studies, residual disease emerging during continuation therapy or off treatment almost invariably anticipated overt relapse by 1–7 months. These data indicate the reliability of immunologic techniques to detect occult leukemia. The combined application of drug sensitivity testing and residual disease monitoring may improve the accuracy of clinical management practices, and, ultimately, lead to improved cure rates.