Cell kinetics with in vivo bromodeoxyuridine assay, proliferating cell nuclear antigen expression, and flow cytometric analysis. Prognostic significance in acute nonlymphoblastic leukemia

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Abstract
Background. The proliferative characteristics of acute nonlymphoblastic leukemia (ANLL) were studied in vivo, and data were correlated with response to chemotherapy and survival. Methods. Sixty‐five patients with untreated ANLL and 15 patients with solid tumors and normal bone marrow (BM) received 250 mg/m2 of bromodeoxyuridine (BUdR); bivariate flow cytometric (FCM) analysis then was used to measure cell BUdR incorporation and DNA content to obtain a complete set of kinetic parameters (i.e., BM BUdR‐labeling index, DNA‐synthesis time, potential doubling time [Tpot], and cell production rate). The percentage of blasts with positive results for proliferating cell nuclear antigen (PCNA) also was obtained by FCM analysis on the same BM samples, and these kinetic parameters were derived specifically for the ANLL proliferating compartment (growth fraction). Induction therapy, consisting of vincristine, arabinosylcytosine, and daunomycin, was administered subsequently to the patients with ANLL. Results. Overall ANLL proliferative activity was lower than normal myelopoiesis, and a short Tpot was found to be a favorable factor for achieving complete remission (CR), the duration of CR, and survival. When the growth fraction was considered, however, ANLL proliferative activity was higher and more like that of normal BM. The kinetic differences detected in the PCNA‐positive cells of patients with CR and no response and those with CR and survival durations above and below the median values for the entire series were highly significant in univariate analysis and retained a strong independent prognostic value when multivariate analysis was performed. Conclusions. These data show the clinical feasibility of a detailed study of cell kinetics by means of new FCM‐based techniques and reinforce the clinical value of pretreatment proliferative activity in ANLL.