of Blast Cell Properties to Outcome Variation in Acute Myeloblastic Leukemia (AML)

The blast cell population in AML includes progenitors capable of colony formation in culture. Certain properties of these progenitors have been determined. including their capacity for self-renewal and their sensitivities to the chemotherapeutic drugs cytosine arabinoside (Ara-C) and adriamycin (Adria). Wide patient to patient variation was found in these properties. although they were stable during the course of the disease in each patient. We tested the properties. together with clinical risk factors. as attributes contributing to the variation in remission induction and T HE DIAGNOSTICALLY and clinically important hemopoietic population in AML patients consists of cells identified morphologically as blasts. This population is maintained by progenitors that form colonies in culture when stimulated by media conditioned by peripheral leukocytes in the presence of phytohemagglutinin (Pl-IA-LC 1,2 We have used this culture system to determine certain blast progenitor properties; these include capacity for self-renewal, as measured by replating cells from pooled colonies,3 sensitivity to adriamycin (Adria) as measured after a brief exposure to the drug,4 and sensitivity to cytosine arabinoside (Ara-C) measured by continuous drug exposure.5 All of these properties were found to vary greatly from patient to patient; however, when they were measured repeatedly in individual patients during the course of the disease, much less variation was observed, indicating that each property may be a stable characteristic in AML clones.6 Such stable properties might be determinants of the course of the disease. Indeed, preliminary work indicated that self-renewal may be negatively correlated with successful remission induction � We are studying the treatment ofAML by conducting a series of sequential clinical trials.8 These trials not only evaluate the effect of different chemotherapeutic regimens but also the contributions of risk factors to variation in outcome. This clinical setting made it possible to mount an investigation of the significance of blast cell properties using a series of patients under controlled protocol management. Blood samples were also available from AML patients excluded from the trials for a variety of reasons and from patients treated at Sunnybrook Medical Center. The results confirm the importance of self-renewal as an attribute contributing to successful remission induction of AML. Further, self-renewal was found to be a significant contributor to the duration of survival. In contrast, sensitivity to Ara-C made only a minor contribution to remission induction and neither sensisurvival. As univariate parameters. self-renewal and AraC sensitivity contributed to remission induction. but only self-renewal was related to survival. In multivariate analysis. self-renewal. age and percentage blasts in the marrow contributed to outcome variation; drug sensitivities were not significant. We conclude that self-renewal. a biological property of malignant AMI clones. although measured in culture. plays a significant role in determining response to treatment and survival in AML. tivity to Ara-C nor Adria was related significantly to duration of survival. The three blast cell properties were not found to be correlated with other risk factors in AML. Moreover self-renewal made a significant contribution to variation after the contributions of known clinical risk factors were included in a statistical model. We condude, therefore, that capacity for self-renewal, a biological property of AML clones, makes an important contribution to outcome in AML independently of other risk factors.