The overall objective of this proposal is to critically evaluate the potential clinical value of all-trans-retinoic acid (tRA) alone and in combination with interferon-alpha (INF) for the treatment of advanced chronic myelogenous leukemia (CML) in accelerated phase (AP) or early blastic crisis (BC). The project is based on our pilot clinical and laboratory observations of potent CML-AP/BC cell inhibitory effects of tRA and will be developed in a unique Phase II clinical trial sponsored by the Eastern Cooperative Oncology Group (ECOG) in which tRA will be administered by a novel 3 day per week schedule preliminarily reported to maximize tRA plasma exposure. There are 3 specific aims: (1) to serially monitor the pharmacokinetics of tRA on the 3 day/week schedule to determine if cumulative plasma exposure, as measured by area under the curve measurements of tRA by high-performance liquid chromatography, is greater and more sustained than those previously reported for continuous or alternate week tRA therapy; (2) to serially monitor in semi-solid (methylcellulose) medium cultures the colony forming cells of multiple progenitor or blastic cell types in the peripheral blood (PB) and bone marrow (BM) to determine if tRA +/- INF therapy reduces the number of these cellular elements involved in the disease process; and (3) to serially monitor the expression of bcr-abl mRNA by reverse transcriptase- polymerase chain reaction (RT-PCR) methods to determine if tRA therapy reduces the effective level of this key tumor-sustaining gene product in a low density cell fraction relatively enriched in CML progenitors (PB) or in clonogenic cells derived from this fraction (BM). Values generated in these aims will be examined for correlations with one another and with hematologic parameters. These studies will greatly complement conclusions derived from clinical analyses regarding the potential efficacy of tRA +\- INF in CML-AP/BC.