Patients with relapsed acute myelogenous leukemia (AML) have a uniformly grim prognosis;only 13-40% achieves a complete response (CR) with currently available salvage chemotherapy regimens. Long-term survival can only be achieved by those who proceed to an allogeneic or autologous stem cell transplant after achieving a CR2. In spite of advances in our understanding of the biology of both AML and relapsed AML, there have been no significant improvements in either treatments or outcomes in the past 10-20 years. This suggests the need for new approaches to overcome inherent biologic resistance of relapsed AML. We hypothesize that targeting the interaction of AML with the bone marrow (BM) microenvironment will overcome the acquired resistance factors inherent in relapsed AML and result in improved CR rates and overall outcomes. We and others have shown that the BM microenvironment provides an important protective effect against genotoxic stresses such as chemotherapy and that physical interruption of this interaction render AML cells sensitive to chemotherapy in vitro and in vivo. We propose to target the CXCR4-SDF-1 axis using a small molecule bicyclam, AMD3100, to promote rapid release of AML blasts from the BM microenvironment in patients with relapsed AML.
In Aim 1 we will perform a phase I/II clinical trial in patients with relapsed AML. AMD3100 will be administered immediately prior to mitoxantrone-etoposide-high dose Ara-C (MEC) salvage chemotherapy, thus sensitizing the AML blasts to MEC chemotherapy. We will assess the safety and toxicities of AMD3100, its impact on multi-lineage hematopoietic recovery and, most importantly, on CR rates.
In Aim 2 we will measure the magnitude and kinetics of AML mobilization after AMD3100 administration and attempt to characterize the phenotype, surface CXCR4 expression and cell cycle status of AML blasts and primitive (CD34?) subsets of AML before and after AMD3100 treatment.
In Aim 3 we will functionally assess the impact of AMD3100 on mobilizing Leukemia Stem Cells (LSCs) using in vitro LTC-IC and in vivo NOD-SCID repopulating cell (SRC) assays. Finally, we will use two separate informative in vitro assays (chemotaxis and intracellular Ca flux) as surrogate endpoints for SDF-1 signaling to determine if SDF-1 signaling is dysregulated in AML blasts after AMD3100 induced mobilization. These studies will provide insights on the effect of disrupting AML-BM microenvironment interactions using AMD3100 and other small molecules in the future. This approach may represent a simple and non-toxic way of increasing chemotherapy sensitivity and overcoming inherent genetic and epigenetic resistance factors associated with AML thus improving outcomes of patients with relapsed and resistant AML.
We will use a rapid stem cell mobilizing agent, AMD3100 to pharmacologically detach leukemic stem cells from the bone marrow thus sensitizing them to chemotherapy. This will be used to treat patients with relapsed AML to improve outcomes.
