Strategies for improving the therapeutic and diagnostic approaches to acute leukemias

Acute leukemia (AL) represents a hematological cancer originated from malignantly transformed myeloid or lymphoid precursors. Steady improvement in the prognosis of patients with AL has been observed over the last 30 years. However, the duration of remission has been still short and the overall survival of AL remains poor. Therefore, novel therapeutic strategies are necessary to enhance the cure rate and the quality of life. Although initial remissions can be obtained with tyrosine kinase inhibitor (TKI) in Ph⁺ AL, drug resistance develops and the responses are short-lived. I chose to study DT₃₈₈IL3 because the target IL-3 receptor is expressed on most Ph⁺AL blast samples and the action mechanism of DT₃₈₈IL3 is different from that of the TKIs. I studied cytotoxicity against malignant progenitors from patients with Ph⁺AL and demonstrated a synergistic interaction between both TKIs and the fusion protein. Normal progenitors were relatively resistant to these drugs alone or in combination. The enhanced selective cytotoxicity of CPX-351 (a liposomal formulation of a fixed ratio combination of cytarabine and daunorubicin) for AML progenitors as compared to normal hematopoietic cells is described. AML cells were shown to be more sensitive to CPX-351 than normal cells. Moreover, it was demonstrated that normal hematopoietic cells and progenitors were less sensitive to CPX-351 in comparison with conventional cytarabine:daunorubicin. These data suggest that CPX-351 might overcome drug resistance in AML without increasing toxicity to normal blood cells. The ability to reliably predict the likelihood of induction failure in a timely fashion would be useful for optimizing treatment plans for leukemia patients. Thus, I developed a flow cytometry-based assay that could predict the outcome of induction chemotherapy. The assay is based on the efflux of mitoxantrone. The median fluorescence intensity (MFI) for AML blasts incubated with mitoxantrone was measured with or without the ABC transporter inhibitor, cyclosporine A, and a ratio between the inhibited and uninhibited MFI was calculated (MFIR). A high MFIR value was shown to be highly predictive of induction failure. In conclusion, these findings may play an important role in developing better therapeutic and diagnostic approaches for AL.Medicine, Faculty ofMedical Genetics, Department ofGraduat