Preliminary Study On Arsenic Trioxide In The Treatment Of Chronic Myeloid Leukemia

Backgroud and ObjectiveChronic myeloid leukemia (CML) is a clonal disease of hemopoietic stem cell origin characterized by the t(9;22) chromosomal translocation that generates the BCR/ABL oncogene. Imatinib. mesylate (Imatinib) selectively inhibits the BCR-ABL tyrosine kinase as the causative genetic aberration in chronic myeloid leukemia (CML). Imatinib induces sustained clinical responses in the vast majority of patients with chronic-phase CML. However, primitive CD34+CML precursor cells may be insensitive to imatinib and to the more potent second-generation ABL tyrosine kinase inhibitors (TKI) nilotinib and dasatinib, leading to persistence of BCR-ABL-positive cells. Detection of residual BCR-ABL mRNA transcripts in the majority of patients with CML despite long-term imatinib treatment supports the notion of disease persistence after TKI therapy. Frequent relapses after imatinib discontinuation even after complete molecular remission (CMR) have been reported. Hence, to prevent relapse and disease progression, indefinite imatinib therapy is currently the recommended standard. However, permanent TKI intake also raises concerns regarding the evolution of drug resistance, long-term safety and tolerability, compliance issues, and costs. Therefore, there is the need to develop new therapeutic approaches that, in combination with TKIs, might be more effective in preventing the outgrowth of TKI-resistant CML cells and target the stem cell population. Arsenic tri oxide (ATO) is one of the most active agents in the treatment of acute promyelocytic leukemia (APO) and it is approved by the FDA for the treatment of patients suffering from this leukemia. In addition, ATO can induce cell death in malignant glioma cells, human T-lymphocytic leukemia cells, myelodysplastic syndrome cells, and acute myeloid leukemia cells (including progenitor cells). There is also emerging evidence that this agent can target and eliminate leukemia stem cells, making this metalloid derivative attractive for other hematological malignancies and solid tumors. Some study suggested that targeting inhibition of promyelocytic leukaemia protein (PML) by ATO disrupted quiescent cells in p210bcr-abl expressing leukemia stem cell-like cells maintenance and increased the efficacy of anti-leukaemic therapy by sensitizing these cells to pro-apoptotic stimuli. Recently, Platanias and his colleagues indicated that ATO could target and eliminate primitive leukemic precursors from CML patients by autophagic degradation of BCR-ABL oncoprotein.In conclusion, the present study was designed to to determine the effect of ATO on the proliferation of Flk1+CD34-CML stem cells isolated from the bone marrow of newly diagnosed CML patients. Furthermore, We want to determine whether ATO alone could maintain remissions achieved by a prior therapy with imatinib.Materials and MethodsFirstly, we isolated Flk1+CD34-CML stem cells from the bone marrow of newly diagnosed CML. CCK-8test was used to detect the growth inhibition of Flkl+CD34-CML stem cells by ATO. Cells apoptosis and cell cycles were determined by flow cytometry. At the same time, the gene expression of P53was also detected by real time quantitative reverse transcription PCR. Imatinib therapy was stopped in6patients who had been pretreated with imatinib and got complete cytogenetic response. ATO was administered at a dose of7mg/m2 intravenously daily for5days every week,3weeks a cycle, for6cycles. After imatinib discontinuation, remission status and adverse events of ATO were monitored.ResultsATO at the concentration of1.5umol/L or3.0umol/L could inhibite the proliferation of Flk1+CD34-CML stem cells and the effect was enhanced as the dose increased. After treatment with ATO, the cells in G0/G1phase increased and those in phase decreased. Furthermore, ATO could induce apoptosis of Flkl+CD34-CML stem cells and increase remarkably the expression of P53gene.The results of clinical observations indicated that after the application of ATO for6cycles, all the6patients remained complete cytogenetic remission. With respect to adverse effects of ATO, all the side effects were modest and responded to symptomatic treatment. No patient discontinued therapy because of ATO-related toxi cities.ConclusionsTreatment with ATO enables discontinuation of imatinib in patients with CML after prior imatinib therapy and may result in improved molecular response without obvious ATO-related toxicities.