Singleagent Therapy

A number of novel chemotherapeutic agents have been studied as single agents in advanced-phase disease. To date, the most promising agents have been the hypomethylating agents, decitabine (5-aza 2'deoxycyti-dine) and azacytidine (5-azacytidine). These agents act in part by reversing the methylation, or silencing, of numerous tumor suppressive genes that exert antiproliferative effects, thus potentially reversing or slowing the progression of CML. Decitabine has been the most extensively studied hypomethylating agent in CML, whereas azacitidine has been used more commonly in patients with myelodysplastic syndrome.30 In a study conducted at MD Anderson Cancer Center, 64 myeloid blast-phase and 51 accelerated-phase Ph+ CML patients were treated with repetitive monthly cycles of decitabine. In blast-phase patients, 28% achieved a response, which included a CHR in approximately 9%. In accelerated patients, a 55% overall response rate, with an approximate 23% CHR rate, was observed.31 Response durations and survival rates were quite poor in blastic phase patients, with a 3-year survival rate of only 5%. Accelerated-phase patients had significantly better outcomes, with 3-year survival rates of 27%, again pointing out the importance of distinguishing between these stages of CML. Despite the myelosuppressive properties of decitabine, only 3% of all patients treated died of complications of cytopenias. These results suggested that single-agent decitabine, although still relatively ineffective, resulted in equivalent outcomes to that of the high-dose cytarabine-based regimens with less toxicity.

Several other agents have been tried alone or in combination with cytarabine in patients with advanced-phase CML. These have included topotecan, carboplatin, homoharringtonine, amsacrine, and mithramycin.32-36 None have demonstrated enhanced activity compared to standard antileukemia agents. Most recently, trox-acitabine, a novel nucleoside analog, has been evaluated both in AML and in myeloid blast-phase CML.37 Of particular interest is that this agent has been tested in patients either previously treated with imatinib or in imatinib-naive patients. In an initial phase II evaluation in myeloid blast phase, 6 of 16 (37%) of patients responded to troxacitabine in a cohort in which only 3 patients had received prior treatment with imatinib.38 In a subsequent larger trial, a 13% response rate was seen in 51 myeloid blast-phase patients in whom 93% had progressed on treatment with imatinib.39 Although no specific data have been reported for response rates for cytarabine-based regimens or hypomethylating agents comparing outcomes by prior exposure to ima-tinib, the results with troxacitabine suggest that patients progressing on treatment with imatinib may be particularly resistant.

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