Topotecan-Based Combination Chemotherapy in Patients with Transformed Chronic Myelogenous Leukemia and Advanced Myelodysplastic Syndrome

BACKGROUND: Patients with transformed chronic myelogenous leukemia(CML) and advanced myelodysplastic syndrome(MDS) have poor prognosis. The aim of this study is to evaluate the feasibility of second chronic phase induction in accelerated phase(CML-AP) or blastic crisis of CML(CML-BC) and remission induction in advanced MDS by combining topoisomerase I inhibitor(topotecan) with topoisomerase II inhibitor(mitoxantrone). METHODS: Twenty-four evaluable patients were entered on this study with a median age of 34 years. Eighteen patients with transformed CML(7 CML-AP, 11 CML-BC) and 6 patients with advanced MDS were treated. Topotecan was administered as 1.5 mg/m(2)/day by continuous infusion over 24 hours daily for 5 days every 4 to 8 weeks until remission. To enhance the tumoricidal effects, mitoxantrone(12 mg/m(2)/day, Days 1–3) was added. RESULTS: Eight patients(33%) achieved a complete remission(CR). Four of 7 patients with CML-AP(57%), 2 of 4 patients with CML-lymphoid blastic crisis (-LBC) (50%) and 2 of 6 patients with advanced MDS(33%) had CR lasting more than 45 days(45 to 400 days). There was no CR in the patients with CML-myeloid blastic crisis(-MBC). The dose level of 1.5 mg/m(2)/day(7.5 mg/m(2)/course) of topotecan was well tolerated in all patients. Mucositis occurred in 69% of patients (severe in 5%) and diarrhea in 67%(severe in 8%). In addition, there were no new or unexpected toxicities in the patients who were treated at this dose(7.5 mg/m(2)/course). In patients who recovered their neutrophil count, the absolute neutrophil count(ANC) remained below 500/μL for a period of 13 to 58 days(median 21 days) and the time to ANC recovery was associated with pretreatment severity of bone marrow fibrosis(mainly CML patients). Likewise, in the patients who recovered unsupported platelets, the platelets remained below 20,000/μL for a period of 0 to 37 days (median 19 days). CONCLUSION: The combination of topotecan-mitoxantrone has shown modest activity in CML-AP, CML-LBC and advanced MDS with acceptable toxicities.