Phase I Clinical Trial of Glivec in Combination with Tetra-Arsenic Tetra-Sulfide in the Treatment of CML Patients in Advanced Phase.

OBJECTIVE: To evaluate the safety and efficacy of Glivec in combination with As4S4 in the treatment of advanced CML patients.

PATIENTS AND METHODS: 9 Ph+ CML patients in advanced phase were entered into the study. The first 3 patients received Glivec 400mg/d plus As4S4 150mg/kg/d (day 1–14, each month). If no patient were to experience grade 3/4 CTC toxicity after one month of treatment, the dose of Glivec would be increased to 600mg. All the patients were treated and followed up for 6 months. Adverse events, hematological, cytogenetic, molecular response and real-time RT-PCR were evaluated in each regular visit.

RESULTS: From Dec.2003 to June.2004, 9 patients consisting of 6 males and 3 females were enrolled in this trial, 5 in accelerated phase and 4 in blast crisis, aged 22–53 years (median 33). The first 3 patients received Glivec 400mg/d plus As4S4, and other 6 patients received increased dosage of Glivec to 600mg/d. By the time of report, 6 patients had finished the study. 7/9 patients (77.8%) achieved complete hematological response (CHR). 2 patients relapsed after 4 and 5 months of treatment, respectively, and 2 patients withdrew from the study after 1 and 2 months respectively to receive chemotherapy due to progression of the disease. Notably, 3 of these 4 patients had complex cytogenetic abnormalities. Cytogenetic response was observed in 3 patients (33.3%), including 2 major cytogenetic response (1 complete response) and 1 minor response. No molecular response was obtained so far in any patients. Bcr-Abl fusion transcript copy number was measured by real-time RT-PCR in 3 patients, 1 patient with CCR had 3140 fold reduction of BCR-ABL DoseN. Non-hematologic toxicities such as gastrointerstinal discomfort, edema, liver dysfunction and myalgia/bone pain were common and mild (grade 1/2). Grade 3/4 hematological toxicities including neutropenia, thrombocytopenia and anemia occurred in 3 patients.

CONCLUSIONS: Glivec in combination with As4S4 has potential effect in advanced CML with acceptable toxicities. Further investigation will be performed to compare the efficacy of Glivec/As4S4 combinative therapy with Glivec mono-therapy in advanced CML.