Phase I Clinical Study of Imatinib Mesylate in Combination with Tetra-Arsenic Tetra-Sulfide in the Treatment of CML Patients in Advanced Phase.

OBJECTIVE: We performed a Phase I study to evaluate the toxicity and potential efficacy of Imatinib Mesylate (Glivec) in combination with Tetra-arsenic tetra-sulfide (As4S4) in patients with advanced CML.

PATIENTS AND METHODS: Ten CML patients in advanced phase were enrolled in this study. All patients received imatinib with As4S4 150mg/kg/d (day 1–14, each month) for 6 months. The initial dose of imatinib was 400mg/d in first 3 patients, with subsequent escalation to 600mg/d in other 7 patients. Adverse events and potential hematological, cytogenetic and molecular response was closely monitored. A concurrent control group of 10 patients received imatinib monotherapy at 600mg/d was included for the analysis of toxicity profile and clinical efficacy.

RESULTS: From Dec.2003 to Jun.2004, a total of 10 patients (6 males and 4 females with median age at 33.5) were enrolled in this trial, in which 5 in accelerated phase(AP)and 5 in blast crisis (BC). There were no significant differences in base-line characteristics between the study group and the concurrent control group. Non-hematologic toxicities such as gastrointestinal discomfort, edema, liver dysfunction and myalgia/bone pain were common and mild (Grade 1/2). Grade 3 or 4 hematologic toxicities, including neutropenia, thrombocytopenia and anemia, occurred in 3 patients. There was no difference in either hematological or non-hematological toxicities between the study and the control group. The patients in both group had equivalent complete hematological response (CHR= 70%) and complete cytogenetic response (CCR= 30%) rates. All 3 patients in the study group with CCR achieved more than 3 log reduction of BCR-ABL transcripts level while only one patient obtained a molecular response in control group. With a median follow-up of 14 months (2 to 18 months) in both group, the patients in study group showed a similar overall survival (1yr OS 68.6%±15.2%) and a slight better progress free survival (1yr PFS 75.0%±17.3%) compared to concurrent control group (1yr OS 70.0%±14.5% and 1yr PFS 50.5%±17.7%). Of notice, all patients with cytogenetic and molecular response did not have additional cytogenetic abnormality besides the Ph chromosome before the treatment.

CONCLUSIONS: The combination therapy with 600mg daily imanitib and 150mg/d As4S4 is safe and feasible for advanced CML patients. Though patients with additional cytogenetic abnormality were unlikely to response to the combination therapy, complete hematological, cytogenetic and even molecular response was documented in the advanced CML patients with combination therapy. The primary data suggested a potential clinical benefit in patients with advanced CML, thus clinical trial to further test in chronic phase CML without additional cytogenetic abnormality will be warranted.