Design and first interim analysis of a randomized phase III trial comparing imatinib versus imatinib (IM) based combination therapies in newly diagnosed chronic myelogenous leukemia patients in chronic phase

Abstract

6589 Background: Despite impressive results achieved with IM 400 mg/day alone, only a minority of pts reached a complete molecular remission at 12-month. Higher dose of IM or its combination with other therapies might improve molecular remission. Design of the trial: the 3 experimental arms are IM 400mg daily in combination with Peg-IFN-α2a (Peg-IFNα2a, 90 μg weekly) or with Ara-C (20 mg/m2/day, days 15–28 of 28-day cycles) or IM 600mg daily. The reference arm is IM 400mg daily. All pts (over 18 years of age with Bcr-Abl positive CML) receive IM 400 mg/day as monotherapy days 1–14 and then start the assigned regimen for at least 12 months. The endpoints are overall survival (primary), rate and duration of hematologic, cytogenetic and molecular responses and tolerability. An interim analysis of the first 636 pts at 1 year from randomization will allow evaluation of molecular response rates, one of the experimental arm being selected for further comparison with IM 400. An experimental arm would be selected if it increased the 4 log reduction response rate at 12-month by at least 20 percentage points, (15% to 35%), with an acceptable tolerability. Results: This evaluation is based on a cohort of 370 pts with a median time of observation of 16 months, recruited between 9/2003 and 9/2005. [median age 53 yrs (18–81); Sokal distribution: 38% of pts low, 38% intermediate, and 24% high]. At 1 month 80% of pts achieved complete hematologic response. At 12 months, 138 pts (72%) achieved a major cytogenetic response, being complete in 120 pts (63%). Grade 3/4 hematologic toxicity occurred in 8% of IM400 pts, 9% of IM600 pts, 41% of IM+IFN pts and 33% of IM+Ara-c pts respectively. Dose of Peg IFN was reduced in 16% of pts, 45 μg per week being well tolerated. Grade 3/4 non hematological toxicity occurred in 11% of IM400 pts, 16% of IM600 pts, 10% of IM+IFN pts (maily skin rash) and 11% of IM+Ara-c pts. Discontinuation of experimental treatment occurred in 17% of IM600 pts, 36% of IM+IFN pts and 16% of IM+Ara-c pts. Conclusion: This first analysis confirmed both feasibility of IM combinations and high response rates. However a substantial hematological toxicity requires a careful assessment of pts. [Table: see text]