Randomized Comparison of Imatinib with Imatinib Combination Therapies in Newly Diagnosed Chronic Myelogenous Leukemia Patients in Chronic Phase: Design and First Interim Analysis of a Phase III Trial from the French CML Group.

Imatinib (IM) at 400 mg daily has emerged as the preferred therapy for newly diagnosed CML pts. Despite impressive results, only a minority of pts treated with IM achieved a molecular remission. To improve upon these results, the CML French Group designed a phase III, multicentre, open-label, prospective randomized trial. The experimental arms are IM 400mg daily in combination with Peg-IFN-α2a (Peg-IFNα2a, 90 μg weekly) or IM 400mg daily in combination 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 in chronic phase within 3 months of diagnosis) receive IM 400 mg/day as monotherapy days 1–14 and then start the assigned randomized regimen. Treatment continues at least 12 months or until treatment failure (disease progression by hematologic criteria) or major toxicity. The primary endpoint will be the overall survival. Other endpoints will be: rate and duration of hematologic and cytogenetic responses, major (MCyR) and complete (CCyR), molecular response and the tolerability. Using treatment allocation ratio 1.1.1.1, randomization is stratified according to Sokal risk groups. An interim analysis of the first 636 patients (α=0.85%, β=10%) 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. The increased dose of IM or a combination regimen would be considered as promising if it increased the 4 log reduction response rate by at least 20 percentage points, e.g. from 15% to 35%, with an acceptable tolerability. Evaluation of molecular response up to 12 months is centralized and blinded. This evaluation is based on a cohort of 315 pts with a median time of observation of 12 months, recruited between 9/2003 and 6/2005.[median age 53 yrs (18–78), 60% of pts were male; Sokal risk distribution: 39% of pts low risk, 38% intermediate risk, and 23% high risk]. At 3 months 82% of pts achieved complete hematologic response. Cytogenetic data are available from 154 pts. At 6 months, 135 pts (87%) achieved a MCyR, being complete in 105 pts (68%). Grade 3/4 neutropenia and thrombocytopenia occurred in 5% and 0% of IM400 pts, in 5% and 1% of IM600 pts, in 30% and 4% of IM+IFN pts and in 24% and 13% 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 6% of IM400 pts (mainly skin rash and muscle cramps), in 10% of IM600 pts, in 5% of IM+IFN pts (maily skin rash) and in 13% of IM+Ara-c pts (mainly diarrhea). Discontinuation of experimental treatment occurred in 15% of IM600 pts, 28% of IM+IFN pts and in 13% of IM+Ara-c pts. This first analysis of a randomized trial has proven feasibility of IM combinations in addition to high response rates. However a substantial hematological toxicity was recorded with IFN or Ara-c combination, which requires a careful assessment during the first 6 months of treatment. Long-term observation will demonstrate whether these promising results will have the potential to improve survival of CML pts.