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aIM, imatinib.

Abbreviation: CCyR, complete cytogenetic response.

aIM, imatinib.

Abbreviation: CCyR, complete cytogenetic response.

weekly (18). Patients were monitored with real time PCR and cytogenetics every three months for the first year and every six months thereafter. Ninety-four patients have been registered: 49 randomized to imatinib alone and 45 to IM + PEG-IFN + GM. 70 (75%) have been followed for at least six months and 49 (52%) for 12 months (first interim analysis was done when 30 patients were in a position to be evaluated at 12 months). Ten patients randomized to PEG-IFN did not start therapy (two refused, two physician's decision, six off study before six months because of noncompliance n = 3, melanoma n = 1, financial reasons n = 1, or progressive disease n = 1). There is a trend for improved response after 12 months with the combination (Table 5). Toxicity with high-dose imatinib was similar to previous reports. The most common grade >3 toxicity associated with PEG-IFN in the 26 patients reported included fatigue (n = 7, 27%), rash (n = 5, 19%), depression (n = 3, 11%), and headache (n = 2, 7%). Twelve patients have required dose reductions of PEG-IFN and three of them (13%) permanently discontinued it. The actual median (range) dose of IM at 12 months was 800 mg (600-800 mg) for IM alone and 800 mg of PEG-IM. It was concluded that the combination of imatinib and PEG- IFN as done here was associated with acceptable toxicity profile.

Based on these preliminary results using combination therapies as well as in vitro data suggesting synergistic or additive effect of imatinib with other agents (19), several national groups are currently conducting trials, exploring various dosages of imatinib (400 mg, 600 mg, and 800 mg) and combination therapies with cytarabine or IFN-a. The U.K. and U.S. groups are exploring a comparison between 400 and 800 mg. In addition, two groups are conducting, in parallel, large phase III trials, exploring dosage of imatinib as well as combination therapies. In July 2002, the German CML-study group activated a four arm randomized controlled trial comparing imatinib 400 mg with imatinib plus IFN-a, imatinib plus cytarabine and imatinib after IFN-a failure. In this trial, high risk patients are randomly assigned to primary imatinib-based therapies including a treatment arm with 800 mg daily (20). A recent evaluation was based on 416 patients with 12 months of followup. Of the 335 patients with cytogenetic evaluation, 63% achieved MCyR and 53% CCyR. The number of patients who progressed each year was very low and 27% of patient achieved a major molecular response. However, an analysis of outcome for the individual treatment groups is not yet available.

In September 2003, the French CML study group started a similar phase III trial (21). The experimental arms are IM 400 mg daily in combination with

Peg-IFN-2a (Peg-IFN2a, 90 mg weekly) or IM 400 mg daily in combination with Ara-C, (20 mg/m2/day, days 15-28 of 28-day cycles) or IM 600 mg daily. The reference arm is IM 400 mg daily. A first evaluation based on 315 patients with a median time of observation of 12 months demonstrated the feasibility of combination therapies with CHR rate of 82% at three months. Cytogenetic data were available from 154 patients. At six months, 135 patients (87%) achieved a MCyR, being complete in 105 patients (68%). A substantial number of patients experienced grade three-fourth hematological as well as nonhematological toxicities. Similarly, analysis of outcome by treatment group is forthcoming. These studies will be very valuable in establishing the role of high dose imatinib and imatinib-based combinations in the management of CML.

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