A Randomized Trial of High-Dose (HD) Imatinib Mesylate (IM) with or without Peg-Interferon (PEG-IFN) and GM-CSF as Frontline Therapy for Patients with Chronic Myeloid Leukemia (CML) in Early Chronic Phase (CP).

Some studies suggest that HD IM may be more effective than standard dose in CP CML. Still, only a minority of patients (pts) may reach undetectable levels of Bcr-Abl transcripts, and the use of single agent therapy may eventually result in development of resistance. IFN is thought to be effective in CML due to its immunomodulatory properties and may be valuable for management of minimal residual disease. Pre-clinical studies suggest synergy with imatinib. GM-CSF combined with IFN is a potent stimulator of dendritic cells. We designed this randomized phase II study to investigate if adding PEG-IFN to imatinib may improve the rate of complete molecular responses and prolong remission duration. Pts with previously untreated CP CML started treatment with imatinib 800mg daily and randomized after 6 months (mo) of therapy to either continue HD IM alone or add PEG-IFN 0.5mcg/kg/week and GM-CSF 125 mg/m² three times weekly. Pts were monitored with real-time PCR and cytogenetics (CG) every 3 mo for the 1^st year and every 6 mo thereafter. Ninety-four pts have been registered to date: 49 randomized to IM alone and 45 to IM + PEG-IFN+GM. 70 (75%) have been followed for at least 6 months and 49 (52%) for 12 months. (First interim analysis done when 30 pts evaluable at 12 mo). Ten pts randomized to PEG-IFN did not start therapy (2 refused, 2 physicians decision, 6 off study before 6 mo because of noncompliance n=3, melanoma n=1, financial n=1, progressive disease n=1). Patient characteristics and response (intention to treat) are as follows:

Toxicity with HD imatinib was similar to previous reports. The most common grade ≥3 toxicity associated with PEG-IFN in the 26 pts included fatigue (n=7, 27%), rash (n=5, 19%), depression (n=3, 11%), and headache (n=2, 7%). Twelve pts have required dose reductions of PEG-IFN and 3 (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 (400–800 mg) for combination arm. Among pts randomized to PEG-IFN arm, the dose of IM had to be reduced after 6 mo (i.e., after start of PEG-IM) in 4 (16%) pts. We conclude that the combination of IM and PEG-IM as done here is associated with acceptable toxicity profile. There is a trend for improved response after 12 months with the combination.