Immune Modulation of Minimal Residual Disease (MRD) in Patients (pts) with Chronic Myelogenous Leukemia (CML) in Early Chronic Phase (CP): A Randomized Trial of Frontline High-Dose (HS) Imatinib Mesylate (IM) with or without Pegylated-Interferon (PEG-IFN) and GM-CSF.

Some studies suggest that HD IM renders higher molecular response rates than standard dose IM in CP CML. Yet, most patients have MRD detectable by PCR and in vitro studies suggest the CML stem cell is insensitive to IM. The efficacy of IFN in CML has been linked to its immunomodulatory properties and preclinical studies have shown synergy with IM. IFN may be used as adjunct for the management of MRD. IFN combined with GM-CSF is a potent dendritic cell stimulator. In this phase II study we investigated whether the addition of PEG-IFN to IM improves complete molecular response (CMR) rates and prolong remission duration in pts with early CP CML. Pts received IM 800 mg daily for 6 months (mo) before randomization to either continuing HD IM as single-agent or combined with PEG-IFN 0.5 mcg/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 12 mo and every 6 mo thereafter. Ninety-four pts were randomized between Arm A (IM alone; 49 pts) and Arm B (IM+PEG-IFN+GM; 45 pts) and 91 (97%) were followed for at least 12 mo (2 pts in Arm A and 1 in Arm B did not start therapy). Ten pts randomized to Arm B did not start PEG-IFN (4 refused, 3 off study before 6 mo, 1 melanoma, 1 heart disease, 1 financial). The primary objective was to increase by 50% the rate of major molecular response (BCR-ABL/ABL ratio <0.05%) at 12 mo. Pt characteristics and response are shown in Table 1. Median follow-up for pts on study was 24 mo (range, 12 to 38) and 8 mo (range, 1 to 22) for those taken off-study. Toxicity in Arm A was similar to that reported in prior studies of HD IM. The most common grade 3–4 toxicities among 39 pts assessable in Arm B were fatigue (n=12, 31%), depression (n=3, 8%), pruritus (n=3, 8%), and headache (n=3, 8%) and were all significantly more frequent in Arm B than Arm A. PEG-IFN was discontinued in 43% of pts and GM-CSF in 45%, mainly due to fatigue, rash, and flu-like symptoms. Nine pts were taken off study in Arm A (3 resistant, 2 liver toxicity, 4 other) and 10 in Arm B (3 resistant, 2 financial, 1 liver toxicity, 4 other). Median IM dose intensity at 12 mo was 98% (range, 47% to 100%) in Arm A and 99% (range, 46% to 100%) in Arm B. By contrast, PEG-IFN dose intensity was only 45%, with 75% of pts receiving < 60% of the planned dose. We conclude that the combination of HD IM and PEG-IFN is associated with acceptable toxicity but does not impact significantly the achievement of molecular response after 12 mo of therapy at the dose schedule used in this study. The high drop-out rate observed in the PEG-IFN arm may have compromised any potential immunomodulatory benefit.