Abstract
Resistance to imatinib is a well-recognized problem in chronic-phase chronic myeloid leukemia (CP-CML). Increased potency of BCR-ABL inhibition by escalating imatinib doses to 800 mg/d (‘high-dose imatinib’) can be effective in some cases that are resistant to lower doses, but tolerability and durability of response limit the utility of this approach. Dasatinib (SPRYCEL®) has been shown to be effective in imatinib-resistant CML and its potency against BCR-ABL relative to imatinib (325-fold more potent against BCR-ABL in vitro) as well as its activity against nearly all imatinib-resistant BCR-ABL kinase domain mutations auger its potential in this setting. In this international phase-II study, 150 patients with CP-CML resistant to imatinib 400–600 mg/d were randomized on a 2:1 basis to dasatinib 70 mg BID (n=101) or imatinib 800 mg/d (n=49). Crossover was permitted for confirmed progression, lack of major cytogenetic response (MCyR) at 12 weeks, or intolerance despite dose reduction (grade 3–4 non-hematologic toxicity). Dasatinib dose could be escalated to 90 mg BID for inadequate response at 12 weeks, or reduced to 50 or 40 mg BID for toxicity. Dose reduction of imatinib to 600 mg/d was allowed for patients who had not previously received that dose. Median treatment duration with dasatinib was 13.7 mo and 3.1 mo with imatinib. With a median follow-up of 15 mo, complete hematologic response (CHR) rates were 93% and 82% for patients receiving dasatinib and high-dose imatinib, respectively (p=0.034). Dasatinib was also associated with higher MCyR rates (52% vs 33%, p=0.023); the difference being attributable to complete cytogenetic responses (40% vs 16%, p=0.004). For patients with no prior CyR to imatinib, 49% achieved a MCyR with dasatinib vs 7% with high-dose imatinib. Major molecular responses were also more frequent with dasatinib (16% vs 4%, p=0.038). Responses achieved with dasatinib were highly durable, and superior to historic experience with imatinib. Analyses of progression-free survival (PFS) favored dasatinib (hazard ratio [HR] 0.14, p<0.0001). Results were consistently in favor of dasatinib for PFS irrespective of the prior imatinib dose received (400 mg/d - HR 0.10, p=0.0177; 600 mg/d - HR 0.15, p=0.0005). Grade 3–4 non-hematologic toxicity was minimal for both treatment groups. All-grade superficial edema (15% vs 43%) and fluid retention (30% vs 45%) were less common with dasatinib than imatinib, whereas pleural effusion (17% vs 0%; grade 3–4, 4% vs 0%) was more common. Cytopenia was more frequent and severe with dasatinib. Treatment discontinuation attributable to toxicity occurred in 7% of patients receiving dasatinib and 18% treated with imatinib. The overall benefit-risk assessment favors dasatinib relative to high-dose imatinib in CP-CML patients with resistance to 400–600 mg imatinib. Updated results reflecting a minimum follow-up of 2 years will be presented.
Dasatinib in imatinib-resistant or -intolerant chronic-phase, chronic myeloid leukemia patients: 7-year follow-up of study CA180-034
