Imatinib Dose Can Be Safely Reduced after Complete Cytogenetic Response (CCyR) in Patients (pts) with Chronic Myeloid Leukemia (CML) in Early Chronic Phase (CP) Treated with High-Dose Imatinib.

Background Imatinib (standard dose, SD, 400mg/d) is standard therapy in CP CML. Several observations suggest that initial therapy with high-dose (HD) imatinib might be more effective. We previously reported that HD imatinib (800mg/d) leads to significantly better rates of complete cytogenetic response (CCyR), major molecular response (MMR) and complete molecular response (CMR), and improved event-free survival compared to SD. However, HD imatinib is associated with more frequent grade 3–4 hematological toxicity compared to SD. In addition, 36% pts required dose reduction due to toxicities. We investigated the outcome of pts who were maintained on 800mg/d compared to those whose dose was reduced from 800mg/d.

Methods Pts enrolled in 3 sequential trials using imatinib for frontline therapy for CP CML were analyzed: 208 treated with HD and 50 with SD. Primary end points were event-free survival (EFS) and transformation-free survival (TFS).

Results The median age was 48 years (range 17–84 years). Median follow up was 49 months. 4 year event-free survival (EFS) and transformation-free survival (TFS) were significantly better for pts treated with HD imatinib compared to SD (EFS: 92% vs. 77%, p=0.01; TFS: 98% vs. 89%, p=0.0045). Among pts treated with HD, 100 (48%) had a dose reduction at any time [600mg/d (n=50), 400mg/d (n=38), 300mg/d (n=12)]. Of them, 45 (45%) were dose-reduced after achieving CCyR including 26 (26%) after MMR. The median time to dose reduction was 3 months (range 1–60 months). For pts starting with HD imatinib, there was no difference between pts continuing with HD and those with a dose reduction in terms of EFS at 4 years (92% in both groups, p=0.65) and TFS at 4 years (98% vs. 97%, respectively, p=0.36). However, EFS at 4 years was significantly worse if the dose reduction was done prior to achievement of CCyR (84% vs. 100%, p=0.02). Similarly, patients who were dose-reduced before MMR had significantly worse 4 year EFS (88% vs. 100%, p=0.02). EFS curve for patients who had dose reduction done prior to CCyR was similar to that of pts treated with SD imatinib (p=0.59).

Conclusions These results indicate that pts treated with HD imatinib can be safely dose reduced once they have achieved CCyR (preferably MMR) without having any impact on EFS or TFS. Such dose reduction may help decrease side effects as well as cost of the treatment. A prospective evaluation of this approach is warranted.