Follow-up Results Favor Dasatinib Over Imatinib as CML Front-Line Therapy

Roxanne Nelson

December 13, 2010

December 13, 2010 (Orlando, Florida) — The newer drug dasatinib (Sprycel; Bristol-Myers Squibb) continues to demonstrate superior efficacy compared with imatinib (Gleevec; Novartis Oncology) in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP).

The 18-month follow-up data from the Dasatinib versus Imatinib Study in Treatment-Naive CML Patients (DASISION) supports the potential use of dasatinib as first-line treatment for patients with CML-CP. The findings were presented here at the American Society of Hematology 52nd Annual Meeting.

"Dasatinib 100 mg once daily continues to demonstrate superior efficacy compared with imatinib, with higher and faster rates of complete cytogenetic response and major molecular response," said study author Neil Shah, MD, PhD, an assistant professor at the University of California–San Francisco. "The longer follow-up continues to support the use of dasatinib as first-line therapy in newly diagnosed chronic phase patients.

"Based on the predictive value of early complete cytogenetic response, we anticipate that further follow-up may demonstrate better long-term outcomes for patients receiving dasatinib, rather than imatinib," he concluded.

Earlier 12-month results from the phase 3 DASISION study were presented at the American Society of Clinical Oncology 2010 Annual Meeting and published simultaneously in the New England Journal of Medicine. As reported by Medscape Medical News at that time, the results showed that complete cytogenic and major molecular responses were higher in the dasatinib group than in the imatinib group, and both responses were obtained significantly faster.

Progression to the accelerated or blast phase was also lower in the dasatinib group, occurring in 5 patients in the dasatinib group (1.9%, all blastic phase) and 9 patients in the imatinib group (3.5%, all blastic phase).

As a result of these data, the US Food and Drug Administration approved an expanded indication for dasatinib as a first-line therapy for CML-CP. Dasatinib was initially approved for patients with CML-CP who had developed resistance or were intolerant to prior therapy, including imatinib.

End of Imatinib?

The extended follow-up data add further evidence to the role of dasatinib as a first-line treatment in CML, commented Elias Jabbour, MD, who was approached by Medscape Medical News for an independent comment.

"The differences in efficacy between dasatinib and imatinib are maintained," said Dr. Jabbour, an assistant professor in the Department of Leukemia, University of Texas MD Anderson Cancer Center, in Houston.

Dr. Jabbour also believes that imatinib will gradually be replaced by next-generation agents such as dasatinib. "Unless it is for financial reasons, patients should start therapy with second-generation tyrosine kinase inhibitors," he said.

Faster and Improved Responses

Dasatinib is 325-fold more potent than imatinib in vitro against unmutated BCR-ABL and has already been established as an effective second-line treatment. The DASISION study was conducted to compare dasatinib with imatinib as initial treatment for newly diagnosed patients with CML-CP.

Dr. Shah and colleagues randomly assigned 519 patients with a median disease duration of 1 month to either dasatinib 100 mg once daily (n = 259) or imatinib 400 mg once daily (n = 260).

The median treatment duration in the current analysis was 18 months for each agent, with 81% of patients in the dasatinib group and 80% in the imatinib group remaining in the trial. Median dose intensity was 99 mg/day for dasatinib and 400 mg/day for imatinib.

The efficacy and safety results in this extended analysis were consistent with those reported after 12 months of follow-up, Dr. Shah explained.

The confirmed complete cytogenetic response at 12 months was 77% with dasatinib compared with 67% with imatinib. At the longer follow-up, it was 78% for dasatinib vs 70% with imatinib (P = .0366). The median time to complete cytogenetic response was 3.1 months for dasatinib compared with 5.8 months for imatinib.

The authors also note that patients treated with dasatinib were 28% less likely to experience a progression event after achieving a confirmed complete cytogenetic response, or never achieving a confirmed complete cytogenetic response, compared with those receiving imatinib.

At 12 months, the rates of major molecular response were 46% for dasatinib and 28% for imatinib. This benefit remained statistically significant for dasatinib at 18 months (57% vs 41% for imatinib; P = .0002), Dr Shah reported. Based on time-to-response analysis, the likelihood of achieving a major molecular response was 1.8-fold higher with dasatinib than with imatinib (P < .0001).

The median time to achieving a major molecular response was 8.3 months with dasatinib compared with 11.8 months with imatinib.

A BCR-ABL transcript level of 0.0032% or less was achieved in 13% of patients in the dasatinib group vs 7% of patients treated with imatinib. Rates of progression-free survival at 18 months were similar for the 2 groups: 94.9% for dasatinib and 93.7% for imatinib. Overall survival rates were also similar, at 96.0% and 97.9%, respectively.

A total of 6 patients (2.3%) receiving dasatinib and 9 (3.5%) receiving imatinib had a transformation to accelerated or blast phase. In addition, 6 patients (2.3%) receiving dasatinib and 11 (4.3%) in the imatinib group stopped therapy as a result of treatment failure.

However, the discontinuation of treatment as a result of adverse events was infrequent in both groups (dasatinib, 6%; imatinib, 4%). Dr. Shah pointed out that nonhematologic grade 3/4 adverse events were infrequent in either study group (≤1%).

The most common grade 3/4 hematologic adverse events observed were (dasatinib vs imatinib) anemia (11% vs 7%), neutropenia (22% vs 20%), and thrombocytopenia (19% vs 10%). Cytopenia was cited as the reason for discontinuing treatment in 6 patients in the dasatinib group (2.3%) and in 3 patients in the imatinib group (1.2%).

Dr. Shah reports relationships with Bristol-Myers Squibb, Novartis, and Ariad. Other study authors disclosed relationships with Bristol-Myers Squibb, Novartis, Pfizer, and Wyeth.

American Society of Hematology 52nd Annual Meeting: Abstract 206. Presented December 6, 2010.

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