Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia resistant to imatinib at a dose of 400 to 600 milligrams daily: two-year follow-up of a randomized phase 2 study (START-R)

Abstract

Background: In patients with chronic-phase chronic myeloid leukemia (CP-CML), imatinib resistance is of increasing importance. Imatinib dose escalation was the main treatment option before dasatinib, which has 325-fold more potent inhibition than imatinib against unmutated Bcr-Abl in vitro. Data with a minimum of 2 years of follow-up were available for the current study of dasatinib and high-dose imatinib in CP-CML resistant to imatinib at daily doses from 400 mg to 600 mg.

Methods: A phase 2, open-label study was initiated of 150 patients with imatinib-resistant CP-CML who were randomized (2:1) to receive either dasatinib 70 mg twice daily (n=101) or high-dose imatinib 800 mg (400 mg twice daily; n=49).

Results: At a minimum follow-up of 2 years, dasatinib demonstrated higher rates of complete hematologic response (93% vs 82%; P=.034), major cytogenetic response (MCyR) (53% vs 33%; P=.017), and complete cytogenetic response (44% vs 18%; P=.0025). At 18 months, the MCyR was maintained in 90% of patients on the dasatinib arm and in 74% of patients on the high-dose imatinib arm. Major molecular response rates also were more frequent with dasatinib than with high-dose imatinib (29% vs 12%; P=.028). The estimated progression-free survival also favored dasatinib (unstratified log-rank test; P=.0012).

Conclusions: After 2 years of follow-up, dasatinib demonstrated durable responses and improved response and progression-free survival rates relative to high-dose imatinib.

Conflict of interest statement

Conflict of Interest Disclosures

Funding for this research was provided by Bristol-Myers Squibb. Professional medical writing and editorial assistance was funded by Bristol-Myers Squibb and was provided by E. Dolgos.

Dr. Kantarjian has received research grants from Bristol-Myers Squibb and Novartis.

Dr. Holowiecki has received research grants from Bristol-Myers Squibb and Novartis.

Dr. Hughes has received honoraria and research funding from Bristol-Myers Squibb and Novartis and has acted in an advisory role for both companies.

Dr. Bleickardt is an employee of Bristol-Myers Squibb and owns stock in the company.

Dr. Dejardin is an employee of Bristol-Myers Squibb and owns stock and stock options.

Dr. Cortes has received research support from Bristol-Myers Squibb, Novartis, and Wyeth.

Dr. Shah has acted as a consultant for Bristol-Myers Squibb and Novartis.

Copyright (c) 2009 American Cancer Society.

Figures

FIGURE 1

Consolidated Standards of Reporting Trials (CONSORT) diagram is shown. Randomization was in a 2:1 ratio of dasatinib:imatinib. An asterisk indicates that patient death was within 30 days of dasatinib discontinuation; dagger, 2 patients who were not listed had withdrawn from dasatinib therapy for intolerance (n = 1) or for another reason (n = 1) but were not yet receiving high-dose imatinib; double dagger, 1 patient had developed disease progression and intolerance. MCyR indicates major cytogenetic response; Ph+, Philadelphia chromosome positive.

FIGURE 2

The duration of major cytogenetic response (MCyR) before patients crossed over to the alternate treatment arm is shown. Patients who achieved an MCyR and crossed over for intolerance before disease progression were censored at the date of the first treatment postcrossover. Patients without disease progression and those who remained alive at the time of last follow-up were censored on the date of their last cytogenetic assessment.

FIGURE 3

The time to treatment failure is shown. This was defined as the time from randomization to disease progression, off-study or crossover, or death. Patients who had not crossed over to the alternate treatment arm or who were off study because of study closure were censored at the date of their last hematologic or cytogenetic assessment.

FIGURE 4

Progression-free survival is shown (a) overall, for patients who received prior imatinib at doses of (b) 600 mg or (c) 400 mg, and for patients with (d) primary resistance and (e) acquired resistance. Patients without disease progression and those who remained alive at the time of last follow-up were censored at the last dosing date if they were off initial treatment or at the last assessment date if they were receiving initial treatment.