Results of Dasatinib Therapy in Patients With Early Chronic-Phase Chronic Myeloid Leukemia

2009 Dec 14; Epub online ahead of print, JE Cortes , D Jones, S O'Brien, E Jabbour, F Ravandi, C Koller, G Borthakur, B Walker, W Zhao, J Shan, H Kantarjian

Supplementary editorial provided by OncologySTAT

TAKE-HOME MESSAGE
Dasatinib as initial therapy for chronic-phase CML produced high cytogenetic and molecular response rates with acceptable toxicity.

STUDY IN CONTEXT
Standard front-line therapy for Philadelphia chromosome?positive chronic myeloid leukemia (CML) is the tyrosine kinase inhibitor imatinib. In a randomized study, 82% of patients achieved a complete cytogenetic response (CCyR) to imatinib, and the projected 7-year survival rate was 86%. However, approximately 10% of patients treated with imatinib experience relapse after attaining CCyR, and 4% to 8% discontinue treatment for safety reasons or intolerance. Thus, newer therapies are being developed to improve long-term outcomes.

Dasatinib is a potent second-generation tyrosine kinase inhibitor that induced CCyR in 50% of patients who did not respond to imatinib. This study by Cortes et al evaluated dasatinib as initial therapy in patients with chronic-phase CML. The results showed rapid response and high rates of cytogenetic and molecular response. In addition, the toxicity profile was favorable.

To be eligible for the study, patients with chronic-phase CML had to have received no prior CML therapy other than hydroxyurea or ?1 month of standard-dose imatinib. Patients were randomized to a dasatinib dosage of either 100 mg once daily or 50 mg twice daily. Treatment continued until patients experienced disease progression or unacceptable toxicity.

Total enrollment was 62 patients (31 patients in each treatment arm). Evaluable data were available for 50 of the 62 patients. Of the remaining 12 patients, 1 patient had discontinued therapy after 3 doses, and 11 patients had been observed for <3 months. Median follow-up time was 24 months (range, 1 to 39 months).

All 45 patients who were not in complete hematologic response (CHR) at enrollment achieved CHR within a median time of 4 weeks. Among the 50 evaluable patients, 49 patients (98%) achieved CCyR; the 1 patient who did not achieve CCyR had experienced a prolonged treatment interruption due to grade 3 thrombocytopenia. The median time to CCyR was 3 months (range, 3 to 9 months). Major molecular response (MMR), defined as a BCR-ABL/ABL transcript ratio <0.1%, was achieved by 41 patients (82%). The median time to MMR was 6 months (range, 3 to 18 months). Rates of response and time to response did not differ between treatment arms.

CCyR has been maintained in 45 of 48 patients (94%); for 1 patient, cytogenetic analysis has not yet been conducted. Of the 3 patients who lost CCyR, 1 patient had a prolonged treatment interruption due to pleural effusion, and 2 patients were nonadherant. The 24-month projected event-free survival rate is 88% (90% excluding the 2 nonadherant patients). No patients have died or transformed to accelerated- or blast-phase disease. By 6 months, 34 of 38 patients (90%) had achieved complete absence of p-CrkL on peripheral-blood leukocytes.

Treatment was well tolerated. Nonhematologic toxicities of grade 3 or greater that each occurred in ?6% of the patients included fatigue, joint and muscle pain, peripheral neuropathy, dyspnea, and memory impairment. One patient (2%) experienced grade 3 pleural effusion. Hematologic toxicities of grade 3 or greater included neutropenia (13 patients, 21%), thrombocytopenia (6 patients, 10%), and anemia (4 patients, 6%). The overall rate of adverse events did not differ in the treatment arms. Transient treatment interruptions were required in 30 patients (48%), with the most common causes being pleural effusion, dyspnea, and headache. Dose reductions were required in 22 patients (35%).

In this study, dasatinib resulted in a high and rapid rate of response and was well tolerated. Given that the follow-up time of this study was only 24 months, the long-term benefits of dasatinib compared with imatinib remain to be determined. Dasatinib was effective as initial therapy for chronic-phase CML.