CHICAGO—Four-year follow-up of patients with chronic-phase chronic myelogenous leukemia (CP-CML) who have been resistant, suboptimally re - sponsive, or intolerant to prior imatinib therapy showed that dasatinib 100 mg once daily has the most favorable risk–benefit profile, with 66% progression- free survival (PFS) and 82% overall survival (OS).
The findings also demonstrated that responses to dasatinib 100 mg once daily at 12 months are predictive of PFS at 48 months, said Neil P. Shah, MD, assistant professor of medicine at the University of California, San Francisco, at the 2010 annual meeting of the American Society of Clinical Oncology.
Dasatinib, a potent tyrosine kinase inhibitor, is indicated for treating imatinib- resistant or -intolerant patients with CML (all phases) or Philadelphia chromosome–positive acute lymphoblastic leukemia.
“These findings argue, in general for this population of patients, that a trial of dasatinib for 1 year to see if they can achieve a CCyR [complete cytogenetic response] is reasonable. With a CCyR, you can expect a 4% to 5% chance of their disease transforming to accelerated or blast phase,” Shah said.
Patients were randomized using a 2 ¥ 2 factorial design to one of four dasatinib treatment arms: 100 mg once daily (n = 167), 50 mg twice daily (n = 168), 140 mg once daily (n = 167), and 70 mg twice daily (n = 168). Prior analysis of the study had resulted in a change of the approved dose from 70 mg twice daily to the 100-mg once-daily dose. The current analysis evaluated efficacy and safety in patients with a minimum followup of 48 months.
Similar percentages of patients achieved the highest standard of response, major molecular responses (MMRs) (44%, 100 mg once daily; 43%, 70 mg twice daily; 42%, 140 mg once daily; 41%, 50 mg twice daily). Fifty percent achieved CCyR in the 100-mg once-daily group (49%-53% for other doses). PFS, defined as no loss of complete hematologic response or major cytogenetic response, development of advanced disease, elevated white blood cells, or death, was 66% for 100 mg once daily and 57% to 69% for other doses. OS was 82% for 100 mg once daily and 75% to 83% for other doses. Rates of progression to accelerated or blast phase for the 100- mg once-daily dose were 1.2% for each of the first 3 years and 0% for year 4.
Landmark analysis of PFS according to response at 12 months with 100 mg once daily showed that 93% of patients who achieved an MMR (+ CCyR) had PFS at 48 months, as compared with a PFS rate of 77% among patients who achieved a CCyR but not an MMR at 12 months. PFS for patients without a cytogenetic response at 12 months was 45%.
In general, first occurrence of an adverse event (AE) was encountered early in the treatment course (<24 months). AEs were typically mild to moderate. First occurrences of pleural effusions (all grades) tended to occur at <24 months (15% by 24 months, 7% between 24 and 36 months, and 2% beyond 36 months). Neutropenia and thrombocytopenia (grade 3-4) occurred mostly within the first 12 months of treatment (33% and 22% by 12 months, decreasing to 0% for both between 36 and 48 months). Discontinuations due to drug toxicity were lowest with the 100-mg once-daily dose (16% vs 19%- 26% for other doses).
Shah concluded that dasatinib 100 mg once daily offers a more favorable 4-year risk–benefit profile with similar efficacy but better tolerability than other doses. He pointed out that this analysis is the longest follow-up reported for any tyrosine kinase inhibitor. He commented further, “I think the less than 4% rate of transformation to accelerated or blast phase in a secondline setting, along with the 82% overall survival, is rather encouraging.”