Long-Term Benefit With Dasatinib After Imatinib Failure in Chronic-Phase CML
Patients with chronic myeloid leukemia (CML) in the chronic phase who are resistant or intolerant to imatinib (Gleevec) can experience long-term benefit with dasatinib (Sprycel), according to results of a randomized phase III study. The CA180-034 study also found that early molecular and cytogenetic responses (at 3 and 6 months) were associated with improved progression-free and overall survival. The study by Shah et al was published in Blood.
Dasatinib is an oral inhibitor of the tyrosine kinase BCR-ABL, which, the investigators explained, “drives the malignant phenotype of leukemic stem cells.” In this dose-optimization study, 670 patients with imatinib-resistant or -intolerant CML in chronic phase were randomly assigned to dasatinib at 100 mg once daily, 50 mg twice daily, 140 mg once daily, or 70 mg twice daily.
The study protocol allowed dose escalation (up to a total daily dose of 180) or dose interruption or reduction (down to a total daily dose of 20 mg) to manage inadequate response or adverse events. The protocol also allowed switching from a twice-daily to a once-daily regimen with the same total daily dose after at least one dose reduction for recurrent anemia, thrombocytopenia, neutropenia, pleural effusion, or any other fluid retention.
Early Molecular Responses Were Highly Predictive
Most patients (74%) were imatinib-resistant, with the remainder being imatinib-intolerant, and most (77%) received once-daily dosing. At 6 years, 188 patients (28%) remained on study treatment. In the intent-to-treat population, the groups receiving 100 mg once daily, 50 mg twice daily, 140 mg once daily, and 70 mg twice daily, respectively, had 6-year protocol-defined progression-free survival rates of 49%, 51%, 40%, and 47% and estimated 6-year overall survival rates of 71%, 74%, 77%, and 70%.
A major molecular response was achieved in 43% (100 mg once-daily arm) and 40% (all other arms) of patients by 6 years. Molecular and cytogenetic responses at 3 and 6 months were highly predictive of progression-free survival and overall survival. “Notably, estimated 6-year [progression-free survival] rates based on ≤ 1%, > 1%–10%, and > 10% BCR-ABL transcripts at 3 months were 68%, 58%, and 26%, respectively,” the researchers reported.
Adverse Events
Dasatinib was generally well-tolerated. The most common nonhematologic adverse events were musculoskeletal pain, headache, infection, and diarrhea. These generally occurred within 2 years of treatment and were typically mild or moderate (grade 1 or 2). The most common grade 3/4 adverse events were infection, occurring in 6% of patients and pleural effusion, occurring in 5%. At 6 years, 9% of patients had discontinued treatment because of pleural effusion and ≤ 2.9% discontinued because of any other individual adverse event. The lowest discontinuation rate due to drug toxicity was at the 100 mg once-daily dose.
The researchers concluded, “This analysis represents the longest reported follow-up of patients with [chronic-phase CML] treated with a second-generation BCR-ABL inhibitor. Findings indicate that a consistent subgroup of [chronic-phase CML] patients resistant or intolerant to imatinib can have a long-term benefit from dasatinib therapy. In particular, those with faster and deeper responses to dasatinib (BCR-ABL ≤ 10% at 3 months) are more likely to have better long-term outcomes.”
They added, “For the substantial proportion of patients who respond well to dasatinib,” the risk of progression to accelerated- or blast-phase disease is low.
Neil P. Shah, MD, PhD, of the University of California, San Francisco, School of Medicine, is the corresponding author for the Blood article.
The study was sponsored by Bristol-Myers Squibb. For full disclosures of the study authors, visit bloodjournal.hematologylibrary.org.
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