Using imatinib to treat chronic-phase chronic myeloid leukemia (CP-CML) first line, with selective switching to nilotinib (Tasigna) “leads to excellent molecular response and survival” and “may be preferable to universal first-line use of more potent agents, considering efficacy, toxicity, and economic factors,” Australian Leukemia and Lymphoma Group investigators reported in Blood.
These conclusions were based on results from the Therapeutic Intensification in De Novo Leukemia (TIDEL)-II study, which built on the previous TIDEL-I study of intensified imatinib for patients failing to achieve interim treatment targets. TIDEL-II incorporated two additional approaches—escalating the imatinib dose to 800 mg/d in patients with imatinib plasma trough serum concentration < 1,000 ng/mL and “a prompt switch to the more potent tyrosine kinase inhibitor nilotinib for either imatinib intolerance or a suboptimal response, as defined by molecular targets,” the researchers explained.
A total of 210 patients with CP-CML were enrolled into two sequential cohorts of 105 patients each. Patients had to be older than age 16 and within 6 months of diagnosis. The median age was 48 in cohort 1 and 49 in cohort 2. Cohort 1 was 49% female, and cohort 2 was 39% female. The primary endpoint was confirmed major molecular response, defined as BCR-ABL1 ≤ 0.1%, on the International Scale.
All patients started with imatinib at 600 mg/d. If imatinib plasma trough levels were < 1,000 ng/mL when assessed at day 22, imatinib was escalated to 800 mg/d. “Patients were then assessed against molecular targets: BCR-ABL1 ≤ 10%, ≤ 1%, and ≤ 0.1% at 3, 6, and 12 months, respectively. Cohort 1 patients failing any target were escalated to imatinib 800 mg/d and subsequently switched to nilotinib 400 mg twice daily for failing the same target 3 months later. Cohort 2 patients failing any target were switched to nilotinib directly, as were patients with intolerance or loss of response in either cohort,” the researchers wrote.
“At 2 years, 55% of patients remained on imatinib, and 30% on nilotinib,” the investigators reported. Only 12% failed to achieve an early molecular response, defined as BCR-ABL1 ≤ 10% at 3 months. Confirmed major molecular responses occurred in 64% of patients at 12 months and 73% at 24 months. Complete molecular response, defined as two consecutive measurements of undetectable BCR-ABL1 within 3 months, was achieved in 11% of patients at 12 months and 25% at 24 months.
Overall survival was 96%, and transformation-free survival was 95% at 3 years. “These results compare very favorably with other current first-line tyrosine kinase inhibitor studies in CP-CML patients, including the first-line use of nilotinib or dasatinib [(Sprycel)],” the authors noted.
The most common severe adverse event associated with imatinib was cytopenia, especially at the beginning of study treatment. Biochemical abnormalities, including elevated serum liver or pancreatic enzymes, and allergic skin reactions were common with both imatinib and nilotinib treatments. “Arthralgia, gastrointestinal disturbances, and edema were also commonly reported with imatinib.
Although postulating that “imatinib 800 mg/d may be beneficial for selected patients,” the investigators found that only about “11% of patients can maintain imatinib 800 mg/d and achieve a major molecular response on this dose, suggesting that the importance of high-dose imatinib may be secondary to therapy switching based on intolerance or failure to reach
The outcome for patients switching to nilotinib was generally favorable for patients with imatinib intolerance. “In contrast, the benefit of nilotinib switching in patients who failed to achieve early TIDEL-II targets is not clearly demonstrated in our cohorts,” the researchers wrote, noting that this “is a likely consequence” of the low early molecular response failure rate. ■
Yeung DT, et al: Blood 125:915-923, 2015.