TIDEL-II: Individualized Approach to Imatinib Yields Promising Results

For patients with chronic-phase chronic myeloid leukemia (CPCML), a strategy of intensifying treatment with imatinib or selective switching to nilotinib based on molecular treatment targets leads to improved overall survival, according to results from a study recently published in Blood.

Although second-generation TKIs, such as nilotinib, lead to faster and deeper molecular responses, there are lingering questions about their long-term safety. Imatinib – the standard of care since its introduction – has a proven low risk of toxicity associated with major morbidity. The TIDEL-II study evaluated a strategy incorporating both imatinib and, when needed, nilotinib in 210 CP-CML patients (divided into two cohorts of 105 patients each).

“Although imatinib is an effective treatment for many, we recognized that some patients will need a more potent kinase inhibitor,” the authors, led by David T. Yeung, MD, wrote in their analysis of the TIDEL-II data. “We believe strategies such as TIDEL-II may be preferable to the universal use of second-generation TKIs as frontline treatment.”

All patients were started on imatinib at a dose of 600 mg/day, with a planned dose escalation to 800 mg/day for patients with imatinib plasma trough levels <1,000 ng/mL on day 22 (19%). Treatment was modulated based on serum imatinib trough levels, achievement of molecular targets, and tolerability.

In Cohort 1, patients who failed to achieve molecular treatment targets (of BCR-ABL1 ≤10 percent, ≤1 percent, and ≤0.1 percent at three, six, and 12 months, respectively) were escalated to imatinib 800 mg/day, then subsequently switched to nilotinib 400 mg/twice-daily for failing the same target three months later. In Cohort II, patients who failed to achieve molecular and trough level targets at three months were switched to nilotinib directly.

Patients with intolerance or loss of response in either cohort were also switched to nilotinib directly.

Overall, the effect of the individualized approach outlined in TIDEL-II led to MMR rates of 64 percent by 12 months, and 73 percent by 24 months, as well as “encouraging” rates of other treatment targets (TABLE).

Furthermore, three-year overall survival and treatment-free survival were 96 percent and 95 percent, respectively. These results compare very favorably with other current studies of frontline TKI studies in CML-CP patients, the authors pointed out.

Most patients at both 12 and 24 months remained on imatinib therapy without switching to nilotinib (83% and 73%, respectively). The higher starting dose of imatinib (600 mg/day) led to greater rates of early molecular response (EMR) at three months – a measure that correlates with greater PFS, OS, and MMR achievement, regardless of the TKI used for frontline treatment.

Switching to nilotinib after imatinib – rather than classifying patients who failed to respond on imatinib alone as “therapeutic failures” like in other clinical trials involving TKIs in CML – allowed an additional 32 patients (15% of the total TIDEL-II population) to achieve MMR, and an additional 22 patients (10% overall) to achieve “deeper” grades of molecular response (MR4.0-4.5).

“A deep molecular response is an increasingly valued treatment goal, associated with improved survival,” Dr. Yeung and colleagues wrote. “Given the increasing availability of generic imatinib in many countries over the next decade, the TIDEL-II strategy is particularly attractive when the increasing economic burden of CML therapy is considered.”

The TIDEL-II treatment schema also allows physicians to more successfully select patients who are less sensitive or intolerant to imatinib, switching their therapy to nilotinib in a time-dependent manner to minimize treatment failure. The majority of patients, though, will be able to achieve EMR and MMR while remaining on a drug with long-term safety data.

“For the vast majority of CML patients, the TIDEL-II approach leads to excellent outcomes,” Dr. Yeung and co-authors concluded. “Future efforts should be directed at early identification of high-risk patients (especially those destined to experience early disease transformation) and the development of experimental strategies targeted at this population.”


Reference

    Yeung DT, Osborn MP, White DL, et al. TIDEL-II: Frontline use of imatinib in CML with early switch to nilotinib for failure to achieve time-dependent molecular targets. Blood. 2014 December 17. [Epub ahead of print]

Cohort 1 Cohort 2 Total
n (%; 95% CI) n (%; 95% CI) n (%; 95% CI)
12 months
BCR-ABL1 ≤1.0% 92 (88%; 82-94) 91 (87%; 81-93) 183 (87%; 82-92)
BCR-ABL1 ≤0.001% 13 (12%;5.8-18) 18 (17%; 10-24) 31 (15%; 10-20)
Confirmed MMR 69 (66%; 57-75) 65 (62%; 53-71) 134 (64%; 56-72)
Confirmed CMR

11 (10%; 4.3-16)

13 (12%; 5.8-18) 24 (11%; 6.8-15)
24 months
BCR-ABL1 ≤1.0% 89 (85%; 78-92) 87 (83%; 76-90) 176 (84%; 79-89)
BCR-ABL1 ≤0.001% 32 (30%; 21-39) 34 (32%; 23-41) 66 (31%; 25-37)
Confirmed MMR 80 (76%; 68-84) 73 (70%; 61-79) 153 (73%; 67-79)
Confirmed CMR 23 (22%; 14-30) 29 (28%; 19-37)

52 (25%; 19-31)

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