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Time-dependent treatment may lead to better CML outcomes
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Switching from imatinib to nilotinib at the right time may be a beneficial treatment strategy for some patients with chronic phase chronic myeloid leukemia, according to results of a study conducted in Australia.
Prior research showed use of imatinib (Gleevec, Novartis) conferred excellent outcomes as front-line treatment for chronic phase CML. In the IRIS trial, 85% of patients remained alive at 8 years; however, 45% ultimately discontinued imatinib because of intolerance, resistance to the drug or disease progression.
The Australasian Leukemia and Lymphoma Group conducted the TIDEL-1 and TIDEL-II trials in an effort to improve outcomes for all patients with chronic phase CML.
The trials were designed to compare the efficacy of two treatment strategies for patients who failed to achieve certain time-dependent treatment targets while on front-line imatinib.
Timothy P. Hughes, MD, head of the department of hematology at SA Pathology, consultant hematologist at Royal Adelaide Hospital and clinical professor of medicine at the University of Adelaide in Australia, and colleagues established two sequential cohorts that enrolled a combined 210 patients between November 2007 and March 2011.
Confirmed major molecular response (MMR) at 12 months — defined as BCR-ABL1 levels of 0.1% or less on the international scale — served as the primary endpoint.
All patients began with imatinib 600 mg/day, with a planned dosage increase to 800 mg/day on day 22 for patients with an imatinib trough level less than 1,000 ng/mL. Each patient was assessed with a series of molecular treatment targets of BCR-ABL1 of 10% or less at 3 months, 1% or less at 6 months, and 0.1% or less at 12 months.
In the first cohort (TIDEL-I), patients who failed to achieve those targets had their imatinib dosage increased to 800 mg/day. If they failed to achieve the same target 3 months later, they were switched to nilotinib 400 mg twice daily.
In the second cohort (TIDEL-II), patients who did not achieve treatment targets while on front-line imatinib were immediately switched to nilotinib (Tasigna, Novartis), a more potent tyrosine kinase inhibitor. Patients who were intolerant to imatinib or had a loss of response also immediately switched to nilotinib.
After 2 years, 55% of patients remained on imatinib and 30% were on nilotinib.
Overall, 64% (95%, 56-72) of patients achieved a confirmed MMR at 12 months, and 73% (95% CI, 67-79) achieved confirmed MMR at 24 months. Molecular response occurred in 19% of patients at 12 months and 34% of patients at 24 months. Researchers reported confirmed complete molecular response in 11% (95% CI, 6.8-15) of patients at 12 months and in 25% (95% CI, 19-31) of patients at 24 months. At 3 years, transformation-free survival was 95% and OS was 96%.
Adverse events were similar to those observed in prior studies of imatinib and nilotinib treatment, according to the researchers. Cytopenia, particularly at the start of treatment, was the most common severe adverse event associated with imatinib.
“Although imatinib is effective treatment for many, we recognized that some patients will need a more potent kinase inhibitor,” they wrote. “In contrast, using second-generation TKIs upfront universally may lead to increased long-term toxicity.”
The trial demonstrates “the feasibility and efficacy” of starting treatment with imatinib but selectively switching to nilotinib, according to the researchers.
“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,” Hughes and colleagues wrote. “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.” – by Anthony SanFilippo
Disclosure: The researchers report research funding from, consultant/advisory roles with and honoraria from Ariad, Bristol-Myers Squibb, CSL Behring, Novartis, Otsuka, Pfizer and Qiagen.
Perspective
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Michael J. Mauro, MD
Yeung and colleagues from the Australasian Leukaemia and Lymphoma Group have now published the second TIDEL trial (TIDEL-II) exploring the concept of early intensification and optimization in newly diagnosed CML based on a starting dose of imatinib 600 mg. The group combined what are now ELN-adapted optimal response milestones with more elusive imatinib trough level testing to tailor therapy. Their results are impressive; such a strategy compares favorably with primary use of nilotinib (Tasigna, Novartis) and dasatinib (Sprycel, Bristol-Myers Squibb) as initial therapy, as the TIDEL-II patients had low rates of early molecular response failure (12%), high rates of confirmed major molecular response (64% at 12 months and 73% at 24 months), 3-year OS of 96% and 3-year transformation-free survival of 95%. Such a strategy may offer mitigation of toxicity risk from second-generation tyrosine kinase inhibitors, as more than half of the patients were able to stay on imatinib; moreover, generic imatinib forthcoming would introduce significant economic advantage to this approach. These data prompt us to not forget the full potential of imatinib and to continue to question what approach really is best for the treatment of newly diagnosed CML, taking response, toxicity and cost all into consideration.
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