Should Elevated Imatinib Doses Become Standard Therapy?

“The second generation inhibitors are already standard therapy for CML,” said Dr Cortes. “In my opinion, higher-dose imatinib deserves further consideration in this setting, particularly considering the imminent introduction of generic imatinib.”

He said that it is also important to mention that at least one randomized trial, from the German cooperative group, has also suggested superiority of higher doses of imatinib. That study assessed 1524 patients for 5-year overall and progression-free survival, and found that molecular response is a predictor of long-term outcomes and that it is achieved faster in patients who were treated with optimized high-dose imatinib than standard dose.2

“It is also worth noting that higher-doses of imatinib are associated with somewhat more toxicity, and careful management of adverse events, including judicious dose adjustments, are necessary,” said Dr Cortes. “Fortunately, imatinib, even at higher doses, appears not to be associated with the increased risk of arterio-thrombotic events seen with other inhibitors.”  

He explained that this is because most adverse events are a loss of cytogenetic response to treatment. “Recognizing this promptly and acting on it, and with the availability of multiple treatment options, most patients can still enjoy long-term survival,” he said.

His takeaway message was that patients need to be monitored properly, frequently, and adequately. Interpretation of the results is critical so that changes in strategy can be implemented at the proper time.

Lack of Large Randomized Trials of Tyrosine Kinase Inhibitors

Dr Cortes said that although this is not a randomized study, because all studies were conducted at the same institution, with similar design, with the same follow-up criteria, with all response assessments done the same way, lends it more credibility.

Dr Cortes said it that it is unfortunate that large randomized trials are difficult to conduct now because of the difficulty in obtaining funds for them and because most patients are not referred to clinical trials. Ideally, he would like to see these treatment options compared head-to-head.

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“The main message is that there are several good treatment options for patients with CML,” he said. “Importantly, the drug to be used is only one of the factors. Adequate monitoring, close follow-up and communication with the patient, proper management of any adverse events, and good interpretation of the results are some of the important elements that may help ensure an optimal outcome of the patient.”

References

  1. Jain P, Kantarjian H, Alattar ML, et al. Long-term molecular and cytogenetic response and survival outcomes with imatinib 400 mg, imatinib 800 mg, dasatinib, and nilotinib in patients with chronic-phase chronic myeloid leukaemia: retrospective analysis of patient data from five clinical trials. Lancet Haematol 2015. 2(3): e118–e128
  2. Hehlmann R, Muller MC, Lauseker M, et al. Deep molecular response is reached by the majority of patients treated with imatinib, predicts survival, and is achieved more quickly by optimized high-dose imatinib: results from the randomized CML-Study IV. J Clin Ocol. 2014;32(5):415-423.