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Initial Choice of TKI in Patients with CML Probably Not Important

With 3 agents showing similar efficacy, drug cost and early response matter
February 2013 Vol 6, No 1, Special Issue - Leukemia
Mark Knight

The initial choice of therapy for patients with chronic myeloid leukemia (CML) is probably not important, because differences in efficacy are not dramatic. What matters is that response is assessed early, and that side effects are managed swiftly, said David Marin, MD, Hammersmith Hospital, Imperial College London, United Kingdom.

Similar Efficacy
“The current data do not justify paying a premium price for any of the tyrosine kinase inhibitors” (TKIs), Dr Martin stressed. An inadequate response or the emergence of side effects should prompt a change to an alternate TKI.

Furthermore, long-term follow-up suggests that a small proportion of patients with CML are candidates for treatment discontinuation without the disease recurring.

Imatinib (Gleevec) has more than 12 years of experience behind it as first-line therapy for CML, and its side-­effect profile is therefore well known, said Dr Marin. The achievement of a complete cytogenetic response (CCyR) is the major objective of therapy. Approximately 70% of patients who receive imatinib as first-line therapy achieve a CCyR by 12 months, and 80% do so by 5 years.

The proportion of patients who achieve a CCyR at 1 year is higher with nilotinib (Tasigna) or dasatinib (Sprycel), but by 2 years, the rate of treatment failure is similar between these 3 drugs, making the initial choice of therapy in the chronic phase (CP) less dependent on efficacy than on price, Dr Marin pointed out.

Although the rate of molecular response is greater with nilotinib and dasatinib compared with imatinib, there is no proof that achieving a molecular response or complete molecular response (CMR) in patients who already achieved CCyR has any added benefit on overall survival or progression to advanced disease, he said.

Assessing Response Early Is Key
Regardless of the choice as first-line therapy, assessing the response early and acting on this assessment is of utmost importance, Dr Marin emphasized. Perhaps the main advantage to using nilotinib or dasatinib as initial therapy is that they may prove to reduce the number of patients who progress early after diagnosis. Monitoring for side effects and changing the medication when necessary does not seem to diminish efficacy in responding patients.

Among the minority of patients who present with advanced disease, Dr Marin prefers dasatinib, although the use of TKIs in this setting should be in conjunction with a more complex strategy that includes conventional chemotherapy and allogeneic stem-cell transplantation, if possible.

Is a Cure Possible?
“Attempting a cure in CML may be possible, as long as a very low level of residual disease is achieved and sustained,” said François-Xavier Mahon, MD, Laboratoire d’Hématologie, Centre Hospitalier Universitaire de Bordeaux, France. Achieving a CMR for at least 2 years appears to be a key criterion in predicting the success of discontinuation.

Among patients with undetectable peripheral blood BCR-ABL transcripts for at least 2 years who stopped imat­inib in the Stop Imatinib (STIM) trial, the overall probability of maintaining a CMR was 39% at 36 months. Most patients who experienced molecular relapses did so within 6 months, but late relapse at 19, 20, and 22 months occurred in 3 cases. “It is clearly necessary to perform molecular assessments using qualitative RT-PCR [reverse transcription polymerase chain reaction] to detect early those patients who exhibit a fast molecular relapse to retreat them as soon as possible,” he said.

In the STIM trial, patients in the low Sokal risk group were more likely to remain in stable CMR than those in intermediate or high Sokal risk groups, Dr Mahon noted.

Candidates for discontinuation represent only approximately 10% of patients with CP-CML, according to enrollment in STIM. The use of a second-generation TKI or combining imatinib with recombinant interferon-alfa may expand the number of patients who will reach the criteria for discontinuing treatment, but each approach requires further study. When used in patients with newly diagnosed CP-CML, molecular responses have been faster and deeper with nilotinib and dasatinib compared with imatinib.

The potential for safe treatment discontinuation relies on close molecular monitoring, commented Susan Branford, PhD, Department of Genetics and Molecular Pathology and Centre for Cancer Biology, University of Adelaide School of Medicine, Australia. Even among patients who continue therapy, long-term molecular monitoring is necessary. Although the loss of response to imatinib is rare after 18 months of achieving a major molecular response, the benefit is dependent on continuous drug adherence, she noted.

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Last modified: March 4, 2013
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