The Savona/Talpaz Article Reviewed
Chronic Myeloid Leukemia: Changing the Treatment Paradigms
JOHN M. GOLDMAN, DM
National Heart, Lung,
and Blood Institute
National Institutes of Health
June 1, 2006
Patients were, however, analyzable on an "intention-to-treat" basis and it seems now that all patients treated with imatinib(Drug information on imatinib)
, whether they received the drug at initial randomization or after failing or withdrawing from the control arm, are still alive at 5 years from the start of therapyvery much superior to any comparable historical control population. Imatinib has thus become the treatment of choice for all or almost all newly diagnosed patients with CML in chronic phase. Transplant can be considered for eligible patients who fail to respond well to imatinib.
What Issues Remain?
First, results in the majority of CML patients seem so good that one wonders whether CML may not have been converted into a chronic disease readily controllable for years or decades with a single agent such as imatinib. Conversely, will long-term treatment with imatinib reveal cumulative toxicities that are not yet apparent? Possibly.
Second, will it be possible to stop imatinib in good responders after some years of treatment? The experience with interferon-alpha suggested that a small number of patients remained in long-term remission after adequate treatment with that agent. Will the same be true for imatinib, or might the proportion of treatment-free responders actually be larger? Could one perhaps maintain the remission with some form of immunotherapy after stopping imatinib? These are questions that must be addressed in the future.
Third, what can we do for the patient who fails to respond to imatinib as initial therapy or who, having initially responded, loses his or her response? Such patients should presumably be considered for treatment with one or another of the second generation of tyrosine kinase inhibitors, namely, dasatinib(Drug information on dasatinib) or nilotinib(Drug information on nilotinib). These two agents are both substantially more active than imatinib, and both are active against the majority of Ph-positive subclones bearing kinase domain mutations, which are considered in some cases to be the primary cause of acquired resistance to imatinib. The most notorious kinase domain mutationthe so-called gatekeeper amino-acid mutation, a threonine-to-isoleucine mutation at position 315 (T315I)confers resistance to imatinib but seems also ineluctably to escape inhibition by dasatinib and nilotinib.
There is a third generation of tyrosine kinase inhibitors, including some that are active against the T315I mutant clone, and some of these are now entering clinical trials. Whether they make a significant difference in the management of patients who fail to respond to imatinib therapy and whether they help in the management of patients who are resistant to imatinib per primum (most of whom have no demonstrable kinase domain mutations) remains to be seen. It is quite possible that optimal therapy will prove to involve the use of two or more tyrosine kinase inhibitors used in combination or in tandem.
What is certain is that the advent of imatinib has fundamentally altered the therapeutic strategy for CML patients and promises substantial prolongation of life in comparison with previous treatments. It has also redirected therapeutic research efforts in CML and has had an impact on research strategies for other neoplastic diseases. It is most salutary that the 21st century has begun with a recognition that the use of small molecules designed on the basis of known molecular mechanisms underlying malignancy should replace the empiric use of much less specific cytotoxic drugs.
John M. Goldman, DM
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