The management of patients with chronic myelogenous leukemia (CML) has been altered dramatically since the introduction of tyrosine kinase inhibitors by Druker et al in the late 1990s. While it seems almost second nature now, the introduction of therapy for CML targeted against a single gene product unique to, and causative of the disease, has created a new paradigm in our approach to cancer. In CML, for example, we now think about changing drugs the way an infectious disease specialist might deal with serially resistant bacteria or patients with HIV infection. Quintás-Cardama and Cortes have provided an excellent review of the frequency of imatinib(Drug information on imatinib) (Gleevec) resistance, the mechanisms of its occurrence, and the therapeutic options for this clinical problem.
In the pre-imatinib era, we were content to keep a CML patient’s white count under control and to prevent constitutional symptoms. Alternatively, patients were referred for allogeneic transplant, an option with a very high curative potential but with significant upfront risks (that patients would universally prefer to avoid). In the post-imatinib era we have eschewed allogeneic transplant except for those patients for whom all other therapeutic options have been exhausted. Our efforts are centered on ensuring that patients are doing well on imatinib or one of the second-generation tyrosine kinase inhibitors that are so completely reviewed in this article.
Reasons for Initiating Alternative Therapy
Although the European Leukemia Net definitions for imatinib resistance to which the review refers are reasonably and widely accepted, the question of whether these should be the only accepted reasons for switching from imatinib to a second-generation kinase inhibitor or alternative therapeutic strategy remains unclear. Patients who fail to achieve a hematologic or cytogenetic response by the “milestones” or in whom molecular evidence of the disease increases over time do more poorly and are enriched for the presence of an imatinib-resistance mutation. Searching for such an imatinib-resistance mutation and treating with dasatinib(Drug information on dasatinib) (Sprycel) or nilotinib(Drug information on nilotinib) (Tasigna) if one is found (or moving to transplant if a T315I mutation is noted) makes logical sense. But such a pristine strategy would do patients a disservice. There may well be other factors—such as the ability of the cells to take up imatinib—that need to be considered.
It is extremely interesting that patients who are switched from imatinib to one of the second-generation tyrosine kinase inhibitors (nilotinib or dasatinib) are as likely to respond to these agents irrespective of mutational status. In other words, either the potency of the newer drugs is critical or other mechanisms of resistance account for the response. Therefore, although one would like to be able to define a mutation and pick a drug, clinically things are not that easy. Given justifiable concerns that the clinical development of these agents would be undertaken in patients who were “too good,” strict clinical/cytogenetic criteria for imatinib resistance were required for enrollment to a second-generation study. For the moment, therefore, we are stuck in the tautology of defining resistance somewhat arbitrarily and using these definitions to justify switching to a novel tyrosine kinase inhibitor.
When to Switch Treatment?
The durability of response to second-generation tyrosine kinase inhibitors after imatinib failure is encouraging. The strategy of trying a higher dose of imatinib in defined resistance settings seems less effective than moving to dasatinib. There are, however, patients with a suboptimal response (not yet resistance) who seem to benefit from doubling the imatinib dose. Given the ability of second-generation tyrosine kinase inhibitors to work very well in most situations where imatinib fails, one could reasonably pose the question of whether we might more aggressively use these more potent agents earlier in the disease, such as in the case of suboptimal response.
The accompanying review article wisely begs the clinical question of which is the better choice for imatinib failure—nilotinib or dasatinib. There simply is no currently useful way to decide. Moreover, the ultimate use of these potent kinase inhibitors might come in the upfront setting. Randomized phase III trials such as the ongoing US intergroup study led by the Southwest Oncology Group (SWOG), which compares dasatinib to imatinib in newly diagnosed patients with chronic phase CML, might help answer this question.
Another issue mentioned briefly in this article is the place of allogeneic transplant. Although early results are encouraging, we don’t know the long-term durability of response to the second-generation kinase inhibitors in patients who fail imatinib. As such, are we making a mistake by not referring more patients for allogeneic stem cell transplant at the first sign of imatinib failure?
The available evidence, scant though it may be, seems to favor a trial of a tyrosine kinase inhibitor and transplanting at signs of failure. Certainly, patient age and personal philosophy factor into this. Thus far, there seems to be no increased risk of deleterious outcome if transplantation is carried out after prolonged exposure to imatinib. Whether this will be true after exposure to other more potent kinase inhibitors is completely unknown.
In summary, our understanding of the biology of CML has made possible the incredible therapeutic advance of imatinib. We are now in an era where our knowledge about the impact of imatinib on the disease is expanding, but still remains insufficient for final judgments on when to use newer agents. Moreover, the molecular heterogeneity involved in relapse is evidenced by T315I patients, for whom there is no useful medical therapy, as well as the uncertain explanation for response in patients without other bcr-abl mutations. The Quintás-Cardama/Cortes article represents an excellent primer on our current state of knowledge about what to do when imatinib fails.
Financial Disclosure: Dr. Stone has received clinical research support from Bristol-Myers Squibb and Novartis.