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Chronic Myelogenous Leukemia: Refining Approaches to TreatmentBy John LeBas Just a decade ago, fewer than half of chronic myelogenous leukemia (CML) patients remained alive 7 years after their diagnosis. Then came the first-generation tyrosine kinase inhibitor imatinib (Gleevec), which reduced leukemia cells in most CML patients to almost undetectable levels. The drug’s effects have proven remarkably durable, boosting the 7-year overall survival rate in CML to nearly 90%. “We’ve clearly changed the natural history of this disease with imatinib, but it doesn’t work for everybody,” said Jorge E. Cortes, M.D., a professor in the Department of Leukemia at The University of Texas M. D. Anderson Cancer Center. “We still need to improve therapy, in both newly diagnosed and resistant disease.” So today, clinicians are focused on refining the treatment of CML, which is diagnosed in about 4,500 Americans each year. Effective treatment approaches have been found to help many of the patients for whom imatinib does not work, thanks to a better understanding of treatment resistance. As happened with imatinib a decade ago, some of the more recent efforts are meeting with remarkable success, according to Dr. Cortes and other specialists at M. D. Anderson. Mechanisms of success The success of imatinib lies in a common molecular aberration in CML. About 95% of CML patients have the Philadelphia chromosome, an abnormality characterized by a translocation between chromosomes 9 and 22. The resulting Bcr-Abl gene encodes a tyrosine kinase that promotes leukemia growth. Imatinib, approved by the U.S. Food and Drug Administration in 2001, acts by inhibiting the activity of this tyrosine kinase, halting the cancer’s proliferation.
Generally, imatinib is easy to administer (it is given as a pill) and is well tolerated. Its more common side effects include myelosuppression (characterized by anemia, thrombocytopenia, and neutropenia), fluid retention, muscle cramps, and diarrhea. Rarely, congestive heart failure has been identified in patients receiving imatinib. Initial myelosuppression usually goes away and does not recur following a temporary cessation of imatinib, but recurrent myelosuppression can occur in some patients and may be treatable with hematopoietic growth factors without further cessation of tyrosine kinase inhibitor therapy. Cardiac effects usually can be managed with dose alteration. However, some patients cannot tolerate the side effects of imatinib despite optimal management of the side effects. Additionally, 20%–25% of CML patients do not respond well to the drug or relapse after experiencing an initial response, even if the imatinib dose is increased. It is these patients who are perhaps the most in need of new treatment options, for they do not benefit from an otherwise highly effective therapy. Fortunately, two agents have been found particularly effective as second-line therapies: dasatinib (Sprycel) and nilotinib (Tasigna). In fact, two recent studies showed that dasatinib and nilotinib, which are currently approved in the United States for treatment of CML after imatinib, elicited even better responses than imatinib in previously untreated patients. Also, toxicity so far has been low. “We think such findings may lead to these drugs becoming the standard of care in the near future,” Dr. Cortes said. Dasatinib and nilotinib, both second-generation tyrosine kinase inhibitors, are similar to imatinib in that they inhibit the activity of the cancer-promoting Bcr- Abl protein. Nilotinib is considered to be 50 times more powerful than imatinib in its inhibition of Bcr-Abl. And dasatinib is some 300 times stronger against Bcr-Abl, plus it inhibits other tyrosine kinases as well. Investigators believe the effectiveness of dasatinib and nilotinib against imatinib-resistant CML is due to their ability to inhibit Bcr-Abl protein variants that may occur when imatinib stops working. Dasatinib also works against Src family kinases, which may have a role in CML. A third investigational tyrosine kinase inhibitor, bosutinib, also appears to be active against CML. Early data from an ongoing international phase II trial also suggest that bosutinib has safety and side effect profiles comparable to those of dasatinib and nilotinib, Dr. Cortes said. “Bosutinib could give us yet another option to treat patients for whom existing front-line therapy is not ideal,” he added. Applying past experience Another treatment quandary is represented by the very small percentage of patients whose CML does not respond or becomes refractory to two or more of the kinase-inhibiting agents. Such patients may be eligible for early-phase testing of drugs that target more specific pathways of CML progression. One of those agents, AP24534, inhibits CML-promoting proteins encoded in patients with the T315I genetic mutation—an anomaly associated with resistance to imatinib, dasatinib, nilotinib, and bosutinib. A second agent, homoharringtonine, so far appears to reduce CML levels in patients who have the T315I mutation or have failed kinase inhibitor therapy. Other agents, including DCC-2036, PHA-739358, and XL-228, may have similar effects and are also being investigated in the clinic.
The investigation of tyrosine kinase inhibitors in this disease has resulted in the understanding that multiple previously unknown genetic mutations are at work in CML. “This is one disease in which we know virtually all patients share one molecular abnormality, the Philadelphia chromosome,” Dr. Cortes said. “But since the introduction of imatinib, the varied responses to therapies targeting the Philadelphia chromosome have allowed us to realize how heterogeneous CML actually is. We are learning that the expression of certain genes is very different in different patients.” The interplay of this varied gene expression with the main chromosomal defect appears to create difficult-to-decipher effects on response—and resistance—to therapy. For example, genetic variations between seemingly similar CML patients might cause them to metabolize a drug very differently. Or, some patients might have a form of CML with greater genetic instability, making it more likely to become therapy-resistant or increasing the chance of a blast crisis. “Research in this area is very active,” said Hagop Kantarjian, M.D., professor and chair of the Department of Leukemia. “The development of second- and third-generation drugs has been based, in part, on our understanding of CML’s genetic variability and mechanisms of resistance.” In one example, dasatinib, which was shown in preclinical studies to inhibit Src, was tested against CML after some patients who relapsed while receiving imatinib were found to have high levels of Src proteins. In another example, Dr. Kantarjian designed the clinical trials that led to the approval of nilotinib as a second-line CML therapy based on the known action of tyrosine kinase inhibition against mutant kinase expression in CML. Ralph Arlinghaus, Ph.D., chair of the Department of Molecular Pathology, said mutations of the Bcr-Abl gene—and mutations of other genes in CML patients who undergo disease progression—likely hold the key to future therapeutic approaches against advanced stages of CML. “Numerous compounds under investigation have been shown to kill imatinib-resistant cells, except in patients with one prevalent type of mutation (T315I). At least in cell culture, drugs that inhibit the Jak2 tyrosine kinase can overcome all forms of imatinib resistance—including those resulting from the T315I mutation—by interrupting the Bcr-Abl/Jak2 pathway,” said Dr. Arlinghaus, among the first to describe this pathway in CML. “Further investigation might enable the development of these compounds as clinically useful agents.” Downsides of long-term therapy Although the current strategies for managing CML have been highly successful, they are not without flaws. “Whether we can achieve a long-term remission is still the main question in CML, because it is difficult to say whether a successfully treated patient is actually free of disease,” Dr. Cortes said. “The most sensitive test for CML, polymerase chain reaction, is very powerful—but when the results are negative, that just means the disease is undetectable. Even patients with undetectable CML can eventually relapse.”
For that reason, long-term maintenance therapy is usually recommended. But this approach inherently creates another treatment problem for which there is no good solution. Some patients, such as those who suffer side effects or those who cannot afford the medication long-term, simply cannot continue therapy indefinitely. Other patients sometimes tire of daily therapy, especially when they appear to be perfectly healthy, and choose to stop. Patients who do not continuously take therapy are at greater risk of relapse. But researchers think they may eventually be able to help such higher-risk patients. As more tolerable agents become available, the incidence of side effects should decrease. Also, immune-stimulating vaccines and other treatment options now under investigation in patients with minimal residual disease could spur the body to keep CML at bay over the long term, negating the need for maintenance therapy. And perhaps then, the remaining problems in CML treatment could be solved for good.For more information, call Dr. Cortes at 713-794-5783. Other articles in OncoLog, June 2009 issue:
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