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Oncology Times:
doi: 10.1097/01.COT.0000397189.69445.7a
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NCCN CML Guidelines Now Include Second- and Third-Generation TKIs

Susman, Ed

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HOLLYWOOD, FL—The second- generation tyrosine kinase inhibitors (TKIs) nilotinib and dasatinib were bumped up to options as first-line treatment for chronic myelogenous leukemia (CML)—alongside imatinib—in new guidelines from the National Comprehensive Cancer Network.

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“We are in the happy position of having a lot of choices for treatment of this disease,” said Susan O‘Brien, MD, Professor of Medicine at the University of Texas MD Anderson Cancer Center, one of the 21 institutions that make up the NCCN.

Although clinical trials suggest that patients treated with nilotinib or dasatinib may achieve a major molecular response to CML more quickly that with imatinib, audience responses during Dr. O‘Brien‘s presentation indicate that more of the clinicians would treat their patients with imatinib first, reserving the second-generation drugs for patients who don‘t tolerate imatinib or develop resistance to it.

Dr. O‘Brien presented the new treatment algorithm here at the 16th NCCN Conference on Clinical Practice Guidelines and Quality Cancer Care. “We now have three different drugs for first-line treatment,” she said.

The only other change in the recommendations for treatment was a suggestion that in the initial workup for suspected CML that doctors measure the patients‘ spleen size through palpitation by noting the centimeters below the costal margin.

That “tweak” aside, Dr. O‘Brien said, the major change was making all three of the tyrosine kinase inhibitors of the BCR-ABL gene Category 1 options for first-line treatment.

Category 1 level of evidence is considered the NCCN‘s highest category, indicating that the results are based on randomized clinical trials.

Imatinib therapy, of course, turned the outcomes in CML upside down. From a disease in which the 10-year survival rate was only about 10%, treatment with imatinib produces a 10-year survival rate that approaches 90%, Dr. O‘Brien said.

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Not a Surprise

“The upgrading of nilotinib and dasatinib to first-line therapy options is not a surprise,” said Len Lichtenfeld, MD, Deputy Chief Medical Officer of the American Cancer Society, one of the approximately 1,600 clinicians and other health care professionals who attended the conference.

Dr. Lichtenfeld suggested that clinical trial data indicated that the drugs were options for treatment in the first-line setting.

Dr. O‘Brien said that despite having three drugs for CML treatment, there was more help on the way:

* Bosutinib—another second–generation TKI—is also being developed, although that drug has a flaw similar to the other three drugs—high resistance to the T315I mutation. It has shown activity in patients who did not respond fully to the other TKIs.

* Ponatinib (also known as AP24534) might be considered a grandson of imatinib. It can potently inhibit BCR-ABL as well as the T315I Achilles‘ heel mutation. Phase 1 studies of the drug demonstrated effectiveness against that mutation, Dr. O‘Brien noted.

* Omacetaxine (homoharringtonine), derived from the Chinese Plum Yew, also has exhibited potent activity against CML resistant to TKIs.

Dr. O‘Brien noted that some of the studies with the second- or third-generation TKIs have used the new drugs because imatinib treatment did not rapidly achieve a major molecular response.

However, she added that the guidelines do not consider imatinib to have failed until at least 18 months and even then that might not be enough time for some patients to achieve the goal with the first drug in the class.

“I have had patients who did not achieve a major molecular for two to three years,” she said.

Dr. O‘Brien noted that studies indicate that instead of imatinib losing effectiveness with extended treatment, it actually tends to lose effectiveness early in treatment, rather than later.

© 2011 Lippincott Williams & Wilkins, Inc.

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