Some patients, however, are diagnosed with “just a bad-biology disease,” Dr Lipton pointed out. “A small number just progress very quickly, regardless of treatment. Another 5% or so are diagnosed with advanced disease.”

No studies have yet shown a survival advantage for second-generation TKIs like dasatinib or nilotinib over imatinib, Dr Lipton and Dr Medeiros noted.1,2

“The first-generation TKI, imatinib, has the longest follow up and also the best long-term toxicity data available,” said Dr Medeiros. “Imatinib therapy will likely be associated with the lowest costs, due to the availability of generic imatinib.”

Second-generation TKIs (nilotinib and dasatinib) are more potent and offer faster responses, but their long-term toxicity profiles are less understood and “elevated costs remain a concern,” Dr Medeiros said. More patients are early responders (a decrease in BCR-ABL transcript levels to less than 10% at the 3-month mark) with second-generation TKIs than imatinib, he said.

“With second-generation TKIs, we see faster responses—and deeper responses—with fewer patients progressing to advanced stage,” Dr Lipton explained. “But at the end of the day, there’s no survival advantage [over imatinib].”

This may partly be due to the effectiveness of imatinib. “Before Gleevec, median survival for CML was 4 to 5 years,” Dr Lipton said. “Now, with newly diagnosed chronic-phase CML, people usually don’t die from CML. They’re surviving long enough to die of something else.”

Evidence “suggests that use of a second-generation TKI as third-line therapy confers limited value in most patients with CML,” according to Elias Jabbour, MD, PhD, and colleagues at the University of Texas MD Anderson Cancer Center’s department of leukemia in Houston, Texas.2

RELATED: Q&A With Elias Jabbour, MD, Highlights Evolving Treatment Landscape for CML, Pricing Barriers

Dr Lipton and colleagues were among those investigating a third-generation TKI, ponatinib, which was shown in early-phase trials to be effective in CML refractory to other treatments.3 But the efficacy of ponatinib compared to imatinib could not be determined in a phase 3 trial because of early trial termination following arterial occlusive events among patients who received ponatinib.4 Secondary endpoint analyses suggested that ponatinib was associated with a better early-response rate than imatinib.4 Ten of the 11 patients who experienced arterial occlusive events had cardiovascular risk factors, including a history of arterial disease. The phase 3 trial was reported in the May 2016 issue of The Lancet Oncology.4