3 Questions on... Why ‘Whatʼs Old Is New’ in CML with Carlo Gambacorti-Passerini, MD

Figure“Imatinib mesylate changed the prognosis for chronic myeloid leukemia (CML) so dramatically that patients with newly diagnosed CML starting treatment with imatinib now have a normal life expectancy, compared with the historical median survival of 2 to 3 years. In addition to its outstanding therapeutic activity, imatinib possesses a remarkably safe profile.” So writes Carlo Gambacorti-Passerini, MD, Professor of Hematology and Director of the Clinical Research Unit at the University of Milano-Bicocca—with coauthor Rocco Piazza, MD, PhD, also of the University of Milano-Bicocca—in a recent “Viewpoint” editorial in JAMA Oncology (2015;1:143-144). In a phone interview Gambacorti-Passerini noted that the article is particularly timely given that generic imatinib is set to be available in the U.S. in 2016—which will make the drug available to patients in the U.S. at a fraction of the cost of the branded product (Gleevec, manufactured by Novatis). Generic versions of imatinib have been available in Canada and South Korea since 2013, costing 10 to 25 percent of the branded product. The coauthors succinctly summarize the argument why imatinib should remain the first choice for first-line treatment for patients with newly diagnosed CML, as well as why second- and third-generation tyrosine kinase inhibitors (TKIs)—developed primarily for second- and third-line use—are best suited for that purpose. “Bosutinib monohydrate, dasatinib, nilotinib, and ponatinib hydrochloride constitute a set of formidable ‘spare wheels’ for patients whose imatinib treatment fails, giving a viable option to more than 50 percent of them,” the article states. But then Gambacorti-Passerini and Piazza go on to explain why the evidence does not quite support those drugs as a replacement for imatinib. “If obtaining ‘faster and deeper’ responses using second-generation TKIs does not convert into a better prognosis, then this phenomenon should not dictate a change in therapy by itself,” they write, adding: “The safety profiles of these drugs are also a matter of debate.” Gambacorti-Passerini summed up the bottom line from the editorial for OT, and commented on his recent work that suggests there is a subset of CML patients who can safely discontinue TKI treatment (a study now available online ahead of print in American Journal of Hematology:DOI: 10.1002/ajh.24120). 1. What is your key message about imatinib? “Imatinib is definitely the safest inhibitor around in terms of long-term toxicity—and it is as active as any other TKI in the setting of first-line use. So, in my opinion, there is no scientific, clinical reason for using second-generation TKIs as frontline treatment. Imatinib remains, as the title of the article [“Imatinib—A New Tyrosine Kinase Inhibitor for First-Line Treatment of Chronic Myeloid Leukemia in 2015”] indicates, the first-line TKI of choice for treating newly diagnosed CML patients. And we need to in every objective way try not to be biased for economic reasons. “Other hematologists have different opinions on the topic, which is quite hot—as one can imagine.” 2. What would you say are the key points about the findings you recently published on safely discontinuing imatinib treatment for some patients with CML? “Number one, imatinib can be safely discontinued in real-world scenarios [in some patients], assuming that close monitoring is guaranteed. “Number two, the risk of relapse is linked to both the age of the patient and the result of the digital PCR test—being old lowers the risk of relapse. “And third, even for patients who did not relapse and for the most part show at least some PCR positivity after discontinuation [of imatinib], this positivity does not seem to be growing as you would expect from leukemic cells. “So our study suggests the patient who is at the lower risk of relapse is the patient who is older—approximately 45 and older—with a negative digital PCR.” 3. Are the findings conclusive enough to suggest clinicians should change practice for these patients? “Although our study is one of the biggest studies performed so far—we had 112 patients enrolled—as for any study, these data need to be confirmed.”

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