SAN FRANCISCO – “We really have an embarrassment of riches in chronic myelogenous leukemia, and the question is, which patients get which drugs? That’s really the major question that drives clinical care right now,” Dr. Jerald P. Radich, chair of the NCCN guidelines panel for chronic myelogenous leukemia (CML), told attendees of the National Comprehensive Cancer Network 10th Annual Congress: Hematologic Malignancies.
Dr. Jerald P. Radich
He discussed a variety of setting-specific quandaries in disease management and recent evidence from trials that is helping to provide some answers. He also reviewed some of the finer points of the NCCN’s CML guidelines, a new version of which was released at the congress.
How do you choose front-line therapy?
Tyrosine kinase inhibitors (TKIs) have dramatically improved the prognosis of CML, according to Dr. Radich, who is a member of the clinical research division, Fred Hutchinson Cancer Research Center, and an associate professor in the medical oncology division, University of Washington, both in Seattle.
Today, three TKIs—imatinib (Gleevec) and the second-generation agents nilotinib (Tasigna) and dasatinib (Sprycel)—are approved by the Food and Drug Administration as front-line therapy.
The 8-year data from the IRIS trial (International Randomized Study of Interferon Vs STI571), which tested imatinib in patients with newly diagnosed chronic-phase CML, showed that event-free survival was 81% and overall survival was 85% (Blood. 2009;114:462. Abstract 1126). “No matter how you slice it, these patients have done fantastically well,” Dr. Radich said.
The two other, newer therapies, nilotinib and dasatinib, have yielded significantly better short-term cytogenetic response and major molecular response rates in numerous trials. “But curiously enough, if you look at overall survival, there is no difference,” he commented. “We don’t know why the short-term efficacy of the second generations hasn’t translated into long-term efficacy yet.”
In the guidelines, the three front-line TKIs are nearly identical with respect to their Evidence Blocks, a new tool added to facilitate treatment comparisons and decision making.
But specific toxicities differ across the agents, which may tilt the decision one way or another. “If somebody has a history of really bad atherosclerotic events previously, then imatinib is probably not the best drug for them. If somebody has a history of pulmonary issues, then dasatinib may not be the best drug for them. And if somebody has diabetes, nilotinib probably isn’t the best drug for them,” Dr. Radich elaborated.
Costs for the three drugs are the same at present, he said. But imatinib will likely become available as a generic next year, which may make that drug the most attractive from the financial perspective.
When do you switch therapies?
There is some debate about how long to persevere with a front-line therapy when monitoring suggests the response is suboptimal, according to Dr. Radich.
Data have identified the BCR-ABL1 transcript level at 3 months to be a good predictor of long-term survival (J Clin Oncol. 2012;30:232-8). “We in the NCCN have said at 3 months or 6 months, you should consider changing [if the response is suboptimal]. You don’t have to, but you should consider changing because there are some other [therapies] that get rid of that,” he said.
However, he cautioned, a true assessment of response hinges critically on patients’ compliance with therapy. Studies using electronic monitors hidden in the caps of pill bottles suggest that even though the majority of patients say they take their TKI daily, only about 15% actually do.
Studies out of Europe and Australia have shown that some patients with a suboptimal response will have progression to accelerated phase/blast crisis in the interim between 3 months and 6 months, Dr. Radich noted. “So if you think that your patient is really, really religiously taking their drug, and if they still have not responded very well at 3 months, that might be an indication that you can consider changing therapy.”
Which second-line TKI should patients get?
The options for second-line TKI therapy include nilotinib and dasatinib, as well as bosutinib (Bosulif) and ponatinib (Iclusig).
About half of patients who experience progression on or become resistant to their first-line TKI have mutations, according to Dr. Radich. Here, a mutational analysis is warranted as the second-line agents differ somewhat with respect to the mutations they act against, which may guide the choice of agent. And toxicity profile may again dictate drugs that can and can’t be used for a specific patient.
Patients who have genuine resistance are unlikely to achieve a cure although they may have a cytogenetic response. “Most of us think that resistance might be forever and if we have a patient who has genuinely become resistant, you don’t need to transplant them necessarily [right away]. But that’s the time you have to have a conversation about doing transplantation and start doing HLA typing and the like,” he said.