NCCN: Practical Considerations in Selecting Tyrosine Kinase Inhibitor Therapy for Chronic Myeloid Leukemia
Although imatinib (Gleevec) is the initial therapy for chronic myeloid leukemia (CML), several second-generation tyrosine kinase inhibitors are now approved for the treatment of this disease. Michael Millenson, MD, of Fox Chase Cancer Center in Philadelphia, reviewed practical considerations in selecting tyrosine kinase inhibitor therapy for CML at the recent NCCN 8th Annual Congress on Hematologic Malignancies, held September 20–21 in New York.
Imatinib received FDA approval for the treatment of chronic myeloid leukemia in 2001; this was followed by approval of nilotinib (Tasigna) and dasatinib (Sprycel) as both front-line and second-line therapy for CML, and more recently bosutinib (Bosulif) and ponatinib (Iclusig) as second-line therapy. Omacetaxine (Synribo), a non–tyrosine kinase inhibitor, was recently approved as third-line therapy for CML.
Response criteria include complete hematologic response, complete cytogenetic response, and major molecular response. The criteria are evolving, Dr. Millenson said, and the best response is both complete cytogenetic response and major molecular response.
If your center does not have molecular testing, then complete cytogenetic response at 12 months is a strong predictor of ultimate outcome, Dr. Millenson said. If this benchmark is not reached, then a switch in therapy and mutational analysis should be considered, he added.
Mutational Analysis in CML
There is no recommended specific sequence of therapy, and the results of mutational analysis will factor into the choice. Mutational analysis should be considered for patients with an inadequate response to treatment, any sign of loss of response, and disease progression to accelerated or blast phase.
Based on mutational analysis, preferred salvage tyrosine kinase inhibitors include ponatinib if the T315I mutation is identified; ponatinib or nilotinib for the V299L mutation; ponatinib, nilotinib, or bosutinib for the T315A mutation and for the F317L, F317V, F317I, F317C mutations; and ponatinib, dasatinib, or bosutinib (but not nilotinib) for the Y253H, E255KV, F359V, F359C, and F359Imutations. If a patient is on front-line dasatinib and the T315A mutation is identified, then imatinib can be used as salvage therapy, Dr. Millenson said.
Dr. Millenson indicated that the goal of treatment is cure, and studies have consistently shown that 1-year complete cytogenetic response and major molecular response are better with the newer drugs. Longer follow-up is needed to show improved overall survival with these new agents, Dr. Millenson said, and he added "stay tuned."
Unique Toxicities
The NCCN Guidelines favor second-generation drugs for patients with newly diagnosed CML, especially those who are considered to be at high risk. However, it is important to be aware of the unique toxicities associated with each of these agents.
Side effects associated with all tyrosine kinase inhibitors can include rash, nausea, myalgias, diarrhea, edema, and effusions; these are manageable with practice measures. Patients should be reassured that many of these side effects are self-limiting and improve over time.
Dr. Millenson cited unique toxicities for each of the newer tyrosine kinase inhibitors.
Nilotinib is associated with food-drug interactions and has a black box for QT interval prolongation, liver function test (LFT) abnormalities, and peripheral arterial disease. Dasatinib is associated with pleural and/or pericardial effusion, reversible pulmonary arterial hypertension, and reversible inhibition of platelet aggregation. Bosutinib is associated with diarrhea and liver function abnormalities. Ponatinib is associated with elevations of serum lipase, liver function abnormalities, and pancreatitis.
Drug-drug interactions are an important issue, since all tyrosine kinase inhibitors are substrates for cytochrome P450 enzymes. Proton pump inhibitors should be avoided in patients on tyrosine kinase inhibitors. Specific drugs that prolong the QT interval should be used with caution; these include antiarrhythymic agents, psychiatric drugs, antihistamines, antibiotics, and calcium channel blockers.
Dr. Millenson noted that online tools are available for evaluating drug-drug interactions, and patients on tyrosine kinase inhibitors should be carefully managed in this regard.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
