Dr. Daver Compares Toxicity Profiles of TKIs in CML

Naval G. Daver, MD, associate professor, Department of Leukemia, The University of Texas MD Anderson Cancer Center, discusses safety differences between the TKIs ponatinib, dasatinib (Sprycel) and nilotinib (Tasigna) in the treatment of patients with chronic myeloid leukemia (CML).

Although all TKIs pose thrombotic risk, ponatinib has shown the greatest frequency of blood clot development in patients, says Daver. Although initially approved for use in CML, ponatinib was withdrawn as treatment because post-marketing surveillance showed increased blood clots in patients who received it. Many of these events occurred in patients who received a higher dose of the agent, at 45 mg. However, when administered at a lower dose—15 mg to 30 mg—the incidence of clotting was significantly lower in these patients.

In his study exploring ponatinib as frontline treatment in patients with Philadelphia-positive acute lymphoblastic leukemia (ALL), Daver says that he has seen success in giving a lower initial dose and employing dose de-escalation. Patients are started on 30 mg until achieving complete hematological and molecular remission; 80% of patients are able to achieve this in 2 months. Then, the dose is reduced to 15 mg. As a result, the treatment was found to be well tolerated, with no major thrombotic risk or complications reported.

With dasatinib, the major adverse event (AE) observed is fluid retention such as pulmonary edema and pleural effusion, says Daver. However, a dose reduction was found to reduce these events in 80% to 90% of patients. Although nilotinib has not been used extensively in Philadelphia-positive ALL, its application in CML has shown similar AEs—cardiac or biliary complications. As such, cardiac intervals need to be monitored with the agent, as well as liver enzymes, pancreatic enzymes, and triglycerides.

Although 90% of patients are able to tolerate these TKIs, dose reduction can help those 5% to 10% of patients who experience AEs, Daver explains. Selecting the TKI based on the patient’s profile is another way to potentially reduce risk of AEs, he adds. For example, ponatinib should not be prescribed in patients who are severely obese or have a history of thrombotic events, he concludes.