How to Select the Optimal BCR-ABL TKI Therapy for Treatment of Chronic-Phase CML

Key issues related to clinical decision making for patients with chronic phase chronic myeloid leukemia (CML), with a focus on the role of the pharmacist within the multidisciplinary oncology care team, were discussed in a review article published in the Journal of Oncology Pharmacy Practice.

With the availability of tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL fusion mutation, the life expectancy of patients with chronic phase CML is now similar to the general population. However, selection of the optimal BCR-ABL TKI — imatinib, dasatanib, nilotinib, or bosutinib — for frontline treatment of chronic phase CML requires careful consideration of disease risk, the safety profiles of these agents with respect to patient comorbidities, and potential drug interactions associated with concomitant medications. Furthermore, assessment of treatment response, facilitation of long-term patient adherence to these oral therapies, and management of treatment-related adverse effects are critically important components of therapy effectiveness.

The following factors are important considerations regarding patient comorbidities and the optimal BCR-ABL TKI to use as frontline therapy:

• Avoid using nilotinib in patients with peripheral vascular or cardiovascular disease.
• Avoid using dasatinib and nilotinib in patients with hypokalemia or hypomagnesemia due to their association with QT interval prolongation.
• All 4 BCR-ABL TKIs, particularly dasatinib, are associated with an increased risk of bleeding.
• Dasatinib is associated with an increased risk of pleural effusions and pulmonary hypotension.
• Nilotinib should be used with caution in patients with diabetes or a history of pancreatitis due to its association with increased serum lipase and glucose levels.
• Monitor lipid levels of patients receiving nilotinib frequently due to its association with hyperlipidemia.
• Patients receiving dasatinib are at risk of gastrointestinal hemorrhage.
• Diarrhea is an early and common adverse effect of bosutinib
• All 4BCR-ABL TKIs are associated with hepatotoxicity but it is least pronounced with dasatinib, for which dose reductions are not required in this setting.
• Dose reductions are not required for dasatinib or nilotinib in patients with renal impairment, but may be needed for those treated with imatinib or bosutinib.
• BCR-ABL TKI therapy may cause congenital abnormalities in fetuses of pregnant women receiving these drugs.

The researchers also cite the following important considerations related to potential drug-drug interactions with BCR-ABL TKIs:

• Rosuvastatin or pravastatin are preferred statin therapies. Because they are not metabolized by the CYP3A4 enzyme, their risk of interaction with BCR-ABL TKIs is lower.
• H2 antagonists or proton-pump inhibitors should be avoided in patients receiving dasatinib, and antacids or H2 antagonists are preferred over proton-pump inhibitors for patients receiving bosutinib or nilotinib.
• BCR-ABL TKIs are metabolized by the CYP3A4 enzyme; therefore, plasma levels of these drugs can be affected by coadministration with either CYP3A4 inhibitors (eg, azole antifungals, grapefruit juice) or CYP3A4 inducers (eg, dexamethasone, St John’s Wort).
• Nilotinib is also an inhibitor of CYP2C8, CYP2C9, CYP2D6, and UGT1A1 enzymes and can affect plasma levels of concomitantly administered drugs metabolized by these enzymes.

Once BCR-ABLTKI treatment has been initiated, pharmacists can be an important member of the oncology care team and assist patients, physicians, and the wider health care team with monitoring and reporting adverse effects, implementing modifications to treatment plans, improving patient-health care team communication, managing drug-drug interactions and patient comorbidities, and suggesting pharmacologic and nonpharmacologic strategies for managing adverse effects.

Reference

Reff MJ, Shillingburg A, Shah B, Elder C, Prescott H, Kennerly-Shah J. Front-line use of tyrosine kinase inhibitors in chronic phase chronic myeloid leukemia: practice considerations [published online July 27, 2019]. J Oncol Pharm Pract. doi: 10.1177/1078155219864640