Targeted therapies for CML: practical considerations and comparisons

It has been eight years since imatinib was approved as the first oral tyrosine kinase inhibitor indicated for the treatment of Philadelphia chromosome positive chronic myeloid leukemia.

Debbie Blamble

Laura Boehnke Michaud

Ph+CML and imatinib (Gleevec, Novartis) together represent pioneering coupling of a therapy to target a specific physiologic cause of cancer, in this case the tyrosine kinase produced by the Philadelphia chromosome. Since the approval of imatinib, numerous other targeted therapies have been approved for Ph+CML, including two new TK inhibitors, dasatinib (Sprycel, Bristol-Myers Squibb) and nilotinib (Tasigna, Novartis). Many more compounds are under investigation. Although these agents have similarities in their mechanisms of action, it is important to recognize the practical and clinical differences between these three commercially available products for the treatment of Ph+CML.

Approval of new agents for Ph+CML continues to be important, as 20% to 30% of patients will not respond or will develop resistance to first-line therapy with imatinib. Dasatinib differs from imatinib and nilotinib in several ways. Of the three agents, dasatinib is the most potent inhibitor and binds to the BCR-ABL protein in both its active and inactive conformations. Imatinib and nilotinib only bind to the inactive conformation. In addition, dasatinib also inhibits the Src-family kinases, potentially contributing to its clinical activity. Unfortunately, none of these three agents are active against the T315I BCR-ABL kinase domain mutation seen in more advanced stages of Ph+CML. See table 1 for a comparison of the activity of the three agents.

Since imatinib has been commercially available much longer than the other TK inhibitors, it has an increased number of FDA-approved indications compared with the others, including indications for several non-hematologic malignancies. Notably, nilotinib is not currently FDA approved for the treatment of imatinib-resistant/intolerant Ph+CML blast crisis and Ph+ acute lymphoblastic leukemia, although it has been evaluated in these disease states. See table 2 for a full list of FDA-approved indications.

Differences between agents

Although there are similarities in adverse event profiles for the three commercially available tyrosine kinase inhibitors for Ph+CML, notable differences exist between the agents. Direct comparative trials between the agents are not currently available. However, early trials with dasatinib appeared to be associated with higher rates of myelosuppression compared with the other agents. Recent changes in the recommended dose and schedule of administration for dasatinib (100 mg daily vs. 70 mg twice daily) appear to produce similar rates of myelosuppression compared with imatinib and nilotinib. Dasatinib also appears to have higher rates of severe fluid retention, especially in patients with more advanced stages of CML. Unlike imatinib, where mild peripheral edema is common, the fluid retention with dasatinib often manifests as pulmonary effusions and rarely pericardial effusions. Regardless of the agent in question, fluid retention is managed with diuretics, dose interruption, drainage of the fluid from a third space and occasionally corticosteroids.

Nilotinib, on the other hand, is associated with higher rates of asymptomatic lipase elevations and QT prolongation. The QT prolongation effect appears to be concentration-dependent and drug–drug and/or drug–food interactions that increase nilotinib concentrations may increase the risk for this effect. Potassium and magnesium should be periodically monitored and kept in the normal range. Electrocardiogram monitoring should be performed at baseline, seven days after initiation of therapy and regularly during treatment. In addition, an ECG should be checked at the time of any dose adjustments or addition of any potentially interacting medications. See tables 3 and 4 for details regarding adverse events associated with these agents.

Drug interactions

As chronic oral therapies, clinicians must also consider the possibility of drug interactions when prescribing these medications. All three of these agents are substrates for the cytochrome P450 3A4 isoenzyme (CYP3A4). Coadministration of these TK inhibitors with strong inhibitors and/or inducers of CYP3A4 should be avoided if at all possible. All three agents also inhibit CYP3A4 to varying degrees. Caution should be used when adding or removing medications from a patient’s medication regimen if agents are susceptible to this interaction. Nilotinib may inhibit or induce other cytochrome P450 isoenzymes, particularly CYP2C8 and CYP2C9. The clinical significance of these interactions needs to be further investigated in phase-4, postmarketing clinical trials.

Dasatinib’s absorption is pH-dependent, requiring an acidic environment for optimal absorption. Long-acting antacids, such as H2-antagonists and proton pump inhibitors, decrease systemic exposure to dasatinib. It is recommended that concomitant administration of long-acting antacids and dasatinib be avoided. Alternatively, short-acting antacids are recommended provided that the antacid dose is separated from any dasatinib dose by two hours. Calcium carbonate being used as a calcium supplement should also be separated by dasatinib in this manner. See table 5 for further information on drug interactions with these agents.

Imatinib and dasatinib are available in multiple tablet strengths. The imatinib tablets are also scored, increasing dosing flexibility. Nilotinib is currently only available as blister packs of 28 capsules, a seven-day supply when using the normal starting dose. Dose administration guidelines differ for these agents regarding food. Imatinib should be taken with a meal and a full glass of water. Nilotinib must be taken on an empty stomach, two hours after or one hour before any food consumption. Nilotinib concentrations increase significantly with food, particularly a fatty meal, and could increase the rate of adverse events. As mentioned previously, all of these agents are metabolized by CYP3A4, which may lead to interactions with grapefruit/grapefruit juice, which inhibits the activity of this isoenzyme. Regular consumption of grapefruit and grapefruit juice should be avoided by patients on these agents.

Although imatinib, dasatinib and nilotinib are all members of the tyrosine kinase inhibitor family of medications used to treat Ph+CML, there are some significant practical differences between them. Imatinib is currently the only agent with the indication for front-line treatment of newly diagnosed Ph+CML. When faced with a patient who has failed or progressed on imatinib, consideration of the adverse effects profile and drug interaction risks, in addition to the mutational status of the patient, will help clinicians decide between the other available agents.

Debbie Blamble, PharmD, BCOP, is an Oncology Clinical Pharmacy Specialist at The University of Texas M.D. Anderson Cancer Center.

Laura Boehnke Michaud, PharmD, BCOP. is a Clinical Pharmacy Specialist - Breast Oncology at the University of Texas M.D. Anderson Cancer Center.

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