Emerging resistance patterns, as seen in >20% of patientstreated with imatinib in the IRIS study,7 and adverse eventshave led clinicians to consider alternative therapies formanaging their Ph+ CML patients. It was hypothesizedthat treatment with more potent TKIs—such as the second-generationagents nilotinib and dasatinib, which are lessvulnerable to resistance-conferring mutations in the bcr-ablkinase domain and may have an improved tolerabilityprofile—would decrease disease progression in CML.6,23Initial results of recently completed clinical studies suggestthat use of more potent TKIs first-line will begin to changethe treatment paradigm for this disease.5,8

Nilotinib, originally approved as a second-line agent forCML patients who developed resistance or intolerance toimatinib, is now approved as a first-line agent for newlydiagnosed CML patients.8 Although the study on whichthe recent indication approval is ongoing, further data willbe required to determine long-term survival and safetyoutcomes.7 Dasatinib, currently being studied for first-lineapproval, has been granted an accelerated review by theFDA.9

SECOND-GENERATION TYROSINE KINASEINHIBITORS
Treatment considerations depend on disease stage, adverse-eventprofile of the drug selected, and the drug’s relativeeffectiveness against bcr-abl mutations.1 Although nilotiniband dasatinib are both second-generation TKIs and aremore potent than imatinib, differences exist between theseagents.


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Nilotinib
Approved by the FDA in 2007, nilotinib was first indicatedfor the treatment of chronic-phase and accelerated-phasePh+ CML in adult patients who are intolerant or resistantto prior therapy, including imatinib.8 Based on the resultsof the Evaluating Nilotinib Efficacy and Safety in ClinicalTrials—Newly Diagnosed Patients (ENESTnd) study,which is discussed in more detail throughout this article,nilotinib gained a second indication in 2010 for use as afirst-line treatment option in patients with newly diagnosedPh+ CML in the chronic phase.8 Efficacy of nilotinib isbased on major molecular response and cytogenetic responserates, and ongoing, long-term studies will help determinelong-term outcomes.8

In newly diagnosed Ph+ CML patients, the recommendeddose of nilotinib is 300 mg orally twice daily.8 Conversely,a dose of 400 mg orally twice daily is recommended forpatients who are resistant or intolerant to other treatmentsincluding imatinib.8 Each dose of nilotinib should be takenon an empty stomach, either 2 hours before food or at least1 hour after food, at 12-hour intervals.8

Dose adjustments and reductions for nilotinib may bemade based on the occurrence of QTc prolongation(>480 msec), neutropenia, and thrombocytopenia unrelatedto the underlying condition, and for nonhematologic laboratoryabnormalities, including grade 3/4 elevations inserum lipase, amylase, bilirubin, and hepatic transaminases.8Nilotinib is primarily metabolized by the liver; therefore,patients with hepatic impairment should be closely monitoredsince elevated serum levels of nilotinib may induce or enhanceQT interval changes.8 In newly diagnosed Ph+ CML patientswith mild, moderate, or severe hepatic impairment, initialrecommended dosing of nilotinib is 200 mg twice dailyfollowed by an increase to 300 mg twice daily, if tolerated.8The dosing regimen for second-line use of nilotinib in patientswith mild or moderate hepatic impairment is 300 mg twicedaily, with a subsequent dose increase to 400 mg twice daily,if tolerated. It is recommended that patients with severehepatic impairment receive 200 mg twice daily initially,followed by sequential dose escalations to 300 mg twice dailyand, subsequently, 400 mg twice daily, if tolerated.8

It is important to monitor for drug interactions in patientstreated with nilotinib. Concomitant use of nilotinib withmedication and food products that inhibit or induce cytochromeP450 (CYP) enzymes, particularly CYP3A4, shouldbe avoided.8 Nilotinib is metabolized primarily byCYP3A4; strong CYP3A4 inhibitors (ie, ketoconazole,clarithromycin, grapefruit juice) may significantly increasenilotinib exposure, thus increasing the likelihood ofdrug-related adverse events.8 Concomitant use of CYP3A4inducers (ie, carbamazepine, rifampin, dexamethasone)may lead to significant decreases in nilotinib serum levels,rendering the treatment ineffective.8

Antiarrhythmics, such as amiodarone and procainamide,as well as other medications that may cause QT prolongation,should be avoided with nilotinib. QT prolongationmay also occur if nilotinib is inappropriately administeredwith food or with strong CYP3A4 inhibitors, due to thesignificant elevations in serum levels that may occuras a result.8 The effect leading to an increased risk of QTprolongation may be enhanced if hypokalemia and hypomagnesemiaare also present; to minimize this risk,hypokalemia and hypomagnesemia should always be correctedprior to administration of nilotinib.8 If simultaneoususe of these treatment options and nilotinib is necessary,and alternatives are not available, close monitoring becomesa crucial component of patient management and care.8

Nilotinib has decreased solubility at higher pH levels; asa result, an important drug interaction to note involvesagents that alter gastric pH levels, such as H2-receptorantagonists (H2RAs), antacids, and proton-pump inhibitors(PPIs). Concomitant use of these agents and nilotinib maydecrease the bioavailability, and ultimately the efficacy, ofnilotinib.8 It is recommended to separate the dose of H2RAsand antacids by several hours from that of nilotinib.8 Sincegastric pH may be affected for an extended period withcertain agents, as seen with PPIs, separating the dose ofnilotinib from the PPI may not be sufficient to eliminatethe drug interaction.8 Therefore, if an alternative is notavailable, caution is recommended when a PPI is used withnilotinib.8

The clinical trial supporting first-line use of nilotinibshowed a favorable safety profile. The most commonlyreported (>10%) nonhematologic adverse events withnilotinib included rash, pruritus, headache, nausea, fatigue,and myalgia.8 Less commonly observed adverse events(>5% and ≤10%) are upper abdominal pain, alopecia, constipation,diarrhea, dry skin, muscle spasms, arthralgia,peripheral edema, and asthenia, all of which were mild tomoderate in severity and did not require the dose of nilotinibto be reduced.8 Pleural and pericardial effusions have alsobeen documented in 1% of patients.8 Increases in QT intervals>60 msec from baseline were also reported in 0.4% ofpatients in the clinical trial using nilotinib as a frontlineoption; however, no patient had an absolute QTcF>500 msec.8 The most common hematologic adverse events(all grades) included thrombocytopenia (17%), neutropenia(15%), and anemia (7%).8 The incidence of grade 3/4myelosuppression was less common: neutropenia (12%),thrombocytopenia (10%), and anemia (4%).8

Dasatinib
Dasatinib is also a potent second-generation TKI that gainedits original FDA approval in 2006.24 Currently, dasatinibholds an indication for the treatment of chronic, accelerated,myeloid, or lymphoid blast-phase CML in adultswho are resistant or intolerant to prior therapy, includingimatinib; and for the treatment of Ph+ acute lymphoblasticleukemia in adults who are resistant or intolerantto prior therapy.24 However, a supplemental NDA for anew indication as a treatment for newly diagnosed adultswith CML in chronic phase was submitted to the FDA andis currently undergoing a priority review. Results of thereview are expected in late 2010.9

Dasatinib can be taken either in the morning or in theevening, without regard to meals.24 For the treatment ofchronic-phase CML, the recommended starting dose fordasatinib is 100 mg orally once daily; for CML in theaccelerated phase or blast phase (myeloid or lymphoid),140 mg of dasatinib orally once daily is recommended asthe starting dose.24

Dasatinib is also a substrate of the CYP450 enzyme system,particularly CYP3A4. Coadministration of strong inhibitorsof CYP3A4 (ie, ketoconazole) and dasatinib should beavoided due to an increase in dasatinib plasma concentrationsthat may result.24 If an alternative is unavailable, a dosereduction of dasatinib and close monitoring for toxic effectsare recommended.24 Conversely, using a strong inducer ofCYP3A4 with dasatinib may reduce dasatinib plasma concentrations;as a result, a dose increase of dasatinib may benecessary, and patients should be monitored for toxicity.24

Agents that alter gastric pH, such as antacids, H2RAs,and PPIs also interact with dasatinib; the solubility ofdasatinib is pH dependent, and simultaneous use of theseagents can decrease dasatinib plasma concentrations.24As a result, H2RAs and PPIs should be avoided; on the otherhand, if acid suppression is needed, antacids may beadministered either 2 hours before or 2 hours after thedasatinib dose.24

Dasatinib may also affect plasma concentrations of othertherapeutic agents. Drugs that have a narrow therapeuticindex and are substrates of CYP3A4 (ie, cyclosporine,simvastatin) should be used with caution due to potentialplasma concentration elevations.24

The use of dasatinib is associated with the developmentof severe (grade 3 or 4) thrombocytopenia, neutropenia,and anemia; these adverse events were more commonlyreported in patients with more advanced stages of CML.24Overall, grade 3 or 4 myelosuppression was less likely tobe reported with the 100 mg once-daily dose.24 Dosing ofdasatinib may be adjusted if neutropenia or thrombocytopeniadevelops.24

Throughout clinical studies with dasatinib, severebleeding, primarily associated with severe thrombocytopenia,has also been reported.24 Approximately 1% and4% of patients experienced severe central nervous systemhemorrhages or severe gastrointestinal hemorrhages,respectively.24 As a result, caution should be used whenadministering dasatinib to patients taking anticoagulantsor other medications that alter platelet function.24

Fluid retention has also been reported throughout clinicalstudies with dasatinib; in 10% of patients, fluid retentionwas severe and reports included pleural effusions (7%) andpericardial (1%) effusions.24 It is recommended that patientswho develop signs of pleural effusion, such as dyspnea ordry cough, be evaluated with a chest X-ray and, if resultsare positive, managed with supportive care measures(ie, diuretics, steroids).24

Caution should be used when dasatinib is administered topatients at risk of developing QT prolongation. High-riskpatients include those with hypokalemia, hypomagnesemia,those who have previously developed prolonged QT intervals,or patients taking medications that may lead to QT prolongation(ie, antiarrhythmics, high-dose anthracycline therapy).In clinical studies with dasatinib, QT prolongation was notedin <1% (14/2182) of patients; QT intervals >500msec hadbeen reported in 1% of patients (21/2182).24

It is important to note that certain adverse events may bemore frequent with one agent compared to another, as hadbeen reported in clinical studies. With an understandingof differences and similarities of second-generationTKIs, oncology nurses can play a pivotal role in addressingpatient concerns as well as be in a better position to setpatient expectations.