Dasatinib has also been evaluated in newly diagnosed,chronic-phase CML patients in the Dasatinib versus ImatinibStudy in Treatment-Naïve CML Patients (DASISION)study. DASISION, an open-label, multinational, randomizedphase III trial, compared the efficacy and safety ofdasatinib to that of imatinib when used in newly diagnosedCML patients.6 The primary objective was to determinewhether patients who received dasatinib had a higher rateof confirmed complete cytogenetic response after 12 monthsof treatment, compared to imatinib.6
A complete cytogenetic response was defined as a completeresponse documented on 2 consecutive assessments at least28 days apart; bone marrow samples were used to assesscytogenetic response within 6 weeks after randomizationand every 3 months thereafter. Patients who had a completecytogenetic response by 12 months and an assessmentconfirming the complete response thereafter were consideredto have a complete cytogenetic response at the12-month time frame.6
Secondary study end points included a major molecularresponse at any time, the time to a confirmed completecytogenetic response, and the time to a major molecularresponse.6 Major molecular response rates were determinedusing QRT-PCR to measure bcr-abl transcripts; a majormolecular response was defined as a bcr-abl transcript level≤0.1%, which corresponds to a reduction of 3-log10copies or more in bcr-abl transcripts on the InternationalScale.6
For participation in the study, patients were required tohave Ph+ CML in chronic-phase diagnosed by bone marrowcytogenetic studies within 3 months of study entry.6Previous treatment for CML, with the exception ofanagrelide or hydroxyurea, was not allowed, and patientswere required to have an ECOG performance status of 0to 2.6 Patients were randomized to receive either dasatinib100 mg once daily (with or without food) or imatinib400 mg once daily (with food) in a 1:1 ratio; dose escalations,reductions, and interruptions were allowed forboth treatment groups, based on predetermined criteria.6Treated patients were evaluated for all adverse events,including pleural effusion, throughout the entire study.6
Of the patients randomized, 258 patients in both treatmentgroups received their respective study drug; themedian duration of the treatment was 14 months for thedasatinib group and 14.3 months for the imatinib group.6
By 12 months of treatment, 77% of patients receivingdasatinib, compared to 66% of those taking imatinib, hada confirmed complete cytogenetic response; the differencebetween both groups was significant (P=0.007).6 Completecytogenetic response observed in at least 1 assessment by12 months of treatment was also higher, respectively, withdasatinib compared to imatinib (83% vs 72%, P=0.001).6The rates of a complete cytogenetic response were achievedat earlier time frames with dasatinib than with imatinib,as noted in Figure 5 (HR 1.5, P<0.0001).6
Additionally, patients who received dasatinib, comparedto those who received imatinib, had a significantly higherrate of major molecular response at any time (52% vs 34%,P<0.0001) and by the end of the 12-month study period(46% vs 28%, P<0.0001).6 The time to major molecularresponse was significantly shorter with dasatinib comparedto imatinib (HR 2.0, P<0.0001) as denoted inFigure 6.6
Disease progression occurred in 1.9% of patients receivingdasatinib (5/259), compared to 3.5% of patients receivingimatinib (9/260); all patients’ disease progressed to theblastic phase.6 Progression-free survival was similar betweenboth treatment groups.6
Adverse events in the dasatinib and imatinib groups wereprimarily grade 1 or 2. Nonhematologic adverse eventsoccurring in at least 10% of patients included nausea, vomiting,muscle inflammation, rash, and fluid retention; theseadverse events occurred more frequently in the imatinibgroup. All grades of fluid retention, as well as superficialedema, were more frequently reported in the imatinibgroup, compared to the dasatinib group (42% vs 19% and36% vs 9%, respectively).6 Grade 1 or 2 pleural effusionevents were reported by 10% (26 patients) receivingdasatinib; pleural effusion was not reported in patientsreceiving imatinib.6 Hypophosphatemia (grade 3 or 4)also occurred at higher frequencies with imatinib (21%)compared to dasatinib (4%).6
Grade 3 or 4 neutropenia occurred in 21% and 20% ofpatients in the dasatinib group and imatinib group, respectively;thrombocytopenia occurred in 19% of patientsreceiving dasatinib and in 10% of patients receivingimatinib.6 QTc intervals between 450 msec and 500 msecoccurred in 2% and 4% of patients in the dasatinib groupand imatinib group, respectively; one patient in eachtreatment group had a QTc interval >500 msec.6
Discontinuation due to adverse events occurred in 5%and 4% of patients receiving dasatinib and imatinib, respectively.6 Four deaths occurred in the dasatinib group, whereas1 death occurred in the imatinib group; 1 death in eachgroup was attributed to the study treatment and was theresult of a myocardial infarction.6
Overall, the results of this study demonstrated thatdasatinib is effective in newly diagnosed Ph+ CML chronic-phasepatients. Both complete cytogenetic response andmajor molecular response rates were significantly higher inpatients who received dasatinib, which can potentiallyindicate a lower risk for long-term disease progression. Theadverse events reported in this trial also demonstrated thatthe safety profile for dasatinib is acceptable, compared tothat of imatinib.6 Long-term results from this ongoing studywill better evaluate the potential benefits and risks of usingdasatinib in treatment-naïve patients, as well as determinethe potential of improved progression-free survival.6
DISCUSSION: ENESTnd and DASISION
When considering the potential impact both trials may haveon treatment selection, the relevance and strength of thestudy end points are of critical importance. Evaluation ofthe major molecular response rate, based on the reductionsin bcr-abl transcript levels, is a recommended measure inthe evaluation of residual disease CML patients. In 2005,an expert committee concluded that residual disease shouldbe expressed on an international scale based on a standardbaseline value (established in the IRIS trial) and a standardizedmajor molecular response value of 0.1% (equivalent toa 3-log10 reduction from the standard baseline).25 Past studieshave demonstrated that major molecular response rates basedon bcr-abl transcript reductions serve as better long-termprognosticators for disease progression.26 Moreover, a majormolecular response can potentially lead to higher rates ofprogression-free survival and event-free survival.25 Acytogenetic evaluation using Ph+ metaphases may not beas sensitive in the detection of minimal residual disease.26
With regard to adverse events, both nilotinib and dasatinibare well tolerated. Based on QT prolongation warningsthat apply to both nilotinib and dasatinib, ENESTndexcluded all patients with impaired cardiac function5;similarly, DASISION excluded patients with uncontrolledor serious cardiovascular disease, including patients withcorrected QT intervals.6 Despite these exclusions, therewere patients in DASISION who experienced QT prolongation>500 msec as an adverse event; in addition, onedocumented death in each treatment group was related toa cardiac event.6 This occurrence not only demonstratedthat cardiac patients necessitate additional monitoring iftreated with dasatinib or imatinib, but also that QTprolongation is not limited to certain agents within theTKI class—it is a warning that applies to this pharmacologicalclass as a whole.
Ultimately, both nilotinib and dasatinib have demonstratedefficacy in the treatment of patients with Ph+ CML inchronic phase.5,6 The key differentiating factor that willdetermine which agent is better for a given patient is thesafety profile, tolerability, and the management of adverseevents, when encountered.