Nilotinib is Superior to Imatinib as First-line Therapy of Chronic Myeloid Leukemia: The ENESTnd Study

Francis J Giles; Gianantonio Rosti; Photis Beris; Richard E Clark; Philipp le Coutre; Francois-Xavier Mahon; Juan-Luis Steegmann; Peter Valent; Giuseppe Saglio


Expert Rev Hematol. 2010;3(6):665-673. 

In This Article


Saglio et al. have recently reported on the pivotal ENESTnd results ( number, NCT00471497[103]) from an international, Phase III randomized open-label active-control multicenter study.[17] A total of 840 patients with Ph-positive CML CP were randomized in a 1:1:1 ratio to receive nilotinib (at a dose of either 300 mg or 400 mg twice daily) or imatinib (at a dose of 400 mg once daily) (Figure 4). Dose escalation was not allowed on either nilotinib arm, while patients being treated on the imatinib arm were allowed dose escalation to 800 mg once daily. All efficacy data were reported on an intent-to-treat (ITT) population analysis. The study protocol and statistical plan are available as online appendices to the New England Journal of Medicine publication.[17] Eligible patients were allowed no prior therapy for CML except hydroxyurea or anagrelide and/or a maximum of 2 weeks prior imatinib therapy. Patients were aged 18 years or older, had ECOG performance scores of 0–2, ECG confirmation of QTcF less than 450 ms, and adequate organ function. As one would expect with such a large sample size, patient characteristics at study entry were well balanced across all three study groups – in the nilotinib 300 mg twice daily, nilotinib 400 mg twice daily and imatinib 400 mg once daily arms, respectively, the median/range for ages in years were 47 (18–85), 47 (18–81) and 46 (18–80); median time between CML diagnosis and study entry were 31, 31 and 28 days. The Sokal risk groups were also very well balanced with 37, 36 and 28% of patients being in the low-, intermediate- and high-risk group in each of the three study arms. Dose intensity was close to planned dose across all arms. In the nilotinib 300 mg twice daily, 400 mg twice daily and imatinib 400 mg once daily arms at a median time on treatment of 18.6, 18.5 and 18.1 months, respectively, the median dose intensities in mg/day were 593, 779 and 400, respectively.[18,19]

Figure 4.

Evaluating Nilotinib Efficacy and Safety in Clinical Trials – Newly Diagnosed Patients (ENESTnd): design and end points.
AP: Accelerated phase; BC: Blastic crisis; b.i.d.: Twice daily; CCyR: Complete cytogenetic response rate; EFS: Event-free survival; MMR: Major molecular response; OS: Overall survival; PFS: Progression-free survival; q.d.: Once daily.
Adapted from [17].

Response assessments were collected during study treatment. MMR was defined as: BCR–ABL of 0.1% or less using international standardization of results, with unavailable samples considered as lack of response and atypical transcripts at baseline considered as lack of response (eight patients). CCyR was defined as no Ph+ metaphases out of 20 or more analyzed. Unavailable or insufficient samples were considered as lack of response and FISH was not used for assessment. Progression to AP/BP on treatment was defined as per the European Leukemia Network 2006 criteria.[9] Overall survival included data from follow-up after discontinuation of treatment. The primary study objective was to compare the rate of MMR at 12 months between either of the nilotinib arms and the imatinib control arm – the statistical design did not allow for comparisons between the nilotinib arms. The MMR rate at 12 months for nilotinib was 44% in the 300 mg twice daily recipients and 43% for the 400 mg twice daily recipients, with both MMR rates being nearly twice that seen in the imatinib-treated patients (22%; p < 0.001 for both comparisons). Complete molecular response (CMR) was defined as a BCR–ABL1 of 0.0032% or less and occurred in approximately 20% of patients receiving nilotinib therapy in contrast to approximately 6% of patients receiving imatinib therapy.

The rates of CCyR by 12 months were also significantly higher for nilotinib (80% for the 300 mg twice daily recipients and 78% for the 400 mg twice daily recipients) than for the imatinib recipients (65%; p < 0.001 for both comparisons). Patients receiving either the 300 mg twice daily or the 400 mg twice daily nilotinib regimens had a significant improvement in the time to progression to AP or BP, compared with those receiving imatinib (p = 0.01 and p = 0.004, respectively). No patient with progression to AP or BP had a prior MMR. With further follow-up of the ENESTnd population, the difference in MMR rates remain statistically significantly in favor of both nilotinib arms (Figure 5). Patients who received imatinib dose escalation did not achieve responses comparable to those seen in either nilotinib arm. In the ENESTnd study, the population used for safety analyses (n = 836) included all randomized patients who received at least one dose of study medication and were then analyzed by the treatment they received. Grade 3/4 extramedullary events were very infrequent in all study arms, not only on the initial report, but also with the further follow-up presented at the American Society of Clinical Oncology (ASCO) and EHA 2010 (Table 3). Gastrointestinal and fluid-retention adverse events were more frequent among patients receiving imatinib, whereas dermatologic adverse events and headache were more frequent in those receiving nilotinib. Elevations in lipase, glucose and bilirubin were more frequent with nilotinib therapy than imatinib therapy, while hypophosphatemia was equivalent with both therapies (Table 4). Discontinuation of study therapy due to aminotransferase and bilirubin elevations was rare in all three study groups. There was no clinically relevant rate of pericardial or pleural effusion observed.[6,20] Myelosuppression was significantly less severe on both nilotinib arms when compared with the control imatinib arm, a pattern which is quite distinct from that seen on the DASISION randomized study of dasatinib versus imatinib, particularly in terms of thrombocytopenia (Figure 6). Vascular events observed in patients on the ENESTnd study were typical of an age-matched population but as one myocardial infarction per drug was reported as being related to dasatinib and imatinib on the DASISION study, longer term follow-up is necessary to fully assess the relationship between vascular events and chronic TKI therapy.

Figure 5.

Evaluating Nilotinib Efficacy and Safety in Clinical Trials – Newly Diagnosed Patients (ENESTnd): incidence of major molecular response. 12 months indicates the intent-to-treat population population; 18 months indicates the evaluable patients. b.i.d.: Twice daily; IM: Imatinib; MMR: Major molecular response; NI: Nilotinib.
Adapted from [19]. Figure courtesy of G Saglio.

Figure 6.

Evaluating Nilotinib Efficacy and Safety in Clinical Trials – Newly Diagnosed Patients (ENESTnd) and DASISION studies: summary of hematologic adverse events.
b.i.d.: Twice daily; DA: Dasatinib; IM: Imatinib; NI: Nilotinib; q.d.: Once daily.
Figure courtesy of F Giles.

With the ASCO and EHA updates of ENESTnd, the data show that the MMR and CCyR rates remain significantly superior for both nilotinib arms compared with imatinib (although it will be important to see at the ASH 2010 and subsequent updates that the differences are ongoing), the percentage of patients with a CMR continues to increase, there is ongoing relative protection from AP/BP in both nilotinib arms, there is a significant survival advantage with nilotinib 400 mg twice daily over imatinib, and nilotinib at both doses continues to be generally well tolerated.[18,19]


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