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. 

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Expert Commentary

The largest CML-related threat to life on imatinib therapy is development of AP/BP within the first 3 years of imatinib therapy. In terms of both the clinically relevant surrogate markers, CCyR and MMR, and of the clinically vital end points of early transformation events and overall survival, nilotinib has proved superior to imatinib as first-line therapy in CML. US FDA approval has been granted based on the results of the ENESTnd study. Nilotinib has a low incidence of grade 3/4 extramedullary adverse events, predominantly transient biochemical abnormalities, which tend to occur early in therapy. Nilotinib in the frontline setting is associated with less myelosuppression than imatinib. A range of further Phase III studies of nilotinib in newly diagnosed patients have begun or are planned. The ENEST1st study will further examine the efficacy of nilotinib 300 mg twice daily in newly diagnosed patients with CML using CMR rather than MMR as per the ENESTnd study, as the primary study end point (Figure 7). The ENEST1st study has a range of integral international collaborative biology studies, which include a focus on CML stem cells, indices of genomic instability, very sensitive mutated Bcr–abl1 phenotype clone detection and quantitation, and genomic analyses. Nilotinib pharmacokinetics and patient adherence to therapy will also be focused on in this study. The ICORG CML study also focuses on the approved nilotinib 300 mg twice daily dose and examines methodologies of more rapid, reproducible PCR quantitation. We believe that nilotinib will generate a sufficiently high percentage of patients in CMR to allow the conduct of large-scale therapy cessation studies, which offer the prospect of true population-wide cure of CML. Such studies may involve the addition of non-ABL1 inhibitor approaches, for example, interferon. Other definitions of 'cure' are reasonable to consider as study end points and might include no detectable disease (a definition that will evolve as technology changes) or disease that is detectable but incapable of clinical disease recurrence and is associated with a normal life span. The incremental benefit that nilotinib confers to the overall population of CML patients will appropriately increase the pressure on us to identify those small number of patients who are not destined to derive optimal benefit from nilotinib at a point where other interventions will allow them to have a prognosis equivalent to nilotinib-responsive patients with CML.

Figure 7.

ENEST1st-line study design.
AP: Accelerated phase; b.i.d.: Twice daily; BC: Blastic crisis; CCyR: Complete cytogenetic response rate; CML: Chronic myeloid leukemia; CMR: Complete molecular response; IM: Imatinib; MMR: Major molecular response.
Figure courtesy of F Giles.


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