Nilotinib vs. Imatinib for Newly Diagnosed CML

Abstract & Commentary

Andrew S. Artz, MD, Division of Hematology/Oncology, University of Chicago. Dr. Artz reports no financial relationships relevant to this field of study.

Synopsis: Imatinib at 400 mg daily leads to high response rates for chronic-phase CML, but a subset has suboptimal response and/or toxicity. In this study, 846 subjects were randomized to receive nilotinib, a more selective bcr/abl tyrosine kinase inhibitor, at 300 mg BID or 400 mg BID vs. imatinib at 400 mg daily. The rate of one-year major molecular remission for nilotinib arms was 43%-44%, compared to 22% for imatinib (p < 0.001). Similarly, rates of one-year complete cytogenetic remission were superior for nilotinib arms 78%-80%, compared to 65% for imatinib-treated patients (p < 0.001). One-year response rates are significantly greater for nilotinib compared to imatinib for newly diagnosed CML.

Source: G. Saglio, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362:2251-2259.

The 9;22 translocation (a.k.a. philadelphia chromosome) is the characteristic abnormality underlying chronic myeloid leukemia (CML) that creates a mutant oncogene, BCR/ABL. As a consequence, constitutively activated BCR/ABL tyrosine kinase promotes malignant transformation. Imatinib mesylate (Gleevec) inhibits BCR/ABL tyrosine kinase activity and has changed the paradigm of CML therapy based on frequent and durable remissions in the International Randomized Study of Interferon and STI571(IRIS).1 Around 20% of patients, however, do not achieve a complete cytogenetic remission, predisposing to disease progression. Further, imatinib infrequently leads to complete molecular response.2 The more selective ABL kinase binding of second-generation tyrosine kinase inhibitors (i.e., nilotinib and dasatinib) result in significant activity in imatinib-resistant patients, prompting evaluation in the front-line setting.3,4

In the Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients (ENESTnd) study, nilotinib (at either 300 mg or 400 mg twice daily) was compared to 400 mg daily of imatinib for newly diagnosed chronic-phase CML. Escalation of imatinib to 400 mg twice daily was permitted in patients who had a suboptimal response or treatment failure, as defined by the European LeukemiaNet.5 The primary endpoint was the rate of major molecular response (MMR) at 12 months, defined as a BCR-ABL transcript level of 0.1% or less in peripheral blood on RQ-PCR assay, as expressed on the International Scale. A total of 846 patients were randomized to either nilotinib 300 mg twice daily (n = 282), nilotinib 400 mg twice daily (n = 281) and imatinib 400 mg daily (n = 283). In the imatinib group, 45 patients were dose-escalated to 800 mg per day. Rates of major molecular response were 44% for nilotinib 300 mg BID, 43% for nilotinib 400 mg BID, and 22% for imatinib (p < 0.001 comparing either nilotinib arm to imatinib). For patients at higher baseline risk, based upon Sokal score, the rates of molecular response at 12 months were 41%, 32%, and 17% for nilotinib 300 mg BID, nilotinib 400 mg BID, or imatinib 400 mg QD, respectively. One-year complete cytogenetic response (CCyR) was achieved in 80% of nilotinib 300 mg BID, 78% of nilotinib 400 mg BID, and 65% of imatinib daily (p < 0.001). High Sokal risk scores were associated with complete cytogenetic rates of 63%-74% for nilotinib and 49% for imatinib at one year.

Progression to accelerated or blast crises occurred in 14 patients, of whom 11 received imatinib. Thus, the rates of disease evolution were 4% for imatinib and < 1% for nilotinib. Time to progression was reduced with nilotinib (p = 0.01). No patients reaching a MMR evolved, whereas three imatinib-treated patients reaching CCyR evolved. Finally, of the 45 patients who received an escalation in imatinib dose, only one had a molecular response and one a complete cytogenetic response.

For adverse events, rates of nausea, diarrhea, vomiting, muscle spasm, and edema, of any grade, were higher for patients in the imatinib group than for those in either nilotinib group. In contrast, rash, headache, pruritus, and alopecia were higher in both nilotinib groups than in the imatinib group. Many patients underwent dose reduction or holding, including 59% receiving 300 mg of nilotinib, 66% receiving 400 mg of nilotinib, and 52% receiving imatinib. Discontinuations related to toxicity occurred in 5% of patients receiving 300 mg of nilotinib, 9% of those receiving 400 mg of nilotinib, and 7% of those receiving imatinib.


Although treatment options for CML have dramatically improved, treatment and monitoring have become increasingly complex. Imatinib has been the standard of care for newly diagnosed chronic-phase CML since the drug received approval. Although response rates are quite high, and many durable, a subset of patients do not meet the initial milestone of complete cytogenetic response, and only a minority achieve major molecular remissions.2,6,7

This study compared nilotinib at 300 mg or 400 mg administered BID (thus, 600 mg or 800 mg total, respectively) against imatinib 400 mg daily for newly diagnosed CML. Nilotinib resulted in significantly greater rates of MMR, and complete cytogenetic response (CCyR) at one year (p < 0.001 in both comparisons). Specifically, nilotinib achieved MMR of 43%-44%, compared to 22% for imatinib. CCyR occurred in 78%-80% of nilotinib patients vs. 65% of imatinib-treated patients. Importantly, in this same issue of the Journal, a study comparing dasatinib to imatinib for newly diagnosed CML showed rates of MMR of 46% for dasatinib vs. 28% for imatinib, and complete cytogenetic response of 77% for dasatinib and 66% for imatinib. Further, disease evolution occurred in 3.5% of imatinib, the same rate as the 4% found in this nilotinib trial. Thus, both dasatinib and nilotinib showed similar activity and considerably higher one-year response rates compared to imatinib.

One alternative might be higher-dose imatinib, such as 400 mg BID; however, data for higher-dose imatinib has not shown a benefit in one-year response rates over standard dose, although toxicities are significant.8

The major limitation relates to the short follow-up and, thus, limited ability to detect survival differences. Further follow-up will be invaluable to determine long-term disease control and survival.

While the results suggest that with longer-term evaluation, nilotinib (and dasatinib) may improve outcomes, we lack mature data. In addition, other drugs, such as bosutinib, are under review. At present, it remains reasonable to employ imatinib as initial therapy. However, these data also provide a rationale for discussing with patients the use of nilotinib or dasatinib as initial therapy for chronic-phase CML, especially since around 4% of patients in both trials on imatinib had disease evolution even over a short follow-up. Alternatively, an individualized approach can be employed, perhaps reserving front-line, second-generation tyrosine kinase therapy for higher-risk patients, such as high Sokal risk, more advanced disease stages, or only after suboptimal response to imatinib, such as lack of complete cytogenetic response. Finally, for some patients, pre-existing comorbidity may indicate toxicity profiles of certain drugs may be preferred.

In summary, nilotinib leads to significantly improved response rates for newly diagnosed CML at one year. Longer-term follow-up data will confirm the role of nilotinib and other more selective tyrosine kinase inhibitors for initial therapy.


1. Druker BJ, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408-2417.

2. Hochhaus A, et al. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia. 2009;23: 1054-1061.

3. Guilhot F, et al. Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood. 2007;109:4143-4150.

4. Kantarjian H, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006;354:2542-2551.

5. Baccarani M, et al. Evolving concepts in the management of chronic myeloid leukemia: Recommendations from an expert panel on behalf of the European Leukemia Net. Blood. 2006;108:1809-1820.

6. Druker BJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344: 1031-1037.

7. O'Brien SG, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348:994-1004.

8. Cortes JE, et al. Phase III, randomized, open-label study of daily imatinib mesylate 400 mg versus 800 mg in patients with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase using molecular end points: tyrosine kinase inhibitor optimization and selectivity study. J Clin Oncol. 2010;28:424-430.