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Adobe Flash Player is required to view this feature. If you are using an operating system that does not support Flash, we are working to bring you alternative formats. Original Article Nilotinib versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia Giuseppe Saglio, M.D., Dong-Wook Kim, M.D., Ph.D., Surapol Issaragrisil, M.D., Philipp le Coutre, M.D., Gabriel Etienne, M.D., Clarisse Lobo, M.D., Ricardo Pasquini, M.D., Richard E. Clark, M.D., Andreas Hochhaus, M.D., Timothy P. Hughes, M.D., M.B., B.S., Neil Gallagher, M.D., Ph.D., Albert Hoenekopp, M.D., Mei Dong, M.D., Ariful Haque, M.S., Richard A.

Larson, M.D., and Hagop M. Kantarjian, M.D., for the ENESTnd Investigators N Engl J Med 2010; 362:2251-2259 DOI: 10.1056/NEJMoa0912614. Results At 12 months, the rates of major molecular response for nilotinib (44% for the 300-mg dose and 43% for the 400-mg dose) were nearly twice that for imatinib (22%) (P. The use of the BCR-ABL tyrosine kinase inhibitor imatinib mesylate (Gleevec, Novartis Pharmaceuticals) improved outcomes for patients with Philadelphia chromosome–positive chronic myeloid leukemia (CML) and established BCR-ABL–targeted therapy as the standard of care for this disease. In the International Randomized Study of Interferon and STI571 (IRIS; ClinicalTrials.gov number, NCT00006343), imatinib was associated with a superior response rate and improved progression-free survival, as compared with the previous standard therapy, interferon alfa plus low-dose cytarabine. Eight-year follow-up of IRIS revealed that responses to imatinib were durable and had an acceptable adverse-event profile, with an estimated rate of overall survival of 85%. Despite the positive effect of imatinib, nearly 20% of patients who take the drug do not have a complete cytogenetic response, and others may have intolerable side effects or drug resistance over time.

Download PDF Pathophysiology of Heart Disease: A Collaborative Project of Medical Students and Faculty Full Book. Download PDF Pathophysiology of Heart Disease: A Collaborative Project of Medical Students and Faculty Full Book; 2. Book details Author: Leonard S. Lilly MD Pages: 480 pages.

Loss of response and transformation to advanced disease occur mainly in the first 3 years of imatinib therapy, and the rate of overall survival is poor in these patients. In addition, residual disease, detectable by real-time quantitative polymerase-chain-reaction (RQ-PCR) assay, is measurable in most patients treated with imatinib. Thus, improved first-line therapy is needed.

Nilotinib (Tasigna, Novartis Pharmaceuticals) is an orally bioavailable drug with greater potency and selectivity for BCR-ABL than imatinib. Nilotinib was first approved in the United States and elsewhere in 2007 for patients with CML in the chronic or accelerated phase who had resistance to or could not tolerate imatinib. In this phase 3, randomized, open-label, multicenter trial, called the Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients (ENESTnd) study, we compared the efficacy and safety of nilotinib (at a dose of either 300 mg or 400 mg twice daily) with that of imatinib (at a dose of 400 mg once daily) in patients with newly diagnosed Philadelphia chromosome–positive CML in the chronic phase, with the rate of major molecular response at 12 months as the primary end point. Patients Adult patients were eligible within 6 months after the diagnosis of Philadelphia chromosome–positive CML in the chronic phase.

Diagnosis was determined by conventional cytogenetic analysis of bone marrow containing at least one Philadelphia chromosome–positive metaphase cell. Diagnosis by fluorescence in situ hybridization was not allowed. The definition of chronic-phase CML has been described previously. Patients needed to have adequate organ function and an Eastern Cooperative Oncology Group (ECOG) performance status of at least 2, which indicates that the patient is capable of all self-care but is unable to carry out any work activities and is out of bed more than 50% of waking hours. (The ECOG performance status is graded on a scale from 0 to 5, with a higher score indicating a greater severity of illness.) Patients were excluded if they had received treatment with a tyrosine kinase inhibitor before study entry (except imatinib for ≤2 weeks) or any medical treatment for CML for more than 2 weeks (except hydroxyurea or anagrelide). Patients with impaired cardiac function were excluded.

The use of therapeutic coumarin derivatives, drugs that block or stimulate the activity of the liver enzyme cytochrome P450-3A4 (CYP3A4 inhibitors or inducers), or any medication with the potential to prolong the QT interval was prohibited. Randomization and Treatments Patients with newly diagnosed Philadelphia chromosome–positive chronic-phase CML were randomly assigned 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). Randomization was stratified according to the Sokal risk score at the time of diagnosis.

The Sokal score is based on age, spleen size, and peripheral-blood platelet count and blast count. Patients are classified as being low-risk (Sokal score, 1.2). Patients could discontinue therapy because of treatment failure (including progression), intolerable side effects, or other reasons. An escalation in the imatinib dose to 400 mg twice daily was permitted in patients who had a suboptimal response or treatment failure, as defined by the European LeukemiaNet. Dose escalation of nilotinib was not permitted.

In contrast to the protocol of the IRIS study, crossover was not permitted in our protocol. Instead, patients were eligible to participate in an extension study. Molecular response was assessed for BCR-ABL by means of RQ-PCR at baseline, monthly for 3 months, and every 3 months thereafter. Conventional bone marrow cytogenetic analyses were performed at baseline and at months 6, 12, 18, and 24. Complete blood counts were measured at baseline; at weeks 1, 2, and 4; monthly until month 6; and every 3 months thereafter until study completion. End Points The primary efficacy end point was the rate of major molecular response 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. This corresponds to a reduction of 3 log 10 copies or more in BCR-ABL transcripts, as compared with the standardized baseline established in IRIS.

Patients who did not undergo RQ-PCR assessment at 12 months were considered to have had no response. RQ-PCR assays were performed in a central laboratory (MolecularMD). The assay was standardized through an exchange of samples from patients with the molecular laboratory in Adelaide, Australia. The International Scale conversion factor was 0.81. The key secondary end point was a durable major molecular response by 24 months.

However, for this study, the rate of complete cytogenetic response by 12 months was the main secondary end point. Results on the secondary end point of progression to accelerated phase or blast crisis (defined as such progression or CML-related death) are also provided.

Study Design The study was designed by representatives of the sponsor, Novartis Pharmaceuticals, with input from the investigators on the study-management committee. The data were collected with the use of the sponsor's data-management systems and were analyzed and interpreted by the sponsor's statistical team in close collaboration with the other investigators. An independent data and safety monitoring board reviewed the trial data and made recommendations regarding the continuation of the study.

All authors contributed to the writing, reviewing, and amending of an outline of the manuscript. The first draft of the manuscript was written by a medical writer employed by an independent company with funding provided by Novartis. All authors and representatives of the sponsor reviewed and amended the manuscript and vouch for the completeness and integrity of the reported data. The authors also certify that the study as reported conforms with the protocol (as amended) and statistical analysis plan. (For details, see the, available with the full text of this article at NEJM.org.) For details regarding other secondary end points, the statistical analysis, and ethics and study management, see the Methods section in the, available at NEJM.org.

Patients and Treatments From September 6, 2007, to September 30, 2008, we randomly assigned 846 patients with newly diagnosed, Philadelphia chromosome–positive, chronic-phase CML to receive nilotinib twice daily (with 282 patients assigned to receive 300 mg and 281 patients assigned to receive 400 mg) or imatinib once daily (with 283 patients assigned to receive 400 mg). The cutoff date for this study was September 2, 2009, on the basis of the 12-month visit for the last patient who underwent randomization.

Baseline characteristics and distributions of the Sokal risk score were well-balanced in the three study groups ( Table 1 Baseline Characteristics of the Patients (Intention-to-Treat Population). The median dose intensities of nilotinib were high (and close to the planned regimens) at 592 mg per day (interquartile range, 543 to 600) in the group receiving the 300-mg dose and 779 mg per day (interquartile range, 581 to 800) in the group receiving the 400-mg dose. The median dose intensity of imatinib was 400 mg per day (interquartile range, 389 to 400). At the time of data cutoff, the median duration of treatment was approximately 14 months in all study groups; the proportions of patients receiving a study drug were 84% in the group receiving 300 mg of nilotinib, 82% in the group receiving 400 mg of nilotinib, and 79% in the group receiving imatinib (Table 1 in the ). In the imatinib group, 45 patients had a dose escalation to 800 mg per day. By the time of data cutoff, 13 patients had discontinued treatment (7 patients because of treatment failure, 3 patients because of disease progression, and 1 patient each because of a suboptimal response, adverse events, and a protocol violation). Efficacy At 12 months, rates of major molecular response (the primary end point) were significantly higher in patients receiving 300 mg of nilotinib (44%) or 400 mg of nilotinib (43%) twice daily than in those receiving imatinib (22%) (P.

Adverse Events The safety population consisted of all 836 patients who received at least one dose of a study drug. Nilotinib and imatinib both had good safety and adverse-event profiles, although specific differences were noted. The most frequently reported study-related adverse events of any grade are reported in Table 2 Adverse Events and Newly Occurring or Worsening Hematologic or Biochemical Laboratory Abnormalities in the Safety Population.. Overall, grade 3 or 4 nonhematologic adverse events were uncommon in all patients. 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.

Conversely, rates of rash, headache, pruritus, and alopecia were higher in both nilotinib groups than in the imatinib group. Grade 3 or 4 neutropenia and anemia were more frequent in the imatinib group, whereas thrombocytopenia was more frequent in both nilotinib groups. All newly occurring grade 3 or 4 hematologic laboratory abnormalities occurred within the first 2 months of therapy in the three study groups.

The most frequently reported biochemical laboratory abnormalities are reported in. Grade 3 or 4 laboratory abnormalities were uncommon in any group. Elevations of any grade in levels of alanine aminotransferase, aspartate aminotransferase, and bilirubin were more frequently observed in both nilotinib groups than in the imatinib group, although rates of discontinuation were low and consistent across the study groups. As observed in previous nilotinib trials, these specific laboratory abnormalities are typically manageable and not clinically important. Additional data regarding serious adverse events are available in Table 5 in the. Dose reductions or interruptions occurred in 59% of patients receiving 300 mg of nilotinib, in 66% receiving 400 mg of nilotinib, and in 52% receiving imatinib. Median cumulative durations of dose interruptions because of adverse events or laboratory abnormalities were 19 days among patients receiving 300 mg of nilotinib, 22 days among patients receiving 400 mg of nilotinib, and 15 days among patients receiving imatinib.

Discontinuations because of adverse events occurred in 5% of patients receiving 300 mg of nilotinib, 9% of those receiving 400 mg of nilotinib, and 7% of those receiving imatinib. Up to the data cutoff, nine patients died during the study. Among patients receiving imatinib, four discontinued treatment because of disease progression and died during follow-up from CML-related reasons; among patients receiving 300 mg of nilotinib, two died (one from a small-intestine obstruction and one from suicide) during the study, and one died during follow-up after bone marrow transplantation; and among patients receiving 400 mg of nilotinib, one discontinued treatment because of progression and died during follow-up and one discontinued treatment and died 6 weeks later from gastric cancer. Patients were closely monitored for QT prolongation and changes in the left ventricular ejection fraction.

No patient in any of the study groups had a QT interval corrected for heart rate (QTcF) of more than 500 msec. No decrease from baseline in the mean left ventricular ejection fraction was observed at any time during the study.

A total of 11 patients in all three study groups combined had an ischemic heart disease event, with only one event resulting in treatment discontinuation. Discussion In this trial, nilotinib was superior to imatinib in both the primary end point (major molecular response) and the key secondary end point (complete cytogenetic response). The number of patients who had disease progression or transformation to the accelerated phase or blast crisis was significantly lower in both nilotinib groups than in the imatinib group, showing that nilotinib improved disease control in patients with newly diagnosed CML. Our findings establish both the twice-daily 300-mg and 400-mg doses of nilotinib as highly effective, as compared with imatinib. This study is being reported with a minimal follow-up of 12 months and is ongoing.

In two recent phase 3 trials comparing two daily doses of imatinib (800 mg and 400 mg) — the Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) study and the German CML Study IV — the rate of response with the 400-mg dose was lower than that with the 800-mg dose early in the studies; however, later in the studies, the responses were equivalent to or even better than those for the 800-mg dose. However, in our study, it is not expected that even a higher dose of imatinib would have reduced the number of progressions to the extent that was seen with nilotinib. The 800-mg dose of imatinib has not been shown to have a progression advantage over the 400-mg dose in any study, despite improved early responses.

Indeed, both the TOPS and German CML IV studies show similar rates of progression-free survival and event-free survival with the 400-mg and 800-mg doses of imatinib. Our findings regarding nilotinib differ from results of these studies of imatinib in several important respects. First, nilotinib is a more potent and selective BCR-ABL inhibitor than imatinib. Second, within the first year of therapy, the number of progression events was significantly lower in both nilotinib groups than in the imatinib group, a phenomenon that has not been observed for the 800-mg dose of imatinib. Finally, the overall rates of major molecular response in our study suggest that no plateau of response exists for patients receiving nilotinib. The difference in response between nilotinib and imatinib has increased over time, as compared with 12-month data. These data are further supported by reports from two ongoing trials of nilotinib in patients with newly diagnosed, chronic-phase CML: the phase 2 trial (NCT00481052) conducted by the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) with 15 months of follow-up and the M.D.

Anderson Cancer Center (MDACC) trial (NCT00129740) with 21 months of follow-up. In both of these trials, patients receiving nilotinib had high and rapidly achieved rates of cytogenetic and molecular responses, and only one patient in each study had disease progression while receiving nilotinib (both within the first year of therapy). Possible explanations for the differences in progression that were observed between nilotinib and imatinib are nilotinib's increased potency for unmutated BCR-ABL and activity against imatinib-resistant BCR-ABL mutations. Also, nilotinib does not require transport into cells by human organic cation transporter 1 (hOCT1), unlike imatinib. Therefore, the action of nilotinib is not impaired in patients with intrinsically low hOCT1 activity. Thus, nilotinib may inhibit leukemia that would progress with imatinib because of the emergence of clones bearing mutations associated with imatinib resistance.

The IRIS trial established that a complete cytogenetic response and a major molecular response are critical therapeutic milestones associated with good long-term outcomes. The strong clinical data supporting this notion are embodied by the adoption of these milestones in the definitions of optimal response to imatinib recently put forth by the European LeukemiaNet. In our study, nilotinib led to significantly higher rates of both major molecular response and complete cytogenetic response than did imatinib.

These responses were associated with a significantly lower rate of disease progression. Nilotinib at both doses was also associated with fewer suboptimal responses or treatment failures than imatinib. The 300-mg dose of nilotinib had the lowest rates of discontinuation because of adverse events or laboratory abnormalities among the three study groups. Furthermore, no patient had a QTcF interval of more than 500 msec while receiving either dose of nilotinib, and cardiac events were consistent across all study groups.

Taken together, these data suggest that second-generation agents that target BCR-ABL, like nilotinib, may become a new standard of care for patients with newly diagnosed, chronic-phase CML. Additional follow-up will provide information about the potential long-term benefits or disadvantages of nilotinib therapy. The CML treatment landscape is evolving rapidly. Two ongoing phase 3 studies of two multitargeted, dual BCR-ABL and Src-family kinase inhibitors, dasatinib (NCT00481247) and bosutinib (NCT00574873), may provide further treatment options. It is clear that nilotinib is more effective than imatinib. Further follow-up will provide information on the durability of responses, the development of treatment resistance, and the side-effect profile of nilotinib in the front-line setting.

Further studies will be necessary to evaluate cross-resistance mechanisms, sequencing of treatment options, and combinations of agents. References • 1 Druker BJ, Guilhot F, O'Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006;355:2408-2417 • 2 Hughes TP, Kaeda J, Branford S, et al. Tune Sweeper 3 07 Keygen Generator here. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 2003;349:1423-1432 • 3 O'Brien SG, Guilhot F, Larson RA, 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 • 4 Deininger M, O'Brien SG, Guilhot F, et al. International randomized study of interferon vs STI571 (IRIS) 8-year follow up: sustained survival and low risk for progression or events in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib. Blood 2009;114:Suppl:462-462 • 5 O'Brien SG, Guilhot F, Goldman JM, et al. International randomized study of interferon versus STI571 (IRIS) 7-year follow-up: sustained survival, low rate of transformation and increased rate of major molecular response (MMR) in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib (IM). Blood 2008;112:Suppl:76-76 • 6 Cortes J, Talpaz M, O'Brien S, et al. Molecular responses in patients with chronic myelogenous leukemia in chronic phase treated with imatinib mesylate.

Clin Cancer Res 20-3432 • 7 Hochhaus A, O'Brien SG, Guilhot F, et al. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia 20-1061 • 8 Weisberg E, Manley PW, Breitenstein W, et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 2005;7:129-141 • 9 Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-655 • 10 Sokal JE, Cox EB, Baccarani M, et al.

Prognostic discrimination in “good-risk” chronic granulocytic leukemia. Blood 1984;63:789-799 • 11 Baccarani M, Saglio G, Goldman J, et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2006;108:1809-1820 • 12 Hughes T, Deininger M, Hochhaus A, et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood 2006;108:28-37 • 13 Branford S, Fletcher L, Cross NC, et al. Desirable performance characteristics for BCR-ABL measurement on an international reporting scale to allow consistent interpretation of individual patient response and comparison of response rates between clinical trials.

Blood 2008;112:3330-3338 • 14 Branford S, Cross NC, Hochhaus A, et al. Rationale for the recommendations for harmonizing current methodology for detecting BCR-ABL transcripts in patients with chronic myeloid leukaemia. Leukemia 20-1930 • 15 Muller MC, Erben P, Saglio G, et al. Harmonization of BCR-ABL mRNA quantification using a uniform multifunctional control plasmid in 37 international laboratories. Leukemia 2008;22:96-102 • 16 Muller MC, Cross NC, Erben P, et al. Harmonization of molecular monitoring of CML therapy in Europe.

Leukemia 20-1963 • 17 Cortes JE, Baccarani M, Guilhot F, 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 .

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