Expanding Nilotinib Access in Clinical Trials (ENACT)§

An open-label, multicenter study of oral nilotinib in adult patients with imatinib-resistant or imatinib-intolerant philadelphia chromosome-positive chronic myeloid leukemia in the chronic phase


  • Presented in part at the 2009 European Hematology Association Annual Congress, Berlin, Germany, June 4–7, 2009, and at the 2009 American Society of Hematology Annual Meeting, New Orleans, LA, USA, December 5–8, 2009.

  • This trial is registered at www.clinicaltrials.gov as NCT0030216.

  • §

    We thank Analysis Group, Inc., Boston, Massachusetts for conducting and assisting with statistical analyses; Dr. Coralie Belanger, Novartis Pharma France for her assistance in retrospectively collecting the molecular data from the French dataset; the French molecular biologists of the Groupe des Biologistes Moleculaires des Hémopathies Malignes (Hematopoietic Malignancies Molecular Biologists Group) for their kind help; and Michelle Boehm, PhD, Erinn Goldman, PhD, and Michael Mandola, PhD for medical editorial assistance with the manuscript.

  • See related articles:

    Nilotinib versus imatinib

    Measuring response to BCR-ABL inhibitors in chronic myeloid leukemia



Nilotinib is a selective, potent BCR-ABL inhibitor. Previous studies demonstrated the efficacy and safety of nilotinib in Philadelphia chromosome-positive chronic myeloid leukemia patients in chronic phase (CML-CP) or accelerated phase who failed prior imatinib.


This expanded access trial further characterized the safety of nilotinib 400 mg twice daily in patients with CML-CP (N = 1422).


In this large, heavily pretreated population, nilotinib demonstrated significant efficacy, with complete hematologic response and complete cytogenetic response achieved in 43% and 34% of patients, respectively. Responses were rapid, mostly occurring within 6 months, and were higher in patients with suboptimal response to imatinib, with 75% and 50% achieving major cytogenetic response and complete cytogenetic response, respectively. At 18 months, the progression-free survival rate was 80%. Most patients achieved planned dosing of 400 mg twice daily and maintained the dose >12 months. Nonhematologic adverse events (AEs) were mostly mild to moderate and included rash (28%), headache (25%), and nausea (17%). Grade 3 or 4 thrombocytopenia (22%), neutropenia (14%), and anemia (3%) were low and managed by dose reduction or brief interruption. Grade 3 or 4 elevations in serum bilirubin and lipase occurred in 4% and 7% of patients, respectively. The incidence of newly occurring AEs decreased over time. Of patients who experienced a dose reduction because of AEs and attempted a re-escalation, 87% successfully achieved re-escalation to the full dose.


This large study confirms that nilotinib was well tolerated and that grade 3 or 4 AEs occurred infrequently and were manageable through transient dose interruptions. Cancer 2012;. © 2011 American Cancer Society.

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by the Philadelphia chromosome (Ph), which is formed by a reciprocal translocation1 involving chromosomes 9 and 22 and results in an oncogenic fusion gene encoding the BCR-ABL protein, having a constitutively active tyrosine kinase domain.2 Imatinib mesylate (Glivec/Gleevec; Novartis Pharmaceuticals Corporation, East Hanover, NJ) is a BCR-ABL inhibitor that was established as the standard of care for CML after results from the pivotal phase 3 International Randomized Study of Interferon and STI571 (IRIS) trial showed substantially better efficacy and safety for the patients in the imatinib treatment arm.3

Nilotinib was rationally designed to be a more potent and selective adenosine triphosphate-competitive inhibitor of BCR-ABL than imatinib, while maintaining a high level of activity against imatinib-resistant mutant forms of the enzyme.4, 5 Initial clinical trials demonstrated a favorable safety profile for nilotinib and confirmed the efficacy observed in preclinical animal models of leukemic disease.6-8

In a pivotal phase 1-2 trial in patients with imatinib-resistant or imatinib-intolerant CML in chronic phase (CML-CP) and CML in accelerated phase (CML-AP), nilotinib produced rapid and durable hematologic and cytogenetic response rates, with a manageable safety profile.9 In 321 patients with CML-CP, the rate of major cytogenetic response was 59%, with 44% of patients achieving complete cytogenetic response at 24 months.9 Most responders achieved their response rapidly, within 3 months of starting nilotinib treatment. Nilotinib was generally well tolerated, with infrequent occurrence of grade 3 or 4 nonhematologic and hematologic adverse events (AEs). On the basis of these data, nilotinib has gained approval in patients with imatinib-resistant or imatinib-intolerant Ph+ CML-CP and CML-AP in >50 countries, including the United States and the countries of the European Union. Nilotinib has also gained regulatory approval in the United States, the European Union, Japan, and other countries for the treatment of patients with newly diagnosed CML-CP.

The Expanding Nilotinib Access in Clinical Trials (ENACT) multinational trial is the largest safety trial of any tyrosine kinase inhibitor in CML to date and evaluated the safety profile of nilotinib in patients with imatinib-resistant or imatinib-intolerant Ph+ CML in all phases. The ENACT study was initiated to provide patients with Ph+ CML who failed prior imatinib with access to nilotinib before regulatory approval. It was anticipated that the size of this study, as well as the inclusion of patients heavily pretreated with other therapeutic regimens, would provide data that would more closely reflect patients observed in everyday clinical practice, which would provide physicians with guidance on how to manage CML patients treated with nilotinib. Although testing efficacy was not an objective of this study, guidelines for minimal efficacy assessment were included in the protocol, and data on investigators' assessment of response were collected. The results presented a detailed safety analysis for only the CML-CP patient cohort enrolled between January 2006 and June 2007 and up to the data cutoff date of June 2, 2008.


Study Design and Patient Eligibility

This international multicenter, open-label, nonrandomized expanded access trial, conducted at 310 centers worldwide, enrolled patients between January 2006 and June 2007. Written informed consent was obtained before any study procedures were performed. The study and amendments were reviewed by the ethics committees and review boards for each participating center. The study was conducted according to the ethical principles of the Declaration of Helsinki.

Male or female patients at least 18 years of age were eligible for entry if they had imatinib-resistant or imatinib-intolerant Ph+ CML-CP, CML-AP, or CML in blast crisis. Chronic phase was defined as <15% blasts and <30% of blasts plus promyelocytes in peripheral blood and bone marrow, at least 50 × 109/L (50,000/mm3) platelets, and no evidence of extramedullary leukemic involvement, excluding liver and spleen.

Inclusion criteria required patients to have World Health Organization Performance Status of ≤2, serum electrolytes within normal limits, and adequate hepatic, renal, and pancreatic function. Patients with concurrent severe and/or uncontrolled medical conditions, abnormal cardiac function, clinically significant heart disease, and cytopathologically confirmed central nervous system infiltration were excluded from the trial. Any prolongation of the QT interval, as calculated using the QTcF formula, must have been <450 milliseconds at baseline for a patient to be eligible for the study.

Imatinib resistance in CP was defined as any of the following during imatinib therapy: failure to achieve a complete hematologic response (CHR) after 3 months of imatinib therapy; failure to achieve at least a minimal cytogenetic response (Ph+ ≤95%) at 6 months or major cytogenetic response after 12 months (Ph+ ≤35%); or loss of CHR, minimal cytogenetic response, major cytogenetic response, or increase in bone marrow Ph+ metaphase cells by ≥30% on 2 separate occasions. In addition, patients with clonal evolution who did not meet any of the other criteria outlined above were eligible for enrollment. To be eligible for the study, patients must have received prior imatinib therapy ≥600 mg/d for a minimum of 3 months, unless they met the following 4 criteria: 1) they met the criteria outlined below for the definition of imatinib intolerance; 2) there was evidence of disease progression (a doubling of white blood cells, basophils, blasts, or platelets) documented on 2 separate occasions at least 1 week apart; 3) there was presence of grade 3 or 4 disease-related symptoms (bone pain, fever, weight loss, anorexia); or 4) mutations in the BCR-ABL kinase domain (at amino acids L248, G250, Q252, Y253, E255, T315, F317, or H396) were detected.

Patients were defined as imatinib intolerant if they had discontinued imatinib therapy because of grade 3 or 4 AEs that persisted despite optimal supportive care measures, or experienced grade 2 AEs related to imatinib therapy that persisted for >1 month or that recurred >3×, whether the dose was reduced or discontinued.

Treatment With Nilotinib

All patients received oral nilotinib at a dose of 400 mg twice daily. This dose was selected based on the safety, efficacy, and pharmacokinetic profile in the phase 1-2 registration study. Patients were instructed to fast for at least 2 hours before and 1 hour after taking nilotinib. Dose escalation of nilotinib >400 mg twice daily was not permitted. Dose reduction to 400 mg once daily or interruption was allowed for the management of toxicity, with re-escalation to 400 mg twice daily permitted after resolution of AEs to grade ≤1 severity at the discretion of the investigator. For all other toxicities considered by the investigator to be unlikely to develop into serious or life-threatening events, treatment was continued at the same dose without reduction or interruption. Permanent discontinuation of nilotinib was indicated in the event of recurrent unacceptable toxicity or disease progression, or if the patient was no longer benefiting from treatment. In addition, recurrent grade 2 or higher biochemical abnormalities, such as hyperbilirubinemia, also mandated permanent discontinuation, even if the AE was asymptomatic. At the time of discontinuation (before or at the end of this 1-year study), patients could enter another nilotinib study if nilotinib was not commercially available.

Cancer therapies other than nilotinib were prohibited while patients were enrolled in the study, with the exception of hydroxyurea and anagrelide (to control elevated blast and/or platelet counts). Concomitant medications and therapies deemed necessary for the supportive care and safety of the patient were allowed, including colony-stimulating growth factors (granulocyte colony stimulating factor [CSF] and granulocyte macrophage CSF) for grade 3 neutropenia and recombinant erythropoietin for anemia. For safety, medications known to prolong the QT interval or inhibit cytochrome P450 isoenzyme CYP3A4 were contraindicated unless deemed to be absolutely necessary. Use of coumarin derivatives was prohibited.

Patient Evaluation

Baseline assessments were performed within 4 weeks before the first administration of nilotinib. Mandatory safety evaluations included physical examination, weight, vital signs, performance status, blood and serum chemistries, urinalysis, chest x-ray, and cardiac assessments, including multiple gated acquisition scan or echocardiogram, and 12-lead electrocardiogram. Those with any abnormality in their chest x-ray were monitored by repeated x-rays as clinically indicated.

AEs were evaluated throughout the study and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. Unlike other clinical trials, in this expanded access study, laboratory tests were performed as scheduled in the protocol, but the results were not recorded. Only laboratory abnormalities with grading information were recorded as AEs. To better characterize the frequency of these events, the laboratory abnormality-related AEs were grouped by selected preferred terms. The safety population consisted of all patients who received at least 1 dose of nilotinib and had at least 1 postbaseline safety assessment.

Although testing efficacy was not an objective of this study, the investigators' assessment of response was recommended. Efficacy assessments of hematologic and cytogenetic response and disease progression, performed every 6 months at a minimum, included hematologic analysis, bone marrow cytogenetics, and evaluation of extramedullary disease and cancer-related symptoms to ensure that nilotinib was being provided to patients who were responding and that patients who progressed could discontinue therapy. Hematologic responses were determined by assessment of complete blood counts and categorized by CHR and marrow response/no evidence of leukemia. Patients with progressive disease and without CHR or marrow response were considered nonresponders. All patients who achieved a CHR or marrow response were assessed for a cytogenetic response based on the proportion of Ph+ metaphases from at least 20 metaphase cells from bone marrow aspirates or biopsies. In cases where the standard metaphase cytogenetics were either unsuccessful or unavailable, fluorescent in situ hybridization performed on peripheral blood or bone marrow was used. Cytogenetic response was defined according to the percentage of Ph+ cells in metaphase: complete cytogenetic response (Ph+ 0%), partial cytogenetic response (Ph+ range, 1%-35%), minor (Ph+ range, 36%-65%), and minimal (Ph+ range, 66%-95%). Major cytogenetic response was defined as the number of complete cytogenetic responses plus the number of partial cytogenetic responses. Patients with minor or minimal cytogenetic responses were considered neither responders nor nonresponders. Patients who discontinued nilotinib before either hematologic or cytogenetic response assessment at a given time point were considered to be nonresponders for that time point. In centers reporting molecular response data, quantitative reverse transcriptase-polymerase chain reaction (Q-RT-PCR) assessment of BCR-ABL was performed every 3 months according to International Standardization (IS) methods. Major molecular response was defined as BCR-ABL/ABL ratio ≤0.1%IS. Major molecular response and BCR-ABL/ABL ratios ≤0.003%IS were reported.

Statistical Analysis

The data were summarized with respect to demographic and baseline characteristics, efficacy evaluation, and safety observations and measurements. Continuous variables were summarized by mean, standard deviation, median, minimum, maximum (25% and 75% quartiles, as appropriate), and number of patients without missing data. Categorical variables were summarized by frequencies and percentages and by disease stage classifications. For efficacy evaluation, the number and percentage of responders are presented as well as the associated 95% confidence interval (CI). The efficacy analysis was conducted in the intent to treat population based on patients who had at least 1 postbaseline assessment on or before month 6 assessment, or who discontinued before response assessment. The safety analysis includes all patients who received at least 1 dose of study medication and had at least 1 postbaseline safety assessment.


Patient Characteristics and Disposition

The ENACT CML-CP patient cohort consisted of 1422 patients (696 males, 726 females) enrolled between January 2006 and the data cutoff of June 2, 2008 at 310 centers worldwide. The median age of patients with CML-CP was 53 years (range, 17-85 years). The majority of patients were imatinib resistant (59.6%) (Table 1). The median duration of disease since diagnosis was 55.1 months (range, 2-328 months). Patients were heavily pretreated. Greater than 70% of patients had been treated with ≥600 mg/d imatinib at study entry. Other than imatinib, the most common prior antineoplastic therapies were hydroxycarbamide (85.7%), interferons (45.4%), cytarabine (24.3%), dasatinib (15.3%), and busulfan (7.6%). Furthermore, 77 CML-CP patients (5.4%) had received prior hematopoietic stem cell transplantation. This was also a very resistant patient population, with <⅓ of patients having achieved CHR on prior therapy. Up to the data cutoff date of June 2, 2008, 60.3% of patients completed the study on nilotinib. The most common reasons for discontinuation of nilotinib therapy were drug-related toxicity (14.3%) and an unsatisfactory therapeutic effect (15.6%).

Table 1. Patient Characteristics and Disposition
Characteristic/DispositionCML-CP, N = 1422
  • Abbreviations: CML, chronic myeloid leukemia; CP, chronic phase.

  • a

    Patients who are both imatinib-resistant and imatinib-intolerant are included under imatinib resistant.

  • b

    Eighteen percent of patients who discontinued due to adverse events did so due to hematologic adverse events.

  • c

    Death includes only those patients for whom death was reported as the primary reason for discontinuation of therapy.

  • d

    Includes patients who no longer require study drug, administrative problems, abnormal test procedure results, and protocol deviation.

Patient characteristics 
 Resistant patients,a No. (%)848 (59.6)
 Intolerant patients, No. (%)573 (40.3)
 Median age, y [range]53 [17-85]
 Median duration of CML, mo [range]55.1 [2.0-327.7]
  <6 months, No. (%)33 (2.3)
  ≥6 months, <1 year, No. (%)91 (6.4)
  ≥1 year, <2 years, No. (%)217 (15.3)
  ≥2 years, <5 years, No. (%)407 (28.6)
  ≥5 years, No. (%)674 (47.4)
 Prior highest imatinib dose, No. (%) 
  <600 mg406 (28.6)
  ≥600 mg to <800 mg560 (39.4)
  ≥800 mg449 (31.6)
  Missing7 (0.5)
Patient disposition 
 Completed the study, No. (%)857 (60.3)
 Discontinued treatment, No. (%)565 (39.7)
  Unsatisfactory therapeutic effect222 (15.6)
  Adverse event(s)b204 (14.3)
  Deathc15 (1.1)
  Consent withdrawal46 (3.2)
  Abnormal laboratory value(s)26 (1.8)
  Lost to follow-up18 (1.3)
  Otherd34 (2.3)

Nilotinib Treatment

The median duration of exposure of patients with CML-CP to nilotinib was 266 days (range, 1-807 days), with 36.4% of patients receiving nilotinib for ≥12 months. The median nilotinib dose delivered was 782.5 mg/d (range, 104.3-937.9 mg/d), very close to the planned dose of 800 mg/d. The maximum dose of nilotinib in the aforementioned range is because of a dose escalation of 4 of 1422 patients (<1%) who were treated with at least 1 daily dose of nilotinib 600 mg twice daily in error. These 4 patients have been included in the analysis. The median dose intensity (total amount of drug received divided by the number of days on treatment, including days of zero dose) of nilotinib did not change over time on study. Over progressive 3-month periods from initiation of therapy to >12 months of therapy, nilotinib dose intensity was consistently high, between 794 and 800 mg/d (Fig. 1).

Figure 1.

Nilotinib median dose intensity is shown in patients on treatment at 3-month intervals from study initiation to study completion.

Dose reductions and interruptions lasting >5 days occurred in 5.1% and 41.4% of patients, respectively, and were most commonly because of AEs. The total duration of dose interruptions was quite short, with a median of only 11 days (range, 1-188 days). Re-escalation of nilotinib to the full planned dose after dose reduction was not mandated in the protocol, but was permitted at the discretion of the investigator. Of 444 patients who received a dose reduction of nilotinib to 400 mg once daily and attempted re-escalation to 400 mg twice daily, 385 (87%) successfully re-escalated the dose back to 400 mg twice daily for at least 28 days without a dose interruption of >5 days. The ability to successfully re-escalate nilotinib did not differ across age groups (<60, ≥60, ≥70 years).

Safety and Tolerability

Nilotinib was well tolerated, with only 14.3% of all patients having to discontinue treatment as a result of AEs (with some of these as protocol-mandated discontinuations because of second episodes of asymptomatic biochemical laboratory abnormalities) after a median follow-up of 266 days (range, 1-807 days). The most frequently reported nonhematologic AEs (any grade) suspected to be drug-related were hyperbilirubinemia (25.2%), rash (24.5%), headache (16.4%), and fatigue (14.1%), and these were mostly of mild to moderate (grade 1 or 2) intensity (Table 2). The most common grade 3 or 4 nonhematologic AE was lipase elevation (6.5%). In addition to hyperbilirubinemia and elevated lipase, increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were reported in 13.6% and 8.5% of patients, respectively, although the incidence of severe (grade 3 or 4) aminotransferase elevation was low (2.1% and 0.8%, respectively).

Table 2. Most Commonly Occurring (≥5%) AEs Suspected of Being Nilotinib Related
AECML-CP, All Grades, N = 1422, No. (%)CTC Grade 3 or 4, N = 1422, No. (%)
  • Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CML, chronic myeloid leukemia; CP, chronic phase; CTC, Common Terminology Criteria.

  • a

    These most commonly occurring AEs were identified following grouping of AEs by preferred term.

 Rash349 (24.5)38 (2.7)
 Headache233 (16.4)27 (1.9)
 Fatigue200 (14.1)23 (1.6)
 Pruritus191 (13.4)11 (0.8)
 Nausea165 (11.6)12 (0.8)
 Myalgia158 (11.1)13 (0.9)
 Vomiting105 (7.4)11 (0.8)
 Diarrhea88 (6.2)8 (0.6)
 Muscle spasms84 (5.9)3 (0.2)
 Constipation73 (5.1)1 (0.1)
 Anorexia72 (5.1)5 (0.4)
 Abdominal pain (upper)72 (5.1)6 (0.4)
 Arthralgia71 (5.0)5 (0.4)
 Thrombocytopenia408 (28.7)308 (21.7)
 Neutropenia245 (17.2)204 (14.3)
 Anemia160 (11.3)46 (3.2)
 Leukopenia85 (6.0)35 (2.5)
 Hyperbilirubinemia359 (25.2)59 (4.1)
 ALT elevation193 (13.6)30 (2.1)
 Lipase increased187 (13.2)93 (6.5)
 AST elevation121 (8.5)12 (0.8)
 Hyperamylasemia81 (5.7)12 (0.8)
 Hypophosphatemia75 (5.3)12 (0.8)

First occurrence of most frequent biochemical laboratory AEs (lipase elevation, hyperbilirubinemia, ALT/AST elevation) were within the first 2 months of therapy and were transient, lasting a median duration of 1 to 2 weeks (Table 3). These abnormalities were typically asymptomatic and managed with protocol-mandated dose reductions or brief dose interruptions when needed. Concomitant medications were infrequently used to treat laboratory abnormalities.

Table 3. Timing, Duration, and Management of Selected Grade 3 or 4 Adverse Events Suspected of Being Nilotinib Related
Adverse EventNumber of CTC Grade 3 or 4 AEs, No. (%)Median Elapsed Time Since Nilotinib Start,a d [range]Median Duration of AE,a d [range]Nilotinib dose reduction or interruption, n/N (%)Nilotinib permanently discontinued, n/N (%)Concomitant Medications Used to Manage the AE, No. (%)
  • Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CTC, Common Terminology Criteria.

  • a

    For each AE, only the first occurrence per patient is analyzed.

Thrombocytopenia308 (22)42 [0-336]16 [1-141]254/1422 (18)25/1422 (2)19 (6)
Neutropenia204 (14)49 [0-450]14 [2-100]157/1422 (11)15/1422 (1)31 (15)
Elevated lipase93 (7)7 [0-427]9 [1-107]68/1422 (5)3/1422 (< 1)1 (1)
Hyperbilirubinemia59 (4)18 [1-427]8 [2-240]29/1422 (2)2/1422 (< 1)8 (14)
Elevated ALT30 (2)19 [6-280]10 [1-84]18/1422 (1)3/1422 (< 1)3 (10)
Elevated AST12 (1)45 [2-135]14 [5-84]7/1422 (< 1)1/1422 (< 1)1 (8)
Elevated amylase12 (1)14 [5-400]7 [2-13]11/1422 (< 1)0/1422 (0)0 (0)
Hyperglycemia11 (1)7 [0-63]21 [7-70]3/1422 (< 1)1/1422 (< 1)8 (73)

The incidence of all grade 3 or 4 AEs decreased over time. The percentage of patients with at least 1 AE decreased from the first 90 days of treatment (35%) to the second 90 days of treatment (19%). Of the 19% of patients with an AE in the second 90 days, only 13% had a newly occurring AE.

Thrombocytopenia was the most commonly occurring hematologic AE, with grade 3 or 4 events occurring in 21.7% of patients. Neutropenia and anemia were experienced by 17.2% and 11.3% of patients with CML-CP, respectively, at all grades, and 14.3% and 3.2%, respectively, at grade 3 or 4 (Table 2). Myelosuppression was generally manageable with dose reductions or interruptions, and was associated with discontinuation in only a small proportion of patients (6.4% discontinued because of thrombocytopenia; 2.7% because of neutropenia). Platelet transfusions and growth factor use occurred in 16% and 15% of patients experiencing thrombocytopenia and neutropenia events, respectively.

The most commonly observed drug-related grade 3 or 4 hepatobiliary disorder was hyperbilirubinemia in 59 patients (4.1%). However, hepatobiliary disorders overall only resulted in 8 treatment discontinuations. Similarly, despite the elevation in serum lipase levels, severe clinical pancreatitis was only observed in 10 patients (0.7%). Only 4 of these patients discontinued nilotinib because of the pancreatitis. Eleven patients with CML-CP (0.1%) had grade 3 or 4 hyperglycemia suspected of being study-drug related, and only 1 patient (0.1%) discontinued because of hyperglycemia.

Extensive cardiac monitoring was performed at baseline and throughout the study. Although absolute QTc interval of >480 milliseconds occurred in 30 patients (2.1%), an absolute QTc interval of >500 milliseconds was rare, occurring in only 4 patients (0.3%). QTc increases from baseline of >60 milliseconds were also rare, occurring in only 1.3% of patients. No patients with absolute QTc prolongation >500 milliseconds or QTc prolongation >60 milliseconds above baseline values reported any later cardiac serious AEs. The number of QTc prolongation events decreased over time (conditional probability of .0141 in first 3 months of therapy vs .0068 in months 3-6), and there were no incidences of torsades de pointes.

In total, 19 of 1422 (1.3%) patients with CML-CP died either during the study or within 28 days of discontinuing nilotinib. Very few deaths could be linked unequivocally to nilotinib treatment. Three deaths were classified by the sponsor as sudden deaths and occurred on study or within 28 days after discontinuation of nilotinib: 1 death after triple-bypass surgery, not suspected to be study drug related; 1 death of unknown cause, suspected to be study drug related; and 1 death possibly related to study drug and/or moxifloxacin. All had prior cardiac history (but not excluding them from study.) There were no cardiac failures. There were 3 cardiac-related deaths, none of which were suspected to be related to the study drug. The safety profile of nilotinib was consistent across age groups (<60, ≥60, ≥70 years).


Best hematologic and cytogenetic responses (investigator assessment) to nilotinib for the overall study were similar to prior reports.9 All 1422 patients had at least 1 postbaseline cytogenetic assessment during the study, or discontinued before response assessment. A hematologic response was achieved in 63% of patients. Overall, 43% and 20% of patients achieved CHR or a marrow response, respectively. With regard to cytogenetic response, 45% of patients achieved major cytogenetic response, with the majority of responses (approximately 75%) being complete cytogenetic response (34% overall). Responses to nilotinib were higher in the subset of patients with prior suboptimal response to imatinib (definition retrospectively applied to patients based on 6-month and 12-month cytogenetic response data), with 75% and 50% achieving major cytogenetic response and complete cytogenetic response, respectively. Moreover, the efficacy of nilotinib was consistent across age groups (<60, ≥60, ≥70 years).

Complete efficacy data collection was performed in the subset of ENACT patients (n = 168) from France. The number of French patients achieving major cytogenetic response (54%) and complete cytogenetic response (45%) was higher than in the overall patient population (45% and 34%, respectively). French patients were also monitored for molecular response by Q-RT-PCR at baseline and every 3 months thereafter. As shown in Figure 2, 37% of the French subset of patients achieved major molecular response by 12 months, with nearly 20% of all French patients achieving a molecular response of BCR-ABL/ABL ≤0.003%IS.

Figure 2.

Rate of molecular response to nilotinib in French chronic myeloid leukemia patients from ENACT was captured every 3 months from study initiation to study completion. MMR, major molecular response.

It is important to note that all response monitoring was conducted via investigator assessment of both hematologic and cytogenetic results; no central laboratories were used for these assessments. Although complete blood counts were frequently performed, assessment of hematologic response was only reported on case report forms at the time of bone marrow assessment every 6 months.

In the overall cohort of ENACT patients, the time to progression (progression was as assessed by investigator) or death for the at-risk population is shown in Figure 3. At 18 months, the estimated rate of progression-free survival (defined as progression to AP, blast crisis, or death because of any cause) was 80% (95% CI, 0.77-0.83) for the at-risk population.

Figure 3.

Progression-free survival, defined as survival without progression to accelerated phase, blast crisis, or death from any cause, was analyzed in all patients with chronic myeloid leukemia in chronic phase from ENACT.


The ENACT international, multicenter, expanded access study further evaluated the safety of nilotinib in a large patient population that more closely resembles clinical practice. The trial also provided patients with imatinib-resistant or imatinib-intolerant Ph+ CML in all phases expanded access to nilotinib, outside of a registration study. Before regulatory approval of nilotinib, these patients had limited therapeutic options. The data from ENACT presented in this report extend the findings of the earlier, pivotal phase 2 study, affirming the safety of nilotinib in patients with Ph+ CML-CP who have been heavily treated with prior antineoplastic therapies.

As in the phase 2 registration trial, nilotinib was well tolerated.9 Patients achieved a median dose intensity of 782.5 mg/d, very close to the planned dose for the trial (800 mg/d), despite dose escalation not being permitted. The majority of AEs were mild to moderate in severity and could be adequately managed by dose modification or supportive treatment. Cytopenias were the most frequently reported grade 3 or 4 AEs; they were managed effectively by dose reduction or interruption and seldom caused nilotinib discontinuation (<8% of patients). Most AEs first occurred within the first 2 months of therapy and were short, lasting a median duration of 1 to 3 weeks. The vast majority of patients who attempted dose re-escalation after reductions for AEs or other reasons were able to do so successfully.

A consistent spectrum of AEs was observed in this trial compared with the phase 1-2 registration trial of nilotinib, and no new safety signals were observed compared with findings from the nilotinib registration program.9 Although 6.5% (93 of 1422) of patients experienced grade 3 or 4 elevations in lipase, only 10 patients (0.7%) experienced pancreatitis, and only 4 patients (0.3%) discontinued because of the pancreatitis. Grade 3 or 4 hyperbilirubinemia occurred in 4.1% (59 of 1422) of patients, and only 2 patients (0.1%) discontinued the study for this reason. Thus, these effects were clinically manageable and usually resolved with continued therapy with or without dose reduction. Reports of edema or pleural effusion associated with nilotinib in this large cohort of patients were quite rare, with both occurring in 0.1% of patients. This is significant because a chest x-ray was performed in all patients at baseline. Those with any clinically relevant chest x-ray abnormality (27 of 1422 patients) or pleural effusion (13 of 27 patients) at baseline were monitored by repeated x-rays as clinically indicated. Twelve of the 13 patients with pleural effusions at baseline received dasatinib before the start of the study. None of these 12 patients had reported any AE related to pleural effusion while receiving nilotinib. Only 1 grade 3 or 4 pleural effusion was observed on nilotinib therapy. Overall, the safety profile of this large cohort was consistent with that observed in the nilotinib phase 1-2 registration trial that included 321 patients with CML-CP.

Safety assessments in the nilotinib phase 1-2 registration trial showed that significant prolongation of QTc intervals rarely occurred.10 Nevertheless, information on the incidence of these events in a similar patient population is largely unknown because of the lack of available age-matched and disease-matched controls. This study confirms that the incidence of significantly prolonged QTc intervals (>500 milliseconds) was rare and occurred in only 4 of 1422 patients (0.3%). Furthermore, no patients with absolute QTc prolongation of >500 milliseconds or increase from baseline of >60 milliseconds reported any later cardiac serious AEs. This large study also confirms the significant hematologic and cytogenetic responses to nilotinib observed in the registration study in patients with Ph+ CML-CP.9

In summary, the results of this phase 3 trial in a large patient population provide important supportive safety data and confirm earlier published findings of nilotinib in pivotal phase 1-2 studies. Safety and efficacy results were consistent across age groups, including in very elderly patients (≥70 years). Because clinical trial populations tend to have much lower median ages than would typically be seen in a real clinical setting, establishing the safety and efficacy of nilotinib in older patients with such a large international dataset was an important finding. Overall, these data support the excellent toxicity and efficacy profile for selective BCR-ABL inhibition with nilotinib at 400 mg twice daily in patients with imatinib-resistant or imatinib-intolerant CML-CP.


This work was supported by research funding from Novartis Pharmaceuticals Corporation. Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals.


F.E.N. is a consultant for Novartis Pharma France and Bristol Myers Squibb France, has been provided a grant by Novartis Pharma for heading this study in France, and has lectured for Novartis Pharma, Bristol Myers Squibb, and Chemgenex Inc. A.N. has received speaker's honoraria and consultancy or advisory fees from Novartis. Z.-X.S. has no relevant financial disclosures. N.G. is a Novartis employee and shareholder. S.J. has no relevant financial disclosures. B.L.P. received research support from Novartis. C.D.S. has no relevant financial disclosures. M.Z. and T.S. are Novartis employees. P.l.C. has received speaker's honoraria from Novartis and Bristol Myers Squibb, and research funding from Novartis.