Nilotinib (Tasigna) is a BCR–ABL1 tyrosine kinase inhibitor approved for the treatment of patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (CML-CP) who are newly diagnosed or intolerant of or resistant to imatinib. The 48-month follow-up data for patients with CML-CP treated with nilotinib after imatinib resistance or intolerance on an international phase II study were analyzed. Overall, 59% of patients achieved major cytogenetic response; 45% achieved complete cytogenetic response while on study. The estimated rate of overall survival (OS) and progression-free survival (PFS) at 48 months was 78% and 57%, respectively. Deeper levels of molecular responses at 3 and 6 months were highly positively correlated with long-term outcomes, including PFS and OS at 48 months. Of the 321 patients initially enrolled in the study, 98 (31%) were treated for at least 48 months. Discontinuations were primarily due to disease progression (30%) or adverse events (21%). Nilotinib is safe and effective for long-term use in responding patients with CML-CP who are intolerant of or resistant to imatinib. Further significant improvements in therapy are required for patients who are resistant or intolerant to imatinib.
Chronic myeloid leukemia (CML) is a clonal myeloproliferative disease characterized by the clonal expansion of hematopoietic cells carrying the oncogenic BCR–ABL1 fusion gene. BCR–ABL1 is the gene product of the reciprocal translocation of the long arms of chromosomes 9 and 22, known as the Philadelphia chromosome (Ph).1, 2 Imatinib (Gleevec/Glivec; Novartis Pharmaceuticals, East Hanover, NJ, USA) is a BCR–ABL1 tyrosine kinase inhibitor (TKI) that has significantly improved the prognosis for patients with CML.3, 4 Approximately 25–30% of patients discontinue imatinib within 5 years because of unsatisfactory response, resistance or toxicity.5, 6
Nilotinib (Tasigna; Novartis Pharmaceuticals) is a second-generation TKI that was rationally developed to maintain activity against BCR–ABL1 mutations associated with resistance to imatinib.7 Compared with imatinib, nilotinib has increased potency and improved pharmacological properties. In a phase I dose-escalation study and in phase II studies, nilotinib treatment led to significant hematological and cytogenetic responses in imatinib-resistant patients in all phases of CML.8, 9, 10 After 24 months of patient follow-up, data from the open-label, multicenter phase II registration trial (CAMN107A2101; NCT00109707) demonstrated that nilotinib 400 mg twice daily was effective in imatinib-resistant or imatinib-intolerant patients with Ph+ CML in chronic phase (CML-CP)11 and accelerated phase,12 including patients with a wide range of ABL kinase domain mutations, and that nilotinib was associated with a 24-month rate of overall survival (OS) of 87% and 70%,11, 12 respectively. Data from the initial analysis of the 2101 trial contributed to the accelerated regulatory approval of nilotinib 400 mg twice daily in patients with Ph+ CML-CP and CML in accelerated phase with intolerance or resistance to prior therapy, including imatinib. The present analysis includes data on 321 patients with CML-CP with a minimum follow-up of 48 months.
Materials and methods
Patients, study design and treatments
Study criteria for eligibility have been described in detail previously.11, 13 Adult patients with Ph+ CML-CP (age ⩾18 years) were eligible if they had normal renal, cardiac and hepatic function, a World Health Organization performance status ⩽2, and resistance or intolerance to imatinib. The definitions of resistance and intolerance to imatinib were as previously described.11, 13
After completing 24 months of study treatment, patients were allowed to continue on the study drug by enrolling in the extension protocol until they had received nilotinib for ⩾5 years or had discontinued early from the study. Key efficacy and safety data were collected less frequently after 24 months of treatment. Efficacy data collected after 24 months included cytogenetic response, molecular response, progression to AP/blast phase and OS. Patients taken off nilotinib therapy were followed for survival (information on date and cause of death were collected). After 24 months, safety reporting included adverse events (AEs) if they were defined as serious AEs, AEs requiring dose adjustments or interruptions and AEs leading to permanent discontinuation of study drug. Hematological laboratory abnormalities were also reported. The present analysis is based on a data cutoff of when all patients received ⩾48 months of nilotinib treatment or had discontinued study therapy.
The primary endpoint of this open-label, multicenter, single-arm phase II study was to determine the rate of major cytogenetic response (MCyR) in patients intolerant of or resistant to imatinib, as previously described.11, 13 Of the secondary endpoints previously described, updated data on progression-free survival (PFS) and OS are presented. PFS was defined as the time from the start of nilotinib treatment to the earliest date of progression to AP/blast phase, discontinuation due to failure (as assessed by the investigator) or death from any cause during nilotinib therapy. OS was defined as the time from start of nilotinib to the date of death due to any cause and included all deaths occurring on treatment and during follow-up after discontinuation of study treatment.
Statistical analysis and ethics
All time-to-event analyses were presented as Kaplan–Meier plots. For patients without events, PFS time was censored at the data cutoff date for patients still on treatment or at the discontinuation date for patients who discontinued nilotinib for reasons other than progression or death. OS time was censored at the data cutoff date for patients still on treatment or at the date of last contact for patients who discontinued. This study was conducted in accordance with the Declaration of Helsinki. All patients gave written informed consent according to institutional guidelines.
Patient demographics and disposition
A total of 321 patients were enrolled and patient baseline demographics have been previously published.11, 13 Of the 321 patients, 226 (70%) were imatinib resistant and 95 (30%) were intolerant of prior imatinib; 78 patients (24.3%) had chromosomal abnormalities at baseline. The median age was 58 years (range, 21–85), and 98 patients (31%) were aged ⩾65 years. The median duration of CML before study entry was 58 months (range, 5–275), and patients received prior imatinib for a median of 32 months (range, <1–94 months). Approximately one-third (n=114 (36%)) of patients had complete hematological response (CHR) at baseline, and 232 (72%) had received a prior imatinib dose of ⩾600 mg/day. Other prior therapies included hydroxyurea (266 (83%)), interferon-α (187 (58%)) and cytarabine (78 (24%)).
At 48 months, 224 patients (70%) had discontinued the study, most commonly because of disease progression (n=96 (30%)) and AEs (n=66 (21%)) (Table 1). The median dose of nilotinib was close to the planned dose of 800 mg/day (789 mg/day; range, 151–1110 mg/day), and 62% of patients were receiving ⩾400 mg twice daily at the last available assessment. The median time on treatment (from start of treatment to discontinuation of treatment) with nilotinib 400 mg twice daily was 561 days (range, 1–1826 days) and median time on study (from start of treatment to last available date on treatment or during follow-up after discontinuation of treatment) was 1555 days. Overall, 135 (42%) patients were treated for ⩾24 months and 98 (31%) were treated for ⩾48 months.
Overall, 190 patients (59%) achieved MCyR by 24 months on study, with no additional patients achieving MCyR since the 24-month update.11 The majority of these patients who achieved MCyR also had complete cytogenetic response (CCyR), with 45% of patients achieving CCyR on study; five patients improved from partial cytogenetic response (PCyR) to CCyR since the 24-month analysis.11
At 48 months, the estimated rate of PFS was 57% (95% CI, 51–64%) (Figure 1). Of the 102 patients with PFS events, only 11 (3%) progressed to AP or blast phase. The remainder discontinued due to disease progression as assessed by the investigator (n=87) or died (n=4). Patients with a baseline CHR had significantly higher PFS rates than patients who were not in CHR at study entry (71% (95% CI, 61–81%) vs 49% (95% CI, 40–57%), respectively; P=0.001) (Figure 1).
Earlier response on treatment was related to PFS. Patients with a lower BCR–ABL1 transcript level at 3 and 6 months had higher PFS rates at 48 months. Among patients with BCR–ABL1 levels of ⩽1%, >1–10% and >10% at 3 months, the estimated rates of PFS at 48 months were 85%, 67% and 42%, respectively, (P=0.01 for ⩽1% vs >1–10%; P=0.03 for >1–10% vs >10%) (Figure 2a). Among patients with BCR–ABL1 levels of ⩽1%, >1–10% and >10% at 6 months, the estimated rates of PFS at 48 months were 86%, 58% and 39%, respectively, (P=0.001 for ⩽1% vs >1–10%; P=0.03 for >1–10% vs >10%) (Figure 2b). Similarly, patients with a CCyR at 12 months had higher PFS rates at 48 months than patients not in CCyR at 12 months; the estimated rate of PFS at 48 months was 89% in patients with CCyR at 12 months vs 56% in patients with no CCyR at 12 months (P<0.0001) (Figure 3).
The estimated rate of OS at 48 months was 78% (95% CI, 73–83%), with the median survival time not yet reached (Figure 4). Patients with a lower BCR–ABL1 transcript level at 3 and 6 months had higher rates of OS. Among patients with BCR–ABL1 levels of ⩽1%, >1–10% and >10% at 3 months, the estimated rates of OS at 48 months were 95%, 81% and 71%, respectively, (P=0.03 for ⩽1% vs >1–10%; P=0.05 for >1–10% vs >10%) (Figure 5a). Among patients with BCR–ABL1 levels of ⩽1%, >1–10% and >10% at 6 months, the estimated rates of OS at 48 months were 95%, 82% and 73%, respectively, (P=0.009 for ⩽1% vs >1–10%; P=0.107 for >1–10% vs >10%) (Figure 5b).
Safety and tolerability
Overall, minimal new hematological toxicity was observed with nilotinib since the 24-month analysis. Newly occurring or worsening grade 3/4 neutropenia and thrombocytopenia occurred in two patients (<1%) and one patient, respectively, between 24 and 48 months of follow-up.
The most frequent drug-related non-hematological AEs included rash (31%), pruritus (26%) and nausea (25%) (Table 2). No new grade 3/4 non-hematological AEs were observed between 24 and 48 months. Grade 3/4 drug-related non-hematological AEs occurred in <2% of patients and most commonly included diarrhea (1.9%), rash (1.9%), headache (1.6%) and arthralgia (1.6%). Pleural effusions of any grade were uncommon on study (1%), and no new pleural effusion events were reported after longer patient follow-up. It should be noted that after 24 months, non-hematological AEs were captured when a serious AE occurred, dose adjustment was made because of an AE or a patient permanently discontinued therapy because of an AE. Drug-related AEs led to discontinuation of study treatment in 53 patients (17%).
Between 24 and 48 months of follow-up, there were no new events of QT interval corrected for heart rate using Fridericia’s format (QTcF) prolongation >500 ms. In this period, three new cases of increased QTcF >60 ms from baseline were reported; no patient discontinued nilotinib therapy because of QTcF prolongation.
Overall, nine patients (2.8%) died during treatment or within 28 days of discontinuation; one death owing to lung cancer was newly reported between 24 and 48 months of follow-up. The causes of the other eight deaths have been previously reported;11 one was CML related.
After a minimum follow-up of 48 months, nilotinib continued to be effective and well tolerated in one-third of patients with CML-CP with imatinib resistance or intolerance. With estimated 48-month OS and PFS rates of 78% and 57%, respectively, second-line nilotinib was confirmed to be an effective long-term treatment option for some patients with CML-CP who are resistant to or intolerant of imatinib therapy. No new safety signals were observed, and few additional AEs occurred since the 24-month follow-up, with fewer than 1% of patients experiencing newly occurring or worsening grade 3/4 hematological laboratory abnormalities.
Approximately one-third of patients remained on study treatment with 48 months of follow-up. The majority of patients discontinued because of disease progression or AEs. These data are comparable to the discontinuation rates observed in other studies of TKIs in this patient population (for example, dasatinib14 and bosutinib15) Current European LeukemiaNet provisional recommendations for nilotinib and dasatinib treatment in patients with CML-CP who failed imatinib16 are based on limited follow-up from second-line studies of nilotinib13 and dasatinib17, 18 in patients with resistance or intolerance to imatinib. At 3 months, suboptimal response was defined as minor cytogenetic response (Ph+ 36–65%) and failure was defined as no cytogenetic response (Ph+ >95%). A recent analysis of 167 newly diagnosed patients treated with second-generation TKIs (nilotinib or dasatinib) at the MD Anderson Cancer Center (Houston, TX, USA) concluded that achievement of CCyR and partial cytogenetic response at 3 months should be considered optimal and suboptimal responses, respectively.19
In our study, degree of molecular response at 3 and 6 months was significantly correlated with OS and PFS at 48 months. Specifically, these results suggest that achievement of BCR–ABL1 levels ⩽10% by 3 months on therapy and ⩽1% (comparable to CCyR) by 6 months is predictive of favorable long-term outcomes in patients with prior failure on imatinib. These results are consistent with other landmark analyses in patients treated with TKIs.20, 21, 22, 23, 24, 25 The clinical implications of these findings require prospective analyses before they can be used to influence treatment decisions.
In addition, patients with baseline CHR were significantly less likely to progress than those without baseline CHR. This suggests that switching patients to nilotinib therapy before hematological failure on imatinib, in accordance with current treatment recommendations,16 may maximize the efficacy of nilotinib.
With a minimum of 4 years of follow-up, data from the present analysis confirm the long-term safety and efficacy of nilotinib in a minority of patients with CML-CP who are intolerant of or resistant to imatinib. These findings indicate that the optimal use of nilotinib is in the setting of newly diagnosed patients with CML-CP26 and that more effective treatment options than the currently available TKI are needed in patients with imatinib failure are needed, particularly in the setting of imatinib resistance.
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We thank Susan Branford, Philipp Erben, Neil Gallagher, Ariful Haque, Martin Müller and Simona Soverini for their contributions. Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals. We thank Cornel Phillip and Erinn Goldman for medical editorial assistance with this manuscript. The research work of Francis Giles, Philipp D le Coutre, Javier Pinilla-Ibarz, Richard A Larson, Norbert Gattermann, Oliver G Ottmann, Andreas Hochhaus, Jerald P Radich, Giuseppe Saglio, Timothy P Hughes, Giovanni Martinelli, Dong-Wook Kim, Jorge Cortes, Michele Baccarani and Hagop M Kantarjian was funded by Novartis Pharma.
Conception and design: Francis Giles, Philipp D le Coutre, Javier Pinilla-Ibarz, Richard A Larson, Norbert Gattermann, Oliver G Ottmann, Andreas Hochhaus, Jerald P Radich, Giuseppe Saglio, Timothy P Hughes, Giovanni Martinelli, Dong-Wook Kim, Jorge Cortes, Michele Baccarani and Hagop M Kantarjian. Collection and assembly of data: all authors. Manuscript writing: all authors. Final approval of manuscript: all authors. Provision of study materials or patients: Francis Giles, Philipp D le Coutre, Javier Pinilla-Ibarz, Richard A Larson, Norbert Gattermann, Oliver G Ottmann, Andreas Hochhaus, Jerald P Radich, Giuseppe Saglio, Timothy P Hughes, Giovanni Martinelli, Dong-Wook Kim, Jorge Cortes, Michele Baccarani and Hagop M Kantarjian.
Steven Novick, Kathryn Gillis and Xiaolin Fan are either employed or hold a leadership position in Novartis Pharma. The remaining authors declare no conflict of interest.
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Giles, F., le Coutre, P., Pinilla-Ibarz, J. et al. Nilotinib in imatinib-resistant or imatinib-intolerant patients with chronic myeloid leukemia in chronic phase: 48-month follow-up results of a phase II study. Leukemia 27, 107–112 (2013). https://doi.org/10.1038/leu.2012.181
- imatinib resistance
- imatinib intolerance
- imatinib failure
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