Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up

Larson, Richard A.; Hochhaus, Andreas; Hughes, Timothy P.; Clark, Richard E.; Étienne, Gabriel; Kim, D. W.; Flinn, Ian W.; Kurokawa, Mineo; Moiraghi, Beatriz; Yu, Ruey J.; Blakesley, Rick E.; Gallagher, Neil J.; Saglio, Giuseppe; Kantarjian, Hagop M.

doi:10.1038/leu.2012.134

Cited by 402 publications

(419 citation statements)

References 12 publications

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“…There was also much less progression to AP or BP on the nilotinib arm. Recently, a 36 month follow-up was published, and differences in deep molecular responses continued to favor nilotinib at either dose [25].…”

Section: Nilotinibmentioning

confidence: 99%

Chronic myeloid leukemia: 2014 update on diagnosis, monitoring, and management

2014

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Disease overview: Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm with an incidence of 1–2 cases per 100,000 adults, and accounts for ∼15% of newly diagnosed cases of leukemia in adults. Diagnosis: CML is characterized by a balanced genetic translocation, t(9;22)(q34;q11.2), involving a fusion of the Abelson oncogene (ABL) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome. The molecular consequence of this translocation is the generation of a BCR‐ABL fusion oncogene, which in turn translates into a Bcr‐Abl oncoprotein. Frontline therapy: Three tyrosine kinase inhibitors (TKIs), imatinib, nilotinib, and dasatinib have been approved by the US Food and Drug Administration for the first‐line treatment of patients with newly diagnosed CML in chronic phase (CML‐CP). Clinical trials with second generation TKIs reported significantly deeper and faster responses; their impact on long‐term survival remains to be determined. Salvage therapy: For patients who fail frontline therapy, second‐line options include second and third generation TKIs. Although second and third generation TKIs are potent and specific BCR‐ABL TKIs, they exhibit unique pharmacological profiles and response patterns relative to different patient characteristics, such as patients comorbidities, disease stage, and BCR‐ABL mutational status. Patients who develop the T315I “gatekeeper” mutation display resistance to all currently available TKIs except ponatinib. Allogeneic transplantation remains an important therapeutic option for CML‐CP who have failed at least 2 TKIs, and for all patients in advanced phase disease. Am. J. Hematol. 89:547–556, 2014. © 2014 Wiley Periodicals, Inc.

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Section: Nilotinibmentioning

confidence: 99%

Chronic myeloid leukemia: 2014 update on diagnosis, monitoring, and management

2014

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“…Throughout 6 years of follow‐up in ENESTnd, both nilotinib doses resulted in improved efficacy versus imatinib, including faster and higher rates of molecular responses and lower rates of disease progression and death due to advanced CML (Saglio et al , 2010; Kantarjian et al , 2011; Larson et al , 2012; Hughes et al , 2014a, 2015; Hochhaus et al , 2016a). By 6 years, 77·3% (nominal P < 0·0001 versus imatinib), 79·0% (nominal P < 0·0001 versus imatinib) and 61·1% of patients in the nilotinib 300‐mg twice‐daily, nilotinib 400‐mg twice‐daily and imatinib arms, respectively, achieved a major molecular response [MMR; defined as BCR‐ABL1 ≤ 0·1% on the International Scale ( BCR‐ABL1 IS )]; among all randomized patients in each arm, 11 of 282 (nilotinib 300 mg twice daily; nominal P = 0·0661 versus imatinib), 6 of 281 (nilotinib 400 mg twice daily; nominal P = 0·0030 versus imatinib), and 21 of 283 patients (imatinib) progressed to accelerated phase/blast crisis (AP/BC) by 6 years (including after discontinuation of study treatment) (Hughes et al , 2015).…”

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confidence: 99%

“…Estimated rates of overall survival at 6 years were 91·6% in the nilotinib 300‐mg twice‐daily arm (nominal P = 0·7085 versus imatinib), 95·8% in the nilotinib 400‐mg twice‐daily arm (nominal P = 0·0314 versus imatinib) and 91·4% in the imatinib arm (Hughes et al , 2015). The safety profile of nilotinib is well established and distinct from that of imatinib (Saglio et al , 2010; Kantarjian et al , 2011; Larson et al , 2012; Hughes et al , 2015; Hochhaus et al , 2016a). …”

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confidence: 99%

Nilotinib dose‐optimization in newly diagnosed chronic myeloid leukaemia in chronic phase: final results from ENESTxtnd

et al. 2017

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SummaryThe Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Extending Molecular Responses (ENESTxtnd) study was conducted to evaluate the kinetics of molecular response to nilotinib in patients with newly diagnosed chronic myeloid leukaemia in chronic phase and the impact of novel dose‐optimization strategies on patient outcomes. The ENESTxtnd protocol allowed nilotinib dose escalation (from 300 to 400 mg twice daily) in the case of suboptimal response or treatment failure as well as dose re‐escalation for patients with nilotinib dose reductions due to adverse events. Among 421 patients enrolled in ENESTxtnd, 70·8% (95% confidence interval, 66·2–75·1%) achieved major molecular response (BCR‐ABL1 ≤ 0·1% on the International Scale) by 12 months (primary endpoint). By 24 months, 81·0% of patients achieved major molecular response, including 63·6% (56 of 88) of those with dose escalations for lack of efficacy and 74·3% (55 of 74) of those with dose reductions due to adverse events (including 43 of 54 patients with successful re‐escalation). The safety profile of nilotinib was consistent with prior studies. The most common non‐haematological adverse events were headache, rash, and nausea; cardiovascular events were reported in 4·5% of patients (grade 3/4, 3·1%). The study was registered at clinicaltrials.gov (NCT01254188).

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“…In the last few years, several communications of arterial thrombotic events have been described during nilotinib therapy, but the exact pathogenetic mechanisms are still unknown [2]. In the ENESTnd trial at the last follow-up of 5 years, an increased rate of ischemic events with nilotinib has been reported (6.8% with nilotinib 300 mg BID and 12.6% with nilotinib 400 mg BID) as compared to imatinib (2.1%) [3]. Thus, it has become of great importance to evaluate the benefit/risk ratio at baseline, considering the overall cardiovascular risk profile of patients, taking into account pre-existing comorbidities and risk factors predisposing to atherosclerotic events.…”

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confidence: 99%

Cardiovascular risk assessments in chronic myeloid leukemia allow identification of patients at high risk of cardiovascular events during treatment with nilotinib

2015

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Cardiovascular risk assessments in chronic myeloid leukemia allow identification of patients at high risk of cardiovascular events during treatment with nilotinibTo the Editor Nilotinib, a second-generation tyrosine kinase inhibitor, has been approved at the dose of 300 mg bis in die (BID) for newly diagnosed chronic phase chronic myeloid leukemia patients and at the dose of 400 mg BID for chronic or accelerated phase patients with resistance or intolerance to imatinib [1]. In the last few years, several communications of arterial thrombotic events have been described during nilotinib therapy, but the exact pathogenetic mechanisms are still unknown [2]. In the ENESTnd trial at the last follow-up of 5 years, an increased rate of ischemic events with nilotinib has been reported (6.8% with nilotinib 300 mg BID and 12.6% with nilotinib 400 mg BID) as compared to imatinib (2.1%) [3]. Thus, it has become of great importance to evaluate the benefit/risk ratio at baseline, considering the overall cardiovascular risk profile of patients, taking into account pre-existing comorbidities and risk factors predisposing to atherosclerotic events.Our group and other investigators tried to retrospectively apply the European 2012 cardiovascular risk assessment model (SCORE chart) in order to identify patients at risk of atherosclerotic events during nilotinib treatment: both studies were able to demonstrate the validity of the ESC criteria to select patients at risk of cardiovascular events during treatment [4,5]. According to these ESC 2012 criteria, patients were stratified on the basis of age, sex, systolic pressure, smoking, and total cholesterol level [6]. Indeed, other prognostic scores already existed: the Framingham risk score [7] which is a sex-specific algorithm developed in 1998 in order to calculate the 10-year cardiovascular individual risk. It was then modified and updated to include dyslipidaemia, age, hypertension treatment, smoking, total cholesterol level, with exclusion of diabetes, that was included in the first version, because this risk factor was considered to be a coronary heart disease equivalent. Another prediction algorithm for cardiovascular disease is the QRisk2 [8] that uses traditional risk factors such as age, systolic pressure, smoking status, a ratio of total serum cholesterol to high-density lipoprotein cholesterol, but also the body mass index, ethnicity, family history, chronic kidney disease, rheumatoid arthritis, atrial fibrillation, diabetes, and anti-hypertensive treatment. A QRisk2 over 10%, indicating 10% risk of cardiovascular disease event over the next ten years, suggests that a therapy with lipid lowering therapy with a statin should be started. We retrospectively applied these two latter prognostic score to the same population of CML patients treated with nilotinib that we previously described [4].We included in this study 82 chronic myeloid leukemia in chronic phase (CML-CP) patients treated frontline with nilotinib (42 patients, with the dose of 600 mg BID) or after failure of othe...

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Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up

Cited by 402 publications

References 12 publications

Chronic myeloid leukemia: 2014 update on diagnosis, monitoring, and management

Chronic myeloid leukemia: 2014 update on diagnosis, monitoring, and management

Nilotinib dose‐optimization in newly diagnosed chronic myeloid leukaemia in chronic phase: final results from ENESTxtnd

Cardiovascular risk assessments in chronic myeloid leukemia allow identification of patients at high risk of cardiovascular events during treatment with nilotinib

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