Safety Of Nilotinib Research Articles

The long-term efficacy and safety of nilotinib in pediatric patients with CML: a 5-year update of the DIALOG study

AbstractThe efficacy and safety of nilotinib in pediatric patients with imatinib/dasatinib resistant/intolerant (R/I) or newly diagnosed (ND) Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP) was demonstrated in the phase 2, open-label DIALOG study. In this final analysis, long-term efficacy and safety are presented for patients who completed 66 cycles (of 28 days) of treatment with nilotinib (230 mg/m2 twice daily) or discontinued early. Overall, 59 patients were enrolled and 58 were treated (R/I, n = 33; ND, n = 25; median time on treatment: 60.5 and 51.9 months, respectively). In the R/I cohort, the cumulative major molecular response (MMR; BCR::ABL1 international scale [IS] ≤ 0.1%) rate was 60.6%, and no patients had a confirmed loss of MMR. Among ND patients, the best overall MMR rate was 76.0%; 3 patients had a confirmed loss of MMR. The cumulative molecular response MR4 (BCR::ABL1IS ≤ 0.01%) and MR4.5 (BCR::ABL1IS ≤ 0.0032%) rates by 66 cycles were 27.3% and 12.1% in the R/I cohort, and 56.0% and 44.0% in the ND cohort, respectively. The safety profile of nilotinib was consistent with those of earlier reports. No on-treatment deaths occurred. These long-term (up to ∼5 years) data support the efficacy and safety of nilotinib in pediatric patients with Ph+ CML-CP. This trial was registered at www.clinicaltrials.gov.uk as #NCT01844765.

Efficacy and safety of nilotinib as frontline treatment in elderly (> 65 years) chronic myeloid leukemia patients outside clinical trials

Here, we report real-world evidence on the safety and efficacy of nilotinib as a first-line treatment in elderly patients with chronic phase CML, treated in 18 Italian centers. Sixty patients aged > 65 years (median age 72 years (65–84)) were reported: 13 patients were older than 75 years. Comorbidities were recorded at baseline in 56/60 patients. At 3 months of treatment, all patients obtained complete hematological response (CHR), 43 (71.6%) an early molecular response (EMR), while 47 (78%) reached a complete cytogenetic response (CCyR). At last follow-up, 63.4% of patients still had a deep molecular response (MR4 or better), 21.6% reached MR3 as best response and 11.6% persisted without MR. Most patients (85%) started the treatment at the standard dose (300 mg BID), maintained at 3 months in 80% of patients and at 6 months in 89% of them. At the last median follow-up of 46.3 months, 15 patients discontinued definitively the treatment (8 due to side effects, 4 died for unrelated CML causes, 1 for failure, 2 were lost to follow-up). One patient entered in treatment-free remission. As to safety, 6 patients (10%) experienced cardiovascular events after a median time of 20.9 months from the start. Our data showed that nilotinib could be, as first-line treatment, effective and relatively safe even in elderly CML patients. In this setting, more data in the long term are needed about possible dose reduction to improve the tolerability, while maintaining the optimal molecular response.

Efficacy and safety of nilotinib in chronic myeloid leukaemia patients who failed to achieve a treatment-free remission period after imatinib discontinuation: Results of the French Nilo post-STIM study.

Molecular recurrence (MRec) occurs in about half of all patients with chronic myeloid leukaemia (CML) who discontinue tyrosine kinase inhibitors (TKI) in sustained deep molecular response. A second TKI discontinuation has been attempted in some patients who regain the discontinuation criteria after resuming treatment. Nilotinib treatment affords faster and deeper molecular responses than imatinib as first-line therapy. We prospectively evaluated the efficacy and safety of nilotinib (300 mg twice daily) in chronic-phase CML patients who experienced MRec, after imatinib discontinuation and analysed the probability of TFR after a new attempt in patients treated for 2 years with sustained MR4.5 for at least 1 year. A total of 31 patients were included in the study between 2013 and 2018. Seven (23%) patients experienced serious adverse events after a median of 2 months of nilotinib treatment leading to discontinuation of treatment. One patient was excluded from the study for convenience. Among the 23 patients treated for 2 years with nilotinib, 22 maintained their molecular response for at least 1 year (median: 22 months) and stopped nilotinib. The TFR rates at 24 and 48 months after nilotinib discontinuation were 59.1% (95% confidence interval [CI]: 41.7%-83.7%) and 42.1% (95% CI: 25%-71%) respectively (NCT #01774630).

Treatment-Free Remission in Chronic Phase Chronic Myeloid Leukemia Patients Treated with Nilotinib Front-Line, in Real-Life Conditions: Influence of Switching to Another TKI Prior to Cessation.

Nilotinib (NIL) as front-line therapy in newly diagnosed chronic phase (CP) CML patients (pts) is able to induce high rates of sustained deep molecular response and high possibilities of treatment-free remission (TFR). However, the identification of factors influencing successful TFR in this population remains imprecise. This observational study retrospectively analyzed TFR rates, outcome, and tried to identify factors related to successful TFR in in- and out-study 221 pts treated in this setting with NIL 600 mg, in "real-life" conditions. All pts with newly diagnosed adult CP-CML receiving NIL 300 mg BID alone front-line between 10/2007 and 06/2022, were eligible. Data were retrospectively collected according to the national regulations with pts' information. All pts were assessed and followed according to ELN recommendations 2006→2020 along treatment and to the recommendations of the Fi-LMC (D. Rea et al., Cancer 2018, i. e. 2 years of sustained MR4.5) in case of TFR. In this regard, a TKI was resumed if loss of MMR on one instance. BCR::ABL1 assessments were performed in the 2 reference laboratories, standardised, and expressed in % (IS) with ≥32,000 copies of ABL1 as control. The primary endpoints were the rate of successful TFR on NIL first-line. Secondary endpoints were the kinetics of molecular response, factors influencing outcome, survival, and safety of NIL. Two hundred and one patients were enrolled with 56% males with a median age at diagnosis of 50 (17.5-83) years, and 26% of them had cardiovascular risk factors at onset (tobacco abuse 10%, hypercholesterolemia 9.55%, diabetes 1.36%, none with history of cardiovascular events [CVE]). ELTS scores were high in 13%, intermediate in 30% and low in 53% of pts, unknown in 4% of pts. Twenty-six (12%) pts harboured additional chromosomal abnormalities (ACA) at diagnosis. The median follow-up after NIL initiation was 85.16 (5.72-174) months. After a median of 37.7 months, 119 pts (58%) were not on NIL anymore for toxicities, resistance or TFR. Sixty-eight (31%) pts obtained the TFR criteria and stopped NIL after a median of 66.7 (27-132) months. The median time between first MR4.5 datapoint and TFR was 39 (15.31-120) months. With a median follow-up of 20.3 (0.03-108) months after NIL cessation, the survival without MMR loss after NIL cessation (figure 1.) is 64.38% (95% CI: 53.35- 77.69). Interestingly, no CVE occurred after NIL cessation, as well as no blast crisis. Two patients died in TFR from competitive events (2 solid tumours). We went on comparing the TFR group vs the non-TFR group. The median age at TFR was 56 (30-87) years with no difference at CML diagnosis in terms of age (49 vs 50 years, p=0.096), ELTS (p=0.276), ACA (15% vs 11%, p=0.483) between the 2 groups. In contrast, there was a difference in favour of female vs male gender in the TFR group (56%) vs non-TFR group (39%, p=0.031), and the median time to reach MMR was shorter in the TFR group 5.04 vs 10.2 months, p<0.001; as well as the median time to reach MR4.5 in the TFR group 18.2 vs 36.1 months, p<0.001. We finally compared the successful vs the unsuccessful TFR pts requiring TKI-rechallenge, in univariate analysis and multivariate analyses. The univariate analysis identified pts that have switched to another TKI before TFR for whatever reasons was a risk factor for subsequent loss of MMR [HR: 3.09 (95% CI: 1.30-7.34), Cox p-value=0.011]. This was confirmed by the log-rank survival curves of TFR in patients with or without switch (figure 2., log-rank p=0.008). Surprisingly, neither the duration of NIL before TFR [HR: 0.98 (0.96-1.00), Cox p-value=0.072], nor the duration of MR4.5 prior to NIL cessation [HR: 0.98 (0.95-1.01), Cox p-value=0.15] were found to have an impact. Additionally, the prognostic scores did not influence TFR success on NIL. The multivariate analysis confirmed that switching to another TKI was an unfavourable risk factor for molecular relapse [HR: 2.87 (1.20-6.84), p-value=0.018], and that the lack of impact of the duration of MR4.5 [HR: 0.98 (0.95-1.01), Cox p-value=0.218] had no significant influence. NIL first-line is able to induce high rates of successful TFR in newly diagnosed CP CML patients and switching to another TKI for toxicity and/or resistance, prior to TFR, represents an unfavourable risk factor for the success of TKI cessation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Real-Life Use of Nilotinib for Chronic Phase CML Demonstrates Similar Efficacy and Rate of Cardiovascular Events As Enestnd

Introduction:Nilotinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor (TKI) widely used for the treatment of Philadelphia chromosome positive chronic myeloid leukemia (CML). ENESTnd, which compared two doses of nilotinib to imatinib for patients with newly diagnosed CML, demonstrated superior rates of major molecular responses (MMRs) at 12 months in patients treated with nilotinib. However, a relative increase in cardiovascular events (CVE) was observed, including ischemic heart disease, stroke, and/or peripheral artery disease among nilotinib-treated patients. Notably, at a median 5-year follow up, 7.5% of patients on nilotinib 300mg twice daily experienced a CVE (Hochaus, Leukemia, 2016) and by 10-years of follow up, approximately 20% of patients treated with nilotinib developed a CVE (Kantarjian, Leukemia, 2021). The baseline Framingham general cardiovascular risk scores and total dose exposure were predictive of patients' risk of developing CVE.In the province of Quebec, Canada, the GQR LMC-NMP (Groupe Québécois de recherche en leucémie myéloide chronique et néoplasie myéloproliférative) has maintained a registry of nearly all patients with CML since 2011. Using this 900+-patient registry, we examined molecular responses and the rate of CVE among patients receiving nilotinib as frontline therapy for CML, to determine if they were similar to those observed in ENESTnd.Methods:We identified all patients with chronic phase CML in the registry who were initiated on nilotinib for chronic phase CML. Baseline patient characteristics included were age, sex, Sokal index, baseline comorbidities, molecular response, cardiovascular complications, duration of exposure to nilotinib, dose adjustment, dose discontinuation and CVE on therapy.Results:In total, 94 patients received nilotinib as frontline treatment starting in 2008 (Table 1). The median age of the population was 58 years, 50.5% were male. The most common cardiovascular comorbidity prior to nilotinib treatment was hypertension (23.4%) followed by elevated cholesterol (21.3%), and prior CVE (12%). Seventeen patients had a low Sokal index, 26 intermediate and 24 high, 25 missing. Sixty-five patients received nilotinib at a total of 600 mg per day, 29 patients had a dose reduction at some point in their treatment and 18 patients were on either 300 or 400 mg daily. The median follow-up time was 67.0 months (range 0.5 to 159), and median nilotinib exposure time was 38.5 months (range 0.5 to 144). Forty-six patients (48.9%) discontinued nilotinib, 6 for a treatment free remission (TFR). While on nilotinib, 63 patients achieved MMR (72.4%) and 43 achieved MR 4.5 (49.6%) by 5 years of treatment, with 52 (55.3%) and 22 (23.4%) patients achieving MMR or MMR4.5 within a year, respectively.There was a total of 7 CVE in 6 patients: six myocardial infarctions and one ischemic stroke (Table 2). No patients developed peripheral artery disease. The mean time of exposure to nilotinib in these 6 patients was 28.6 months. Two patients had a high Sokal index, 3 intermediate and 1 low. One patient received dose-reduced nilotinib. These patients were co-morbid with diabetes (3), hypertension (3), elevated cholesterol (1) and one had a myocardial infarct prior to starting nilotinib, two patients did not have any risk factors. Only one of these patients has remained on nilotinib. All patients with a CVE were alive at the time of this report.Conclusion:We present real world data on the efficacy and safety of nilotinib in the frontline treatment of CML. Our data indicate that molecular responses and toxicities are similar to the ENESTnd trial. Of the 94 treated patients, the rate of MMR and CVE were 72% and 7.4% at 5.5 years of follow up, respectively, which is similar to that observed in ENESTnd, where 77% of patients experienced MMR and 7.5% CVE at this timepoint (Hochaus, Leukemia, 2016). All but one patient with a CVE in our study continued nilotinib, suggesting a reluctance among physicians to continue in the face of CVE. While there were 11 patients with prior CVE, only one of these developed a CVE on nilotinib. Current GQR-LMC CML management guidelines recommend estimation of Framingham score and management of cardiovascular risk factors for all patients with CML. Future follow up of these registry data may demonstrate a decrease in the rate of CVE among nilotinib treated patients, reflecting local adherence to these guidelines. [Display omitted] DisclosuresBusque: Novartis: Consultancy. Assouline: Eli Lilly: Research Funding; Jewish General Hospital, Montreal, Quebec: Current Employment; Novartis: Honoraria, Research Funding; Amgen: Current equity holder in publicly-traded company, Research Funding; Gilead: Speakers Bureau; Johnson&Johnson: Current equity holder in publicly-traded company; Roche/Genentech: Research Funding; Takeda: Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria.

Long-Term Outcome of Chronic Phase Chronic Myeloid Leukemia Patients Treated with Nilotinib Front-Line

Long-Term Outcome of Chronic Phase Chronic Myeloid Leukemia Patients Treated with Nilotinib Front-Line

Nilotinib is reasonably safe and may halt the disease progression in moderately severe Parkinson's disease patients

The primary objective was nilotinib safety and tolerability in moderately severe PD patients, in this phase II study. An exploratory objective is to assess nilotinib effects on motor and non-motor symptoms at baseline, 6, 12 and 15 months. Participants had PD, with a MDS-UPDRS-III motor score 20-40, and MoCA ≥22. 75 participants were randomized 1:1:1 into placebo, 150mg and 300mg nilotinib oral, once daily for 12 months. 88% of participants completed the treatment and there were no drop-outs due to lack of drug tolerability. Niltonib was found to be reasonably safe with no suspected drug related adverse effects. There was no QTc prolongation or myelosuppression. No differences were observed in MDS-UPDRS-I within and between all study groups tested by a single rater. All groups showed a significant decline in MDS-UPDRS-II scores between baseline and 12 months and after washout. All groups slightly improved on MDS-UPDRS-III motor between baseline and 6 months. The placebo and the 300 mg nilotinib groups remained stable at 12 months and after washout but there was a significant improvement in MDS-UPDRS-III score between baseline and 15 months in the 150 mg nilotinib group (-2.82 points, 95% CI, -4.75- -0.89). No significant differences between each visit were observed in MDS-UPDRS-IV. No statistically significant differences in MDS-UPDRS measurements were observed between groups. There were no statistically significant differences in PDQ-39 between groups, but the placebo group significantly deteriorated after 6 months, while the nilotinib groups did not change. In conclusion these exploratory measures show no clinical worsening in MDS-UPDRS in the nilotinib groups compared to the placebo group that worsened after 6 months of treatment. Taken together, our results will guide the future development of a definitive phase III study to evaluate the effects of nilotinib in PD.

Efficacy of nilotinib in the first-line treatment of chronic myeloid leukemia and the analysis of factors affecting molecular responses

目的探讨尼洛替尼一线治疗慢性髓性白血病（CML）的疗效及安全性，并分析影响实现主要分子学反应的因素。方法回顾性分析郑州大学附属肿瘤医院2014年1月至2017年6月收治的86例新诊断为CML的患者，均接受尼洛替尼300 mg每日两次作为一线治疗，其中男性49例，女性37例。结果12个月时获主要分子学反应（MMR）、分子学反应4（MR4）、分子学反应4.5（MR4.5）的患者比例分别为59.3%、22.1%、15.1%；24个月时，获MMR、MR4、MR4.5的患者比例分别为76.2%、44.0%、27.4%。中位随访42（21~66）个月，中位无进展生存（PFS）时间为42（9~66）个月，PFS率为93%。BCR-ABLIS融合基因较诊断时下降一半所需要的时间定义为减半时间（HT），HT是CML患者12个月能否达到MMR（OR=0.896，P<0.001）及MR4.5（OR=0.377，P=0.003）的影响因素。非血液学不良反应中最常见的为皮疹（37.2%）和头痛（32.6%），大多数为1/2级，血液学不良反应主要为中性粒细胞减少（27.9%）和血小板减少（32.4%）。结论尼洛替尼一线治疗CML具有较优的有效性和安全性，HT≤13.68 d可能是长期无进展生存的保护因素。

Nilotinib Safety and Clinical Effects on 'ON' Disability in Parkinson's Disease Patients

Background: Parkinson's disease (PD) involves motor and non-motor symptoms and loss of brain dopamine neurons. Nilotinib is a tyrosine kinase inhibitor that may alter brain dopamine metabolism. Methods: A phase II randomized, double-blind, placebo controlled trial to evaluate Nilotinib effects on safety, tolerability and clinical outcomes in PD. Seventy-five participants were randomized 1:1:1 into placebo, 150mg or 300mg Nilotinib once daily for 12 months. This study evaluated Nilotinib effects on top of the optimal standard of care in mid-stage PD (H&Y 2.5-3) at 6 and 12 months. Findings: Participants well tolerated Nilotinib and rare hematological, hepatic and other systems disorders were observed. Cardiovascular events were seen in all groups. Prior to randomization all participants were stabilized on either Levodopa and/or dopamine agonists and were tested ON time. As expected, all 3 groups were stable at 6 months, indicating the effects of PD medications. However, the placebo group declined on UPDRS II (2.39 points, p=0.007), total UPDRS I-III (4.78 points, p=0.031) and UPDRS I-IV (4.47 points, p=0.038) at 6-12 months but Nilotinib groups remained stable. Similarly, all groups were stable on PDQ39 SI and the emotional well-being subscale at 6 months but the placebo group declined (8.17 points, p=0.001 and 1.7 points, p=0.003, respectively) at 6-12 months, while Nilotinib groups remained stable. Interpretation: Nilotinib is well tolerated and appears to be safe in PD patients. Nilotinib appears to stop the decline in motor and non-motor functions up to 12 months, while the effects of optimized PD medications significantly wear off six months after treatment. Nilotinib may have a significant impact on the care and management of PD patients, leading to delay or elimination of dose adjustment of PD-medications, thus avoiding their side effects. Trial Registration: The study was conducted under FDA Investigational New Drug (IND) # 123183, and registered in ClinicalTrials.gov (NCT02954978). Funding Statement: Lasky and Barajas Family Fund and other philanthropies. Novartis Pharmaceuticals Corporation provided the study drug. Declaration of Interests: Charbel Moussa is an inventor on several US and International Georgetown University patents to use Nilotinib and other tyrosine kinase inhibitors as a treatment for neurodegenerative diseases. No other authors declare any conflict of interests with this study. Ethics Approval Statement: This study was conducted in accordance with Good Clinical Practice guidelines and was approved by the Institutional Review Board (IRB# 2016-0380) at Georgetown University Medical Center as well as by Georgetown-Howard Universities Center for Clinical and Translational Science (GHUCCTS) scientific review board. Informed consent was obtained from all participants and study partners

Monitoring the safety of nilotinib in patients with chronic myeloid leukemia

The aim of the study was to evaluate the safety profile of nilotinib administered to chronic myeloid leukemia (CML) at patients. The study was conducted from March 2018 to May 2019 and it included 20 patients with CML in chronic phase. Of these 20 patients, 17 had previously been treated with imatinib and 3 with hydroxyurea. The mean duration of treatment with Nilotinib was 6.75 months. In nine patients treated with nilotinib (400 mg), 55% complained of fatigue, 33% of headache and 22.2% of pruritus. In five patients treated with Nilotinib (600 mg), 20% complained of headache, 40% of fatigue and 20% of pruritus. In addition, in six patients treated with nilotinib (800 mg), 50% complained of headache and fatigue, 17% with pruritus and visual disorder was observed in 20% of cases. In the study, the adverse reactions were observed between the age of 20 and 40 and it was 7.1%, in contrast to the group of patients between the age of 40 and 60 where the incidence of adverse reactions was 21.42%. The incidence of adverse reactions in patients in the age group over 60 years it was 57.1%. In terms of gender, the incidence of adverse reactions was equal to 50% for both men and women. In conclusion, this study showed that treatment with nilotinib was well tolerated, with adverse reactions of an easy degree. Future evaluation is necessary in order to understanding the adverse reaction of nilotinib in comparison with other tyrosine kinase inhibitors. Keywords: nilotinib, pharmacovigilance, safety, chronic myeloid leukemia

Nilotinib after imatinib first‐line: a real‐life longitudinal cohort of patients with chronic myeloid leukaemia in chronic phase

This prospective, observational study enrolled 150 adult patients with chronic myeloid leukaemia (CML) in chronic phase (CP) treated with nilotinib as second-line after imatinib, in a real life setting in France. Two-thirds of patients switched to nilotinib treatment due to lack of imatinib efficacy. Of 146 evaluable patients, 16 (11·0%) (95% confidence interval: 6·4-17·2%) achieved uMR4 , defined as undetectable molecular disease in cDNA with MR4 sensitivity (≥10000 ABL1 transcripts) at 18months and confirmed at 24months (primary endpoint). Among patients without major molecular response (MMR) or deep molecular response (DMR) at study entry, 66·3% achieved MMR and 44·2% DMR within a median of 5·7 and 6·24months, respectively. Fifty-three patients (36·3%) have prematurely terminated the study before 24months of follow-up, primarily due to nilotinib treatment discontinuation (n=43; 29·5%), mainly motivated by treatment intolerance (n=27; 18·5%) and inefficacy (n=10; 6·8%). The most frequent extra-haematological adverse events (AEs) reported as related to treatment with nilotinib were pruritus (16·4%), asthenia (13·7%) and dry skin (13·0%). Ischaemic cardiovascular AEs were reported in 18 patients (12·3%). This French nationwide large cohort adds valuable information to the body of evidence on the efficiency and safety of nilotinib in the treatment of patients with CP-CML.

Efficacy and safety of nilotinib in patients with KIT-mutated metastatic or inoperable melanoma: final results from the global, single-arm, phase II TEAM trial

BackgroundThe single-arm, phase II Tasigna Efficacy in Advanced Melanoma (TEAM) trial evaluated the KIT-selective tyrosine kinase inhibitor nilotinib in patients with KIT-mutated advanced melanoma without prior KIT inhibitor treatment.Patients and methodsForty-two patients with KIT-mutated advanced melanoma were enrolled and treated with nilotinib 400 mg twice daily. TEAM originally included a comparator arm of dacarbazine (DTIC)-treated patients; the design was amended to a single-arm trial due to an observed low number of KIT-mutated melanomas. Thirteen patients were randomized to DTIC before the protocol amendment removing this study arm. The primary endpoint was objective response rate (ORR), determined according to Response Evaluation Criteria In Solid Tumors.ResultsORR was 26.2% (n = 11/42; 95% CI, 13.9%–42.0%), sufficient to reject the null hypothesis (ORR ≤10%). All observed responses were partial responses (PRs; median response duration, 7.1 months). Twenty patients (47.6%) had stable disease and 10 (23.8%) had progressive disease; 1 (2.4%) response was unknown. Ten of the 11 responding patients had exon 11 mutations, four with an L576P mutation. The median progression-free survival and overall survival were 4.2 and 18.0 months, respectively. Three of the 13 patients on DTIC achieved a PR, and another patient had a PR following switch to nilotinib.ConclusionNilotinib activity in patients with advanced KIT-mutated melanoma was similar to historical data from imatinib-treated patients. DTIC treatment showed potential activity, although the low patient number limits interpretation. Similar to previously reported results with imatinib, nilotinib showed greater activity among patients with an exon 11 mutation, including L576P, suggesting that nilotinib may be an effective treatment option for patients with specific KIT mutations.Clinical Trial RegistrationClinicalTrials.gov, NCT01028222.

Outcomes with frontline nilotinib treatment in Turkish patients with newly diagnosed Philadelphia chromosome–positive chronic myeloid leukemia in chronic phase

ABSTRACTObjective: Nilotinib is a BCR-ABL1 tyrosine kinase inhibitor approved for the treatment of patients with chronic myeloid leukemia in chronic phase (CML-CP). This study was the first prospective evaluation of the efficacy and safety of nilotinib in Turkish patients with newly diagnosed CML-CP. The primary endpoint of the study was the rate of major molecular response (MMR; BCR-ABL1 ≤ 0.1% on the International Scale [BCR-ABL1IS]) by 12 months.Methods: Patients with newly diagnosed CML-CP were treated with nilotinib 300 mg twice daily. This analysis was based on the first 12 months of follow-up in a 24-month study.Results and Conclusions: Of 112 patients enrolled, 66.1% (80% CI, 59.7–72.0%) achieved MMR and 22.3% achieved a deep molecular response of MR4.5 (BCR-ABL1IS ≤ 0.0032%) by 12 months. During the first year of treatment, 1 patient progressed to blast crisis and 2 patients died. Safety results were consistent with previous studies. Most adverse events (AEs) were grade 1/2. Most frequently reported nonhematologic AEs of any grade were elevations in bilirubin, alanine aminotransferase, and triglycerides. These results support the use of nilotinib 300 mg twice daily as a standard-of-care treatment option for patients with newly diagnosed CML-CP.

Update on the management of Philadelphia chromosome positive chronic myelogenous leukemia: role of nilotinib.

Chronic myelogenous leukemia (CML) is a pluripotent stem cell disease characterized by the presence of the Philadelphia chromosome and the bcr-abl gene. The discovery of tyrosine kinase inhibitors (TKIs) revolutionized therapy for CML, such that durable response, increased overall survival, and increased progression-free survival of patients in chronic phase CML is now possible. Due to resistance and intolerance to imatinib, there was need for development of second- and third-generation TKIs for the treatment of CML. This review examines the role of nilotinib, an oral second-generation TKI, in the treatment of Philadelphia positive CML. The pharmacology, efficacy, and safety of nilotinib are critically evaluated. Patient-related issues, including tolerance, drug interactions, and quality of life issues are also examined.

Efficacy and safety of nilotinib as third-line therapy in an elderly patient with CML

This case report describes a 74 year old male patient with low Sokal risk chronic myeloid leukemia (CML). Treatment was started four years ago with imatinib, 400 mg/day. The patient achieved complete hematologic response but, after 3 months of treatment, developed grade 3 skin toxicity. Imatinib was stopped and the patient was started on dasatinib, achieving complete cytogenetic and molecular response. Two months later, physical examination revealed bilateral gynecomastia. After 2 years of treatment the patient presented with pleural effusion and the drug dose was reduced but, following relapse of CML, therapy was switched to nilotinib, 800 mg/day. Treatment with nilotinib is currently ongoing and is well tolerated by the patient who is again in complete molecular response, with no signs of pleural effusion. Considering the growing availability of new and more potent tyrosine kinase inhibitors (TKI) it is important for the clinician to be aware of the possible inhibitory effects of these molecules against other members of the tyrosine kinase family. Safety of TKI in frail and elderly patients with CML is a fundamental goal. The results achieved in our patient show that nilotinib is safe and effective even when used as third line therapy.

Updated review of nilotinib as frontline treatment for newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia

Nilotinib, a second-generation tyrosine kinase, is approved for the treatment of newly diagnosed chronic phase chronic myeloid leukemia patients. The drug showed impressive rates of cytogenetic and molecular responses with only few cases of disease progression in Phase II trials. Five years follow-up of Phase III randomized ENESTnd study demonstrated deep molecular responses, lower rate of transformation in the core treatment compared with imatinib (0.7% for nilotinib 300 mg twice daily [BID], 1.1% for nilotinib 400 mg BID and 4.2% with imatinib). ENEST1st study confirmed the activity of nilotinib in first line at the dose of 300 mg BID. Aim of this review is to provide reported evidences on the efficacy and safety of nilotinib when used for the management of early chronic phase chronic myeloid leukemia patients and to discuss about future possible discontinuation.

Nilotinib Results in Improved Rates of Molecular Response in Turkish Newly Diagnosed CML-CP Patients: A 24-Month Update

IntroductionNilotinib, a more potent and selective BCR-ABL-1 inhibitor than imatinib, is approved by the FDA and EMA 1) for the treatment of chronic and accelerated phase Philadelphia chromosome positive (Ph+) Chronic Myeloid Leukemia (CML) patients resistant or intolerant to prior therapy including imatinib and 2) for the treatment of newly-diagnosed Ph+ CML patients in the chronic phase (CML-CP). The aim of the present study was to evaluate the efficacy and safety of nilotinib in a Turkish population of newly-diagnosed Ph+ CML-CP patients.MethodsThe study was a multicenter, open-label, single-arm phase II clinical trial. All patients were to be treated with nilotinib (AMN107, Tasigna®) 300 mg BID for 24 months.ResultsAs of April 30, 2014, of the 96 patients out of a total 112 enrolled that had 24 month follow-up, 77 completed active treatment period. General characteristics of the patients at baseline are presented in Table 1. [Display omitted] Data are expressed as median (minimum-maximum) or number (%), where appropriate.Molecular response by 24 months is presented in Table 2. [Display omitted] Data are presented as mean±standard deviation or number (%), where appropriate.MMR (Major molecular rate): BCR-ABL/control gene ratio of ≤%0.1 measured by RQ-PCR as %* The number of patients who were still on treatment at 3rd month.Cumulative MMR rates at various time points are shown in Figure 1. [Display omitted] A total of 486 adverse events (AEs) occurred; 93 AE led to discontinuation of the drug temporarily or permanently. Out of 96 patients 39 patients have temporally or permanently discontinued treatment. Permanent discontinuation rate due to adverse event was 9.6% (9 patients) which was the most common reason among all patients (19.8% - 19 patients) who permanently discontinued during 24 months. Thrombocytopenia was the most frequent (10.4%) AE, followed by hyperbilirubinemia (8.3%) and increased lipase level (7.3%) 19.8% of the patients entered in the trial had history of cardiovascular disease prior to trial entry and during the study cardiovascular events have been reported at 20.8% of patients. Despite published peripheral arterial occlusive disease (PAOD) reports related to nilotinib usage, there were no PAOD events reported at our cohort.ConclusionsAt 24 months, in Turkish patients with newly diagnosed CML, the cumulative MMR rate was 80.2%. Month 3 MMR rate was 86.5% and median time to MMR was 260.0±157.5 days. Out of 12 patients whose bcr-abl levels were above 10% at 3rd month, only 5 of them could reach to MMR by 24 months. Only one progression occurred, during the first year of therapy. These results suggest that high efficacy was achieved with nilotinib, an approved first-line therapy for newly diagnosed chronic phase of CML (CP-CML).The results of the present study revealed that efficacy and safety of nilotinib in Turkish cohort are similar to those reported in ENESTnd. This study contribute to well established nilotinib profile for chronic phase CML patients which is a licensed alternative for the treatment of newly diagnosed Ph+ CML-CP in Turkey. DisclosuresSaydam:Novartis Pharmaceuticals Corporation, Turkey: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity’s Board of Directors or advisory committees. Yavuz:Novartis Pharmaceuticals Corporation, Turkey: Membership on an entity’s Board of Directors or advisory committees. Ali:Novartis Pharmaceuticals Corporation, Turkey: Membership on an entity’s Board of Directors or advisory committees. Guvenc:Novartis Pharmaceuticals Corporation, Turkey: Membership on an entity’s Board of Directors or advisory committees. Sonmez:Novartis Pharmaceuticals Corporation, Turkey: Membership on an entity’s Board of Directors or advisory committees. Akkaynak:Novartis Pharmaceuticals Corporation, Turkey: Employment. Dag:Novartis Pharmaceuticals Corporation, Turkey: Employment.

Efficacy and Safety of Nilotinib in First Line Therapy in a Real Life Cohort of Chronic Myeloid Leukemia Patients

IntroductionConsistent data show that the real goal in CML therapy is to obtain a very rapid and deep response because the cinetic of molecular response (MR) is important for quickly reducing the tumor burden by reducing the BCR/ABL level.The second generation TKIs Nilotinib was designed to have enhanced selectivity and potency toward BCR-ABL compared with imatinib and was able to obtain very rapid and deeper response as shown by many clinical trials. Nilotinib has been approved in multiple countries for use in first line therapy in CML-CP Pts. In order to verify the efficacy and safety of Nilotinib used in first line treatment, we collected the results of a real life cohort of Pts treated in some italian hematological Institutions.Patients and Methods68 Pts affected by CML-CP were treated in 9 hematologic units with Nilotinib as first line therapy from 2010 to 2014. The median age was 47.7y with equal distribution by sex. Cytogenetic analysis at diagnosis showed in 66/68 Pts the presence of the typical Ph1 chromosome, 1 pt showed a Ph1 in a complex translocation and 1 pt showed the typical Ph1 chromosome plus der(17). The molecular analysis confirmed the presence of a BCR/ABL hybrid gene (55/68: b3a2 transcript; 12/68 b2a2 transcript; 1/68 both transcripts). The Sokal risk was: Low 24 Pts (35.3%), Intermediate 33 Pts (48.5%), High 11 Pts (16.2%); the Hasford risk was: Low 35 Pts (51.5%), Intermediate 27 Pts (39.7%), High 6 Pts (8.8%); the EUTOS risk was: Low 61 Pts (89.7%) and High 7 Pts (10.3%). All Pts have an ECOG 0/1 out of 1 with an ECOG 2. 45/68 pts received a cytoreduction by HU. All Pts received the Nilotinib standard dose of 600 mg/die except 1 pt who received 300 mg/die. At diagnosis some Pts showed comorbidities (21/68: hypertension; 6/68: diabetes; 5/68: dyslipidemia; 2/68: previous myocardial infarction; 1/68 was in treatment for HIV infection)Results66/68 Pts received at least 3 months of treatment and were considered for analysis. At 3 months, all Pts obtained hematological response; cytogenetic response was complete for 65/68 and partial in 3/68.At 6, 12 and 18 months cytogenetic response was complete in all Pts except for 1 that showed a partial response (pt not compliant); at 24 mo the cytogenetic response was complete for all 25 evaluable Pts.The molecular results at the different time points are summarized in table 1.6/68 Pts showed G1/G2 cutaneous side effects (pruritus, erithema, alopecia) , 6/68 a G1 increase of amylase and/or lipase, but only 1 developed clinical pancreatitis (at diagnosis: hypertension, hypercolesterolemia and cardiac disfunction). One pt underwent to leg amputation for PAOD (at diagnosis: hypertension and hypertriglyceridemia). He discontinued treatment in optimal response at 12mo. One pt had ischemic cerebral event (at diagnosis had hypertension and a previous heart attack). One pt discontinued treatment for pancitopenia in failure of response at 3mo and one pt died at 12mo in failure of response for IMF diagnosed during treatment.No pts developed mutations of BCR/ABL during treatment. In 24 months of observation no Pts lost the response.ConclusionThe response to Nilotinib treatment at 3 months according to ELN revealed that all evaluable Pts were in optimal response; at 6 mo 51/55 (92,7 %) Pts were in optimal response, while at 12 mo 38/45 (86,7%) Pts were in optimal response. At 18 mo 94,1% reached at least MMR with a very deep response (MR>= 4) in 55,9% of Pts. This kind of response was mantained at 24 mo (92% of Pts had at least an MR3 and 15/25 had an MR 4).Notabily starting from 12 months, at least 40 % of pts showed a very deep response (MR >= 4) and the number increased at the subsequent time points.The side effects were few and of low grade. Only 3 Pts discontinued the treatment because side effects. Only a severe side effect (PAOD) was reported in a pt who already had a vascular risk because affected from hypertension and hypertriglyceridemia. It is recommended to check at diagnosis and carefully follow during the treatment for all comorbidities to prevent toxicity.These data collected in a real life treatment with Nilotinib in first line in CML -CP patients, confirmed the results of the clinical trials. The rapid and deep response with a tolerable toxicity profile allow to consider Nilotinib as a good choice for first line treatment also in consideration of a stop therapy in a future.Table 1Time Pts MR1 MR2 MR3 MR4 MR4.5 MR5(mo) (N)3 60 10 31 13 4 2 -6 55 4 16 20 4 11 -12 45 1 6 20 4 13 118 34 0 2 13 6 12 124 25 0 2 8 6 8 1 DisclosuresNo relevant conflicts of interest to declare.

Efficacy and Safety of Nilotinib (NIL) vs Imatinib (IM) in Patients (pts) With Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP): Long-Term Follow-Up (f/u) of ENESTnd

Efficacy and Safety of Nilotinib (NIL) vs Imatinib (IM) in Patients (pts) With Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP): Long-Term Follow-Up (f/u) of ENESTnd

Multicenter phase II clinical trial of nilotinib for patients with imatinib-resistant or -intolerant chronic myeloid leukemia from the East Japan CML study group evaluation of molecular response and the efficacy and safety of nilotinib

BackgroundNilotinib is a second-generation tyrosine kinase inhibitor that exhibits significant efficacy as first- or second-line treatment in patients with chronic myeloid leukemia (CML). We conducted a multicenter Phase II Clinical Trial to evaluate the safety and efficacy of nilotinib among Japanese patients with imatinib-resistant or -intolerant CML-chronic phase (CP) or accelerated phase (AP).ResultsWe analyzed 49 patients (33 imatinib-resistant and 16 imatinib-intolerant) treated with nilotinib 400 mg twice daily. The major molecular response (MMR) rate was 47.8% at 12 months among 35 patients who did not demonstrate an MMR at study entry. Somatic BCR-ABL1 mutations (Y253H, I418V, and exon 8/9 35-bp insertion [35INS]) were detected in 3 patients at 12 months or upon discontinuation of nilotinib. Although 75.5% of patients were still being treated at 12 months, nilotinib treatment was discontinued because of progressing disease in 1 patient, insufficient effect in 2, and adverse events in 9. There was no statistically significant correlation between MMR and trough concentrations of nilotinib. Similarly, no correlation was observed between trough concentrations and adverse events, except for pruritus and hypokalemia. Hyperbilirubinemia was frequently observed (all grades, 51.0%; grades 2–4, 29%; grades 3–4, 4.1%). Hyperbilirubinemia higher than grade 2 was significantly associated with the uridine diphosphate glucuronosyltransferase (UGT)1A9 I399C/C genotype (P = 0.0086; Odds Ratio, 21.2; 95% Confidence Interval 2.2–208.0).ConclusionsNilotinib was efficacious and well tolerated by patients with imatinib-resistant or -intolerant CML-CP/AP. Hyperbilirubinemia may be predicted before nilotinib treatment, and may be controlled by reducing the daily dose of nilotinib in patients with UGT1A9 polymorphisms.Trial registrationclinicaltrials.gov: UMIN000002201