Nilotinib Group Research Articles

Analysis of treatment-free remission outcomes in patients with chronic myeloid leukemia who received sequential nilotinib therapy after achieving deep molecular response to imatinib

Objective: To analyze the treatment-free remission (TFR) outcomes in patients with chronic myeloid leukemia (CML) treated sequentially with nilotinib (NIL) after achieving deep molecular response (DMR) to imatinib (IM). Methods: Retrospectively enrolled 103 CML patients from 6 hematological centers in Henan Province who chose sequential NIL therapy or continued IM therapy after achieving DMR to first-line IM from June 2, 2013 to August 30, 2022. Among them, 42 cases were treated with sequential NIL and 61 cases continued IM therapy. The 42 patients in the sequential NIL group were further divided into 3 subgroups based on the duration of DMR at switching to sequential NIL therapy: Group 1 (17 cases): DMR duration<12 months at switching to sequential NIL therapy; Group 2 (8 cases): DMR duration≥12 months to<24 months at switching to sequential NIL therapy; Group 3 (17 cases): DMR duration≥24 months at switching to sequential NIL therapy. Follow-up ended on January 9, 2024, with a median follow-up of 40 (16, 91) months for the sequential NIL group and 49 (21, 123) months for the continuous IM group. Survival curves were plotted using the Kaplan-Meier method and the log-rank test was performed to compare the TFR rates between groups. Results: There were 19 males and 23 females with a median age [M (Q1, Q3)] of 43 (31, 50) years in the sequential NIL group. There were 32 males and 29 females with a median age of 41 (31, 50) years in the continuous IM group. Kaplan-Meier survival curve analysis showed that the TFR rate was higher in the sequential NIL group than in the continuous IM group (88.1% vs 63.9%, P=0.005). The results of subgroup analysis showed that the TFR rates in Group 1, Group 2 and Group 3 were 94.1%, 87.5% and 82.4%, respectively, with no statistically significant differences (all P>0.05).The TFR rate in Group 1 was higher than in the continued IM group (P=0.017), and there were no statistically significant differences in Group 2 and Group 3 compared with the continuous IM group(all P>0.05). Conclusion: Sequential NIL therapy after achieving DMR with IM therapy can improve the TFR rate in CML patients, especially in those with DMR duration<12 months before switching to sequential NIL therapy.

TKI Dose Optimization Based on Therapeutic Drug Monitoring（TDM) with Encouraging Outcomes and Well-Tolerated for Chronic Myeloid Leukaemia Patients

Background Imatinib, nilotinib, and dasatinib are tyrosine kinase inhibitors (TKIs) that have become first-line treatments for Philadelphia chromosome-positive chronic myeloid leukemia (CML). Series studies indicated TKIs had a high therapeutic index, which led to the registration of these medications at fixed doses. Therapeutic drug monitoring (TDM) is a strategy for dosage optimization to provide individual treatment through dose adjustment to improve efficacy or avoid TKI-related adverse events (AEs). Objective We prospectively analyzed the outcome based on trough plasma concentrations (Cmin) to manage TKI dosage optimization during imatinib, nilotinib, and dasatinib therapy in patients with CML by 12 months. The primary efficacy endpoint was the rate of MMR at 12 months, the secondary endpoints included the cumulative rate of significant AEs defined as grade 3/4 fluid retention, all grade pleural effusion and pulmonary hypertension, grade 3/4 bilirubin increased, and grade 3/4 hematological toxicity related to TKIs within the first 12 months of therapy. Methods We examined 204 CML patients treated with imatinib, nilotinib, or dasatinib in the first line for CML-CP. We used high-performance liquid chromatography-tandem mass spectrometry (UPLC/MS-MS) to detect the Cmin of TKIs. Dasatinib or imatinib Cmin (24±3h post-dose) and nilotinib Cmin (12±3 h post-dose) were assessed after 7~10 days of therapy. We set the Cmin of imatinib at 1000~1500 ng/mL and that of nilotinib at 600~800 ng/mL, dasatinib at 1~3 ng/ml, respectively. Results Imatinib group (n = 67), Nilotinib group (n = 72), and Dasatinib group (n = 65), respectively. The initial dose of imatinib was 400mg qd, based on Cmin of imatinib was 900~1100ng/mL, there were 17 patients with dose reduction(1 case with 100mg qd, 5 cases with 200mg qd, 11 cases with 300mg qd) and 2 patients increased dose to 500mg qd; The initial dose of nilotinib was 300mg bid, based on Cmin of imatinib was 600~800ng/mL, there were 21 patients with dose reduction( 4 cases with 150mg bid, 16 cases with 450mg daily, 1 cases with 150mg qd) and 1 patients increased to 400mg bid; the initial dose of dasatinib was 100mg qd, based on Cmin of dasatinib was1~3 ng/ml, there were 32 patients with dose reduction(1 case with 20mg qd, 4 cases with 40mg qd, 20 cases with 50mg qd, 7 cases with 70mg qd ). Among the patients treated with imatinib, dasatinib, and nilotinib, no statistically significant associations were observed between gender, age, ELT scores, and plasma trough concentration (p&amp;gt;0.05). Early molecular reaction (EMR BCR: ABL(IS) &amp;lt;10%) was achieved by 83.6% (95% confidence interval [CI], 74.6%-92.5%) in the imatinib group, 87.7% (95% CI, 80.0%-95.4%) in the nilotinib group, and 83.3% (95% CI, 75.0%-91.7%) in the dasatinib group of patients at 3 months. The incidence of MMR at 12 months was 82.1% (95% CI, 73.1%-93.0%) in the imatinib group, 73.8% (95% CI, 64.6%-84.6%) in the nilotinib group, and 75.0% (95% CI, 65.3%-84.7%) in the dasatinib group, respectively. The cumulative incidence of grade 3/4 hematological toxicity was 7.8% (16/204), all-grade pleural effusion was 23.1% (15/65) in the dasatinib group, grade 3/4 bilirubin increased was 6.9% (5/72) in the nilotinib group, and there were no patients with pulmonary hypertension. Conclusion There are large individual differences in plasma trough concentrations in CML patients taking TKIs, the TKI dosage should be adjusted based on target plasma concentrations to maximize efficacy and minimize the incidence of adverse events.

Flumatinib Versus Nilotinib for Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia

Introduction Tyrosine kinase inhibitors (TKIs) have considerably improved the long-term clinical outcomes in patients with chronic phase chronic myeloid leukemia (CML-CP). Most of these patients receive 1 st generation TKI imatinib as first-line therapy; however, an increasing number of patients are now receiving 2 nd generation TKIs as first-line therapy, because of the more potent BCR-ABL1 inhibition with proven efficacy in patients resistant or intolerant to imatinib. Flumatinib is a novel 2 nd generation BCR-ABL1 TKI with promising efficacy and manageable safety in newly diagnosed CML-CP. Compared to imatinib, patients treated with flumatinib have achieved significantly higher rates of 12-month major molecular response (MMR) and complete cytogenetic response were observed in patients with CML-CP and that too within a shorter time duration. Though there have been many studies comparing 2 nd generation TKIs vs imatinib in CML-CP, studies comparing clinical outcomes between different 2 nd generation TKIs are scarce. Here, we report the real-world effectiveness and safety of flumatinib and nilotinib in patients with newly diagnosed CML-CP. Methods In this study, adult patients (≥18 years old) with newly diagnosed Philadelphia chromosome-positive (Ph+) CML-CP who received either 300 mg nilotinib twice daily or 600 mg flumatinib once daily, were included, with a follow-up duration of roughly 3 years (NCT04739826). The primary endpoint was the rate of MMR at 12 months as defined by European LeukemiaNet 2020 recommendations (BCR-ABL1 transcript level ≤0.1% in peripheral blood on RT-PCR assay on International Scale [IS]).The secondary endpoints were the rate of early molecular response (EMR) at 3 months (BCR-ABL1 IS ≤10%), the rate of molecular response at 6 months (BCR-ABL1 IS ≤ 1%) and safety (adverse events [AEs] reports in accordance to Common Terminology Criteria for Adverse Events, version 4.03). Results A total of 446 patients were enrolled in the study between November 2020 and August 2022, of which 150 and 296 patients were enrolled in nilotinib and flumatinib groups, respectively. The baseline characteristics were comparable between the two groups (Table 1). No significant difference in the rate of MMR was observed at 12 months between nilotinib and flumatinib (78% vs 80%; P=0.68) . Similarly, no significant difference was observed in the rate of EMR at 3 months (85% vs 89%; P=0.26) and the rate of optimal molecular response at 6 months (93% vs 92%; P=0.70; BCR-ABL1 is ≤1%) between the two groups. The overall safety profile was similar between the two groups. However, hyperbilirubinemia (47% vs 7%), increased ALT (33% vs 12%), increased AST (24% vs 9%), rash (30% vs 18%) and anemia (19% vs 10%) were more frequent in nilotinib group than flumatinib group, whereas diarrhea was lower in nilotinib than flumatinib (2.7% vs 8.8%). The incidence rate of grade 3-4 AEs were reported to be 13% in nilotinib group and 10% in flumatinib group. The safety of flumatinib was more favorable compared to nilotinib in terms of hepatic toxicities, skin toxicities, etc. (Figure 1). Conclusion The efficacy of flumatinib is comparable to nilotinib in Chinese patients with newly diagnosed Ph+ CML-CP. The overall incidences of grade 3-4 AEs were also accessible for the two drugs, nevertheless, a few AEs inclusively hepatic toxicity, anemia and skin toxicity were remarkably lower with flumatinib intervention.

BCR-ABL Tyrosine Kinase Inhibitors in Parkinson’s Disease and Lewy Body Dementia: A Systematic Review (P2-11.009)

<h3>Objective:</h3> To assess the effect of BCR-ABL Tyrosine Kinase Inhibitors (TKI) on Parkinson’s Disease (PD) and Lewy Body Dementia (LBD). <h3>Background:</h3> Abelson tyrosine kinase activation is higher in PD. Inhibiting its activation could be a disease-modifying therapy. <h3>Design/Methods:</h3> On a systematic review of MEDLINE, Embase, and Cochrane, 427 papers were selected after deduplication. RCTs and Non-RCTs on BCR-ABL TKI in PD and LBD were included using a PRISMA protocol. After full-text screening, 6 articles remained. <h3>Results:</h3> 189 patients were randomized into 2 groups: BCR-ABL TKI vs Levodopa equivalent daily dose. Pagan et al., 2016 analyzed Nilotinib in PD and LBD with an average decrease of 3.4 and 3.6 points on the UPDRS-III, and 7 and 11.1 in the UPDRS I–IV score with 150 and 300 mg, respectively. Simuni et al., 2020 evaluated 76 patients for both doses of Nilotinib in moderately advanced PD; the results showed no difference in MDS-UPDRS-III OFF and a worsening in MDS-UPDRS-III ON. Pagan et al., 2019 randomized 75 patients into both doses of Nilotinib, resulting in a 2.82 points reduction in the MDS-UPDRS-III for Nilotinib 150 mg. MDS-UPDRS I-III and MDS-UPDRS I–IV scores increased by 2.47 and 2.13 points in the placebo group but remained stable in the Nilotinib groups. Pagan et al., 2021 randomized 63 of the same patients for Nilotinib 150 vs 300 mg, suggesting that Nilotinib 300 mg maintained stability for 27 months while Nilotinib 150 mg did not. Pagan et al., 2022 randomized 26 patients for Busotinib in LBD with no impact in UPDRS I, II, or III. Also, Watson-Fargie et al., 2018 reported in a review of 2 cases that Imatinib could reduce UPDRS-III progression in PD. <h3>Conclusions:</h3> Reviewed data suggests possible stabilization but no solid clinical improvement. Larger-sample trials might bring further information on all 3 drugs and BCR-ABL TKI in general. <b>Disclosure:</b> Mr. Berton has nothing to disclose. Ms. Rodrigues has nothing to disclose. Mr. Borges has nothing to disclose. Miss Cardoso has nothing to disclose. Dr. Marques has nothing to disclose. Dr. OLIVEIRA has nothing to disclose.

Kinetic of liver enzymes and serum electrolytes in HCV, HBV, and HIV negative chronic phase chronic myeloid leukemia patients treated with imatinib or nilotinib

The outcome for chronic phase (CP) chronic myeloid leukemia (CML) patients was changed dramatically since the introduction of tyrosine kinase inhibitor (TKI) therapy. This study intended to evaluate side effects of TK Imatinib or Nilotinib on liver enzymes and serum electrolytes in relation to hematologic and molecular response in HCV-, HBV-, and HIV-, CP-CML patients. The study was a quasi-experimental pre-post single group design, included 38 HCV-, HBV-, and HIV-newly diagnosed Philadelphia positive CP-CML patients with normal hepatic and renal function. They were divided equally into two groups, 19 received Nilotinib, and 19 received Imatinib. Hematologic, BCR-ABL gene expression by RT-PCR, electrolytes and liver enzymes were measured at baseline and after 6 months of treatment. Patients age ranged between 20 and 62 years. Anemic manifestations represented the highest rate (n=23, 60.5%). The mean WBCs count was significantly reduced after treatment (p < 0.001). The WBCs count was significantly reduced in the Nilotinib group than the Imatinib group (97% and 94%, respectively, p=0.049). The mean hemoglobin level was significantly increased after treatment (p=0.010). The mean platelet level did not change over the treatment period. The mean AST, ALT, and ALP levels were significantly increased after treatment, (p=0.014, p=0.002, and p=0.047, respectively). The ALP level was significantly increased in both groups (p=0.001). The mean sodium potassium, phosphorous, and calcium level was not changed over the treatment period. The mean BCR-ABL gene expression was sharply decreased after treatment (p < 0.001). A higher reduction was observed in the Nilotinib group (99%) than the Imatinib group (91.5%) (p=0.025). Imatinib resulted in rise of AST and ALP levels than Nilotinib, while both had the same effect on the ALT level. Higher reduction in BCR-ABL gene expression was achieved by Nilotinib. Nilotinib and Imatinib did not affect serum levels of sodium, potassium, phosphorous, or calcium.

Induction–maintenance approach for the chronic phase of chronic myeloid leukaemia (IMPACT-I): a prospective, single-arm, phase 2 study

Imatinib and second-generation tyrosine-kinase inhibitors (2G-TKIs) are standard options for the first-line treatment of chronic myeloid leukaemia. Although 2G-TKIs are superior to imatinib in terms of rate and depth of molecular response, they do not bring significant improvements in survival outcomes, and concerns exist over their long-term safety. The availability of a generic formulation makes imatinib an attractive economical option. We propose a novel induction-maintenance approach that would have the advantage of inducing early molecular response with 2G-TKIs, followed by maintenance with the safer and more affordable imatinib. IMPACT-I was a prospective, single-arm, phase 2 study done at Queen Mary Hospital, a university-affiliated tertiary hospital in Hong Kong. Adult patients with chronic myeloid leukaemia in chronic phase were enrolled after providing written informed consent. Inclusion criteria were having received a 2G-TKI as a first-line treatment for at least 12 months, and to have had a sustained and good molecular response (defined as a BCR-ABL1 level of ≤0·1%) for at least 6 months. Patients who had documented mutations in the kinase domain or a history of switching tyrosine-kinase inhibitors due to unsatisfactory responses were excluded. After switching to imatinib, participants were followed up for clinical, haematological, and molecular monitoring (bimonthly in the first 6 months, quarterly in months 7-12; and every 3-6 months thereafter, with follow-up ongoing at the time of writing). Molecular response was assessed according to the International Scale as the ratio of BCR-ABL1 transcripts to ABL1 transcripts with an assay sensitivity of molecular response of at least 4·5 (MR4·5) at least. Molecular tests were repeated at 1-month intervals if BCR-ABL1 was higher than 0·1% but less than 1%. Molecular progression was defined as BCR-ABL1 of at least 1% at one timepoint, or BCR-ABL1 higher than one 0·1% but less than 1% in two consecutive tests. The primary outcome was molecular progression-free survival at 6 months after switching to imatinib. Ten patients were enrolled between Aug 9, 2017, and April 27, 2021. Six patients had had dasatinib for at least 12 months, and four patients had had nilotinib for at least 12 months. The median duration of 2G-TKI treatment before the switch was 42·5 months (IQR 32·5-52·5) and the median durations of good molecular response before the switch was 30·0 months (IQR 19·5-41·5). All except one patient (on the nilotinib group) had adverse reactions of grades 1-3 on the Common Terminology Criteria for Adverse Events (CTCAE) to 2G-TKIs, with rash (two in the nilotinib group, two in the dasatinib group) and pleural effusion (none in the nilotinib group, three in the dasatinib group) being the most common. After a median follow-up of 41·0 months (IQR 11·0-50·6), all ten patients continued to have good molecular response. Molecular progression-free survival at 6 months was 100%. One patient, who was in molecular response 3 before withdrawal, exited the trial after 9 months of imatinib therapy for personal reasons. The other nine patients remained on generic imatinib as of the last follow-up on Dec 22, 2021; eight (89%) of nine were in deep molecular response (MR4·5 or greater). Imatinib was well tolerated. Only grade 1-2 toxic effects were observed, namely peripheral oedema, diarrhoea, and dyspepsia. Our study suggests that the induction-maintenance approach is safe and efficacious. All patients remain in good molecular response after switching to imatinib, and the vast majority of them had a deep molecular response. This practical strategy not only implies substantial pecuniary savings (estimated at US$30 000 per annum per patient), but also retains the possibility of treatment-free remission, bringing important and positive health-cost implications for low-income regions. 2017 Young Investigator Research Grant from the Hong Kong College of Physicians.

Comparative Risk Assessment of Imatinib, Nilotinib and Dasatinib in Randomized Controlled Trials: A Meta-Analysis

Background:Imatinib, nilotinib and dasatinib are standard frontline therapy for chronic myeloid leukemia (CML). Although generally safe, they are associated with adverse events (AEs), each with a distinct toxicity profile. We conducted a meta-analysis of reported AEs to assess their toxicity profile at a larger scale.Methods:We searched reports from Pubmed/Medline, CENTRAL Cochrane registry, clinicaltrials.gov, and available final trial reports from pharmaceutical companies. We selected randomized phase 2 and 3 trials where imatinib, nilotinib and/or dasatinib were used and all-grade and grade 3-4 AEs were reported. We calculated the relative risk (RR), 95% confidence interval (95CI), and I2 statistic testing of heterogeneity.Results:A total of 24 randomized clinical trials were included (11 phase 2, 13 phase 3) including 7491 pts treated for CML (15 studies), gastrointestinal stromal tumor (2), prostate cancer (3), breast cancer (2), pancreatic cancer (1), glioblastoma (1) and portal hypertension (1). (Table 1).Imatinib had a high risk of fluid retention: RR of all-grade peripheral edema 2.04 (95CI 1.68-2.49); periorbital edema 18.46 (10.38-32.83); face edema 4.31 (2.72-6.84); eyelid edema 10.43 (6.58-16.53); superficial edema 5.24 (4.22-6.5), fluid retention 2.19 (1.77-2.71). Correlation with grade 3-4 of these events was not statistically significant.Musculoskeletal AEs were also most common with imatinib: musculoskeletal pain, muscle spasm and elevated blood creatine phosphokinase had RR of 3.59 (2.86-4.51), 3.97 (3.15-4.99) and 3.26 (1.85-5.72). Muscle inflammation and muscle cramps were reported in 1 trial as 5.1 (2.65-9.82) and 5.2 (3.77-7.16). All-grade eye disorders in imatinib-treated patients had RR 2.07 (1.76-2.45).Hepatobiliary disorders dominated in the nilotinib group with RR 3.85 (2.82-5.27), specifically: elevated AST, elevated ALT, elevated GGT and hyperbilirubinemia : 1.8 (1.49-2.16), 2.83 (2.4-3.35), 2.83 (2.4-3.35), 11.98 (2.58-55.5) and 5.46 (4.33-6.88).Dasatinib-induced pleural effusion and associated symptoms were reported with RR of all-grade pleural effusion 6.21 (95CI: 4.51-8.56; p<0.00001); cough 1.39 (1.16-1.68; p=0.0005) and dyspnea 1.57(1.32-1.87; p<0.00001).Hematological toxicities, all-grade leucopenia, neutropenia and lymphopenia were more pronounced with imatinib RR 1.65 (1.41-1.93), 1.42 (1.31-1.53) and 1.21 (1.03-1.41), respectively. Corresponding values for grade 3-4 were 1.81 (1.15-2.86), 1.39 (1.17-1.65) and 3.02 (1.24-7.38). There was higher RR of high-grade infections with imatinib 2.07 (1.44-2.97). Dasatinib was associated with higher risk of all-grade anemia and thrombocytopenia : 1.25 (1.16-1.35) and 1.23 (1.1-1.37).For dermatological toxicities, nilotinib was associated with higher RR of all-grade rash, pruritis and alopecia : 2.46 (2.03-2.99), 2.4 (1.74-3.31) and 2.55 (1.65-3.96). Dasatinib was associated with dermatitis acneiform in 2 trials, RR 21.26 (3.67-123.07).Gastrointestinal toxicities varied by drug. All-grade nausea and vomiting were more common with imatinib: 1.19 (1.11-1.29) and 1.22 (1.06-1.4); nilotinib correlated with all-grade constipation 2.46 (1.8-3.37); and all-grade diarrhea with dasatinib 1.23 (1.13-1.33).Metabolic/electrolyte disturbances with imatinibincluded all-grade hypophosphatemia,hypocalcemia and hypokalemia : 1.8 (1.55-2.1), 1.31 (1.01-1.7) and 1.99 (1.51-2.63), and grade 3-4 hypophosphatemia 3.15 (2.28-4.36). Nilotinib had higher RR of hyperglycemia and elevated lipase 1.81 (1.48-2.22) and 1.46 (1.18-1.79).Conclusion:Our meta-analysis further demonstrates the different toxicity profile of different TKIs across several trials and different diseases. This information may be useful when selecting therapy for patients in need of a TKI. [Display omitted] DisclosuresKantarjian:Novartis: Research Funding; Delta-Fly Pharma: Research Funding; Pfizer: Research Funding; Amgen: Research Funding; Bristol-Meyers Squibb: Research Funding; ARIAD: Research Funding. Jabbour:Bristol-Myers Squibb: Consultancy. Cortes:Sun Pharma: Research Funding; Teva: Research Funding; Pfizer: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding.

Association of Tyrosine Kinase Inhibitors with Vascular Adverse Events: A Cohort Study Using Pooled Electronic Health Record

IntroductionTyrosine Kinase Inhibitor (TKI)-associated vascular adverse events (VAE) have emerged as one of the challenges in the management of chronic myeloid leukemia (CML). Available knowledge on association of TKIs with VAE mostly comes from randomized clinical trials but there are concerns about comprehensiveness of the reported data. This is because different trials have relied on differing definitions to capture VAE. It is generally considered that TKI-associated VAE reported in clinical trials are underestimates. In this retrospective cohort study, we used a clinical informatics approach to collect data on CML pts from multiple, distinct electronic health records across several different healthcare systems and report on the prevalence of VAE in CML cohorts treated on different TKIs.MethodsExplorys Enterprise Performance Management (EPM) is a HIPAA-compliant database containing de-identified clinical data on 50 million pts from 26 healthcare networks comprising 360 hospitals since 1999. As this database is HIPAA-compliant, IRB approval was waived by Cleveland Clinic IRB. In this study, we used the EPM database's “power search” tool to create CML cohort and then identified VAE events occurring after TKI initiation using specific temporal relationships. Power searches for data extraction relies on associating clinical informatics standard ontologies that includes Current Procedural Terminology (CPT) (for procedures), International Classification of Diseases 9th edition (ICD-9) and 10th edition (for diagnoses), logical observation identifiers names and codes (LOINC) (for laboratory information), Medical Subject Headings (MeSH) (for medical topics), RxNorm (for pharmacy information), and Systematized Nomenclature for Medicine - Clinical Terms (SNOMED-CT) (for medical terms). We created temporal attributes linking the CML cohort to outcome of interest (VAE) using SNOMED-CT diagnosis for VAE (included coronary, cerebrovascular and peripheral arterial disease, venous thrombosis among others) and subsequently mapping it with RxNorm (all anticoagulants or antiplatelet agents in clinical use for the study time period) and CPT codes (use of inferior vena cava filter or thrombectomy). All generated quantitative data using EPM database are rounded to the nearest 10 for the purposes of de-identification.ResultsUsing Explorys, we identified a total of 2750 CML pts who were treated with imatinib, 680 pts with dasatinib, 600 pts with nilotinib and 870 pts with 2 or more TKI's. Of the five TKIs, we excluded bosutinib and ponatinib from analysis because of low pt numbers (<100). Baseline demographic characteristics showing overall distribution of atherosclerotic disease in CML pts treated with these three TKIs are shown in Table 1. Of note, there was a high prevalence of coronary arteriosclerosis in these TKI-treated cohorts - 29% in imatinib cohort, 28% in nilotinib group and 22% in pts who received dasatinib. A total of 780 VAE (28%) were identified after initiation of imatinib - 19% (520/2750) of them were arterial events and 9.5% (260/2750) were venous. Following initiation of nilotinib, 160 VAE occurred with a prevalence rate of 26.6% - 18.3% (110/600) of them were arterial and 8.3% (50/600) were venous. After starting dasatinib, 150 VAE was identified with a prevalence rate of 22% - 14.7% (100/680) of them were arterial events and 7.4% (50/680) were venous. In CML pts treated with 2 or more TKIs, the prevalence of VAE was highest at 36.8% (320/870) - 24.1% (210/870) were arterial and 12.6% were venous events.Conclusions:In this population based study of CML pts using clinical informatics approach, we report a much higher rate of VAE, both arterial and venous in TKI cohorts compared to that reported in clinical trials. Ontology based linking of CML with outcomes of interest and cross confirmation with subsequent anticoagulation treatment received ensures accuracy of the reported events using this approach. Arterial vascular events ranged from 15-20% whereas venous events were reported in the range of 8-9% for the three TKIs examined. Surprisingly high rates of VAE noted in the imatinib cohort could be the result of lead time bias because of earlier introduction of imatinib. Additional analysis of this cohort is underway to characterize this association. [Display omitted] DisclosuresGerds:Incyte: Consultancy; CTI BioPharma: Consultancy. Advani:Takeda/ Millenium: Research Funding; Pfizer: Consultancy. Majhail:Sanofi: Honoraria; Anthem, Inc.: Consultancy. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees.

Preliminary Experience of Imatinib after Nilotinib in the First Line Treatment of Chronic Myeloid Leukemia

Background Chronic myeloid leukaemia (CML) is a clonal myeloproliferative disorder, hallmarked by the BCR-ABL fusion gene which encodes for a constitutively activated BCR/ABL tyrosine-kinase, effectively treated with Tyrosine-Kinase Inhibitors (TKIs). The first line TKI Imatinib (IM) can obtain a high cumulative CCyR; compared to IM, deeper and faster molecular responses can be obtained in newly diagnosed CML patients with the second generation TKIs, Nilotinib (NIL) and Dasatinib. Despite the three TKIs have been evaluable as first line therapy for a long time, our experience largely concern the second generation TKIs after IM but not evidence are reported regarding IM after second generation TKIs.On behalf of the Rete Ematologica Lombarda (REL) we designed the PhilosoPhi34 study (EudraCT: 2012-005062-34). This study was divided into three consecutive phases. An initial recruitment phase, a “core” phase of treatment lasting for 12 months (mos) and an “observational” phase lasting for an additional period of 24 mos. NIL 300 mg BID standard dose was administered for one year (“core” phase). At the end of this “core” phase of the trial, during the “observational” period, treatment options were up to the Investigator's choice (i.e. any TKI approved as first line treatment could be used), based on individual patient evaluation.Furthermore, fluctuations of BCR/ABL ratio are known, in particular during the two first years of CML treatment, characterized by a higher risk of disease progression or relapse.Aims Despite this consideration, our purpose is to verify time courses of Molecular Response (MR) IS in the IM treated patients, during the “observational” phase of the PhilosoPhi34 study.Methods We evaluate the PhilosoPhi34 database. MR IS is reported at 3, 6 and 12 mos of NIL treatment (“core” phase) and every 6 mos in the “observational” phase. Until now, the “observational” phase is ongoing and the database is unlocked.Results Among the 74 reported pts who started the “observational” phase, with at minimum a CCyR, 62 pts maintained NIL, 10 pts switched to IM and 2 pts switched to other TKI. Other two pts switched to IM after 18 and 24 months of NIL treatment (i.e. +6 mos and +12 mos of the “observational” phase, respectively). Among the 62 pts that maintained NIL, 33 showed a MR ≥ 4.0 IS and 20 showed a MR 3.0 IS. In the NIL group 15/62 pts showed an increase of the BCR/ABL ratio after 6 mos of the “observational” phase, but only 5/33 (15%) pts lost MR4.0 IS and 1/20 (5%) pts transient lost MR3.0 IS. Overall, 1/62 pts failed at 26 mos of treatment (+14 mos of “observational” phase) harbouring a resistant mutation. All the other NIL treated pts, despite molecular fluctuations, maintained or improved MR over time. Among the 10 pts that switched to IM after 12 mos of NIL treatment, 6 were in MR ≥ 4.0 IS and 4 in MR3.0 IS. Of them, 7/10 pts showed an increase of the BCR/ABL ratio but only 1/6 (16,6%) pts lost MR4.0 IS and 1/4 (25%) pts lost MR3.0 (Table1). No pts failed treatment. Of note, the probability to lose MR≥ 4.0 IS or MR 3.0 IS between NIL treated pts vs IM treated pts proved not significant with the Fisher's test (p: 0.43 and p: 0.28, respectively).Conclusion As expected, our preliminary data show fluctuation of BCR/ABL ratio and of MR IS. IM treated pts present initial molecular fluctuations statistically similar to the fluctuation showed by NIL treated pts evaluated at the same time point. Despite fluctuations, MR IS is maintained or improved, over time. More data are necessary to confirm these exploratory results. Pointing out the possible adverse events occurring during long-term NIL treatment and the percentage of CML pts with vascular or metabolic disease at diagnosis, we consider a short-term treatment with NIL before IM a new possible strategy for CML cure. [Display omitted] DisclosuresOrlandi:Novartis: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Incyte: Speakers Bureau. Iurlo:Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Rossi:Sanofi: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees.

Second Generation Tyrosine Kinase Inhibitors (2G-TKI) in the Frontline Treatment of Elderly Patients with Chronic Myeloid Leukemia

Background and Aims. Second generation tyrosine kinase inhibitors (2G-TKI) dasatinib (DAS) and nilotinib (NIL) have been recently licensed for the first-line treatment of patients (pts) with chronic myeloid leukemia (CML) of any age. However, real-life data related to the toxicity and efficacy of 2G-TKI in elderly CML pts are still lacking. To address this issue, we revised a cohort of 126 CML pts in chronic phase aged >65 years and treated frontline with 2G-TKI in 33 Italian Centers.Methods. Data from all consecutive CML pts aged >65 years treated frontline with 2G-TKI in both clinical trials and in the real-life setting from 10/2007 to 11/2016 at each participating Center were collected, focusing on efficacy and toxicity. Seventy-two pts were treated with DAS and 54 pts with NIL. The main clinical features of the pts at diagnosis are reported in the Table. In the DAS group, pts were significantly older and with a worse ECOG PS.Results. In the DAS group, the median interval from diagnosis to treatment was 23 days (IQR 14 - 32). The DAS starting dose was 100 mg/day in 61 pts (84.7%) and <100 mg/day in 11 pts (15.3%). Grade 3-4 hematologic and extra-hematologic toxicities were recorded in 8 (11.1%) and 12 (16.7%) pts, respectively. DAS therapy was permanently discontinued in 12 pts (16.6%) due to toxicity (in 6 pts during the first 12 months of treatment and in 6 subsequently). Pleural effusions of all WHO grades occurred in 14 pts (19.4%) after a median period of DAS treatment of 3.6 months (IQR 1.4 - 13.1): in 5 of them, pleural effusion occurred during the first 3 months. Overall, 66/72 pts (91.6%) achieved a complete cytogenetic response (CCyR), 56/72 (77.7%) a major molecular response (MR3) and 29/72 (40.3%) a deep molecular response (MR4.0/4.5). After a median treatment period of 27.8 months (IQR 19.1 - 37.5), 7 pts have died (1 due to a blastic transformation and 6 for unrelated causes). The cumulative overall survival at 24 months was 90.4% (95% CI 82.9 - 97.9).In the NIL group, the median interval from diagnosis to treatment was 27 days (IQR 15 - 71). The NIL starting dose was 600 mg/day in 49 pts (90.7%), 800 mg/day in 3 patients (5.6%) and <600 mg/day in 2 pts (3.7%), respectively. Grade 3-4 hematologic and extra-hematologic toxicities were detected in 5 (9.3%) and 10 (18.6%) pts, respectively. NIL therapy was permanently discontinued in 7 pts (13.0%) due to toxicity (in 1 pt during the first 12 months of treatment and in 6 subsequently). Grade 3-4 cardiovascular toxicities occurred in 7 pts (13.0%). Overall, 51/54 patients (94.4%) achieved a CCyR, 47/54 (87.0%) a major molecular response (MR3) and 30/54 (55.5%) a deep molecular response (MR 4.0/4.5). After a median treatment period of 41.1 months (IQR 20.3 - 52.6), 5 pts have died from unrelated causes. The cumulative overall survival at 24 months was 95.7% (95% CI 89.8 - 100).Conclusions. The present data shows that 2G-TKI could have a major role in the treatment of real-life CML pts aged >65 years. Indeed, both DAS and NIL proved very effective and with a favorable safety profile also in elderly subjects with comorbidities. [Display omitted] DisclosuresAbruzzese:Pfizer: Consultancy; Novartis: Consultancy; BMS: Consultancy; Incyte: Consultancy. Castagnetti:Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Iurlo:Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Bocchia:Novartis: Other: Travel grant; Celgene: Other: Travel grant; Roche: Other: Travel grant; Jansen: Other: Travel grant. Crugnola:Novartis: Honoraria; BMS: Honoraria; Celgene: Honoraria. Fava:Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Bonifacio:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees. Galimberti:Novartis: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Pfizer: Speakers Bureau; Incyte: Speakers Bureau. Tiribelli:Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Breccia:Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Pfizer: Consultancy; Incyte: Consultancy. Rosti:Bristol Myers Squibb: Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Incyte: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Foa:Gilead: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Sandoz: Consultancy, Speakers Bureau.

Hepatoprotective effect of the tyrosine kinase inhibitor nilotinib against cyclosporine-A induced liver injury in rats through blocking the Bax/Cytochrome C/caspase-3 apoptotic signaling pathway.

Cyclosporine-A (CsA) is a powerful immunosuppressive agent and hepatotoxicity results from CsA treatment. This study aimed to elucidate the effectiveness of tyrosine kinase inhibitor nilotinib against CsA-induced hepatotoxicity and the underlying molecular mechanisms. Male Sprague-Dawley rats were allocated into four groups and received drugs for 28 days as follows: Control group: received vehicle, Nilotinib group: received nilotinib (20 mg/kg orally), CsA group: received CsA by subcutaneous injection (20 mg/kg daily), CsA-nilotinib: received nilotinib and CsA. Serum lactate dehydrogenase (LDH), liver function biomarkers, hepatic levels of oxidative stress biomarkers, nuclear factor erythroid-2 like-2 (Nrf2), total antioxidant capacity (TAC), interleukin-2 (IL-2), IL-1β, IL-6, and cytochrome-C were assessed. Additionally, the protein levels and mRNA expression of Bcl2 associated X protein (Bax), caspase-3, nuclear factor-κB (NF-κB), hemoxygenase-1 (HO-1) were measured. Moreover, liver tissues were assessed histopathologically using hematoxylin-eosin and Masson trichrome stain. Nilotinib treatment decreased serum LDH, alanine aminotransferase, aspartate aminotransferase, and γ-glutamyltransferase (γ-GT), hepatic malondialdehyde, andcytochrome-C. It also increased superoxide dismutase, reduced glutathione, glutathione reductase, glutathione peroxidase, glutathione-S-transferase (GST), TAC, and Nrf2 compared to CsA-injected rats. In addition, nilotinib decreased NF-κB, IL-1β, IL-6, Bax, and caspase-3, while elevated IL-2 and immunoexpression of HO-1. Additionally, mRNA expression of Bax and caspase-3 was elevated and that of HO-1 and inhibitory protein κB-α was reduced in the nilotinib-treated group. Moreover, nilotinib significantly attenuated CsA-induced histopathological alterations.Nilotinib may have a promising role as a hepato-protective through its antiapoptotic, antioxidant, and anti-inflammatory effects.

Cardiovascular events and atherogenic lipid profile in chronic myeloid leukemia patients treated with nilotinib versus imatinib.

The aim of this study was to assess cardiotoxicity and potential adverse effects related to lipid metabolism during treatment with tyrosine kinase inhibitors (TKIs) imatinib and nilotinib in patients with chronic myeloid leukemia (CML). Eighty-two consecutive patients with CML, who received nilotinib and/or imatinib in a single haemato-oncological Slovak center between years 2002-2018 were evaluated in a retrospective study. The mean age was 55.8 years (range 22-77 years). Median of follow-up was 61.3 months. A significantly higher incidence of dyslipidemia, significantly higher levels of potential risk markers of cardiovascular disease small dense LDL cholesterol (sdLDL-CH) and a significant increase in total cholesterol were found in the patients during treatment with nilotinib in comparison to imatinib. Dyslipidemia led to drug therapy in 22 % of the patients in the nilotinib group. Fourteen percent of the patients in the nilotinib group had one or more cardiovascular events, including peripheral artery disease (10 %), myocardial infarction (4 %) and stroke (4 %). A higher risk of cardiovascular events and atherogenic dyslipidemia were associated with nilotinib therapy. Patients treated with TKI, especially nilotinib, require an early modification of cardiovascular risk factors and a careful cardiologic surveillance so that antileukemic therapy with this highly effective agent could continue (Tab. 4, Fig. 3, Ref. 32). Text in PDF www.elis.sk Keywords: tyrosine kinase inhibitors, cardiovascular events, dyslipidemia, small dense LDL-cholesterol, nilotinib, imatinib.

Global Longitudinal Strain of Chronic Granulocytic Leukemia Patients treated with Imatinib and Nilotinib

Objective: To determine left ventricular function of patients with Chronic Granulocytic Leukemia in Chronic Phase (CGL-CP) who received imatinib and nilotinib by using Global Longitudinal Strain (GLS) examination. Methods: This was a descriptive study involving 46 CGL-CP patients who received imatinib and nilotinib therapy at the Hemato-Oncology Clinic of the Internal Medicine Departement of Dr. Hasan Sadikin General Hospital,, Bandung, Indonesia. Sampling was performed consecutively during the period of October to December 2019. Variables assessed in this study were age, gender, BMI, length of treatment, hemoglobin level, Left Ventricular Ejection Fraction (LVEF) value, and Global Longitudinal Strain (GLS). Primary data were tested for normality using the Saphiro-Wilk test. Statistical analysis was performed using SPSS software version 25.0. Results: Thirty-nine patients (seventeen males and twenty-two females with a mean age of 42±11) who had been in therapy for about 8 to 179 months at the time of the study were included as subjects. On average, the GLS results for both treatment groups indicated a normal value based on the classification of the American Society of Echocardiography. The imatinib group gained a score of -22.4% (average range = -16.4% to (-28.1%)), while the nilotinib group gained a score of -21.6% (average range = -18.0% to (-25.9%)). Conclusion: This study described the left ventricular function based on results of GLS in CGL-CP patients receiving imatinib and nilotinib.

Movement disorders in 2020: clinical trials, genetic discoveries, and COVID-19

Movement disorders in 2020: clinical trials, genetic discoveries, and COVID-19

Nilotinib effects on safety, tolerability, and biomarkers in Alzheimer’s disease: A phase 2, double‐blind, randomized, placebo‐controlled trial

AbstractBackgroundThe goal is to assess the safety, tolerability, and pharmacokinetics of nilotinib, and measure biomarkers in participants with mild to moderate dementia due to Alzheimer’s disease. We hypothesized that nilotinib is safe and detectable in cerebrospinal fluid. Nilotinib may alter disease biomarkers and potentially slow clinical decline.MethodThis is a single‐center, phase 2, randomized, double‐blind, placebo‐controlled study. Of 117 individuals approached, 13 declined, 51 were excluded, 51 were screened, and 37 were randomized 1:1 to placebo or nilotinib groups. The Alzheimer’s disease diagnosis was supported by cerebrospinal fluid or amyloid positron emission tomography biomarkers. Nilotinib 150 mg vs matching placebo was taken orally once daily for 26 weeks followed by nilotinib 300 mg vs placebo for another 26 weeks.ResultOf the 37 individuals enrolled, 27 were women (73%), and the mean (SD) age was 70.7 (6.48) years. Nilotinib was safe and well‐tolerated, although more adverse events, particularly mood swings, were noted at the 300 mg dose (70.6%) vs placebo (0%) groups (p&lt;.01). In the nilotinib group, amyloid burden was reduced in the temporal (‐0.08, 90% CI, ‐0.21 to ‐0.01, p=.04) and frontal lobes (‐0.19, 90% CI, ‐2.29 to ‐0.08, p&lt;.001) compared to the placebo group. Cerebrospinal fluid Aβ40 was reduced at 6 months (566ng/ml, 90% CI, 135 to 1018, p=.02) and Aβ42 was reduced at 12 months (73.9 ng/ml, 90% CI, 14.3 to 137.9, p=.02) in the nilotinib group compared to the placebo. Hippocampal volume loss was attenuated (‐27%) at 12 months and phospho‐tau181 was reduced at 6 months (‐31.6%) and 12 months (‐39.6%) in the nilotinib group.ConclusionNilotinib is safe and well‐tolerated, and achieves pharmacologically relevant brain concentrations. Biomarkers of Alzheimer's disease were altered in response to nilotinib treatment. These data support a larger, multi‐center, phase 3 study to determine the safety and efficacy of nilotinib in Alzheimer’s disease. ClinicalTrials.gov NCT02947893.

Four-Dimensional Echocardiographic Evaluation of Left Ventricular Systolic Functions in Patients with Chronic Myeloid Leukaemia Receiving Tyrosine Kinase Inhibitors.

Tyrosine kinase inhibitors (TKIs) are established treatment for haematological malignancies. However, cardiac adverse effects, including the reduction in left ventricular ejection fraction and symptomatic heart failure remain clinical problems. The purpose of this study was to evaluate the left ventricular systolic functions in patients with chronic myeloid leukaemia receiving TKIs. A cross-sectional and observational study was conducted of 37 patients with chronic myeloid leukaemia receiving dasatinib or nilotinib after imatinib failure. Left ventricular systolic functions were evaluated using four-dimensional speckle tracking echocardiography derived global longitudinal (GLS), circumferential (GCS), radial (GRS), and area (GAS) strain indices. Mean ejection fraction, stroke volume, cardiac output and left ventricular mass index were similar between control and patient groups and within normal limits. GLS (- 16.7% vs - 20.8%, p < 0.001), GCS (- 13.0% vs - 15.6%, p = 0.002), and GAS (- 26.2% vs - 31.0, p < 0.001) values were significantly higher in the patient population than those of the controls. Dasatinib and nilotinib groups did not show differences regarding strain indices. In multivariate regression analysis, only the usage of dasatinib or nilotinib was found to be an independent risk factor for diminished GAS (β = 4.406, p = 0.016), GLS (β = 3.797, p = 0.001), and GCS (β = 2.404, p = 0.040). Although imatinib, nilotinib, and dasatinib seem to be clinically safe in terms of cardiac function, monitoring of systolic functions using strain imaging, and long-term observation of patients may provide early detection of the possible cardiac toxicity.

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.

Nilotinib Effects on Safety, Tolerability, and Biomarkers in Alzheimer's Disease

ObjectivePreclinical evidence with nilotinib, a US Food and Drug Administration (FDA)‐approved drug for leukemia, indicates improvement in Alzheimer's disease phenotypes. We investigated whether nilotinib is safe, and detectable in cerebrospinal fluid, and alters biomarkers and clinical decline in Alzheimer's disease.MethodsThis single‐center, phase 2, randomized, double‐blind, placebo‐controlled study investigated the safety, tolerability, and pharmacokinetics of nilotinib, and measured biomarkers in participants with mild to moderate dementia due to Alzheimer's disease. The diagnosis was supported by cerebrospinal fluid or amyloid positron emission tomography biomarkers. Nilotinib 150 mg versus matching placebo was taken orally once daily for 26 weeks followed by nilotinib 300 mg versus placebo for another 26 weeks.ResultsOf the 37 individuals enrolled, 27 were women and the mean (SD) age was 70.7 (6.48) years. Nilotinib was well‐tolerated, although more adverse events, particularly mood swings, were noted with the 300 mg dose. In the nilotinib group, central nervous system (CNS) amyloid burden was significantly reduced in the frontal lobe compared to the placebo group. Cerebrospinal fluid Aβ40 was reduced at 6 months and Aβ42 was reduced at 12 months in the nilotinib group compared to the placebo. Hippocampal volume loss was attenuated (−27%) at 12 months and phospho‐tau‐181 was reduced at 6 months and 12 months in the nilotinib group.InterpretationNilotinib is safe and achieves pharmacologically relevant cerebrospinal fluid concentrations. Biomarkers of disease were altered in response to nilotinib treatment. These data support a larger, longer, multicenter study to determine the safety and efficacy of nilotinib in Alzheimer's disease. ANN NEUROL 2020 ANN NEUROL 2020;88:183–194

Induction and maintenance for chronic myeloid leukemia-chronic phase: A novel treatment strategy.

e19526 Background: Imatinib remains the standard of care for CML-CP in many countries because of its affordability and safety with long term use. Given that upfront Nilotinib has higher rates of major molecular response and early deep responses predict long term responses, we hypothesized that upfront Nilotinib as induction followed by Imatinib maintenance may help to capitalize on the efficacy of Nilotinib without sacrificing the safety and efficacy of Imatinib. Methods: CML CP patients were divided into 3 groups at the time of diagnosis. Group 1 received Imatinib 400mg OD upfront, Group 2 and 3 received Nilotinib 300 mg BD for 1st 3 and 6 months respectively then switched over to Imatinib 400 OD. Quantitative real time PCR for BCR-ABL (RQ PCR for BCR-ABL) was done at 3, 6,12, 18, 24, 30, and 36 months to assess response. 3 early molecular responses were defined for analysis. EMR 1 was defined as Bcr-abl RQPCR &lt; 10% at 3 months, EMR 2 as &lt; 1% at 6 months and EMR 3 as &lt; 0.1% at 6 months. Results: Patients on Nilotinib induction had deeper responses than patients on Imatinib at 3 and 6 months. However, subsequent molecular responses were similar in all 3 groups. The rates of Early Molecular responses were significantly better in the Nilotinib group compared to the Imatinib group. Significantly lesser patients in Group 1 had EMR 1 compared to Groups 2 and 3 [80.49% vs 100% vs 95.56%, p value 0.001]. Results were similar for EMR 2 and 3 [EMR 2: 34.15% vs 42.11% vs 60%, p value 0.017, EMR 3: 25.71% vs 25.53% vs 44.44%, p value Group 1 vs Group 3: 0.030]. TKI failure/progression rates were significantly better amongst patients who achieved EMR vs those who did not achieve EMR for EMR 2 and 3 but not EMR 1. For EMR 2, 42.68% who did not achieve EMR eventually had TKI failure compared to 18.03% of those who achieved EMR (p value 0.002). Similarly, 32.95% who failed to achieve EMR 3 progressed vs 11.9% of those who achieved EMR 3 (p value 0.011). 3 patients in group 1 and 1 patient in group 2 developed T315I mutation while none did in Group 3. Conclusions: The early advantage achieved with Nilotinib Induction was not sustained after switching to Imatinib maintenance. Nevertheless, target responses were still achieved and similar failure rates were present in all 3 groups. Patients who attained an EMR &lt; 1 % at 3 months or &lt; 0.1% at 6 months tend to have higher EFS and lower rates of TKI failure/progression irrespective of the treatment arm.

Nilotinib Effects on Safety, Tolerability, and Potential Biomarkers in Parkinson Disease

This study evaluated nilotinib safety and its effects on biomarkers as a potential disease-modifying drug in Parkinson disease. To assess nilotinib effects on safety and pharmacokinetics and measure the change in exploratory biomarkers in patients with moderately severe Parkinson disease. This was a single-center, phase 2, randomized, double-blind, placebo-controlled trial with 300 patients approached in clinic; of these, 200 declined to participate, 100 were screened, 25 were excluded, and 75 were randomized 1:1:1 into placebo; nilotinib, 150-mg; or nilotinib, 300-mg groups. Recruitment started on May 17, 2017, and ended April 28, 2018, and follow-up ended August 10, 2019. Parkinson disease was confirmed according to the UK Brain Bank diagnostic criteria and symptoms were stabilized with use of optimal levodopa and/or dopamine agonists and other medications used in Parkinson disease. Nilotinib vs placebo, administered orally once daily for 12 months followed by a 3-month washout period. It was hypothesized that nilotinib is safe and can be detected in the cerebrospinal fluid, where it alters exploratory biomarkers via inhibition of Abelson tyrosine kinase and potentially improves clinical outcomes. Of the 75 patients included in the study, 55 were men (73.3%); mean (SD) age was 68.4 (8.2) years. Doses of 150 or 300 mg of nilotinib were reasonably safe, although more serious adverse events were detected in the nilotinib (150 mg: 6 [24%]; 300 mg: 12 [48%]) vs placebo (4 [16%]) groups. The 150-mg nilotinib group showed an increase in cerebrospinal fluid levels of the dopamine metabolites homovanillic acid (159.80nM; 90% CI, 7.04-312.60nM; P = .04) and 3,4-dihydroxyphenylacetic acid (4.87nM; 90% CI, 1.51-8.23nM; P = .01), and the 300-mg nilotinib group showed an increase in 3,4-dihydroxyphenylacetic acid (7.52nM; 90% CI, 2.35-12.69nM; P = .01). The nilotinib 150-mg but not the nilotinib 300-mg group demonstrated a reduction of α-synuclein oligomers (-0.04 pg/mL; 90% CI, -0.08 to 0.01 pg/mL; P = .03). A significant reduction of hyperphosphorylated tau levels was seen in the nilotinib 150-mg (-10.04 pg/mL; 90% CI, -17.41 to -2.67 pg/mL; P = .01) and nilotinib 300-mg (-12.05 pg/mL; 90% CI, -19.21 to -4.90 pg/mL; P = .01) groups. In this study, nilotinib appeared to be reasonably safe and detectable in the cerebrospinal fluid. Exploratory biomarkers were altered in response to nilotinib. Taken together, these data will guide the development of a phase 3 study to investigate the effects of nilotinib therapy in patients with Parkinson disease. ClinicalTrials.gov identifier: NCT02954978.