Nilotinib Group Research Articles

PHC-016 Nilotinib Versus Imatinib For the Treatment of Patients with Newly-Diagnosed Philadephia Chromosome-Positive, Chronic Myeloid Leukaemia in the Chronic Phase

BackgroundNilotinib is a BCR-ABL inhibitor designed to be more potent and selective than imatinib. Imatinib was the first of a new class of drugs that act by specifically inhibiting a...

Nilotinib-mediated mucosal healing in a rat model of colitis

To investigate the effects of nilotinib in a rat model of trinitrobenzene sulfonic acid (TNBS)-induced colitis. Twenty-one Wistar albino female rats obtained from Dokuz Eylul University Department of Laboratory Animal Science were categorized into a control (n = 7), TNBS (n = 7) and nilotinib group (n = 7). Saline was administered orally for 14 d to the control and the TNBS group. The TNBS group received rectal TNBS on the first day while saline was administered to the control group. The nilotinib group received 20 mg/kg nilotinib for 14 d in 2 divided doses, starting the same day as TNBS administration. For 14 d, the rats were fed a standard diet, and their weights were recorded daily. After sacrifice, colon tissue samples from each group were scored for macroscopic and microscopic pathology. Apoptotic indices were determined by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling method. Platelet-derived growth factor receptor (PDGFR) alpha and beta levels were assessed through immunohistochemistry staining scores and compared among the groups. Tissue and serum tumor necrosis factor (TNF) alpha levels were determined by enzyme-linked immunosorbent assay. Between days 1 and 14, the nilotinib group rats lost significantly less weight than the TNBS group rats (-0.7 g vs -14.0 g, P = 0.047). The difference in weight between the control and nilotinib groups was also statistically significant (+8.3 g vs -0.7 g, P = 0.031). From day 7 to day 14, the weight differences of the control group vs the TNBS group, the TNBS group vs the nilotinib group, and the control group vs the nilotinib group were all statistically significant (+8.0 g vs -11.1 g, P = 0.007; -11.1 g vs +2.9 g, P = 0.015; +8.0 g vs +2.9 g, P = 0.042, respectively). Macroscopic and microscopic scores were significantly lower in the nilotinib group than in the TNBS group (0.00 ± 0.00 vs 1.43 ± 0.65, P = 0.009; 2.86 ± 0.55 vs 7.71 ± 1.48, P = 0.030, respectively). However, these scores were similar between the nilotinib and control groups. While no significant difference for the nilotinib vs control groups could be determined for PDGFR alpha and beta scores, PDGFR alpha and beta scores were lower in the nilotinib group than in the TNBS group. Furthermore, the TNF alpha levels in the serum, tissue and apoptosis scores were similar between the nilotinib and TNBS groups. Nilotinib prevents weight loss, facilitates mucosal healing by improving the pathological scores without introducing variation into the apoptotic scores or TNF alpha levels.

Effect of tyrosine kinase inhibitors, imatinib and nilotinib, in murine lipopolysaccharide-induced acute lung injury during neutropenia recovery

IntroductionNeutrophil recovery has been implicated in deterioration of oxygenation and exacerbation of preexisting acute lung injury (ALI). The aim of this study was to investigate whether imatinib or nilotinib was effective on lipopolysaccharide (LPS)-induced ALI during neutropenia recovery in mice.MethodsMice were rendered neutropenic with cyclophosphamide prior to the intratracheal instillation of LPS. Imatinib or nilotinib was administrated by oral gavage during neutropenia recovery. In order to study the effects of drugs, mice were killed on day 5 and blood, bronchoalveolar lavage (BAL) fluid and lung tissue samples were obtained. The lung wet/dry weight ratio and protein levels in the BAL fluid or lung tissue were determined.ResultsTreatment with imatinib or nilotinib significantly attenuated the LPS-induced pulmonary edema, and this result was supported by the histopathological examination. The concentrations of tumor necrosis factor-α, interleukin (IL)-1β, IL-6 and myeloperoxidase in BAL fluid were significantly inhibited by imatinib or nilotinib in mice of ALI during neutropenia recovery. The mRNA expressions of platelet-derived growth factor receptor-β and c-KIT in imatinib or nilotinib group were significantly lower than LPS group.ConclusionsOur data indicated that imatinib or nilotinib effectively attenuated LPS-induced ALI during neutropenia recovery. These results provide evidence for the therapeutic potential of imatinib and nilotinib in ALI during neutropenia recovery.

Restrospective Multicenter Study Evaluating Efficacy and Safety of Dasatinib and Nilotinib in Patients with Imatinib-Resistant or –intolerant Chronic Myeloid Leukemia in Chronic Phase: Korean CML Working Party

AbstractAbstract 1691Dasatinib and nilotinib have been founded to be effective and well-tolerated in patients who develop resistance or intolerance to imatinib. Not enough data are currently available to recommend one over the other as the preferred second-line therapy based on efficacy data. Therefore we planned a multicenter retrospective study to analyze the efficacy and safety of dasatinib and nilotinib in patients with imatinib-resistant or –intolerant chronic myeloid leukemia in chronic phase. In this Korean multicenter study, 126 patients imatinib-resistant or –intolerant chronic myeloid leukemia in chronic phase were treated with dasatinib (n=76) or nilotinib (n=50) The purpose of this study was to compare rates of cytogenetic and molecular response rate, event-free survival (EFS), progression-free survival (PFS) and overall survival (OS), and toxicities of nilotinib and dasatinib treatment of imatinib-resistant or –intolerant chronic myeloid leukemia in chronic phase. PFS was defined as the time from the start of treatment to the earliest date of any of following event: loss of complete hematologic response (CHR), loss of major cytogenetic response (MCyR), progression to accelerated phase (AP) or blastic phase (BP), discontinuation due to treatment failure as assessed by the clinician, and death from any cause on therapy. Event was defined by any one of the following: loss of CHR, loss of MCyR, progression to AP or BP, discontinuation due to treatment failure as assessed by the clinician, treatment discontinuation due to toxicity, and death from any cause on therapy. For dasatinib and nilotinib group, median ages (51 years old vs. 53), median durations of CML (23.7 months vs. 19.8 ) before receiving dasatinib or nilotinib and duration of prior imatinib treatment (21.7 months vs 17.7) were comparable. Nilotinib group had a higher proportion of intermediate and high sokal scores at the time of diagnosis than dasatinib group (41.5 vs 29.3% (high), 41.5% vs 32.5%(intermediate), 17.1% vs 37.9(low), p= 0.04). After median follow-up durations of 20.2 months of dasatinib group and 25.3 months of nilotinib group, the rates of major molecular response were 50.0% for dasatinib group and 59.6% for nilotinib group (p=NS) and the rates of MCyR (complete and partial cytogenetic response) were 78.4% for dasatinib group and 74.5% for nilotinib group (p=NS). The estimated EFS at 24 months was 67% and 48% in dasatinib and nilotinib group, respectively. (p<0.05). The estimated PFS at 24 months was 85% and 56% in dasatinib and nilotinib group, respectively. (p<0.05) Overall survival rates were comparable in both treatment groups (24-months OS; dasatinib 91%, nilotinib 94%; p=0.65). Both were generally well tolerated. Hematologic toxicities were more frequent among patients receiving dasatinib. 10 patients (13%) had pleural effusion in dasatinib; 9 events were grade 1 or 2. Elevated liver enzyme were more frequent among patients receiving dasatinib. In conclusion, In this study population, nilotinib and dasatinib showed similar cytogenetic and molecular response rates and survival. Toxicity profiles of two drugs were different and both drugs showed tolerable toxicities. In terms of event-free survival and progression-free survival, dasatinib was superior to nilotinib, but caution is warranted in interpretation because baseline characteristics including hematologic and cytogenetic response at the time of start with dasatinib and nilotinib and sokal scores at the time of diagnosis were different. Disclosures:No relevant conflicts of interest to declare.

Progressive Peripheral Arterial Occlusive Disease and Other Vascular Events During Nilotinib Therapy in Chronic Myeloid Leukemia

AbstractAbstract 1679Recent data suggest that second-generation tyrosine-kinase inhibitor (TKI) dasatinib and nilotinib can be responsible for increased non-hematologic adverse events in comparison to imatinib. In particular, there are a few reports of severe peripheral arterial occlusive disease (PAOD) and other vascular occlusive events (infarction) in patients receiving nilotinib. With this in mind we retrospectively evaluated incidence of PAOD or other vascular occlusive events in our cohort including 82 consecutive chronic myeloid leukemia (CML) patients treated at our institution with imatinib alone (n=55) or nilotinib as first-line (n=17) or second-line treatment after imatinib failure (n=10). After a median time of exposition to nilotinib of 24 months (range, 7–34 months) 4 (14.8%) out of 27 patients developed an episode of severe and previously unrecognized PAOD or other vascular occlusive events (2 PAOD, 1 myocardial infarction, 1 ictus). All 4 patients were more than 60 years old and 3 out of 4 were male while obesity was never observed. A history of nicotine abuse could be found in 2 out of 4 patients. The same applied when we looking for the presence of arterial hypertension (2/4) or dyslipidemia (2/4). When 55 patients treated with imatinib were analyzed for PAOD or other vascular occlusive event incidence we detected only one patient who experienced myocardial infarction after 135 months of therapy.We then evaluated the likelihood of developing PAOD in the subset of patients treated only with imatinib and in those who received nilotinib, respectively. The projected 10-year actuarial probability of remaining PAOD-free was 100% in the imatinib group and 67% in the nilotinib group (HR, 14.6; P=0.0008). Interestingly, the two patient cohorts were alike with respect to age (P=0.76), gender (P=0.80), number cardiovascular risk factors (P=0.62) and body mass index (P=0.59). The only difference we observed was a significantly longer exposition to drug among patients treated only with imatinib in comparison to those who received nilotinib (P<0.001).In conclusion this study although hampered by the relatively small patient number suggests that in CML front-line and second-line treatment should be adapted to the individual situation in each patient. Parameters related to risk of developing TKI-associated adverse PAOD events should be considered before choosing a second-generation TKI. Disclosures:No relevant conflicts of interest to declare.

Incidence and Outcomes of Chronic Myeloid Leukemia (CML) Patients (pts) with Other Chromosomal Abnormalities (OCA) Treated with Second Generation Tyrosine Kinase Inhibitors (TKI)

AbstractAbstract 4311 Background:Development of OCA (i.e., chromosomal abnormalities in the Philadelphia chromosome negative metaphases) has been reported among patients receiving imatinib as initial therapy for CML. Little is known about incidence and outcomes of OCA in CML pts treated with frontline 2nd generation TKI (dasatinib, nilotinib). Objectives:We describe incidence of OCAs in CML pts treated with frontline 2nd generation TKI and determine the outcomes of pts who develop OCA events. Methods:We reviewed pts treated with frontline 2nd generation TKI, dasatinib (n=99) or nilotinib (n=117), treated on 2 parallel ongoing prospective single-arm Phase II protocols at our institution. An OCA was defined as a cytogenetic abnormality in one or more non-Philadelphia chromosome positive clones (different than clonal evolution). Pts were followed with cytogenetic analysis at 3 month (mo) intervals for the first year, then every 6–12 mo. 30 pts with OCA were identified. Pts in chronic (n=25) or accelerated phase (n=5) at diagnosis were included in the analysis. Results:With a median follow-up of 30 mo (range 0–71), 11 (11%) pts treated with dasatinib and 19 (16%) pts treated with nilotinib developed OCA. The difference in incidence of OCA with dasatinib and nilotinib was not statistically significant (p=0.280). At start of therapy, median age of pts developing OCA was 53 (41–71) with dasatinib and 52 (37–82) with nilotinib, compared to those pts without OCA: 48 (18–83 yrs) with dasatinib and 49 (17–87) with nilotinib. The most common OCA event overall was abnormality of chromosome 7 found in 5 pts (one pt with both inv(7) and +7) for total of 6 occurrences (including inversion (n=1), 2 different translocations (n=2), deletions (n=2), and additions (n=1) involving chromosome 7). The most common translocation event was t(6;13) in 2 pts. No pts developed trisomy 8 (historically most common OCA among imatinib treated pts). Median time to first appearance of OCA was 9 mo (range 3–58) for all 2nd generation TKI pts (12 mo (range 3–58) for dasatinib group and 9 mo (3–48) for nilotinib group). 9 pts had OCA on more than one occasion. OCA disappeared in 25 pts during course of follow-up. Outcomes for OCA group versus non-OCA group are shown in Table 1, and outcomes with focus on chronic phase pts only in Table 2. For pts in accelerated phase, 3/6 pts (50%) in dasatinib group and 2/17 pts (12%) in nilotinib group developed an OCA. None of the pts who developed OCA has developed AML or MDS. Conclusions:OCA are observed in 10–15% of pts receiving initial therapy with 2nd generation TKI. At median follow up of 30 mo, occurrence of OCA confers no statistically significant adverse impact on outcomes when compared to non-OCA pts treated with 2nd generation TKI and has not resulted in other hematologic disorders.Table 1Outcomes in OCA group versus non-OCA group at 36 months (n=216)EFS (by iris) %TFS %OS %OCA100100100Non OCA939799p value0.0950.3650.517Table 2Outcomes in OCA group versus non-OCA group at 36 months (Chronic Phase pts only, n=193)EFS (by iris) %TFS %OS %OCA100100100Non OCA959999p value0.1870.5280.304 Disclosures:Off Label Use: Dasatinib and Nilotinib originally used in investigational setting when trials were begun. Kantarjian:Novartis Pharmaceuticals Corp: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Research Funding. Jabbour:BMS: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Cortes:Novartis, BMS, ARIAD, Pfizer: Consultancy, Research Funding.

Clinical Significance of Deeper Molecular Responses with Four Modalities of Tyrosine Kinase Inhibitors As Frontline Therapy for Chronic Myeloid Leukemia

AbstractAbstract 164▪▪This icon denotes a clinically relevant abstract Background:The achievement of a major molecular remission (MMR) after imatinib therapy in pts with chronic myeloid leukemia (CML) in chronic phase (CP) predicts for decreased risk of events, but has little impact in overall survival (OS) among patients with complete cytogenetic response (CCyR). Deeper molecular responses (MR), including undetectable transcripts, are frequently sought in patients with CML treated with tyrosine kinase inhibitors (TKI), but the prognostic significance of these responses is not known. Objectives:To determine the long-term clinical significance of achieving deeper level of MR achieved after therapy with TKI for CML in CP. Methods:Pts were included in clinical trials for initial therapy for CML with one of the following modalities: imatinib 400mg/day (IM400), imatinib 800mg/day (IM800), nilotinib (NILO) and dasatinib (DASA). We defined the level of MR as MMR, MR4, MR4.5 and undetectable transcripts (UND), corresponding to an ABL/BCR-ABL ratio (International Scale) of ≤0.1%, ≤0.01%, ≤0.0032%, and undetectable transcripts (minimum sensitivity 4.5-log), respectively. Results:A total of 495 pts were treated: 83 pts with IM400, 204 with IM800, 106 with NILO and 102 with DASA. At presentation leukocyte counts were higher in the NILO group (41.5 vs 22.2, 27.5 and 27×109/L for IM400, IM800 and DASA pts). All other patient characteristics were equally distributed across the 4 treatment groups. After a median follow-up of 73 months (2 to 142), complete cytogenetic response (CCyR) was achieved in 88%. CCyR rates for IM400, IM800, NILO and DASA pts were 82%, 88%, 90% and 90%, respectively. Best level of MR for the entire population was: <MMR in 17% of pts, MMR in 13%, MR4 in 5%, MR4.5 in 19%, UND in 44%. In IM400 pts MR was <MMR in 28% of pts, MMR in 10%, MR4 in 8%, MR4.5 in 14%, UND in 40%. In IM800 pts MR was <MMR in 14% of pts, MMR in 8%, MR4 in 5%, MR4.5 in 19%, UND in 54%. In NILO pts MR was <MMR in 18% of pts, MMR in 20%, MR4 in 7%, MR4.5 in 22%, UND in 33%. In DASA pts MR was <MMR in 18% of pts, MMR in 18%, MR4 in 7%, MR4.5 in 23%, UND in 39%. There was a trend for earlier achievement of MR with NILO: median times to MMR, MR4, MR4.5 and UND were 12, 17.4, 17.9 and 25.1 months, respectively, for IM400 pts; 5.8, 8.7, 11.8 and 23.7 months, respectively, for IM800 pts; 5.7, 7, 8.3 and 16.4 months, respectively, for NILO pts; 5.7, 8.8, 17.4 and 27.2 months, respectively, for DASA pts. To analyze the relationship between the degree of MR and clinical outcome we excluded pts not achieving a CCyR as their best response since the clinical significance of CCyR is well known. For the remaining 438 pts, the depth of molecular remission was inversely correlated with the risk of losing CCyR (19%, 16%, 11%, 7%, 2% in pts with <MMR, MMR, MR4, MR4.5 and UND, respectively) or losing MMR (31%, 42%, 24%, 2%, respectively), as well as the risk of events (22%, 20%, 15%, 12%, 3%, respectively), transformation (3%, 5%, 0%, 1%, 0%, respectively), or death (25%, 11%, 8%, 6%, 4%, respectively). The 6-year OS for pts with <MMR, MMR, MR4, MR4.5 and UND is 74%, 84%, 95%, 96% and 99%, respectively (p<.0001); transformation-free survival (TFS) is 95%, 93%, 100%, 99% and 100%, respectively (p<.014); event-free survival (EFS) is 74%, 74%, 86%, 89% and 99%, respectively (p<.0001). To adjust for the lead-time to achieve deeper responses, we then calculated OS, TFS and EFS rates at 6 years according to the depth of molecular response at 18 or 24 months. Results are summarized in table 1. Conclusion:Most patients treated with TKI as initial therapy for early CP CML achieve a MR during the course of treatment. BCR-ABL transcripts become undetectable in a significant fraction of them. Achieving a MMR or better at 18 months or 24 months is associated with significantly superior 6-years OS, TFS and EFS. These result suggest that deeper molecular responses (MMR and beyond) are associated with clinical benefit, with a particularly good outcome for those achieving undetectable transcript levels.Table 1Survival at 6 years by level of molecular response at 18- and 24-month landmarks.OutcomeMolecular response at 18 monthsp-valueNo MRMMRMR4MR4.5UND6-years OS93%98%97%95%100%.1536-years TFS90%100%100%100%100%.036-years EFS78%94%97%93%100%<.0001OutcomeMolecular response at 24 monthsNo MRMMRMR4MR4.5UND6-years OS92%97%100%97%100%.0186-years TFS90%100%100%100%100%.0576-years EFS80%90%97%95%100%<.0001 Disclosures:Off Label Use: Imatinib, dasatinib and nilotinib frontline for chronic phase chronic myeloid leukemia on clinical trial. Kantarjian:Bristol-Myers Squibb: Research Funding; Ariad: Research Funding; Pfizer: Research Funding; Novartis: Research Funding. Jabbour:Pfizer: Honoraria; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria. Ravandi:Bristol-Myers-Squibb: Research Funding. Cortes:Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

The Month Three Major Molecular Response in Chronic Phase Chronic Myeloid Leukemia on imatinib400, Nilotinib and Dasatinib Is a Major Prognostic Factor for Failure-Free and Progression-Free Survival

Abstract 1684The early assessment of molecular responses to tyrosine kinase inhibitors (TKI) used as a front line therapy for chronic phase chronic myeloid leukemia (CML) might represent an attractive surrogate marker for survival and help to discriminate poor prognosis patients (pts). So, we studied in a retrospective bicentric institutional analysis a series of 142 de novo CP CML pts diagnosed between 2000 and 2011, receiving imatinib (IM) 400 mg daily (n=85 pts), second generation TKI (TKI2) (n=57 pts) with 37 dasatinib (DAS) pts 100 mg daily and 20 nilotinib (NIL) pts 600–800 mg daily as front-line therapy, enrolled or not in clinical trials. All pts were assessed for their cytogenetic and molecular responses (local RQ-PCR for BCR-ABL, expressed as BCR-ABL/ABL ratios (IS) in %). Failure to TKI was defined as progression to accelerated phase or blast crisis, death, loss of complete hematologic response, loss of complete cytogenetic response, confirmed loss of major molecular response (MMR), discontinuation of TKI because unacceptable toxicity, primary cytogenetic resistance. The definition of progression included the same variables except the two last. Pts were considered in MMR with a BCR-ABL/ABL ratio ≤0.1% (IS). There were 87 males (61%) and 55 females with a median age of 55 years (21–83) at diagnosis. Six pts (4%) had an additional clonal abnormality, 4 a masked Philadelphia (Ph) chromosome, and 4 a variant Ph. Three pts had an atypical BCR-ABL transcript, all in IM400 group. Sokal scores were low for 37 (26%), intermediate for 61 (43%) and high for 43 (31%) (1 NA), and Euro scores were low for 49 (35%), intermediate for 78 (55%), and low for 14 (10%) (1 NA). These scores were similarly balanced in the IM400, NIL and DAS groups. The median time between diagnosis and TKI was 1 (0.9–1.28) month, not significantly different between TKI groups. The median follow-ups were 56, 37, and 19 months for IM400, NIL and DAS groups respectively. Fifteen percent, 6%, and 14% of pts achieved MMR at 3 months (M3) (p=ns); 31%, 37%, and 40% at M6 (p=ns); 55%, 70% and 71% at M12 (p=ns); 67%, 90% and 87% at M18 (p=ns) in IM400, NIL and DAS groups respectively, taken into account the limited numbers of pts at latest time-points in the 2 TKI2 arms. Twenty-three pts achieved 4-log molecular response MR4 in IM400, 10% in NIL and 11% in DAS at latest follow-ups. Four pts died, 3 in blast crisis in IM400 group and 1 for unrelated reason to disease or treatment in NIL group. A multivariate analysis adjusted on progression-free survival (PFS) performed, did not identify any significant parameter including age, gender, Sokal and Hasford scores, ACA, type of transcript, interval between diagnosis and TKI start. The progression-free survival (PFS) was 94 (83–100)% for pts achieving M3 MMR vs 86 (74–100)% if MMR occurred at later time points vs 86 (73–100)% for pts that never achieved MMR (p=0.02). There was no difference for PFS between the 3 TKI (log-rank p=0.9). None of the M3 MMR switched to another treatment, whereas 10 % of other pts did so for resistance (n= 10, 1 and 2 for IM400, NIL and DAS respectively), 9% for intolerance (n=10, 1 and 4), and 3% for other reasons (n=4, 0 and 0) with no difference between the 3 drugs (p=0.74). The failure-free survival (FFS) was 95% for M3 MMR pts vs 65% for pts with MMR occurring at later time points, versus 0% if MMR has not been achieved (p<0.0001). Again, there was no difference in the FFS survival rates at any times between the 3 TKI (p=0.78), (figures 1a &1b below). [Display omitted] [Display omitted] In conclusion, this academic retrospective study suggests that the achievement of M3 MMR represents a major prognostic factor for progression-free and failure-free survival in CP CML pts on TKI. Disclosures:Nicolini:consultant for Novartis Pharma France and Bristol Myers Squibb: Consultancy. Michallet:consultant for Novartis Pharma France and Bristol Myers Squibb: Consultancy. Mahon:consultant for Novartis Pharma France and Bristol Myers Squibb: Consultancy. Etienne:consultant for Novartis Pharma France and Bristol Myers Squibb: Consultancy.

Comparison of Adherence Between Nilotinib and Dasatinib As Second-Line Therapies in Chronic Myeloid Leukemia

Abstract 2754 Background:According to the NCCN guidelines, the recommended treatment option for patients diagnosed with Philadelphia-positive (Ph+) chronic myeloid leukemia (CML) in chronic or accelerated phases who are resistant or develop intolerance to first-line imatinib is to switch to one of the two second-generation BCR-ABL tyrosine kinase inhibitors, nilotinib or dasatinib. There is limited information on their comparative adherence. Analysis of adherence may reveal whether these two drugs are being used as intended and how adherence issues may potentially affect clinical outcomes. Nonadherence to imatinib has been associated with loss of cytogenetic response, imatinib failure, and higher rates of inpatient visits. A prior study covering the period up to 6/2009 has revealed a better adherence profile for nilotinib versus dasatinib. Since dasatinib was approved for once daily use in addition to twice daily use in 05/2009, this study replicated the analysis using more recent data to compare adherence between nilotinib and dasatinib as second-line therapies in CML. Methods:Medical and pharmacy records from two databases from January 1997 to April 2010 were combined to identify adult patients diagnosed with CML (ICD-9 code 205.1x) with ≥1 prescription for either nilotinib or dasatinib. Patients were required to have continuous enrollment ≥1 month prior to and after the index date, defined as the first prescription for nilotinib or dasatinib, and to continue their treatment ≥1 month before discontinuing or switching to another TKI. Adherence over an up-to 180-day period was evaluated based on the proportion of days covered (PDC; sum of days of medication on hand for nilotinib or dasatinib divided by the number of calendar days in the study period). Medication possession ratio (MPR) was also evaluated in a sensitivity analysis. PDC and MPR were compared between cohorts using linear regression models. Discontinuation was defined as a treatment gap ≥30 days, and rates were compared between cohorts using Kaplan-Meier survival analyses and Cox proportional hazard regression models. In a sensitivity analysis, discontinuation was defined as a treatment gap ≥90 days. All multivariate regression models were controlled for age, gender, CML complexity, adverse events at baseline, number of inpatient days, emergency room (ER) visits and outpatient visits during baseline, medical costs during baseline, CML year of diagnosis, Charlson Comorbidity Index, and bone marrow or stem cell transplant before the index date. Results:Adherence and discontinuation were analyzed for a total of 558 CML patients receiving a second-line TKI (473 dasatinib and 85 nilotinib). Patient characteristics were generally similar. Patients in the dasatinib cohort had a longer mean follow-up period compared with those in the nilotinib cohort (162 days vs. 146 days; P = 0.0007) and greater utilization and costs associated with inpatient and ER services. The mean PDC over the study period for nilotinib was higher compared with dasatinib (0.81 vs 0.68). After adjusting for confounding factors, the nilotinib group had a 0.115 higher PDC (approximately 17% higher) compared to the dasatinib group (P = 0.0004). Additionally, patients in the nilotinib group had a significantly higher MPR compared to patients in the dasatinib group (0.90 vs. 0.77 P = 0.0043). Discontinuation rates (gap ≥30 days) were significantly higher for dasatinib users than for nilotinib users, with an adjusted hazard ratio of 2.15 (P = 0.0013). Dasatinib-treated patients had higher discontinuation rates than nilotinib-treated patients after 3 months (40% vs 22%) and 6 months (50% vs 28%). These unadjusted differences were robust in the sensitivity analysis with discontinuation defined as a treatment gap ≥90 days, but the difference between the cohorts was no longer significant after adjusting for confounding factors (HR 1.76, P = 0.1328). Conclusions:This retrospective study showed that CML patients treated with nilotinib for second-line treatment were significantly more adherent to therapy, based on PDC and MPR, and had a lower discontinuation rate than did patients receiving dasatinib in this analysis. Further studies are needed to better understand treatment-specific factors affecting adherence and persistence (e.g., treatment cost, tolerability profile, dosing convenience). Disclosures:Guerin:Novartis Pharmaceutical Corporation: Annie Guerin is an employee of Analysis Group, Inc, which has received research funds from Novartis Pharmaceuticals. Bollu:Novartis Pharmaceutical Corporation: Employment, Vamsi K. Bollu worked for the Novartis Pharmaceuticals Corporation while performing this analysis but is currently employed by Sunovion Pharmaceuticals Inc. Sunovion Pharmaceuticals Inc. was not in any way associated with this study. Guo:Novartis Pharmaceutical Corporation: Employment. Stepner:Novartis Pharmaceutical Corporation: Michael Stepner is an employee of Analysis Group, Inc, which has received research funds from Novartis Pharmaceuticals. Griffin:Novartis Pharmaceutical Corporation: James D. Griffin is an employee of the Dana Farber Institute which has received consultancy fees from Analysis Group, Inc, which has received research funds from Novartis Pharmaceuticals Corporation. Wu:Novartis Pharmaceutical Corporation: Eric Q. Wu is an employee of Analysis Group, Inc, which has received consultancy funds from Novartis Pharmaceutical Corporation.

Nilotinib Exerts Direct Effects on Vascular Endothelial Cells and May Act As a Co-Trigger of Atherosclerosis in Patients with Ph+ CML

Abstract▪2753▪This icon denotes a clinically relevant abstractThe second-generation BCR/ABL tyrosine kinase inhibitor nilotinib is increasingly used for the treatment of patients (pts) with newly diagnosed Ph+ CML or imatinib-resistant CML. So far, nilotinib has been considered a well-tolerated drug that shows little if any relevant side effects. However, long-term results are not available yet. Known recurrent side effect of nilotinib include an increase in pancreatic enzymes (lipase, amylase) and an increase in fasting glucose levels. More recently, several centers have reported on the occurrence of progressive peripheral arterial occlusive disease (PAOD) in some of their pts treated with nilotinib. The exact relationship with drug intake and the potential mechanisms underlying PAOD development remain unknown. To address these questions, we have extended and updated our retrospective analysis and examined the in vitro effects of nilotinib. A total number of 34 pts (second line nilotinib, n=33; first line nilotinib, n=1; females, n=15; males, n=19, median age: 57.5 years) receiving nilotinib in our center were examined (observation period 2006–2011). Vascular events related to atherosclerosis were recorded in 9 pts (26.5%). Of these, 6 (17.6%) had PAOD, including 2 cases of severe PAOD requiring repeated surgical interventions or amputation (n=1). One patient had a myocardial infarction, one an acute coronary artery syndrome requiring bypass surgery, and one a spinal infarction. Although in all 9 pts, one or more pre-existing risk factors for atherosclerosis were identified, none of these pts had developed a vascular event during prior imatinib therapy. The JAK2 V617F mutant was not found in any of the 9 pts. Three pts died during the observation period, two from major bleeding episodes, and one from sudden death of unknown etiology. In 5 cases, an increase in blood glucose levels was found, and 1 patient developed overt diabetes mellitus. The frequency of PAOD development in age-, observation time-, and risk factor-matched control cohorts (CML pts receiving imatinib, lymphoproliferative neoplasms, JAK2 V617F+ myeloproliferative neoplasms, each n=34 pts) was significantly lower (<5%) than in the nilotinib group (p<0.05 by Chi Square test with Boneferroni correction). As assessed by 3H-thymidine uptake, nilotinib was found to inhibit the growth of the human microvascular endothelial cell line HMEC-1 (IC50: 0.5–1.5 μM), whereas no substantial effect was seen with imatinib. Furthermore, nilotinib, but not imatinib, was found to inhibit umbilical vein endothelial cell (HUVEC) migration and sprouting in a scratch-wound healing assay. Finally, nilotinib but not imatinib, was found to block the growth of various human pancreatic cell lines, including PANC-1 and the insulin- producing cell line 1.4E7. Together, our data show that nilotinib exerts direct inhibitory effects on endothelial cells and pancreatic cells. Whether these drug effects contribute to vascular events seen in our nilotinib-treated pts remains at present unknown. In addition, the exact pro-atherogenic effect of nilotinib in second-line and first-line treated patients with CML remains unknown since no data from prospective clinical trials focusing on this issue, are available. Until these questions and safety-issues have been clarified, it may be advisable to take certain co-morbidities into account when considering the use of nilotinib in CML patients. In addition, the follow up of long-term treated patients should include parameters that can detect vascular events and predisposing co-morbidities as early as possible. Disclosures:Valent:Novartis: Consultancy, Honoraria, Research Funding.

Immunoprofile of Patients with Chronic Myeloid Leukemia Treated with Imatinib, Nilotinib or Dasatinib,

Abstract 3764Recent reports showed that dasatinib induces significant immunostimulation with clonal expansion of large granular lymphocytes (LGL) which, in chronic myeloid leukemia (CML), is related to both better prognosis and to autoimmune-like side effects. It is speculated that lower levels of circulating T-regulatory cells play a partial role in LGL proliferation in patients receiving dasatinib.The immunoprofile was studied using flow cytometry to evaluate lymphocyte subsets and NK-cell reactivity in the peripheral blood of 61 patients in the chronic phase of CML during treatment with a tyrosine kinase inhibitor (TKI) (Median age: 58 years; imatinib 36, nilotinib 9, dasatinib 16). Furthermore, we measured plasma levels of 27 types of cytokines or chemokines in 58 patients in the chronic phase of CML so that a comprehensive comparison could be made of the differences in immunoprofile among the patients receiving these three TKIs.There were no significant differences between the three TKI-treated groups in terms of CD4/8 ratios or the number of T-cells (CD3+CD8+ or CD4+) and NK cells (CD3-CD56+). However, the number of NK-LGL (CD56+CD57+) and T-LGL (CD3+CD57+) increased significantly in the group that received dasatinib. Furthermore, dasatinib significantly enhanced NK-cell reactivity as compared to imatinib and nilotinib. In contrast nilotinib significantly suppressed NK-cell reactivity (E/T ratio =10:1: Median (interquartile range), 8.7% (5.0–16.2), 5.2% (4.8–11.4), 20.8% (13.4–33.3), for imatinib, nilotinib and dasatinib, respectively). In addition, the number of regulatory T-cells (CD4+CD25int-hiCD127low) was similar among the three groups (Median (interquartile range), 36/mm3 (27–53), 48/mm3 (34–60), 39/mm3 (26–53), for imatinib, nilotinib and dasatinib, respectively).Furthermore, in the analysis of cytokines and chemokines, plasma levels of IL-8, IP-10, and MCP-1 were significantly elevated while the level of PDGF-bb was significantly decreased in all three groups compared to those of healthy control. Plasma levels of IL-1 beta, IFN-gamma, and FGF-basic were significantly decreased in only the dasatinib group compared to those of control (P=.02, P=.04, P=.03, respectively). In addition, plasma levels of GM-CSF were significantly elevated in the imatinib and dasatinib groups (Median (interquartile range), 6.1 pg/ml (2.7–11.7) and 7.9 pg/ml (4.5–8.2), P=.02, and P=.03, respectively) but not in the nilotinib group (P=.34) when compared to those of control. In the multiple regression analysis that evaluated the relationship between NK-reactivity and cytokines or chemokines in the patients receiving dasatinib, only plasma levels of GM-CSF were significantly associated with NK-reactivity (P=.03).Notably, in our data, dasatinib and nilotinib exerted opposite effects on NK-cell reactivity, expansion of LGL, and showed different cytokine and chemokine profiles. Based on our results, the activation of NK-cell reactivity induced by dasatinib might be caused by a mechanism other than a decrease in the number of regulatory T-cells. Additionally, in an unphysiological immunological status mediated by dasatinib, GM-CSF might make some contribution to NK-cell reactivity. Disclosures:Nakamae:BMS: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Hino:BMS: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau.

Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial

Nilotinib has shown greater efficacy than imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukaemia (CML) in chronic phase after a minimum follow-up of 12 months. We present data from the Evaluating Nilotinib Efficacy and Safety in clinical Trials-newly diagnosed patients (ENESTnd) study after a minimum follow-up of 24 months. ENESTnd was a phase 3, multicentre, open-label, randomised study. Adult patients were eligible if they had been diagnosed with chronic phase, Philadelphia chromosome-positive CML within the previous 6 months. Patients were randomly assigned (1:1:1) to receive nilotinib 300 mg twice a day, nilotinib 400 mg twice a day, or imatinib 400 mg once a day, all administered orally, by use of a computer-generated randomisation schedule, using permuted blocks, and stratified according to Sokal score. Efficacy results are reported for the intention-to-treat population. The primary endpoint was major molecular response at 12 months, defined as BCR-ABL transcript levels on the International Scale (BCR-ABL(IS)) of 0·1% or less by real-time quantitative PCR in peripheral blood. This study is registered with ClinicalTrials.gov, number NCT00471497. 282 patients were randomly assigned to receive nilotinib 300 mg twice daily, 281 to receive nilotinib 400 mg twice daily, and 283 to receive imatinib. By 24 months, significantly more patients had a major molecular response with nilotinib than with imatinib (201 [71%] with nilotinib 300 mg twice daily, 187 [67%] with nilotinib 400 mg twice daily, and 124 [44%] with imatinib; p<0·0001 for both comparisons). Significantly more patients in the nilotinib groups achieved a complete molecular response (defined as a reduction of BCR-ABL(IS) levels to ≤0·0032%) at any time than did those in the imatinib group (74 [26%] with nilotinib 300 mg twice daily, 59 [21%] with nilotinib 400 mg twice daily, and 29 [10%] with imatinib; p<0·0001 for nilotinib 300 mg twice daily vs imatinib, p=0·0004 for nilotinib 400 mg twice daily vs imatinib). There were fewer progressions to accelerated or blast phase on treatment, including clonal evolution, in the nilotinib groups than in the imatinib group (two with nilotinib 300 mg twice daily, five with nilotinib 400 mg twice daily, and 17 with imatinib; p=0·0003 for nilotinib 300 mg twice daily vs imatinib, p=0·0089 for nilotinib 400 mg twice daily vs imatinib). At 24 months, survival was comparable in all treatment groups, but fewer CML-related deaths had occurred in both the nilotinib groups than in the imatinib group (five with nilotinib 300 mg twice daily, three with nilotinib 400 mg twice daily, and ten with imatinib). Overall, the only grade 3 or 4 non-haematological adverse events that occurred in at least 2·5% of patients were headache (eight [3%] with nilotinib 300 mg twice daily, four [1%] with nilotinib 400 mg twice daily, and two [<1%] with imatinib) and rash (two [<1%], seven [3%], and five [2%], respectively). Grade 3 or 4 neutropenia was more common with imatinib than with either dose of nilotinib (33 [12%] with nilotinib 300 mg twice daily, 30 [11%] with nilotinib 400 mg twice daily, and 59 [21%] with imatinib). Serious adverse events were reported in eight additional patients in the second year of the study (four with nilotinib 300 mg twice daily, three with nilotinib 400 mg twice daily, and one with imatinib). Nilotinib continues to show better efficacy than imatinib for the treatment of patients with newly diagnosed CML in chronic phase. These results support nilotinib as a first-line treatment option for patients with newly diagnosed disease. Novartis.

Effect of Nilotinib on Bleomycin-Induced Acute Lung Injury and Pulmonary Fibrosis in Mice

Background: The tyrosine kinase inhibitor imatinib mesylate was developed as an inhibitor of the kinase activity of BCR-ABL. However, imatinib also has potent inhibitory activity against the platelet-derived growth factor receptor (PDGFR). Nilotinib is approved for treating patients with chronic myeloid leukemia showing resistance or intolerance to imatinib. Like imatinib, nilotinib selectively inhibits the tyrosine kinase activity of PDGFR. Objectives: We examined the effect of imatinib and nilotinib on acute lung injury and pulmonary fibrosis in a mouse model. Methods: Mice were treated by intratracheal instillation of bleomycin. Imatinib or nilotinib were administered by oral gavage. To study the early inflammatory and late fibrotic phases of lung injury, mice were sacrificed on days 3, 7, 14 and 21 after bleomycin instillation. Results: Histopathology showed that imatinib and nilotinib attenuated the extent of lung injury and fibrosis. The numbers of inflammatory cells and levels of IL-6, IL-1β and tumor necrosis factor-α were decreased in the imatinib and nilotinib groups on days 3 and 7. Imatinib and nilotinib therapy significantly reduced the levels of hydroxyproline on days 14 and 21, which was accompanied by decreased expression levels of transforming growth factor (TGF)-β1 and PDGFR-β. Imatinib and nilotinib also significantly reduced the expression levels of the genes for TGF-β1 and platelet-derived growth factor (PDGF). Imatinib and nilotinib treatment also significantly inhibited the PDGF-induced proliferation of lung fibroblasts in vitro. When imatinib or nilotinib was given 7 days after the instillation of bleomycin, only nilotinib attenuated pulmonary fibrosis. Conclusions: Imatinib and nilotinib attenuated bleomycin-induced acute lung injury and pulmonary fibrosis in mice. In a therapeutic model, nilotinib showed more potent antifibrotic effects than imatinib.

Nilotinib Attenuates Renal Injury and Prolongs Survival in Chronic Kidney Disease

The tyrosine kinase inhibitor imatinib is beneficial in experimental renal diseases, but the effect of the new tyrosine kinase inhibitor nilotinib on the progression of renal failure is unknown. We administered either nilotinib or vehicle to Sprague-Dawley rats beginning 2 weeks after 5/6 nephrectomy (Nx) or laparotomy and continuing for 8 weeks. Serum creatinine levels were significantly lower in the nilotinib group after 6 and 8 weeks of treatment. Furthermore, nilotinib-treated rats had less proteinuria, attenuated glomerulosclerosis and tubulointerstitial damage, and reduced macrophage infiltration into the tubulointerstitium. Treatment with nilotinib also significantly decreased renal cortical expression of profibrogenic genes, such as IL-1β and monocyte chemotactic protein-1, which correlated closely with the tubulointerstitial damage score and ED1-positive macrophages score. In addition, nilotinib treatment significantly prolonged survival. Taken together, these results suggest that nilotinib may limit the progression of chronic kidney disease.