Nilotinib Group Research Articles

Characterisation of Molecular Relapse Profiles after Tyrosine Kinase Inhibitor Cessation in Patients Eligible for Treatment-Free Remission Strategies in Chronic Phase CML

Background & aimsTyrosine kinase inhibitors (TKI) still in a majority of cases do not cure chronic phase CML (CP-CML) and leave patients in a minimal residual disease state, requiring the indefinite continuation of TKI. However, in some patients, these agents are able to induce prolonged disease undetectability leading to TKI-cessation strategies and successful treatment-free remissions (TFR) in some. Stable (≥2 years) undetectability can be observed after Imatinib (IM), Nilotinib (NIL) and Dasatinib (DAS) and TKI-cessation strategies have been developed in these 3 settings. In most studies, the overall molecular relapse rate [defined as a loss of MMR, >0.1% BCR-ABL/ABLIS] is ~30-50% requiring the re-initiation of a TKI. The aim of this study is to characterize and compare the molecular relapse profiles in 3 cohorts of patients undergoing IM, NIL or DAS-cessation.MethodsThis is a bicentric observational retrospective analysis on a selected cohort of CP-CML patients fulfilling the following criteria: CP-CML since diagnosis; ≥2 years stable undetectable BCR-ABL (with ≥32,000 ABL copies/sample) evaluated on 4-6 consecutive follow-up samples, on IM, NIL, or DAS; first cessation whatever the reason for TKI prescription was; molecular relapse after TKI cessation defined as MMR loss on 1 occasion. Molecular analyses were performed in 2 reference laboratories belonging to the EUTOS/ELN quality control system. Relevant clinical data were extracted from the 2 databases of these centres, following the rules of our country regulations.ResultsWe identified 29 patients relapsing after IM, 15 after NIL and 14 after DAS cessation with a median age at TKI cessation of 57, 63, and 62.5 respectively (p=0.80). Interestingly, the male/female ratios were 1.41, 0.87 and 0.55 (p=0.38). Sokal score were respectively (L/I/H/NA): 10/12/6/2 for IM, 3/6/6/0 for NIL, 5/4/4/1 for DAS groups (overall p=0.78). Pre-TKI IFN-awas administered in 6 patients in the IM, 4 in the NIL and 1 in the DAS groups (p=0.42). ACA were present at diagnosis in 2, 1 and 1 patients respectively. Two patients had NIL and 7 DAS, in first-line. MR4.5 duration was 37 months for IM, 24.5 months for NIL and 33 months for DAS. Overall TKI duration until TKI cessation were 86 months for IM, 85 months for NIL and 70 months for DAS (p=0.28). The median interval between MR4.5 and TKI cessation was shorter for NIL (25 Months) than for DAS (33 months, p=0.041). The kinetics of relapse are shown in Figure 1 where the evolution of the BCR-ABL ratio by TKI has been smoothed with a polynomial regression.Relapses occurred after a median of 3.94 (0.89-7.2) for IM, 5 (0.69-7.6) for NIL and 4 (2.87-7.52) months for DAS (p=0.86). Kaplan-Meier analysis of the molecular disease-free survival (DFS) according to TKI and since TKI cessation is surprisingly not different (log-rank test p=0.95) between the 3 TKI, suggesting that TKI2 do not slow down the kinetics of relapse. When looking at the KM estimates of molecular DFS since stable MR4.5, it seems longer with DAS than with NIL (long-rank test p=0.018), despite the fact that the duration of MR4.5 before cessation was significantly longer with NIL than with DAS. This might suggest a differential effect of these 2 compounds on the BCR-ABL+ stem cell compartment. TKI were re-initiated after a median of 0.9, 0.8 and 0.75 months after relapse for IM, NIL and DAS. After relapse 6 patients switched from IM to NIL, 1 from NIL to Peg-IFN-a, 4 from NIL to DAS, whereas all DAS restarted the same TKI. MR4.5 was regained after 6.5, 3.9 and 7.41 months in the IM, NIL and DAS groups with a median follow-up of 43, 23.75 and 25 months after relapse respectively. Two patients died, 1 in the IM group from terminal cardiac insufficiency and 1 in the DAS group from metastatic secondary tumor. At last follow-up, patients regained ≥ MMR in all groups except 1 (0.16% at 3 months DAS rechallenge).ConclusionDespite its obvious limitations (relatively low number of patients, retrospective non randomized study) this study characterizes the kinetics of molecular relapse after TKI cessation for TFR and might point out differences suggesting that in these patients the BCR-ABL+ cells responsible for relapse might be different, or that the differential kinase inhibition profile by each TKI induces a different behaviour at relapse. However, these data need to be confirmed ideally in a prospective setting. [Display omitted] DisclosuresNicolini:Ariad, BMS: Consultancy, Speakers Bureau; Novartis: Speakers Bureau. Dulucq:Novartis: Speakers Bureau. Mahon:Pfizer: Honoraria; Ariad: Honoraria; Novartis: Honoraria, Research Funding; BMS: Honoraria. Etienne:BMS: Speakers Bureau; Pfizer: Speakers Bureau; ARIAD: Speakers Bureau; novartis: Consultancy, Speakers Bureau.

Mutation Analysis and Treatment Outcomes of BCR-ABL Tyrosine Kinase Domain in CML Patients with Imatinib Treatment Failure - Data from a Large Tertiary Center in India

Introduction:Tyrosine kinase inhibitor (TKI) therapy results in excellent responses in the majority of patients with chronic myeloid leukemia (CML). However, point mutations in the BCR-ABL kinase domain that render the kinase less sensitive to imatinib are observed in approximately 40% of patients who relapse on therapy, but only in a minority of patients with primary resistance. The goal of our study was to determine the mutation patterns and treatment outcomes of patients with imatinib resistance in India.MethodsThe study was performed on a series of 309 CML patients between June 2003 and April 2016 who were tested for imatinib resistance as defined by primary or secondary imatinib failure. Mutation analysis on these patients was done upon treatment failure as per the definitions of the European LeukemiaNet. Survival estimates were calculated using Kaplan-Meier product-limit method. Overall survival was defined based from both time of imatinib failure and time of first detection of mutation to date of death or last follow-up. Direct sequencing of the BCR-ABL transcript by the Sanger method was used for IRMA (Imatinib Resistance Mutation Analysis) testing.Results309 patients failing imatinib therapy who were screened for mutations were included in the study. The study group comprised of 67% (208) Male; median age of the study population was 38 years (Range 18 - 66 years) and the median duration of Imatinib usage until the resistance was 24months (Range 3 - 60 months). Of the 309 patients 42% (129) had primary failure and 58% (180) had secondary failure. 33% (102) of the study population had mutations detected of which 18 patients (18%) had primary failure and 84 patients (82%) had secondary failure to imatinib therapy. Specific mutations are detailed in table 1 and 2. Among the 309 patients a total of 226 patients underwent subsequent treatment. Among these 226 patients 180 patients underwent Imatinib dose hike and 31 patients had second line TKI with Nilotinib and 15 patients with Dasatinib. 98 patients (54%) in the Imatinib dose hike group had <1% BCR-ABL at 12months compared to 19 patients (61%) in the Nilotinib and 10(66.6%) in the Dasatinib group. Hematological response in these groups was assessed at 3months and Dasatinib induced notable response with 86% compared to 78.5% in the Nilotinib and 75.8% in the Imatinib dose hike groups (Table 3). Hematologic adverse events were generally mild to moderate in the Dasatinib and Nilotinib groups compared to Imatinib dose escalation, and most cytopenias were effectively managed with dose modifications. On survival analysis (after Imatinib resistance) the 2 year and 4-year survival for the whole group was 91.9% and 69.9% respectively. After a median follow-up of 48 months (Since Imatinib Resistance) the Median overall survival among patients with T315I mutation group (n=29) was 20 months and it was not achieved in those with non T315I mutations (n= 73 )Conclusion:BCR-ABL1 kinase domain point mutations were detected in 33% of patients with treatment failure and progression. More than 50% of patients had optimal response to 2nd line TKI and Imatinib dose hike. Presence of the T315I mutation impairs overall survival. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Switching to nilotinib versus imatinib dose escalation in patients with chronic myeloid leukaemia in chronic phase with suboptimal response to imatinib (LASOR): a randomised, open-label trial

Optimal management of patients with chronic myeloid leukaemia in chronic phase with suboptimal cytogenetic response remains undetermined. This study aimed to investigate the safety and efficacy of switching to nilotinib vs imatinib dose escalation for patients with suboptimal cytogenetic response on imatinib. We did a phase 3, open-label, randomised trial in patients with chronic myeloid leukaemia in chronic phase with suboptimal cytogenetic response to imatinib according to the 2009 European LeukemiaNet criteria, in Latin America, Europe, and Asia (59 hospitals and care centres in 12 countries). Eligible patients were aged 18 years or older with Philadelphia chromosome-positive chronic myeloid leukaemia in chronic phase and Eastern Cooperative Oncology Group performance status of 0-2. Before enrolment, all patients had received 3-18 months of imatinib 400 mg once daily and had a suboptimal cytogenetic response according to 2009 ELN recommendations, established through bone marrow cytogenetics. By use of an interactive response technology using fixed blocks, we randomly assigned patients (1:1) to switch to nilotinib 400 mg twice per day or an escalation of imatinib dose to 600 mg once per day (block size of 4). Investigators and participants were not blinded to study treatment. Crossover was allowed for loss of response or intolerance at any time, or for patients with no complete cytogenetic response at 6 months. The primary endpoint was complete cytogenetic response at 6 months in the intention-to-treat population. Efficacy endpoints were based on the intention-to-treat population, with all patients assessed according to the treatment group to which they were randomised (regardless of crossover); the effect of crossover was assessed in post-hoc analyses, in which responses achieved after crossover were excluded. We present the final results at 24 months' follow-up. This study is registered with ClinicalTrials.gov (NCT00802841). Between July 7, 2009, and Aug 29, 2012, we enrolled 191 patients. 96 patients were randomly assigned to nilotinib and 95 patients were randomly assigned to imatinib. Complete cytogenetic response at 6 months was achieved by 48 of 96 patients in the nilotinib group (50%, 95·18% CI 40-61) and 40 of 95 in the imatinib group (42%, 32-53%; difference 7·9% in favour of nilotinib; 95% CI -6·2 to 22·0, p=0·31). Excluding responses achieved after crossover, 48 (50%) of 96 patients in the nilotinib group and 34 (36%) of 95 patients in the imatinib group achieved complete cytogenic response at 6 months (nominal p=0·058). Grade 3-4 non-haematological adverse events occurring in more than one patient were headache (nilotinib group, n=2 [2%, including 1 after crossover to imatinib]; imatinib group, n=1 [1%]), blast cell crisis (nilotinib group, n=1 [1%]; imatinib group, n=1 [1%]), and QT prolongation (nilotinib group, n=1 [1%]; imatinib group, n=1 [1%, after crossover to nilotinib]). Serious adverse events on assigned treatment were reported in 11 (11%) of 96 patients in the nilotinib group and nine (10%) of 93 patients in the imatinib group. Seven (7%) of 96 patients died in the nilotinib group and five (5%) of 93 patients died in the imatinib group; no deaths were treatment-related. While longer-term analyses are needed to establish whether the clinical benefits observed with switching to nilotinib are associated with improved long-term survival outcomes, our results suggest that patients with suboptimal cytogenetic response are more likely to achieve improved cytogenetic and molecular responses with switching to nilotinib than with imatinib dose escalation, although the difference was not statistically significant when responses achieved after crossover were included. Novartis Pharmaceuticals.

Retrospektywna analiza skuteczności nilotynibu i dazatynibu w drugiej linii terapii przewlekłej białaczki szpikowej w polskich ośrodkach hematologicznych

Until now, there has been no randomized study directly comparing the activity of second-generation BCR-ABL tyrosine kinase inhibitors (TKI-2G) nilotinib and dasatinib in chronic myeloid leukemia (CML). The aim of our study was to retrospectively analyze efficacy of nilotinib and dasatinib in the real life setting of CML with resistance or intolerance of imatinib. Of 108 included patients treated in polish hematology centers, 75 received dasatinib and 33 patients received nilotinib. Rates of complete cytogenetic response (CCyR) did not differ between the two groups of patients. After six months of therapy, CCyR was achieved in 34.7% of patients treated with dasatinib and 38.7% treated with nilotinib (p=0.86), while after 12 months, the CCyR rates were 60.0% and 77.0% in dasatinib and nilotinib groups, respectively (p=0.11). Moreover, we have not observed any significant difference in the probability of progression-free survival (p=0.89) or overall survival (p=0.99) between patients treated with these two TKI-2G. In conclusion, the results of our analysis indicate that nilotinib and dasatinib have comparable and satisfactory efficacy in the treatment of CML patients refractory or intolerant to imatinib. Our findings support current strategy of choice of IKT-2G according to drug toxicity profile and risk of specific adverse events in an individual patient.

Effects of Imatinib, Nilotinib, Dasatinib on VEGF and VEGFR-1 Levels in Patients with Chronic Myelogenous Leukemia

Objective:Vascular endothelial growth factor (VEGF) is a protein that binding to VEGF receptors 1 (VEGFR-1) and accelerates angiogenesis. The relationship between angiogenesis and progression of tumors were observed in both solid and hematologic cancers. Monoclonal antibodies capable of inhibiting angiogenesis, tyrosine kinase inhibitors use for haematological cancer treatment. In this study; we investigated the effects of Imatinib mesylate (STI-571; Gleevec), Nilotinib (AMN107; Tasigna) and Dasatinib (BMS-354825; Sprycell) on serum levels of VEGF and VEGFR-1, in patients with chronic phase of chronic myeloid leukemia (CML).Method:Serum levels of VEGF and VEGFR-1 were measured in 65 patients with chronic phase of CML. Serum VEGF and VEGFR-1 levels were determined using quantitative sandwich enzyme immunoassay technique according to the manufacturers’ instructions.Results:There were 33 (51%) male and 32 (49%) female patients in this study. 38 of 65 patients were using Imatinib, 15 Nilotinib, 12 Dasatinib. Mean serum VEGF and VEGFR-1 levels for the 65 patients with CML were 172.21±127.46 pg/mL and 199.62±122.22 pg/mL, respectively. In Dasatinib and Imatinib group, serum VEGF and VEGFR-1 levels were significantly higher than in control group ( p= 0.008, p< 0.0001, and p< 0.0001, p< 0.0001). In Nilotinib group, serum VEGF levels were higher than control group, but; it was not statistically significant (p= 0.06) while . VEGFR-1 levels were significantly higher than those of controls (p< 0.0001).Conclusion:Imatinib, Nilotinib and Dasatinib were not superior to each other regarding to serum VEGF and VEGFR-1, but it may be said that Nilotinib may has slightly more effect on inhibition of anjiogenesis.

Comparative Analysis of Tyrosine Kinase Inhibitors-Related Pulmonary Hypertension in the Patients Treated By Imatinib, Dasatinib and Nilotinib

▪Introduction:Tyrosine kinase inhibitors (TKIs) have dramatically improved outcome of patients with chronic myeloid leukemia (CML) and Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) with lesser incidence of serious adverse events. Recently, cases with fatal pulmonary hypertension (PH) have been sporadically documented in association with dasatinib treatment. French group reported incidence of PH diagnosed by cardiac catheterization as 0.45% (13 of 2900 patients) in the symptomatic patients treated with dasatinib. In contrast, a Korean group prospectively evaluated PH by non-invasive echocardiography in CML patients treated with dasatinib, and demonstrated 8 of 66 patients (12.1%) exhibited a significant increase in right ventricular systolic pressure, indicating subclinical PH might be more common event in dasatinib-treated patients. In this study, we prospectively examined the patients treated with three TKIs by echocardiography to clarify incidence of clinical and subclinical PH as well as factors associated with PH.Patients and Methods:Total of 108 patients (99 with CML, 9 with Ph+ ALL) receiving TKIs in our institutions were enrolled to this study. Forty-one patients have been on treatment with dasatinib (38%), 37 with imatinib (34%) and 30 with nilotinib (28%). Patients underwent echocardiography to evaluate values of tricuspid regurgitation pressure gradient (TRPG), which relates to severity of PH. Patients with higher values of TRPG than the upper limit (30mmHg) was suspected of PH by European Society of Cardiology criteria.Results:Among 108 patients, median age was 63 years old, and median duration of TKIs treatment was 26.5 months. Median daily dosage was 100 mg for dasatinib, 300 mg for imatinib, 600 mg for nilotinib groups, respectively (Table 1). In imatinib group, patients' age was significantly higher, and duration of treatment was also longer than those of the 2nd generation TKIs. Echocardiography revealed mean values of TRPG as 23.2, 23.2 and 23.1 mmHg in dasatinib, imatinib and nilotinib groups, respectively. There was no significant difference in TRPG values among 3 groups (p=0.99). We also found no relationship between TRPG values and duration of TKIs treatment in each group. Interestingly, we detected a significant inverse correlation between daily dosage of imatinib and TRPG values (p=0.012, Figure 1), while such relationship was not observed in dasatinib and nilotinib groups (p=0.68 and p=0.49). TRPG values higher than 30 mmHg were documented in 13 of 108 patients (12.0%); 5 of 41 (12.2%) in dasatinib group, 4 of 37 (10.8%) in imatinib group, and 4 of 30 (13.3%) in nilotinib group (p=0.95).Discussion:PH is characterized by proliferation of pulmonary vascular smooth muscle cells (SMCs). Recent reports showed that imatinib suppresses abnormal proliferation of SMCs through inhibiting platelet-derived growth factor receptors (PDGFR), resulting in improvement of PH in animal models. Clinical studies in symptomatic PH patients reported that imatinib considerably improved pulmonary hemodynamics. Of note, in our study, dosage of imatinib was significantly correlated with lower values of TRPG, suggesting imatinib possibly decreases TRPG values in a dose-dependent manner. This finding strongly supports the reports indicating imatinib as a therapeutic agent of PH. In contrast, in vitro studies have shown that dasatinib has stronger potential to inhibit PDGFR compared to imatinib; nevertheless, onsets of PH have been reported in dasanitib-treated patients, but not with imatinib nor nilotinib. Our study demonstrated the incidence of TRPG elevation as 12.0% in dasatinib group, which was consistent with Korean report (12.1%). However, there was no significant difference in TRPG values among 3 groups, indicating no apparent evidence which dasatinib treatment might be specifically associated with occurrence of PH. These results suggested that subclinical PH might be more common than expected. Careful follow-ups with echocardiography are necessary for the patients under any TKI treatments.Table 1Patient characteristicsDasatinib group (n=41)Imatinib group (n=37)Nilotinib group (n=30)pMedian age55(17-77)68(22-92)62.5(24-85)0.0004Median dosage (mg/day)100(18-100)300(100-600)600(300-800)Mean months from start of TKI68.5(2-287)104.8(2-228)61.3(3-153)0.007Mean TRPG(mmHg)23.2(9-40)23.2(8-46)23.1(7-35)0.995 [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Bone Marrow Lymphocytic Status during Tyrosine Kinase Inhibitor Therapy and Its Relation to Therapy Response in Chronic Phase Chronic Myeloid Leukemia Patients

IntroductionThe introduction of tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of chronic myeloid leukemia (CML). In addition to blocking their main target kinase, the BCR-ABL oncoprotein, several studies have reported that TKIs could also have secondary effects on the immune system and lymphocyte behavior. The aim of this study was to assess the bone marrow (BM) lymphocyte status at diagnosis and during different first-line TKI therapies and correlate it with treatment responses.MethodsAltogether 105 first-line TKI treated patients were included in the study (imatinib n=71, dasatinib n=25 and nilotinib n=9) and samples from 14 healthy bone marrow donors served as controls. BM aspirate samples were taken from patients at the diagnosis and at 3, 6, 12 and 18 months after the TKI therapy start, and MGG-stained BM aspirate slides were examined for cellularity and individual cellular proportions. Treatment responses were evaluated with standard karyotyping and real-time quantitative PCR. Patients were divided in different groups according to ELN criteria based on their therapy response at 12 months. In addition, multi-color flow cytometry was done from both BM and peripheral blood (PB) samples using 5 different antibody panels including markers for T, B, NK and regulatory T cells.ResultsWe found an early (3 months) expansion of BM lymphocytes during all different TKI therapies (imatinib median lymphocyte count 20%; dasatinib 21%; nilotinib 22%; healthy controls 12%, p<0.0001). Increased PB lymphocyte count was only observed during dasatinib therapy, possibly due to mobilization phenomenon observed only in dasatinib, and not in imatinib or nilotinib treated patients. The BM lymphocytic expansion was associated with better early molecular response; patients with 3 months BCR-ABL<10% showed higher lymphocyte counts than patients with BCR-ABL>10% (median 23% and 17% respectively; p<0.05). Interestingly, patients with suboptimal (warning) response (no major molecular remission at 12 months) showed significantly higher lymphocyte counts at 3 months than patients with optimal response or failure (28%, 19.5%, and 18.5% respectively, p<0.0001). During the treatment at 12 and 18 months when patients were already in complete cytogenetic and molecular remission, BM lymphocytosis seemed to persist (median lymphocyte counts 19% and 18%), thus suggesting that the lymphocyte increase is TKI therapy induced and not only related to myeloablation and eradication of leukemia cells.Detailed phenotypic analysis showed that lymphocyte expansion consisted of various lymphocyte subclasses, but especially the proportion of CD19+ B cells and CD3negCD16/56+ NK cells increased from diagnostic values (3 months NK cells: 19.4% vs. 16.8 % at diagnosis, p<0.05; B cells 10.7% vs. 8.6%, p<0.05). Among different TKIs studied, the proportion of CD3+CD16/56+ NKT-like cells was higher in dasatinib treated patients, but no differences were observed in the amount of B, NK or T cells. However, within the T cell population dasatinib group had significantly more BM CD8+ T cells (48% and 51% at 3 and 6 months) when compared to imatinib (41% and 39%) and nilotinib treated patients (43% and 33%). The percentage of CD57+ expressing T cells was also clearly increased in dasatinib patients (40% vs. 21% and 25% in the imatinib and nilotinib groups, p=0.004) as well as the percentage of HLA-DR expressing cells (HLA-DR+ from CD4+ T cells 18% vs. 7% and 7% in imatinib and nilotinib groups, p<0.05 and from CD8+ T cells 41% vs. 22% vs. 15%, respectively, p<0.05). The proportion of regulatory T cells in the BM was significantly lower in dasatinib-treated patients (3.2%) than in the imatinib (5.7%, p<0.05) or nilotinib group (5%).ConclusionBM lymphocytosis occurs during all current first-line TKI treatments, and it is associated with early molecular response. On the contrary, PB lymphocytosis occurs only during dasatinib treatment, and the overall lymphocyte balance in dasatinib group is shifted more to cytotoxic direction (increased CD8+CD57+ and CD8+HLA-DR+ cells, and low T regulatory cells). In accordance with shared kinase inhibition spectrum, no marked changes in the immunoprofile are observed between imatinib- and nilotinib-treated patients. DisclosuresBjerrum:Bristoll Myers Squibb, Novartis and Pfizer: Other: educational activities. Porkka:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Hjorth-Hansen:Novartis: Honoraria; Ariad: Honoraria; Bristol-Myers Squibb: Research Funding; Pfizer: Honoraria, Research Funding. Mustjoki:Novartis: Honoraria, Research Funding; Academy of Finland: Research Funding; the Finnish Cancer Societies: Research Funding; Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Sigrid Juselius Foundation: Research Funding; Finnish Cancer Institute: Research Funding; Signe and Ane Gyllenberg Foundation: Research Funding.

Effects of first- and second-generation tyrosine kinase inhibitor therapy on glucose and lipid metabolism in chronic myeloid leukemia patients: a real clinical problem?

Tyrosine kinase inhibitors (TKIs) have dramatically changed the prognosis of patients with chronic myeloid leukemia (CML). They have a distinct toxicity profile that includes glycometabolic alterations: i.e. diabetes mellitus (DM), impaired fasting glucose (IFG), and the metabolic syndrome (MS). The aim of this study was to evaluate the prevalence of these alterations in a cohort of CML-chronic phase patients treated with imatinib, dasatinib or nilotinib. The study involved 168 consecutive CML-chronic phase patients with no history of DM/IFG or MS. Anthropometric and metabolic parameters were assessed, and DM/IFG and MS were diagnosed based on the criteria of the American Diabetes Association and the National Cholesterol Education Program-Adult Treatment Panel III, respectively. The nilotinib group had significantly higher levels of fasting plasma glucose, insulin, C-peptide, insulin resistance, and total and LDL cholesterol than the imatinib and dasatinib groups. DM/IFG were identified in 25% of the imatinib- and dasatinib-treated patients, and 33% of those in the nilotinib cohort (p = 0.39 vs imatinib and p = 0.69 vs dasatinib). A diagnosis of MS was made in 42.4% of the imatinib-treated patients, 37.5% of the dasatinib-treated patients, and 36.1% of the nilotinib-treated patients (p = 0.46 vs imatinib and p = 0.34 vs dasatinib). Treatment with nilotinib does not seem to induce DM/IFG or the MS to a significantly higher extent than imatinib or dasatinib, though it causes a worse glycometabolic profile. These findings suggest the need for a close monitoring of glucose and lipid metabolism and a multidisciplinary approach in patients treated with nilotinib.

Deep molecular responses achieved in chronic myeloid leukemia in chronic phase patients with BCR-ABL1 >10% at 3 months who are early switched to nilotinib

Objectives: There are still controversies about whether or when to change therapy for those chronic myeloid leukemia in chronic phase (CML-CP) patients with BCR-ABL1 transcript level at 3 months higher than 10%. Here we studied the clinical significance of early switching to nilotinib in CML-CP patients with BCR-ABL1 >10% at 3 months.Methods: We investigated 495 first-line imatinib-treated patients with CML-CP and identified 117 (23.6%) patients with BCR-ABL1 >10% at 3 months, including 46 patients with warning response defined according to ELN-2013 recommendations. In 46 patients with warning response, 26 of them continued imatinib therapy and 20 patients early switched to nilotinib therapy.Results: Compared to continued imatinib group, nilotinib group showed significantly higher percentage achieving BCR-ABL1 <1% at 6 months (85.0% vs. 19.2%, P = 0.0004), better cumulative rates of MR3.0 and MR4.0 of 4 years (82.1% vs. 41.2%, P = 0.0091; 61.5% vs. 18.6%, P = 0.035).Conclusion: In summary, early switching to nilotinib enabled more CML-CP patients with warning molecular response at 3 months to achieve early and deeper molecular response vs. remaining on imatinib.

Nilotinib versus imatinib as first-line therapy for patients with unresectable or metastatic gastrointestinal stromal tumours (ENESTg1): a randomised phase 3 trial

Nilotinib inhibits the tyrosine kinase activity of ABL1/BCR-ABL1 and KIT, platelet-derived growth factor receptors (PDGFRs), and the discoidin domain receptor. Gain-of-function mutations in KIT or PDGFRα are key drivers in most gastrointestinal stromal tumours (GISTs). This trial was designed to test the efficacy and safety of nilotinib versus imatinib as first-line therapy for patients with advanced GISTs. In this randomised, open-label, multicentre, phase 3 trial (ENESTg1), participants from academic centres were aged 18 years or older and had previously untreated, histologically confirmed, metastatic or unresectable GISTs. Patients were stratified by previous adjuvant therapy and randomly assigned (1:1) via a randomisation list to receive oral imatinib 400 mg once daily or oral nilotinib 400 mg twice daily. The primary endpoint was centrally reviewed progression-free survival. Efficacy endpoints were assessed by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00785785. Because the futility boundary was crossed at a preplanned interim analysis, trial accrual terminated in April, 2011. Between March 16, 2009, and April 21, 2011, 647 patients were enrolled; of whom 324 were allocated nilotinib and 320 were allocated imatinib. At final analysis of the core study (data cutoff, October, 2012), 2-year progression-free survival was higher in the imatinib group (59·2% [95% CI 50·9-66·5]) than in the nilotinib group (51·6% [43·0-59·5]; hazard ratio 1·47 [95% CI 1·10-1·95]). In the imatinib group, the most common grade 3-4 adverse events were hypophosphataemia (19 [6%]), anaemia (17 [5%]), abdominal pain (13; 4%), and elevated lipase level (15; 5%), and in the nilotinib group were anaemia (18; 6%), elevated lipase level (15; 5%), elevated alanine aminotransferase concentration (12; 4%), and abdominal pain (11; 3%). The most common serious adverse event in both groups was abdominal pain (11 [4%] in the imatinib group, 14 [4%] in the nilotinib group). Nilotinib cannot be recommended for broad use to treat first-line GIST. However, future studies might identify patient subsets for whom first-line nilotinib could be of clinical benefit. Novartis Pharmaceuticals.

Real-life comparison of severe vascular events and other non-hematological complications in patients with chronic myeloid leukemia undergoing second-line nilotinib or dasatinib treatment

We retrospectively analyzed the rates of significant non-hematological adverse events (AEs) in 105 patients with chronic myeloid leukemia (CML) treated with second-generation tyrosine kinase inhibitor (TKIs) dasatinib or nilotinib used as second-line therapy in Polish tertiary care centers. Our analysis revealed that in a “real life setting,” nearly half of patients with CML on second-generation TKIs suffer from therapy complications. Grade 2–5 non-hematological AEs were observed in 40% of patients treated with nilotinib and in 42% treated with dasatinib (p = 0.83). Severe vascular events including peripheral artery occlusive disease (PAOD) occurred in 11% of patients on nilotinib and 4% on dasatinib (p = 0.16). Pleural effusion occurred more often in the dasatinib group (26%) than in the nilotinib group (2%) (p = 0.003). Importantly, most AEs occurred late, after more than 1 year of treatment. Since AEs are most often the reason for poor therapy compliance, careful monitoring of tolerability is crucial for an optimal treatment response in CML.

Mucosal healing effect of nilotinib in indomethacin-induced enterocolitis: A rat model.

To investigate the effects of nilotinib in a rat model of indomethacin-induced enterocolitis. Twenty-one Wistar albino female rats obtained from Dokuz Eylul University Department of Laboratory Animal Science were divided into the following three groups: control (n = 7), indomethacin (n = 7) and nilotinib (n = 7). A volume of 0.25 mL of physiological serum placebo was administered to the control and indomethacin groups through an orogastric tube for 13 d. To induce enterocolitis, the indomethacin and nilotinib groups received 7.5 mL/kg indomethacin dissolved in 5% sodium bicarbonate and administered subcutaneously in a volume of 0.5 mL twice daily for three days. Nilotinib was administered 20 mg/kg/d in two divided doses to the nilotinib group of rats for 13 d through an orogastric tube, beginning on the same day as indomethacin administration. For 13 d, the rats were fed a standard diet, and their weights were monitored daily. After the rats were sacrificed, the intestinal and colonic tissue samples were examined. The macroscopic and microscopic pathology scores were evaluated. The pathologist stained all tissue samples using terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling method. Mucosal crypts and apoptotic cells were quantified. The platelet-derived growth factor receptor (PDGFR) α and β scores assessed by immunohistochemical staining method and tissue and serum tumor necrosis factor (TNF) α levels were determined by enzyme-linked immunosorbent assay. Between days 1 and 13, the rats in the nilotinib and indomethacin groups lost significantly more weight than the controls (-11 g vs +14.14 g, P = 0.013; -30 g vs +14.14 g, P = 0.003). In the small intestinal and colonic tissues, the macroscopic scores were significantly lower in the nilotinib group than in the indomethacin group (1.14 ± 0.38 and 7.29 ± 2.98, P = 0.005; 1.14 ± 0.38 and 7.43 ± 2.64, P = 0.001, respectively), but the values of the nilotinib and indomethacin groups were similar to the control group. In the small intestinal and colonic tissues, the microscopic scores were significantly lower in the nilotinib group than in the indomethacin group (3.43 ± 2.99 and 7.67 ± 3.67, P = 0.043; 2.29 ± 0.76 and 8.80 ± 2.68, P = 0.003, respectively), but the values were similar to the control group. The PDGFR β scores in the small intestine and colon were significantly lower in the nilotinib group than in the indomethacin group (1.43 ± 0.79 and 2.43 ± 0.54, P = 0.021; 1.57 ± 0.54 and 3 ± 0, P =0.001), and the values were similar to controls. The colonic PDGFR α scores were significantly lower in the nilotinib group than in the indomethacin group (1.71 ± 0.49 and 3 ± 0, P = 0.001). The colonic apoptosis scores were significantly lower in the controls than in the nilotinib group (1.57 ± 1.13 and 4 ± 1.29, P = 0.007). Furthermore, the serum and tissue TNF-α levels were similar between the nilotinib and indomethacin groups. In the indomethacin-induced enterocolitis rat model, nilotinib has a positive effect on the macroscopic and microscopic pathologic scores, ensuring considerable mucosal healing. Nilotinib decreases PDGFR α and β levels and increases the colonic apoptotic scores, but it has no significant effects on weight loss and the TNF-α levels.

The Effect of Nilotinib in Chronic Myeloid Leukemia Treatment Dose on Spermatogenesis and Folliculogenesis in a Healthy Mouse Model

Abstract Introduction&amp;Aim:Chronic myeloid leukemia (CML) is a hematopoietic pluripotent stem cell disease where myeloid cells lead to uncontrolled proliferation. Current treatment of Ph (+) CML is based on the inhibition of tyrosine kinase inhibitors (TKI), especially second generation drugs. Majority of CML patients are male and 46% of them are between 20 and 64 years of age. Therefore, it is conceivable that inhibition of c-kit or PDGFR by TKI may have deleterious effects on spermatogenesis or folliculogenesis, resulting in male or female subfertility. Aim of this study is to determine the effect of nilotinib on spermatogenesis and folliculogenesis which is used routinely to treat CML. Materyal&amp;Method: Here we present the results of testicular and ovarian changes after nilotinib administration to five-week old male and female C57bI6 mice. Mice received 0.4 mg of nilotinib per day dissolved in the drinking water for 2 months. Control group received only drinking water. Treatment dose was determined according to the clinical studies regarding the plasma concentrations (20 mg/kg, orally). After sacrification of both groups, testicular and ovarian tissues were fixed and parafin sections were stained with hematoxylene-eosin. In the ovaries, the follicles were counted and their developmental stages were recorded from the serial sections. In the testes, 24 seminiferous tubules with approximately circular cross-sectional profiles were assessed using a classification according to the degree of spermatogenic activity to generate a mean score for each mouse. In addition, tubule diameters were measured using an eyepiece micrometer to provide an additional indication of the level of function. Results:There was less distance between the cortex and medulla than normal, and the follicles were widely scattered instead of organized in a normal hierarchy from the least mature at the periphery to the largest growing stages towards the medulla. The numbers of follicles were significantly different between nilotinib and control groups (268±110 vs. 170±60; p= 0.03). Virtually every seminiferous tubule from all animals had active spermatogenesis with either spermatids or spermatozoa present. Mean tubular diameter measurements were 190,61±8,33 vs. 194,32±7,26 in control and nilotinib groups, respectively (p=0.475). Spermatogenic activity index were not significantly different between control and nilotinib groups (3.1 vs. 3.4; p=0.241). Conclusion: Unlike the manufacturer’s results; we showed the supression of folliculogenesis and prevention of spermatogenesis during the long-term nilotinib treatment. Our results indicate that nilotinib, within the dose of CML treatment regimen, may create gonadotoxicity and therefore its usage may be an indication for fertility preservation. In the second part of our ongoing study, we are investigating the effect of nilotinib on fertility and teratogenicity. Disclosures No relevant conflicts of interest to declare.

Distinct Associations Between UGT1A1 Gene Promoter Polymorphism and Hyperbilirubinemia in Korean CML Patients Treated with Nilotinib and Radotinib

Background: Second-generation BCR-ABL tyrosine kinase inhibitors (2nd generation TKIs) including nilotinib (NIL) and radotinib (RAD) are approved for the treatment of newly diagnosed and other TKI failed chronic myeloid leukemia (CML). Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene promoter polymorphism, distinct number of TA repeats in promoter, has been reported for an association with hyperbilirubinemia on nilotinib therapy (Singer et al. Leukemia (2007) 21, 2311–2315). However, the distribution of UGT1A1 (TA)7 repeat polymorphism differs greatly between Caucasians and Japanese, namely, the frequency of UGT1A1(TA)7 repeat polymorphism is high in Caucasians, whereas it is low in Asians (Beutler et al. Proc. Natl. Acad. Sci. USA 95 (1998) 95, 8170–8174 ).Aims: The aim of this study was to investigate the association between UGT1A1 gene promoter polymorphism and hyperbilirubinemia in Korean CML patients treated with NIL and RAD as a frontline therapy.Methods: A total of 88 newly diagnosed chronic phase CML patients who treated with frontline NIL (n=39) and RAD (n=49) was screened for UGT1A1 promoter polymorphism genotype analysis. We used the High Pure PCR Template Preparation Kit (Roche, Germany) to prepare genomic DNA from whole blood and genotyped by direct sequencing of the 253- to 255-bp fragments produced by PCR.Results: The (TA)6/(TA)6 homozygote and (TA)6/(TA)7 heterozygote were seen in all genotyped population and frequency of (TA)6/(TA)6 homozygote was 79.5% (70/88) in our patients. (TA)6/(TA)6 homozygote predominated with 81.6% of the alleles in the RAD group and 76.9% in the NIL group. Relative riskfor each genotype presented in Table 1, with hyperbilirubinemia defined as CTCAE grade 2 or greater observed at any post-baseline point. The relative risks for 6/6 genotype versus 6/7 genotype was 3.5 with 95% CIs of (0.6, 18.9) in the RAD group compared with 8.1 (1.5, 43.8) in the NIL group and NIL group showed significantly high association with UGT1A1 gene promoter polymorphism (P<0.05).Conclusions: This finding suggests that UGT1A1 gene promoter polymorphism may be an important determinant of hyperbilirubinemia in CML patients with NIL therapy, but not in RAD. However other mechanisms should be explored in patients who have significant hyperbilirubinemia with RAD therapy. Updated data with longer follow-up duration will be presented in the meeting.Table 1Relative risk calculations for prevalence of hyperbilirubinemiaRadotinibNilotinibMax grade=,<1Max grade>,=2TotalMax grade=,<1Max grade>,=2Total(TA)6/(TA)6202040(TA)6/(TA)62643050.00%50.00%65.00%10.00%(TA)6/(TA)7279(TA)6/(TA)745922.22%77.78%44.44%55.56%Total222749Total30939Relative risk=3.5, 95% CI of (0.6, 18.9)Relative risk=8.1, 95% CI of (1.5, 43.8)Abbreviation: CI, confidence interval. DisclosuresNo relevant conflicts of interest to declare.

Prospective Analysis of the Quality of Life of Chronic Phase CML Patients on Second Generation Tyrosine Kinase Inhibitors after Imatinib Failure. an Observational Study

Imatinib (IM) failure in chronic phase CML patients is a peculiar situation where the quality of life (QoL) of patients has rarely been appreciated and assessed. A majority of patients is rescued by second generation tyrosine kinase inhibitors (TKI2) licensed in this setting. In the retrospective and prospective national observational POSTIM study we have already reported the value of the Hammersmith score in this population of patients. In the same population, we have also have prospectively analysed the QoL and the compliance of these IM-resistant or intolerant patients, on TKI2 (i. e. Nilotinib and Dasatinib) as a secondary objective, using a series of scores currently used to assess such characteristics (Morisky score, Functional Assessment of Cancer Therapy (FACT) subdivided in Physical Well Being (PWB), Social/Family Well Being (SWB), Emotional Well Being (EWB), Functional Well Being (FWB), Social/Family well being (SAC), (FACT+SAC=FACT-total), and FACT-Leu) calculated at 6 months and 12 months following first TKI2 initiation. These scores have been correlated to general characteristics of the patients, cytogenetic and molecular responses to TKI2 at one year of TKI2, and to survival.Among the 174 patients enrolled in the POSTIM study, 76 patients have been enrolled in this QoL study in 16 university and non-university academic institutions between 2009 and 2012, and their data collected after informed consent. There were 36 males (47%) and 40 females with a median age at enrolment of 62 (25-86) years and a median duration of CML of 6.5 (3-18) years. Sokal score was low for 37%, intermediate for 28% and high for 35 % (6 pts unknown). IM was stopped because of IM-resistance in 41% (n=29) of the patients, IM-intolerance in 40% (n=28), IM-intolerance + resistance in 19% (n=13) of the patients (6 patients unknown). None of the patients had been allotransplanted previously. Eleven % (n=6) of the patients had a high Hammersmith score (HS), 20% (n=11) an intermediate HS, and 69% (n=37) a low HS of evaluable patients (22 patients non evaluable). Sixty-one percent of the patients (n=46) had Dasatinib and 39% (n=30) had nilotinib as a first TKI2. The first TKI2 has been stopped for first TKI2 resistance (7 patients), intolerance (13 patients) and for resistance and intolerance (3 patients). Eleven patients went from Dasatinib to Nilotinib and 18 from Nilotinib to Dasatinib. The median follow-up after initiation of the first TKI2 is 4.5 (2.5-7) years. There was no difference in PWB, SWB, EWB, FWB, and FACT between Dasatinib and Nilotinib groups (p=0.56, 0.36, 0.53, 0.70, 0.66 respectively). Only one patient died, therefore the overall survival analysis was not relevant. Thirty-four patients (45%) failed the TKI2 treatment. We went on analysing the failure free survival [(FFS), failure defined as no hematologic or cytogenetic response, CHR, CCyR, PCyR MMR or MR4.5 loss, death, progression to AP/BC, definitive TKI2 cessation for resistance or intolerance, allogeneic stem cell transplantation]. Cox model analysis demonstrated that FFS was significantly longer in patients with a high FACT score since TKI2 initiation (median not reached for high FACT versus 28 months for low FACT score, p=0.02, see figure 1) and since CML diagnosis (median 161 months for high FACT versus 66 months for low FACT score, p=0.002; median 162 months for high FACT-total versus 87.5 months for low FACT-total score, p=0.012). In addition, the FFS since diagnosis was significantly better for patients with a high PWB score (median 161 months for high PWB versus 66 months for low PWB score, p=0.032). No difference in cytogenetic and molecular responses to TKI2 observed at 1 year have been influenced by any of the scores individually, or grouped (= FACT, FACT-total), neither the Morisky score.In conclusion, this prospective analysis performed on a large population of patients failing imatinib, on TKI2, demonstrated that maintaining a good QoL for these patients evaluated through the FACT scores, can effectively improve failure-free survival on these drugs, and this needs to be a matter of concern for improving the long-term follow-up and the compliance to treatments of such patients. [Display omitted] DisclosuresNicolini:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Roy:Novartis: Honoraria; BMS: Honoraria. Guerci-Bresler:Novartis, BMS, Pfizer: Honoraria. Legros:Novartis, BMS: Honoraria. Gardembas:BMS: Honoraria. Le Maux:BMS: Employment. Guinard-Azadian:BMS: Employment. Mohamed:BMS: Employment. Etienne:Novartis, BMS, Pfizer, Ariad: Honoraria.

Comparative Efficacy Among 3rd Line Post-Imatinib Chronic Phase-Chronic Myeloid Leukemia (CP-CML) Patients after Failure of Dasatinib or Nilotinib Tyrosine Kinase Inhibitors

INTRODUCTIONPatients with chronic myeloid leukemia (CP-CML) failing 1st line imatinib are most commonly treated with the second-generation (2G) tyrosine kinase inhibitors (TKIs) dasatinib and nilotinib. However, for patients who experience resistance or intolerance (R/I) to 2G-TKIs in 2nd line, there currently is no consensus on the optimal therapy sequence for 3rd line treatment. The comparative efficacy of using ponatinib in the 3rd line after 2G TKI failure was examined in a previous study (Lipton et al., ASH 2013). This study assesses the comparative efficacy of ponatinib versus sequential treatment of alternate 2G TKIs in 3rdline setting in two separate patient populations, post-imatinib and dasatinib patients and post-imatinib and nilotinib patients.METHODSA systematic review was conducted in MEDLINE, EMBASE and the Cochrane Libraries (2002-2014), as well as 3 conferences (ASH (2008-2014), ASCO (2008-2014), and EHA (2008-2013)). Studies evaluating any TKI were included if they enrolled 10 or more post-imatinib adult patients with CP-CML who were also R/I to dasatinib or nilotinib. All study designs were considered and no restriction was applied with respect to therapy dose, due to incomplete reporting of doses in the available studies. Analyses was run on two groups of patients, those failing imatinib and dasatinib (Group Ima/Das) and those failing imatinib and nilotinib (Group Ima/Nil). Bayesian methods were used to synthesize major cytogenetic response (MCyR) and complete cytogenetic response (CCyR) from individual studies and estimate the overall response probability with 95% credible interval (CrI) for each treatment. Bayesian analysis also was used to estimate the likelihood that each treatment offers the highest probability of CCyR/MCyR based on available evidence.RESULTSSix studies evaluating bosutinib, nilotinib and ponatinib for Group Ima/Das (n= 419) and five studies evaluating bosutinib, dasatinib and ponatinib for Group Ima/Nil (n=83) were included in the analysis. All studies reported CCyR in both groups. Five studies evaluating bosutinib, nilotinib and ponatinib reported MCyR in Group Ima/Das and three studies evaluating bosutinib and ponatinib reported MCyR in Group Ima/Nil.Synthesized treatment-specific probabilities and 95% CrI for CCyR are presented in Figure 1.Synthesized treatment-specific probabilities of CCyR for Group Ima/Das were 27% for nilotinib, 20% for bosutinib and 54% (95% CrI 43%% to 66%) for ponatinib. Treatment-specific probabilities of MCyR for Group Ima/Das were 41% for nilotinib, 28% for bosutinib and 66% (95% CrI 55%% to 77%) for ponatinib. The probability of ponatinib providing superior response to all other included treatments for group Ima/Das was estimated to be >99% for both CCyR and MCyR.Synthesized treatment-specific probabilities of CCyR for Group Ima/Nil were 25% for dasatinib, 26% for bosutinib and 67% (95% CrI 51%% to 81%) for ponatinib. Treatment-specific probabilities of MCyR for Group Ima/Nil were 33% for bosutinib and 75% (95% CrI 60%% to 87%) for ponatinib. The probability of ponatinib providing superior response to all other included treatments for group Ima/Nil was estimated to be >99% for both CCyR and MCyR.CONCLUSIONSThe post imatinib and dasatinib group included more studies with larger sample sizes compared with the post imatinib and nilotinib group. Overall, response rates appear higher for TKIs in the post imatinib and nilotinib group compared with the post imatinib and dasatinib group. For both groups, patients on ponatinib had higher CCyR and MCyR rates compared with the sequential 2G TKIs included in this analysis. Based on available data, ponatinib appears to provide a higher probability of treatment response for patients failing imatinib and dasatinib/ nilotinib compared with sequential 2G TKI therapy commonly used in this indication. [Display omitted] DisclosuresLipton:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ariad: Equity Ownership, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Shah:Ariad Pharmaceuticals: Research Funding. Tongbram:Ariad Pharmaceuticals: Research Funding. Sidhu:Ariad Pharmaceuticals Inc.: Research Funding. Huang:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. McGarry:ARIAD Pharmaceutical, Inc.: Employment, Equity Ownership. Lustgarten:ARIAD Pharmaceuticals Inc: Employment, Equity Ownership. Hawkins:Ariad Pharmaceuticals Inc.: Research Funding.

Efficacy of Nilotinib Vs High-Dose Imatinib Vs Sustaining Standard-Dose Imatinib in Early Chronic Phase CML Patients Who Have Suboptimal Molecular Response to Frontline Imatinib

Background. In chronic myeloid leukemia (CML), achievement of optimal responses by time point has improved long-term outcomes. In IRIS study, patients who achieved major molecular response (MMR) at 18 months had event-free survival (EFS) benefit, compared to those who achieved complete cytogenetic response (CCyR) without MMR. However, the best treatment for these patients is still not confirmed. By the previous studies, sustaining standard-dose of imatinib (IM) is expected to yield less than 20 percent of additive MMR. In this study, we investigated the efficacy of nilotinib (NIL) versus high-dose IM versus sustaining standard-dose IM for CCyR patients with suboptimal molecular response to frontline IM therapy.Methods. Early chronic phase (CP) CML patients who have achieved CCyR but no MMR after at least 18 months and up to 24 months ( 18 to 24 months) on first-line IM therapy at a daily dose of 400 mg were divided into 3 treatment groups; NIL 400mg BID (800 mg/day; group 1) vs IM 400 mg BID (800 mg/day; group 2) vs IM 400mg QD (400mg/day; group 3). Group 1 and 2 patients were selected in RE-NICE multicenter study and group 3 patients were selected with the same inclusion criteria of RE-NICE.The efficacy endpoints are MMR rate by 12 months and MMR rate and undetectable molecular residual disease (UMRD) rates by 36 months. Safety profiles of each group were compared.Patients showing lack of response (lack of complete hematologic response (CHR) at 6 months, increasing WBC, no major cytogenetic response (MCyR) at 24 months), loss of response (loss of CHR or MCyR) or intolerance to treatment were allowed to switch to other treatment.Results. With a data cut-off date of 17 Jul 2014, a total of 83 patients were evaluated; 29 patients in NIL group (group 1), 29 patients in high-dose IM group (group 2) and 25 patients in standard-dose IM group (group 3).With a median follow-up of 36 months (range, 1-63), all patients in group 1 remained in nilotinib treatment, 17 patients in group 2 switched to NIL 400mg BID due to intolerance (n=4) and lack of response (no MMR; n=13). In group 3, with a median follow-up of 71 months (range, 6-132), 15 patients switched to other treatment due to intolerance (n=5) and lack of response (no MMR; n=10).Up to now, all patients in three groups have maintained CCyR without progression or resistance.10 in 29 (35%), 8 in 29 (28%) and 5 in 25 (20%) patients achieved MMR by 12 months, and 20 in 29 (69%), 15 in 29 (51%) and 11 in 25 (44%) patients achieved MMR by 36 months in group 1, group 2 and group 3 respectively. Overall, 3 patients in group 1 (3/29, 10%) achieved confirmed UMRD.Overall 3 years probability of MMR was significantly higher in group 1 than the other two groups (67.8% vs 41.0% vs 40.4%, group 1, 2, 3 respectively, group 1 vs 2, P=0.089, group 1 vs 3, P=0.035, group 2 vs 3, P=0.614).Compare to other groups, the patients in group 2 showed higher toxicities, such as leukopenia, anemia, thrombocytopenia, edema, fatigue, dyspnea and hypophosphatemia.Conclusions. Nilotinib 400mg twice daily treatment showed better efficacy than high-dose or same standard-dose imatinib for the treatment of patients who have suboptimal molecular response to initial standard-dose imatinib. Additionally, a switch to nilotinib in suboptimal molecular responder to imatinib would also be preferable option in terms of tolerability. Updated data with longer follow-up duration will be presented in the meeting. DisclosuresNo relevant conflicts of interest to declare.

Real-Life Comparison Of Severe Vascular Events and Other Non-Hematological Complications In CML Patients Treated With Second Line Nilotinib Or Dasatinib

Despite very good long-term results of imatinib (IM) in chronic myeloid leukemia (CML) patients about 30% of them will need the new treatment option. For these patients, two effective second-generation tyrosine kinase inhibitors (TKI) are available: dasatinib and nilotinib. Although both have good toxicity profile and side effects are usually mild and manageable, some patients have major problems and develop intolerance or even life-threatening adverse events (AEs). A unique spectrum of non-hematological AEs has been reported for both TKI like pleural infusion for dasatinib and elevation of glucose, pancreatic and liver enzymes for nilotinib. Recently several studies have described the clinical manifestation of peripheral artery occlusive disease (PAOD) in patients receiving nilotinib. The risk of developing PAOD on TKI therapy is unknown and causality has not been established yet.We retrospectively analyzed the rates of grade 2-5 non-hematologic AEs in CML patients treated with dasatinib or nilotinib as second line therapy in “real-life” setting. The analysis included 105 patients from 5 Polish Hematological Centers, 57 men (54%) and 48 women (46%), with median age of 57 (range 21-88). Median time of observation was 28 months (range 1-93 months). Fifty-five (52%) patients were treated with nilotinib and 50 (48%) with dasatinib. The reason for stopping first line therapy was resistance to IM in 84% and intolerance in 16% (the proportions were similar in dasatinib and nilotinib group, p=0.77). At the time of the present analysis 73 patients (68%) continued second line therapy while in 28 patients (32%) therapy was changed because of resistance or intolerance. Estimated median time for second line therapy withdrawal duration was 35 months. Interestingly, estimated median time to treatment change was significantly longer for dasatinib (42 months) than for nilotinib (29 months) (log-rank test p=0.17). The non-hematological AEs (grade 2-4) were observed in 22 (40%) patients treated with nilotinib and 21 (42%) patients in dasatinib arm (p=0.83). The median estimated time to AE onset was 70 months for nilotinib and 53 months for dasatinib (log-rank test, p=0.35). Vascular events occurred in 8 patients (8%) in both treatment groups, included 6 (11%) in nilotinib group and 2 (4%) in dasatinib group (p=0.16). In nilotinib group one patient with previously diagnosed hypertension developed PAOD which required stent implantation, 2 patients had myocardial infarction, 2 patients had arrythmia and 1 had ischemic stroke. In dasatinib gruoup one patients had myocardial infarction and 1 ischemic stroke. Among other clinically significant AEs pleural effusion (grade 2-4) occurred more often in dasatinib group than in nilotinib group (26% vs. 2%) (p=0.003). Moreover, in dasatinib group two patients (4%) developed pulmonary hypertension, in both cases completely reversible after stopping the drug. In one of these patients sclerodermia was diagnosed before dasatinib treatment. In conclusion we found that despite generalized opinion on good toxicity profile of second generation TKI about 40% of patients treated with second line nilotinib or dasatinib outside clinical studies suffered from grade 2-4 non-hematological AE. It is worth underlining that most AEs occurred late, after more than 2 years of treatment. Importantly, the total frequency of different AEs did not differ significantly and the number of severe vascular events seems comparable on nilotinib and dasatinib, though larger studies may be needed. Disclosures:Gora-Tybor:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Robak:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Incidence and outcomes of chronic myeloid leukemia (CML) patients (pts) treated with second-generation tyrosine kinase inhibitors (TKI) who develop other chromosomal abnormalities (OCA).

7090 Background: Development of OCA has been reported among pts receiving imatinib as initial therapy for CML. Little is known about OCA development in CML pts treated with frontline 2nd generation TKI (dasatinib, nilotinib). Methods: OCA is defined as cytogenetic abnormality in non-Philadelphia chromosome positive clones as pts respond to TKI. Among pts treated with frontline dasatinib (n=99) or nilotinib (n=117), on parallel prospective single-arm phase II protocols at MDACC, 30 OCA ptswere identified, chronic (n=25) or accelerated phase (AP) (n=5). Results: 11 (11%) pts treated with dasatinib and 19 (16%) with nilotinib developed OCA; median follow-up 30 mo (range 0-71). Difference in OCA incidence with dasatinib and nilotinib was not statistically significant. At start of therapy, median age (years) of OCA pts was 53 (41-71) with dasatinib and 52 (37-82) with nilotinib, compared to those pts without OCA: 48 (18-83) with dasatinib and 49 (17-87) with nilotinib. Most common OCA was abnormality of chromosome 7 with 6 occurrences in 5 pts (1 pt with both inv(7) and +7) (inversion (n=1), 2 different translocations (n=2), deletions (n=2), and additions (n=1)). No pts developed trisomy 8 (historically most common OCA in imatinib-treated pts). Median time to first OCA: 9 mo (range 3-58) for all pts (12 mo (range 3-58) for dasatinib group and 9 mo (3-48) for nilotinib group). OCA disappeared spontaneously in 25 pts during follow-up. Outcomes for OCA versus non-OCA group (Table). For AP pts: 3/6 (50%) in dasatinib group and 2/17 (12%) in nilotinib group developed OCA. None of the OCA pts has developed AML or MDS. Conclusions: OCA is 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 adverse impact on outcomes when compared to non-OCA pts treated with 2nd generation TKI and has not resulted in other hematologic disorders. [Table: see text]

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...