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Kathmandu is Rapidly growing city where the Crisis due to centralization is foreseen in Transportation sector due to lack of proper Planning and Vision prior of establishing settlement. The Current status of Transportation system in Kathmandu is quite alarming in absence of well-organized Public Transportation system. The growth of Vehicles and simultaneously lack of improvements of existing facilities and traffic management have resulted in unorganized improvement of Traffic thereby increasing congestion, accidents and decrease in vehicle speed affecting road capacity. So using managed Scientific system to decrease jam causing parameters with most planned system and replacing the existing Systems by modern facilities, the problem can be reduced. Introduction of Bus rapid transit by gradual replacement of old transportation systems by providing a bus lane can be promising remedial measure to optimize public transportation system in Kathmandu valley

Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with asthma, particularly of late onset. Current treatment options for CRSwNP have limitations, and there is an unmet need for other safe and effective therapies.The aim of the THUNDER study was to determine the efficacy and safety of the prostaglandin DTHUNDER was a phase 3b, randomized, multicenter, double-blind, placebo-controlled, parallel-group, 16-week study of fevipiprant 150 mg or 450 mg once daily versus placebo. All patients received intranasal mometasone furoate 200 μg daily.Ninety-eight patients were randomly assigned to fevipiprant 150 mg (n = 32), fevipiprant 450 mg (n = 34), or placebo (n = 32). Mean (SE) change from baseline in nasal polyp score at week 16 was 0.20 (0.224) for fevipiprant 150 mg, -0.10 (0.216) for fevipiprant 450 mg, and 0.14 (0.233) for placebo. Mean treatment difference was 0.05 (95% confidence interval, -0.59, 0.70; adjusted P = .979) for fevipiprant 150 mg versus placebo and -0.25 (95% confidence interval, -0.88, 0.39; adjusted P = .656) for fevipiprant 450 mg versus placebo. There was no meaningful difference in the secondary end points for fevipiprant versus placebo.THUNDER provided no evidence of a role for fevipiprant in the treatment of patients with CRSwNP and asthma; future studies may establish a role for other DP

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

Sustained deep molecular responses in patients switched to nilotinib due to persistent BCR-ABL1 on imatinib: final ENESTcmr randomized trial results

Background Treatment-free remission (TFR)-that is, stopping tyrosine kinase inhibitor (TKI) therapy without loss of response-is an emerging treatment goal in chronic myeloid leukemia (CML). Objective To evaluate TFR after discontinuation of second-line nilotinib therapy. Design Single-group, phase 2, open-label study. (ClinicalTrials.gov: NCT01698905). Setting 63 centers in 18 countries. Patients Adults with CML in chronic phase who received TKI therapy for at least 3 years (>4 weeks with imatinib, then ≥2 years with nilotinib) and achieved MR4.5 (BCR-ABL1 ≤0.0032% on the International Scale [BCR-ABL1IS]) while receiving nilotinib entered a 1-year consolidation phase. Those with sustained MR4.5 during consolidation were eligible to enter TFR. Interventions Patients received nilotinib during consolidation; those who entered TFR stopped treatment. Patients with loss of major molecular response (MMR) (BCR-ABL1IS ≤0.1%) or confirmed loss of MR4 (BCR-ABL1IS ≤0.01%) during TFR reinitiated nilotinib treatment. Measurements Proportion of patients without loss of MMR, confirmed loss of MR4, or treatment reinitiation within 48 weeks of stopping treatment (primary end point). Results 163 patients who had switched from imatinib to nilotinib (for reasons including resistance, intolerance, and physician preference) enrolled in the study and entered the consolidation phase. Of these patients, 126 met the criteria for entering the TFR phase, and 73 (58% [95% CI, 49% to 67%]) and 67 (53% [CI, 44% to 62%]) maintained TFR at 48 weeks (primary end point) and 96 weeks, respectively. Of the 56 patients who reinitiated nilotinib therapy, 55 regained MMR or better and 52 regained MR4.5. None had CML progression to accelerated phase or blast crisis. Musculoskeletal pain was more frequent during the first 48 weeks after nilotinib discontinuation. Limitation The study included a heterogeneous patient population and was not designed to compare outcomes between patients continuing and those stopping treatment. Conclusion TFR seems achievable in patients with sustained MR4.5 after switching to nilotinib. Primary funding source Novartis Pharmaceuticals Corporation.

7005 Background: In the ENESTop study (NCT01698905) of TFR in pts with CML-CP who achieved a sustained deep molecular response (MR) with 2L NIL, 57.9% remained in TFR 48 wks after stopping NIL (primary endpoint). Analyses at 144 wks showed durability of TFR. Data from longer follow-up (192 wks) evaluating the maintenance of TFR are reported. Methods: Pts treated with ≥2 y NIL after > 4 wks imatinib (≥3 y total) and achieving MR4.5 ( BCR-ABL1IS ≤0.0032%) on NIL were eligible. After a 1 y consolidation, pts with no confirmed loss of MR4.5 could attempt TFR. NIL was resumed upon loss of major MR ( BCR-ABL1IS ≤0.1%) or confirmed loss of MR4 ( BCR-ABL1IS ≤0.01%). At the data cut-off (Sep 24 2018), all pts had completed ≥192 wks of TFR, resumed NIL, or discontinued the study. Results: By the data cut-off, of 126 pts entering TFR, 56 were ongoing, 59 had resumed NIL, and 11 had discontinued. TFR rate at 192 wks was 46.0% (58/126; 95% CI, 37.1–55.1%); all but 1 of the 58 pts were in MR4.5. Only 1/61 pts in TFR at 144 wks lost response by 192 wks (confirmed loss of MR4); another 2 pts discontinued due to serious AE (polycythemia vera) and pt/guardian decision, respectively. Of 59 pts who resumed NIL, 56 (94.9%) and 55 (93.2%) regained MR4 and MR4.5, respectively. 40/56 pts (71.4%) who regained MR4 had stable MR4 at 96 wks (12 discontinued < 96 wks, and 4 remained on study with < 96 wks, after regaining MR4); 37/55 pts (67.3%) who regained MR4.5 had stable MR4.5 at 96 wks (12 discontinued < 96 wks, and 6 remained on study with < 96 wks, after regaining MR4.5). There were no disease progressions, deaths due to CML, or new deaths since the 144-wk analysis. The 192 wk treatment-free survival rate was 50.3% (95% CI, 41.2–58.7%). Of 62 pts who remained in TFR for > 144 wks, 11.3%, 53.2%, 21.0%, 14.5% and 3.2% had musculoskeletal pain AEs during consolidation and each subsequent 48 wk period of TFR. Among 59 pts who resumed NIL, most common AEs were hypertension (20.3%) and arthralgia (13.6%); the majority of AEs were grade 1/2. Conclusions: Results demonstrate long-term durability and safety of TFR following 2L NIL, with no disease progressions or CML-related deaths, and musculoskeletal pain AEs were transient. Clinical trial information: NCT01698905.

7003Background: TFR is a new treatment goal in CML. In the ENESTop study (NCT01698905) in pts with CML-CP who sustained a deep molecular response with 2L nilotinib, 57.9% and 53.2% remained in TFR ...

Background: ENESTop (NCT01698905) is an ongoing, single-arm, phase 2 study evaluating treatment-free remission (TFR) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) who achieved sustained molecular response 4.5 (MR4.5; BCR-ABL1 ≤ 0.0032% on the International Scale [BCR-ABL1IS]) on second-line nilotinib (NIL). In the primary analysis, 57.9% (95% CI, 48.8%-66.7%) of pts who stopped NIL maintained TFR (no loss of major molecular response [MMR; ie, BCR-ABL1IS > 0.1%], confirmed loss of MR4 [ie, consecutive BCR-ABL1IS > 0.01%], or treatment reinitiation) at 48 weeks. Adverse events (AEs) were reported in 73.8% of pts during the first 48 weeks of TFR vs 77.0% during the year prior to stopping treatment. The incidence of musculoskeletal pain-related AEs was higher during TFR (42.1% vs 14.3%). To assess the potential effect of stopping NIL on quality of life (QOL), pt-reported outcomes were assessed before and during TFR. Methods: ENESTop enrolled adult pts with CML-CP with ≥ 3 years of prior tyrosine kinase inhibitor (TKI) therapy (> 4 weeks of imatinib [IM], then ≥ 2 years of NIL). Pts must have achieved sustained MR4.5 on NIL after switching from IM. Enrolled pts entered a 1-year NIL treatment consolidation phase; those without confirmed loss of MR4.5 (ie, consecutive BCR-ABL1IS > 0.0032%) entered the TFR phase and stopped NIL. Pts with loss of MMR or confirmed loss of MR4 during the TFR phase reinitiated NIL. QOL was assessed via questionnaires completed by pts at specified time points. The MD Anderson Symptom Inventory for CML (MDASI-CML) questionnaire assessed, for a defined set of symptoms, the levels of severity and interference with daily life on a scale of 0 to 10, with 0 being the lowest level. The EQ-5D-5L questionnaire assessed problems experienced by pts (no, slight, moderate, severe, or extreme [ie, interfering with functioning] problems) in 5 dimensions: mobility, self-care, usual activities, anxiety/depression, and pain/discomfort; additionally, overall level of health was assessed on a scale of 0 to 100 using the EQ VAS, with 0 being the lowest level. Results: Of 163 enrolled pts, 126 met the criteria for stopping NIL in the TFR phase; of these 126, 53 had loss of MMR or confirmed loss of MR4, of whom 51 reinitiated NIL. Among pts who completed each questionnaire at week 48 of the consolidation phase, week 12 of the TFR phase, or week 48 of the TFR phase, mean MDASI-CML severity scores were 1.7, 1.5, and 1.2, respectively; mean MDASI-CML interference scores were 1.7, 1.6, and 1.4, respectively; and mean EQ VAS scores were 82.2, 78.8, and 82.3, respectively (Table). Among pts with sustained TFR and scores at both week 48 of the consolidation phase and week 12 or 48 of the TFR phase, minimal changes were observed in MDASI-CML and EQ VAS scores during TFR vs week 48 of the consolidation phase. Among pts who reinitiated NIL, mean MDASI-CML severity and interference scores and mean EQ VAS scores at 24 weeks after the start of retreatment were 1.6, 1.5, and 78.8, respectively; changes in scores between week 24 after treatment reinitiation and week 48 of the consolidation phase were minimal among pts with scores at both time points. Among pts who completed the EQ-5D-5L questionnaire, the proportions who reported problems (any level of severity) in the 5 dimensions were generally similar across time points, although problems with mobility and pain/discomfort were more common during TFR vs week 48 of the consolidation phase, particularly at week 12 of the TFR phase (Table). Conclusion: Changes in QOL after stopping NIL, as assessed using these questionnaires, were minimal. This may be related to pts having a relatively high QOL prior to stopping treatment given that they had tolerated ≥ 3 years of TKI therapy, including ≥ 2 years of NIL, prior to enrollment. Despite the higher incidence of musculoskeletal pain-related AEs observed during TFR (42.1% vs 14.3%), the overall QOL was generally similar between the TFR and consolidation phases. This suggests that these AEs did not have a significant negative impact on QOL. Longer follow-up in ENESTop will be needed to further evaluate trends in QOL after stopping second-line NIL. Disclosures Mahon: NOVARTIS PHARMA: Honoraria, Research Funding; BMS: Honoraria; ARIAD: Honoraria; PFIZER: Honoraria. Boquimpani:BMS: Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Takahashi:Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; BMS: Honoraria. Shuvaev:Novartis pharma: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Ailawadhi:Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Lipton:Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Turkina:Novartis Pharma: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Moiraghi:NOVARTIS: Speakers Bureau; BMS: Speakers Bureau. Nicolini:Ariad: 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, Research Funding; BMS: Consultancy, Honoraria. Sacha:Pfizer: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Adamed: Consultancy, Honoraria. Kim:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Fellague-Chebra:Novartis: Employment. Acharya:Novartis Healthcare Pvt. Ltd.: Employment. Brandt:Novartis: Employment. Gnanasakthy:Novartis: Consultancy, Equity Ownership, Research Funding. Jin:Novartis: Employment, Equity Ownership. Hughes:Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Background: ENESTop, an ongoing, single-arm, phase 2 study (ClinicalTrials.gov, NCT01698905), is the first trial specifically evaluating treatment-free remission (TFR; ie, stopping tyrosine kinase inhibitor [TKI] treatment without a loss of response) in patients with chronic myeloid leukemia in chronic phase (CML-CP) who achieved a sustained deep molecular response after switching from imatinib (IM) to nilotinib (NIL). Of 126 patients in ENESTop who were eligible to stop NIL, 57.9% (95% CI, 48.8%-66.7%) maintained TFR at 48 weeks. Here we present results from a subgroup analysis based on reasons for switching from IM to NIL, categorized as intolerance, resistance, and physician preference. Methods:Eligible patients were adults with CML-CP who received ≥ 3 years of total TKI therapy (> 4 weeks of IM, followed by ≥ 2 years of NIL) and achieved a sustained MR4.5 (BCR-ABL1 ≤ 0.0032% on the International Scale [BCR-ABL1IS]) on NIL therapy; patients with a documented MR4.5 at the time of switch from IM to NIL were not eligible. Enrolled patients continued NIL treatment in a 1-year consolidation phase, and those without confirmed loss of MR4.5 (ie, consecutive BCR-ABL1IS > 0.0032%) were eligible to stop NIL in the TFR phase. Patients with loss of major molecular response (MMR; ie, BCR-ABL1IS > 0.1%) or confirmed loss of MR4 (ie, consecutive BCR-ABL1IS > 0.01%) during the TFR phase reinitiated NIL treatment. The primary endpoint was the proportion of patients who maintained TFR (ie, no loss of MMR, confirmed loss of MR4, or treatment reinitiation) at 48 weeks after stopping NIL. In this post hoc analysis, rates of TFR at 48 weeks after stopping NIL and a Kaplan-Meier (KM) analysis of treatment-free survival (TFS; defined as the time from the start of TFR to the earliest occurrence of any of the following: loss of MMR, confirmed loss of MR4, reinitiation of NIL due to any cause, progression to accelerated phase/blast crisis, death due to any cause) were evaluated in subgroups of patients who switched from IM to NIL due to intolerance, resistance, or physician preference. These categories were determined by grouping the reasons for switching from IM to NIL, as reported by the investigators, based on relatedness to safety (intolerance), loss of response/treatment failure (resistance), and the physician's clinical judgment (physician preference); individual reasons included within each category are presented in the Figure. Results:A total of 125 patients who entered the TFR phase were included in this analysis; 1 patient who was found to have had atypical transcripts was excluded. Among these 125 patients, the reasons for switching to NIL were categorized as intolerance in 51 patients (40.8%), resistance in 30 patients (24.0%), and physician preference in 44 patients (35.2%). The proportion of patients who maintained TFR at 48 weeks after stopping NIL was generally similar across the 3 subgroups: 30 of 51 (58.8%; 95% CI, 44.2%-72.4%) in the intolerance subgroup, 16 of 30 (53.3%; 95% CI, 34.3%-71.7%) in the resistance subgroup, and 27 of 44 (61.4%; 95% CI, 45.5%-75.6%) in the physician preference subgroup. KM analysis of TFS showed that in all 3 subgroups, the majority of TFS events occurred within the first 24 weeks after stopping NIL (Figure). There were no notable differences in the kinetics of TFS events among subgroups. The KM-estimated median duration of TFS was not reached by the data cutoff date in all 3 subgroups. Conclusion: Primary analysis from ENESTop showed that among patients with CML-CP who achieved a sustained MR4.5after switching from IM to NIL, 57.9% of those who stopped NIL maintained TFR at 48 weeks. In the present analysis, TFR was maintained at 48 weeks after stopping NIL by > 50% of patients in the intolerance, resistance, and physician preference subgroups, with generally similar results across subgroups. These findings suggest that the rate of successful TFR following second-line NIL does not differ based on the reasons for switching from IM to NIL. Figure. Figure. Disclosures Hughes: Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Australasian Leukaemia and Lymphoma Group (ALLG): Other: Chair of the CML/MPN Disease Group. Boquimpani:Novartis: Research Funding, Speakers Bureau; BMS: Speakers Bureau. Takahashi:Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; BMS: Honoraria. Shuvaev:Pfizer: Honoraria; BMS: Honoraria; Novartis pharma: Honoraria. Ailawadhi:Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Lipton:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Turkina:Pfizer: Honoraria; Novartis Pharma: Honoraria; BMS: Honoraria. Moiraghi:BMS: Speakers Bureau; NOVARTIS: Speakers Bureau. Nicolini:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria; Ariad pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sacha:BMS: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Adamed: Consultancy, Honoraria. Kim:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding. Fellague-Chebra:Novartis: Employment. Acharya:Novartis Healthcare Pvt. Ltd.: Employment. Krunic:Novartis: Employment, Equity Ownership. Jin:Novartis: Employment, Equity Ownership. Mahon:BMS: Honoraria; PFIZER: Honoraria; NOVARTIS PHARMA: Honoraria, Research Funding; ARIAD: Honoraria.

7054Background: The ENESTop (NCT01698905) study explores the discontinuation of NIL therapy in pts who achieved sustained MR4.5 (BCR-ABL1IS≤ 0.0032%) after switching from imatinib (IM) to NIL. Methods: The single-arm phase 2 study enrolled pts with CML-CP treated with tyrosine kinase inhibitor (TKI) for ≥ 3 y (including IM for > 4 wk followed by NIL for ≥ 2 y) and achieved MR4.5 on NIL. On study, pts continued NIL for 1 y (consolidation phase [CONS]). After 1 y, pts without confirmed loss of MR4.5 (consecutive BCR-ABL1IS > 0.0032%), were eligible to stop NIL (TFR). RQ-PCR was monitored every 12 wk in CONS and every 4 wk during first 48 wk of TFR. Upon confirmed loss of MR4 (consecutive BCR-ABL1IS > 0.01%) or loss of MMR (BCR-ABL1IS> 0.1%), NIL was re-initiated (ReRx). Primary endpoint was the proportion of pts with successful TFR (neither loss of MMR nor confirmed loss of MR4 by 48 wk of TFR) after a ≥ 48 wk follow up (data cutoff, 26 Nov 2015). Results: Of the 163 pts in CONS, 126 entered TFR (median dur...

Introduction The 12- and 24-mo results of the Evaluating Nilotinib Efficacy and Safety in clinical Trials–complete molecular response (ENESTcmr) trial showed that pts with CML-CP with minimal residual disease after ≥ 2 y on imatinib achieved deeper molecular responses with switch to nilotinib. Results from ENESTcmr with 36-mo follow-up will be presented. Methods Pts with Philadelphia chromosome–positive (Ph+) CML-CP who had achieved complete cytogenetic response (CCyR) but had detectable BCR-ABL after ≥ 2 y on imatinib were included. Pts (N = 207) were randomized 1:1 to continue the same dose of imatinib (400 or 600 mg once daily [QD]; n = 103) or switch to nilotinib 400 mg twice daily (BID; n = 104). Rates of major molecular response (MMR; BCR-ABL ≤ 0.1% according to the International Scale [IS]) and MR4.5 (BCR-ABLIS ≤ 0.0032%) were evaluated by real-time quantitative polymerase chain reaction (RQ-PCR). Confirmed undetectable BCR-ABL was measured by RQ-PCR with a sensitivity of ≥ 4.5 logs, confirmed with a sensitivity of at least 4 logs in the next sample. Predictors of response were evaluated by multivariate logistic regression. Pts receiving imatinib were allowed to cross over to nilotinib if they had not achieved confirmed undetectable BCR-ABL by 24 mo or if they experienced treatment failure or confirmed loss of undetectable BCR-ABL at any time. Results By 24 mo, 77% of pts in the nilotinib arm and 91% in the imatinib arm remained on study treatment. Discontinuation rates were comparable between arms during year 2; 7% and 5% of pts discontinued study treatment in the nilotinib and imatinib arms, respectively, between years 1 and 2. Three pts crossed over to nilotinib before 24 mo; the no. of pts who crossed over at or after 24 mo will be presented. By 24 mo, more pts in the nilotinib arm achieved confirmed undetectable BCR-ABL compared with imatinib (22.1% vs 8.7%; P = .0087; Table). Regardless of molecular response at study start, more pts in the nilotinib arm than the imatinib arm achieved MR4.5 by 24 mo. None of the pts in the imatinib arm who lacked MMR at study start achieved confirmed MR4.5 or confirmed undetectable BCR-ABL by 24 mo (vs 20.8% and 16.7% in the nilotinib arm, respectively). Twice as many pts achieved and maintained MR4.5 in 3 consecutive assessments in the nilotinib vs imatinib arm (n = 12 vs 6). Age, sex, BCR-ABL level at study start, duration of prior imatinib (≤ 36 mo vs > 36 mo), and prior interferon were analyzed as predictors of response in univariate and multivariate analyses. None of these was clearly predictive of achieving MR4.5 or undetectable BCR-ABL in multivariate logistic regression. No cases of progression to accelerated phase/blast phase were observed with 24 mo follow-up. Three pts in the imatinib arm had confirmed loss of CCyR vs 0 in the nilotinib arm. Conclusions Switching to nilotinib continues to induce deeper molecular responses in pts with minimal residual disease on long-term imatinib therapy. More pts achieved confirmed undetectable BCR-ABL in the nilotinib arm vs the imatinib arm, with the difference between arms increasing between 12 and 24 mo and notably marked in pts lacking MMR at study start. Maintenance of deeper molecular responses achieved with nilotinib therapy may enable more pts to benefit from treatment-free remission trials. Disclosures: Leber: novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Cervantes:Novartis: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Pfizer: Membership on an entity’s Board of Directors or advisory committees. Spector:Novartis: Honoraria, Research Funding. Lipton:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ariad: Equity Ownership, 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. Etienne:Pfizer: Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity’s Board of Directors or advisory committees; novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Ariad: Membership on an entity’s Board of Directors or advisory committees. Guerci-Bresler:Celgene: 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; Novartis : Honoraria, Membership on an entity’s Board of Directors or advisory committees; AMGEN: Honoraria. Forrest:Bristol Myers Squibb: Consultancy. Schwarer:Bristol Myers Squibb: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Acharya:Novartis Healthcare Pvt. Ltd.: Employment. Collins:Novartis: Employment. Szczudlo:Novartis: Employment, Equity Ownership. Hughes:Araid: Consultancy, Honoraria; Bristol Myers Squib: Consultancy, Honoraria, Research Funding; Novarits: Consultancy, Honoraria, Research Funding; CSL: Research Funding.

7025 Background: With 24 mo f/u, ENESTcmr demonstrated higher rates of stable, deep MRs with nilotinib (NIL) vs IM in pts on long-term (≥ 2 y) IM with residual disease. Here, we present 36-mo resul...

Background Frontline nilotinib 300 mg twice daily (BID) provides superior efficacy vs imatinib in pts with CML-CP, with good tolerability. Evaluating Nilotinib Efficacy and Safety in Clinical Trials—Extending Molecular Reponses (ENESTxtnd) is evaluating the kinetics of molecular response to frontline nilotinib 300 mg BID in pts with newly diagnosed CML-CP, as assessed in national and local laboratories, and is also the first study to evaluate the safety and efficacy of nilotinib dose optimization (including dose re-escalation in pts who require dose reductions due to adverse events [AEs] and dose increase in pts with less than optimal response). Here, we present results of a preplanned, interim analysis (IA) based on the first 20% of pts who completed 12 mo of treatment or discontinued early. Methods ENESTxtnd (NCT01254188) is an open-label, multicenter, phase 3b clinical trial of nilotinib 300 mg BID in adults with CML-CP newly diagnosed within 6 mo of study entry. The primary endpoint is rate of MMR by 12 mo. Molecular responses were monitored by real-time quantitative polymerase chain reaction (RQ-PCR) at local laboratories at baseline, at 1, 2, and 3 mo, and every 3 mo thereafter. Bone marrow cytogenetic analyses were performed locally at baseline, 6 mo, and end of study. Dose reductions were allowed for grade ≥ 2 nonhematologic AEs and grade 3/4 hematologic AEs. Pts with dose reductions could attempt to re-escalate (successful re-escalation defined as ≥ 4 wk on nilotinib 300 mg BID with no dose adjustments for any AE) and remain on study. Dose increase to nilotinib 400 mg BID was allowed in cases of BCR-ABL > 10% on the International Scale (BCR-ABLIS) at 3 mo or later, no major molecular response (MMR; BCR-ABLIS ≤ 0.1%) at 12 mo, loss of MMR, or treatment failure. Results This IA includes 85 pts treated in 12 countries (Argentina, Australia, Brazil, Canada, Israel, Lebanon, Mexico, Malaysia, Saudi Arabia, Thailand, Taiwan, and South Africa). Median age was 49 y (range, 19-85 y), and 58% of pts were male. Median time since diagnosis was 35 days (range, 2-157 days). Prior to study entry, 64 pts (75%) received hydroxyurea, and 3 pts (4%) received imatinib (all for ≤ 2 wk). At the data cutoff, 68 pts (80%) had treatment ongoing, and the remaining 17 had discontinued due to AEs/laboratory abnormalities (n = 8; nonhematologic AEs [n = 5], biochemical abnormalities [n = 2], and hematologic abnormalities [n = 1]), loss to follow-up (n = 2), administrative problems (n = 2), intolerance to the protocol-proposed dose (n = 2), suboptimal response (n = 1), withdrawal of consent (n = 1), or protocol deviation (n = 1). Median time on treatment was 13.8 mo (range, 1 day-18 mo). Median actual dose intensity of nilotinib was 597 mg/day (range, 165-756 mg/day), and 85% of pts had an actual dose intensity of > 400 mg/day to ≤ 600 mg/day. Of 30 pts with dose reductions due to AEs, 19 (63%) successfully re-escalated to nilotinib 300 mg BID. Nine pts (11%) dose escalated to nilotinib 400 mg BID due to lack of efficacy. The primary endpoint of MMR by 12 mo was achieved by 57 pts (67%; 99.89% CI, 49%-82%). Complete cytogenetic response by 6 mo was achieved by 48 pts (56%). Median BCR-ABLIS decreased over time, with a median value of 0.05% (range, 0.00%-41.36%) at 12 mo (Figure). Most pts (91%) achieved early molecular response (BCR-ABLIS ≤ 10% at 3 mo). Of the 8 pts (9%) with BCR-ABLIS > 10% at 3 mo (4 of whom were then dose escalated), 3 achieved MMR by 12 mo (1 of whom had been dose escalated). By the data cutoff, no pt had progressed to accelerated phase/blast crisis (AP/BC), and there had been no deaths on study. Nilotinib was well tolerated, with a safety profile similar to that seen in other frontline studies. Drug-related nonhematologic AEs (≥ 10% of pts) were rash (31%), constipation (13%), and headache (13%). Newly occurring or worsening grade 3/4 hematologic or biochemical abnormalities (≥ 10% of pts) were neutropenia (17%), thrombocytopenia (17%), increased lipase (13%), and increased bilirubin (12%). Conclusions These results demonstrate that dose-optimized nilotinib affords high rates of molecular response in pts with newly diagnosed CML-CP. Further, they support the feasibility of nilotinib dose re-escalation in pts who require temporary dose reductions due to AEs, with 63% of dose-reduced pts able to successfully re-escalate to nilotinib 300 mg BID and safely continue therapy. Disclosures: Lipton: Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: 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. Meillon:Bayer: Honoraria; Novartis: Honoraria; Bristol Myers Squibb: Honoraria; Pfizer: Honoraria. Louw:Novartis: Congress attendance support Other, Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Congress attendance support, Congress attendance support Other, Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding. Pavlovsky:Novartis: Research Funding, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Jin:Novartis: Employment. Acharya:Novartis Healthcare Pvt. Ltd.: Employment. Woodman:Novartis: Employment, Equity Ownership. Hughes:Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria; CSL: Research Funding. Turkina:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria.

TPS6638 Background: Family planning decisions for cancer patients of childbearing age are impacted by their diagnosis. IM and NIL are category D drugs (demonstrated risk to the fetus based on mechanism of action and findings in animals; however, the benefits of therapy may outweigh the potential risk to the fetus); women should be advised not to become pregnant when taking these drugs. Limited data exist concerning safety of these drugs during pregnancy and consequences of interrupting treatment. The registry does not recommend patients receiving IM or NIL become pregnant, but serves only to document exposures that occur, and collect information on pregnancy outcome, maternal course of disease, and infant follow-up. Methods: The registry intends to enroll 150 women (≥18 years) treated with branded IM and NIL within 6 mo before or during pregnancy (generic IM and NIL reports are excluded). Schedule of visits and treatment is according to local standard of care. Women are divided into 2 exposure cohorts: 1) pregnancy/fetal: received tyrosine kinase inhibitors (TKIs) within 14 d of conception or at any time during pregnancy; 2) interrupted TKI: received TKIs within 6 mo before conception but interrupted TKIs in preparation for/due to pregnancy. To identify signals of teratogenicity, the registry uses a general population baseline rate of birth defects, and the prevalence of defects in cohorts 1 and 2 may be compared. Cases are quantitatively analyzed for the emergence of unique defects or patterns of defects. Primary objective: monitor TKI-exposed pregnancies to estimate the prevalence of birth defects (calculated by dividing number of birth defects by total number of exposed live births from cohort 1). Secondary objectives are to: 1) determine the impact of treatment interruption on maternal disease status; 2) assess and estimate the prevalence of serious adverse pregnancy outcomes; and 3) assess and estimate the prevalence of developmental delays and functional deficits among infants during the first year of life. Maternal disease status is analyzed, comparing disease status at registration, pregnancy outcome, and 1 y after birth, stratified by length of TKI interruption.