ALBERT

Beschreibung: 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.

Beschreibung: Background: With effective tyrosine kinase inhibitor (TKI) therapy, CML-CP disease burden can be reduced to minimal levels, and pts with CML-CP can have a life expectancy similar to that of the general population. Current guidelines recommend that pts continue TKI therapy indefinitely; however, in clinical trials (eg, the Stop Imatinib trials), some pts with deep molecular responses were able to suspend therapy and remain in TFR. This qualitative study assessed pt perspectives on CML treatment and TFR. Methods: Adults with CML-CP were recruited via third-party panels and interviewed by telephone (≈ 45 min) by trained staff from Oxford Outcomes using a standardized semistructured interview guide and open-ended questions. Some questions were not asked in all interviews; reported data are based on pts with responses for the indicated topic. Key themes and perceptions about TFR and potential impacts on health-related quality of life were identified by thematic analysis. Basic demographic information was also collected. Results: Of 40 participants, 68% were female and 68% were 〈 60 y old. Mean ± SD time since CML diagnosis was 5.2 y ± 4.6 y. Current CML treatment was imatinib (53%), dasatinib (25%), nilotinib (15%), or ponatinib (3%); 33% of pts were receiving second- or later-line TKI therapy; others were not receiving therapy due to a physician-supervised medication holiday (3%) or pregnancy (3%). Frequency of blood work (hematology/chemistry and/or molecular monitoring) for CML was every 3 mo for 60% of pts; 23% and 18% of pts had more frequent or less frequent blood work, respectively. Approximately half of pts (55%) had been told they achieved complete molecular response (CMR). Most pts (85%) did not experience/expect any positive physical impacts of CMR, but 68% said it would provide peace of mind that their CML was not progressing. Pts reported a variety of negative impacts of CML treatment, including financial burden (53%), limited ability to perform normal activities (social activities [25%], hobbies/physical activities [18%], work productivity [15%], and/or housework [10%]), and concern about long-term effects on their physical well-being (23%); 35% of pts reported low or no impact of CML treatment on their daily lives. Most pts (75%) reported having medication side effects, most commonly fatigue (60%), bone/joint pain (28%), nausea (18%), and active bowels/gastrointestinal issues (15%). Most pts (77%) said they had some understanding of TFR, and 58% were cautiously positive about attempting TFR. If their physician recommended it, 77% of pts ≥ 60 y old and 52% of pts 〈 60 y old said they would consider attempting TFR. The most frequently expressed expected positive impacts of TFR were relief of medication side effects (75%), reduced financial burden (58%), convenience (43%), positive emotional impact (43%), and increased activity level (30%). The most frequently expressed concerns about TFR included fear of resistance to therapy upon relapse (90%), low chance of successfully maintaining TFR (45%), emotional response to relapse and re-initiation of therapy (35%), desire for more frequent disease monitoring (33%), and fear of severe side effects upon re-initiation of therapy (33%). Some pts (28%) said their families may not want them to risk their health by attempting TFR. Among pts 〈 60 y old, 15% expressed concerns about the well-being of dependent children if they were to attempt TFR and relapse. Pts expressed a desire for more long-term data evaluating the safety of TFR in clinical trials. Pts reported a willingness to attempt TFR if there was at least a 10% chance of sustaining TFR for 2 y (range, 10%-100%), and the shortest duration of TFR they found acceptable ranged from “any amount of time” to 7 y. Conclusions: In this qualitative study, pts perceived many potential positive impacts of TFR, with relief of medication side effects being the most frequently expressed. Although TFR clinical trials have shown high rates of response to re-initiation of TKI therapy in pts with molecular relapse, a perceived risk of developing resistance to therapy was the most notable pt concern about TFR, and pts felt more clinical data are needed. Pt responses also revealed the importance of considering family when discussing TFR. With effective education and in the context of a controlled clinical trial, TFR may be an appropriate goal associated with meaningful pt benefits. More research into the pt perspective on TFR is needed. Disclosures Boquimpani: Bristol Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau. Off Label Use: Current CML treatment recommendations indicate that BCR-ABL TKI therapy should be administered indefinitely, and treatment-free remission (TFR) is an investigational approach that falls outside of current BCR-ABL TKI labels. However, this concept is not new, and promising preliminary results from several clinical trials of TFR have been reported. This abstract does not include any clinical data, but focuses on patient preferences and perceptions of TFR. . Szczudlo:Novartis: Employment, Equity Ownership. Mendelson:Novartis: Employment, Equity Ownership. Benjamin:Novartis Pharmaceuticals Corporation: Consultancy. Masszi:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Beschreibung: Introduction In patients with imatinib-resistant chronic myeloid leukemia (CML) treated with a second generation tyrosine kinase inhibitor (2GTKI), the initial molecular response at 3 months (3m-IMR) has been shown to be predictive of long-term outcomes. However, there is no consensus regarding the best cutoff for the BCR-ABL1 transcript levels, with 1% and 10% being proposed in different studies. Also, additional prognostic factors such as baseline tyrosine kinase (TK) mutations and a prognostic scoring system (PSS) (Jabbour, 2011) have been proposed. In this study, we addressed those issues in an homogeneous group of imatinib-resistant CML patients treated in a single center for a median follow-up of 36 months (14-60). Patients and Methods 134 patients with a diagnosis of CML treated either with dasatinib (N=64) or nilotinib (N=70) due to imatinib failure were included. Imatinib failure was defined as any of the following: no complete hematologic response at 3 months, no cytogenetic response at 6 months, no major cytogenetic response at 12 months, no complete cytogenetic response (CCR) at 18 months, or loss of hematologic or cytogenetic response at any time. Patients with the T315I mutation were excluded. Molecular analysis was performed in a properly standardized laboratory every 3 months from the beginning of the 2GTKI, and results are presented according to the international scale. The study's primary endpoint was the 3-year event-free survival (EFS) after 2GTKI. Secondary endpoints were the best response levels attained under 2GTKI (BMR). The factors analysed were the 3m-IMR, age, gender, Sokal and EUTOS scores at diagnosis, failure to achieve a complete cytogenetic response, TK mutations, PSS score and type of 2GTKI. A multivariate analysis with the factors significant at P

Beschreibung: 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.

Beschreibung: Objectives: To estimate the savings and opportunity costs of nilotinib considering treatment free remission after 2nd line treatment of chronic myeloid leukemia (CML) with Nilotinib to fund BCR-ABL molecular test under the Brazilian public healthcare system (SUS) perspective Materials and methods: A budget impact analysis was developed to estimate the savings for the public health system with TFR eligible patients. ENESTop (Mahon FX et al., 2018), an ongoing, single-arm, phase 2 study 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 to nilotinib. In this trial, patients using nilotinib, who had 4.5 log molecular response after at least 24 months of Nilotinib treatment after switching from imatinib, entered into 12 months of consolidation phase and if they maintain MR 4.5 log response (77%), treatment was discontinued as planned in study protocol (57.9% TFR rate at 48 weeks - primary endpoint). A systematic review of the literature was developed over the efficacy of the use of nilotinib in 2nd line for patients diagnosed with CML. Efficacy data used to input the economic model is informed in a published randomized controlled clinical trial (ENESTcmr trial, Hughes TP et al., 2015), a 48 month, open-label, randomized, phase 3 study designed to investigate whether patients with complete cytogenetic response but persistent minimal residual disease on long-term imatinib ( ≥ 2 years prior imatinib) could achieve MR 4.5 log response by switching from imatinib to Nilotinib 400 mg BID. In this study, 33%, 42%, 46% and 52% of patients achieved 4.5 log molecular response by 12, 24, 36 and 48 months of nilotinib treatment after switching from imatinib. The total annual cost in 2017 with nilotinib was extracted from an official Brazilian database (http://paineldeprecos.planejamento.gov.br). Results: Considering that MR 4.5 log response patients will start consolidation in the first year, the economic impact will reduce in BRL 7,2M in the second year year, reaching a saving of BRL 11,4M in the fifth year. The total accumulated saving for the Brazilian public system (SUS) in 5-years was over BRL 38,1M. We also evaluated the necessary investments on BCR-ABL monitoring tests for all CML patients in the public market, as this test is not reimbursed by Brazilian public healthcare system (SUS). We estimated a budget impact of BRL 4.5M per year considering an average of 2 monitoring tests per patient, thus in 5 years an investment of 22,5M in BCR-ABL would be necessary. Discussion: The deep molecular response (MR 4.5 log) in may lead to patient discontinuation in those patients achieving 4.5 log molecular response after at least 24 months of nilotinib treatment and maintaining this response after 12 months. Furthermore, the possibility of TFR with nilotinib will save resources in health sytems allowing to invest in other needs. As demonstrated in this study, savings generated by nilotinib in 2nd line considering the possibility of TFR could allow the incorporation of BCR-ABL test for all CML patients in the public health system (SUS), which is essential in the current management of CML. Conclusion: Nilotinib in 2nd line treatment may generate savings for the public healthcare system (SUS) that could fund the BCR-ABL test for all CML patients. Disclosures Vivona: Novartis: Employment. Leite:Novartis: Employment. Matsuo:Novartis: Employment. Teich:Novartis: Consultancy.

Beschreibung: Introduction: In Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients (ENESTnd), patients with CML-CP achieved deeper molecular responses and lower rates of progression to accelerated phase/blast crisis (AP/BC) with nilotinib (NIL) vs imatinib (IMA) during the first 5 y of follow-up. Here, we report long-term outcomes with ≥ 10 y of follow-up. Methods: Patients with newly diagnosed CML-CP were randomized to receive NIL 300 mg twice daily (NIL300; n = 282), NIL 400 mg twice daily (NIL400; n = 281), or IMA 400 mg once daily (n = 283) in the ENESTnd core study. Some patients who discontinued their assigned core treatment due to suboptimal response/treatment failure entered an extension study to receive NIL 400 mg twice daily (for those assigned to NIL300 [n = 26] or IMA [n = 48] in the core study) or IMA 400 mg twice daily (for those assigned to NIL400 [n = 3]). In the current analysis, cumulative efficacy and safety results were analyzed by combining all data from the core and extension studies; extension study results were ascribed to each patient's assigned core study treatment arm. Progressions, deaths, and cardiovascular events (CVEs) were also analyzed according to time intervals (time since randomization for progressions; time since treatment initiation for deaths and CVEs), defined as events occurring up to 5 y and those occurring beyond 5 y. Analyses were based on a data cutoff date of April 1, 2019, when all patients had completed ≥ 10 y of treatment or discontinued. Results: As previously reported, patient demographics were well balanced between arms. By the data cutoff, 105 (37.2%), 96 (34.2%), and 98 (34.6%) patients assigned to NIL300, NIL400, and IMA, respectively, completed the full study treatment duration; 175 (62.1%), 182 (64.8%), and 184 (65.0%) patients, respectively, discontinued core treatment early. Cumulative 10-y major molecular response (MMR) rates among patients assigned to NIL300, NIL400, and IMA were 82.6%, 80.4%, and 69.6%, respectively. The cumulative MMR rate reached a plateau at ≈ 3.5 y with NIL300 or NIL400 and 4.5 y with IMA. With NIL300, NIL400, and IMA, cumulative 10-y MR4 rates were 72.7%, 68.7%, and 55.5%, respectively, and cumulative MR4.5 rates were 63.8%, 61.6%, and 45.2%, respectively. The difference between MR4.5 rates achieved with NIL vs IMA by 5 y was similar to that observed by 10 y of study treatment (Figure). Among patients assigned to NIL300, NIL400, and IMA, a total of 11, 7, and 24 patients, respectively, progressed to AP/BC by the data cutoff (including 1, 1, and 5, respectively, after 5 y) (Table). A total of 32, 23, and 29 deaths on study from any cause were reported in the NIL300, NIL400, and IMA arms, respectively; the most common causes were CML (6, 5, and 15 patients, respectively) and infections/infestations (5, 3, and 8, respectively). Of all deaths on study, 16, 14, and 11 in the NIL300, NIL400, and IMA arms, respectively, occurred after 5 y; almost all (37/41) were not CML related (including 10 due to general disorders, 9 due to infections/infestations, 8 due to neoplasms, and 7 due to cardiac or vascular disorders). Kaplan-Meier-estimated 10-y rates of event-free survival and overall survival (OS) are shown in the Table. Adverse events (AEs) leading to discontinuation of study treatment occurred in 67 (24.0%), 98 (35.4%), and 56 (20.0%) patients assigned to NIL300, NIL400, and IMA, respectively; serious AEs occurred in 112 (40.1%), 127 (45.8%), and 97 (34.6%) patients, respectively. Safety profiles of NIL and IMA remained consistent with previous analyses (nonhematologic AEs in ≥ 30% of patients: NIL [either dose], rash, headache, nausea; IMA, diarrhea, nausea, muscle spasms). In each arm, CVE rates in the first 5 y of study treatment were similar to the rates beyond 5 y (Table). Conclusions: NIL showed better long-term efficacy than IMA, with fewer progressions to AP/BC during both the early and later years of the study, and fewer CML-related deaths. MMR and deep molecular response rates were higher with NIL than with IMA throughout the follow-up period. However, CVEs were more frequent with NIL than with IMA in the first 5 y and continued to occur at similar rates beyond 5 y. While the study was not powered for OS, observed 10-year OS rates were similar between NIL and IMA. Overall, these results suggest that the superior efficacy but higher vascular toxicity observed early on with frontline NIL treatment is maintained with long-term treatment. Disclosures Hughes: Novartis: Other: Advisory Board and Symposia, Research Funding; BMS: Research Funding. Saglio:Ariad: Consultancy; Incyte: Consultancy; Jansen: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Pfizer: Consultancy. Larson:Agios: Consultancy; Celgene: Consultancy; Novartis: Honoraria, Other: Contracts for clinical trials. Kantarjian:Daiichi-Sankyo: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Jazz Pharma: Research Funding; Immunogen: Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria; AbbVie: Honoraria, Research Funding; Ariad: Research Funding; Astex: Research Funding; Agios: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Cyclacel: Research Funding; Novartis: Research Funding. Kim:Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Il-Yang co.: Research Funding; Takeda: Research Funding. Le Coutre:Bristol-Myers Squibb: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Etienne:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Boquimpani:Novartis: Speakers Bureau; BMS: Speakers Bureau. Clark:Ariad/Incyte: Honoraria; Pfizer: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Flinn:F. Hoffmann-La Roche Ltd: Research Funding; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding; AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding. Sondhi:Novartis: Employment, Other: Stock; Sanofi: Other: Stock. Titorenko:Novartis: Employment. Nourry-Boulot:Novartis: Employment. Aimone:Novartis: Employment. Hochhaus:Incyte: Research Funding; BMS: Research Funding; MSD: Research Funding; Pfizer: Research Funding; Novartis: Research Funding. OffLabel Disclosure: This pivotal study of nilotinib for frontline therapy of CML-CP was designed to investigate 2 nilotinib doses. One of the 2 doses is now the approved frontline dose. To accurately report the study results, data for both doses will be presented.

Beschreibung: Introduction Chronic myeloid leukemia (CML) is a clonal malignant disease characterized by excessive proliferation of myeloid lineage, followed by a progressive loss of cell differentiation, with evolution including progression from chronic phase to accelerated or blastic phase. The disease is associated with a specific cytogenetic abnormality, the Philadelphia chromosome, which results from a reciprocal translocation between the long arms of chromosomes 9 and 22 [t(9;22)(q34;q11)], leading to the generation of the new leukemia-specific gene BCR-ABL, resulting in the production of an oncoprotein with tyrosine kinase activity, responsible for the pathophysiology of disease. Effective treatments with tyrosine kinase inhibitors (TKI) are available for CML patients and differences in adverse events (AE) and incidences occurring during therapy are reported in the literature depending on the type of TKI. Objective Improve the standard of resources used and reduce later treatment costs of treatment-related haematological and non-hematological adverse events of CML patients, from the perspective of the Brazilian National Health System. Cost of treatment per event will be presented as a result. Method A Delphi methodology was applied in Brazil to study the management of adverse events related to CML treatment by collecting data on resource used., considering the resource use and its cost associated.  Based on the literature, a questionnaire was developed on the available resources for the treatment of select adverse events. Ten experts completed the questionnaires and the results were compiled and validated. The data collected were related to percentage of patients affected by each AE and percentage of each resource used to manage the AE. A consensus meeting was held after questionnaire completion. The unit cost of resources was based on the Bank Price and Health Management System Procedures Table of SUS (SIGTAP). Cost of treatment of the AEs consisted of the cost of the treatment options and monitoring costs (e.g., outpatient visits, laboratory tests and procedures, hospitalizations) in the Brazilian Public Health System. Results Among non-hematologic adverse events grade 3-4, gastrointestinal bleeding and central nervous system (CNS) hemorrhage presented the highest costs of treatment per event (R$ 1.022,90 and R$ 1.173,34, respectively).  Hospitalization is the resource with more impact; mainly in CNS hemorrhage, with an average length of hospitalization reported by the experts of 1 week and also being demanded by 100% of patients affected by this AE. Management of cardiac events is R$973,35 and Pericardial effusion is R$3.896,55. Cytopenias are the most commonly occurring events in patients with CML receiving BCR–ABL inhibitors. Experts suggest the use of growth factors, such as granulocyte colony-stimulating factor, interleukin-11 and erythropoietin in patients with CML receiving TKI therapy. The Panel experts agreed the cost associated with the management the hematologic adverse events are: Anemia: R$14,93, Thrombocytopenia: R$14,47 and neutropenia: R$211,54. Conclusion All adverse events related to treatment of CML, with differences in the occurrence and intensity should be valued and recorded as contributing to the estimated total cost of treating the disease. Adverse event management in CML patients has important clinical and economic impact. I Banco de Preço em Saúde. Disponível em: http://bps.saude.gov.br/visao/consultapublica/publico_interno_item.cfm  - Accessed in 08/04/2013 II Sistema de Gerenciamento da Tabela de Procedimentos, Medicamentos e OPM do SUS. DATASUS – SIGTAP.  Available in http://sigtap.datasus.gov.br/tabela-unificada/app/sec/inicio.jsp  -  Accessed in: 08/04/2013 Disclosures: Alves: Novartis: Employment. Lemos: Novartis: Employment. Boquimpani: Novartis: Consultancy.

Beschreibung: Abstract 3440 Nilotinib and dasatinib are second-generation tyrosine kinase inhibitors (TKI) used in patients with chronic myeloid leukemia (CML) resistant or intolerant to imatinib. There are no randomized clinical trials comparing these drugs in this context. The aim of this study was to compare, retrospectively, the hematological, cytogenetic and molecular response in patients submitted to these second-generation TKI at Hemorio, a public brazilian institution. A total of 114 patients were analyzed, 63 received nilotinib and 51 dasatinib as second-line therapy (55.3% and 44.7%, respectively). The following variables were equally distributed between these two groups (nilotinib vs. dasatinib, respectively): male sex (54% vs. 60.8%, p=0.46), median age at diagnosis (46 vs. 45 years, p=0.76), median time in months using imatinib before the switch (45.2 vs. 44.1, p=0.96), resistance to imatinib (98.4% vs. 98%, p=0.88), presence of the mutation T315I (3.2% vs. 3.9%, p=0.09), patients in chronic phase before the switch (85.7% vs. 86.3%, p=0.93). Use of another second generation TKI, as a third-line therapy, was necessary in 30 out of the 114 patients analyzed (26.1%) because of lack of response. This modification was slightly more frequent in the group initially submitted to nilotinib (31.7% vs. 19.6%, p=0.21). Patients who used a third-line therapy were excluded from response and survival analyzes. Response rates after the second-generation TKI were similar between these two groups (nilotinib vs. dasatinib): complete hematological response until three months (77.8% vs. 87.3%, p=0.24), complete cytogenetic response until six months (21.6% vs. 22.2%, p=0.95) and 12 months (32.4% vs. 33.3%, p=0.94) and major molecular response reached before 12 months (32.7% vs. 21.6%, p=0.25). Two-year overall survival (OS) and progression free-survival (PFS) were similar between these two groups (nilotinib vs. dasatinib, respectively): 92.2% vs. 87.8% (p=0.38) for OS and 87.8% vs. 83.7% (p=0.14) for PFS. Although not statistically significant, two-year OS was inferior in the group of patients who needed a third-line therapy (70.5% vs. 95.6%, p=0.70). Our results suggest that the response and survival rates are similar between nilotinib and dasatinib as second-line therapy for patients with imatinib resistant or intolerant CML. Also, they suggest an inferior prognosis for patients who need a third-line therapy. In this way, the choice between these two TKI for second-line therapy should be guided by the clinical characteristics and the mutation status of the patient. Disclosures: Lobo: NOVARTIS: Research Funding.

Beschreibung: Abstract 1701 Mutations within the BCR-ABL domain are the most frequent mechanism of imatinib (IM) resistance. The second generation inhibitors (SGI) are indicated for imatinib intolerance or resistance and the initials trials showed similar response rates in IM resistant patients after IM failure, independent of mutation status, with exception of T315I. The aim of this work was to report the frequency of BCR-ABL mutations in chronic myeloid leukemia (CML) patients of a Latin American population and to evaluate the clinical impact of the presence and type of mutations in overall survival (OS), progression free survival (PFS) and in the response to second generation inhibitors (SGI). Methods: retrospective analysis of 17 centers from Latin America. A total of 529 CML patients with mutation analysis performed in samples collected between 2002 and 2011 were included. Mutations were detected by direct sequencing from bone marrow or peripheral blood samples, collected from CML patients. After imatinib resistance, patients were treated with SGI (69%) or other treatments. Overall survival (OS) was calculated from date of mutation detection until last follow-up or death, and progression-free survival (PFS) from date of mutation detection until progression to accelerated phase or blast crisis, last follow-up or death. Survival curves were calculated using the log-rang test (SPSS 14.0 software).Results: the median age of patients at diagnosis was 45 years (5–87). 81% were in chronic phase (CP), 13% in accelerated phase (AP), 6% in blast crisis (BC). According to Sokal score, patients were stratified in low (36%), intermediate (30%) and high risk (34%); 36% had previously used Interferon. The median time from diagnosis until Imatinib treatment was 8 months (0–310) and from Imatinib start until mutation detection was 31 months (1–104). Mutations were found in 188 patients, in the following sites: P-loop (75/40%), nucleotide contact site (34/18%), catalytic domain (44/23%), A-loop (11/6%) and others (24/13%). The most frequent mutations detected were: T315I (30/16%), F359V/C/I (27/14%), M244V (18/9.6%), E255K/V (17/9%), G250E (17/9%), Y253H/F/Y (15/8%), M351T/L (12/6%); Ten patients presented concomitant mutations. On dasatinib treatment 29 mutations (27% T315I) were detected whereas 18 during nilotinib (16.5% T315I). Overall survival in the total group was 61% (95%CI: 51–71%) with a median time of 12 months. There was a significant difference in OS and PFS between non-mutated and mutated patients (76% vs 44% and 64% vs 44% respectively (P= 0.008 and P= 0.001). There was no difference in survival comparing P-loop mutations and others, excluding T315I. Patients with T315I mutations had a poorer outcome in comparison with other mutations (OS 21% vs 62%; PFS 35% vs 55%) (P= 0.04 and 0.06, respectively). In the group with BCR-AL mutations, OS was superior in patients that received a SGI in comparison with other treatments after resistance (50% vs 36% P= 0.007). One hundred patients (19%) died due to: disease progression (72), infections (8), graft versus host disease (2), central nervous system bleeding (2), cardiac failure (1), second neoplasia (1). 14 causes were not reported. Conclusions: Patients with BCR-ABL mutations had an inferior OS and PFS. T315I mutations were associated to a poor outcome. Treatment with SGI prolonged survival of patients after imatinib failure. Disclosures: Pagnano: Novartis: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Boquimpani:Novartis: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Pasquini:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Spector:Novartis: Membership on an entity's Board of Directors or advisory committees.