ALBERT

Description: Key Points Nilotinib induced deeper molecular responses than continued imatinib in patients with minimal residual disease on long-term imatinib. These deeper responses may enable more patients to benefit from treatment-free remission trials.

Description: Abstract 2765 In CML, achievement of major molecular response (MMR) is a significant prognostic factor as it has been shown to be associated with longer duration of complete cytogenetic response (CCyR) and long-term progression-free survival. In IRIS study, patients who achieved both CCyR and MMR showed higher progression-free survival rates, compared to those who had CCyR without MMR. Higher doses of imatinib are expected to yield higher CCyR and MMR rates, compared to standard dose of imatinib, and second-generation tyrosine kinase inhibitor, nilotinib also produces high CCyR and MMR rates in patients with CP CML who are resistant to imatinib. In this prospective study, the efficacy of nilotinib and high-dose imatinib was investigated in suboptimal molecular responders who received standard-dose imatinib as first-line therapy. Early 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 imatinib therapy at a daily dose of 400 mg were enrolled in this clinical trial, and informed consents were obtained from all patients prior to participation. In nilotinib arm, patients received oral dose of 400 mg BID (800 mg/day), and patients received 800 mg/day administrated as 400 mg BID in imatinib dose-escalation arm. To assess the drug efficacy, cytogenetics and RQ-PCR analysis were performed at regular intervals, and baseline mutational analysis was conducted for every patient with subsequent mutational analyses performed in patients demonstrating either lack of response or disease progression. Primary endpoint is to evaluate the cumulative MMR rates by 12 months, and secondary endpoints are to evaluate the cumulative CMR rates and time to and duration of MMR and CMR during further 24 month follow-up. Progression-free survival and safety profiles will also be assessed as secondary endpoints. 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 severe intolerance to treatment were allowed to crossover to the alternative treatment arm. With a data cut-off date of 18 Jul 2011, a total of 30 patients were randomized into nilotinib arm (n =13) or imatinib arm (n = 17), and 6 patients have crossed-over to nilotinib arm due to lack of response. With a median follow-up of 11 months (range, 0.2–28 mos), all patients have maintained CCyR without progression to advanced disease, and progressive decrease in BCR-ABL transcript levels was observed in all patients. Cumulative MMR rates at 20 months were significantly higher in nilotinib arm compared to imatinib dose-escalation arm (59.00% vs. 27.40%, P = 0.047), and patients treated with nilotinib also showed faster molecular response rates, with 5 patients achieving MMR within 3 months of nilotinib therapy. At the last follow-up, 7/13 (53.85%) and 2/11 (18.18%) patients achieved MMR in nilotinib arm and in high-dose imatinib arm, respectively, with 1 patient in nilotinib arm achieving 4-log reduction of BCR-ABL transcripts. Although toxicity was observed more frequently in imatinib dose-escalation arm, all patients currently maintain the initial dose (except 1 patient who interrupted imatinib therapy due to neurosurgical operation), and based on the toxicity data, no additional or serious adverse events were developed except for pre-existing toxicities before randomization. These preliminary results demonstrate that early intervention using nilotinib or dose escalation of imatinib could be recommended in suboptimal molecular responders, with nilotinib being more preferable. Through further clinical investigation on a large patient population and longer period of observation, efficacy and safety of early intervention of suboptimal molecular response using nilotinib or dose escalation of imatinib will be assessed. Updated data with longer follow-up duration will be presented in the meeting. Disclosures: Woodman: Novartis: Employment, Equity Ownership. Szczudlo:Novartis: Employment, Equity Ownership. Kim:Novartis: Employment.

Description: Abstract 694 Background: Superior rates of deeper molecular responses were achieved with nilotinib vs imatinib in patients newly diagnosed with Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP) in the Evaluating Nilotinib Efficacy and Safety in Clinical Trials—newly diagnosed patients (ENESTnd) trial. In addition, the 12-month (mo) analysis of the ENEST—complete molecular response (ENESTcmr) study demonstrated that switching to nilotinib after a minimum of 2 years on imatinib led to increased rates of major molecular response (MMR) and deeper molecular responses vs remaining on imatinib. Results from ENESTcmr are presented here with minimum 24 mo of patient follow-up. Methods: Patients with Ph+ CML-CP who had achieved complete cytogenetic responses but still had persistent BCR-ABL positivity by real-time quantitative polymerase chain reaction (RQ-PCR) after ≥ 2 years on imatinib were eligible. Patients (n = 207) were randomized to switch to nilotinib 400 mg twice daily (BID; n = 104) or to continue on the same dose of imatinib (400 or 600 mg once daily [QD]; n = 103). Rates of MMR, MR4 (BCR-ABL ≤ 0.01% according to the International Scale [IS], corresponding to a 4-log reduction), MR4.5 (BCR-ABL ≤ 0.0032%IS, corresponding to 4.5-log reduction), and undetectable BCR-ABL via RQ-PCR with ≥ 4.5-log sensitivity were measured. Results: Among all randomized patients (intent-to-treat population), significantly more patients treated with nilotinib continued to achieve undetectable BCR-ABL by 24 mo (32.7% on nilotinib vs 16.5% on imatinib; P =.005; Table).The difference between the arms in achievement of this endpoint increased between 1 and 2 years (from 12.4% to 16.2%). The median time to MR4.5 and undetectable BCR-ABL was also significantly faster on nilotinib than on imatinib (P = .005 and .003, respectively). Cumulative rates of MR4.5 and undetectable BCR-ABL continued to be higher with nilotinib in patients without those responses at baseline, and the difference between arms appeared to increase over time. The safety profiles for nilotinib and imatinib were consistent with prior studies. By 24 mo, no patients in either arm progressed to accelerated phase/blast crisis. No patients on nilotinib died since the 12-mo analysis; 1 patient on imatinib died from metastatic prostate cancer in follow-up after discontinuation from the study. Conclusions: Switching to nilotinib led to significantly faster, deeper molecular responses in patients with minimal residual disease on long-term imatinib therapy. Since the 12-mo analysis, rates of deep molecular response (MR4.5 and undetectable BCR-ABL) have remained significantly higher in patients who did not have the response at baseline and were switched to nilotinib (vs those remaining on imatinib). In fact, the difference in favor of nilotinib increased between 1 and 2 years. These results suggest that switching to the more potent, selective tyrosine kinase inhibitor nilotinib is beneficial in patients with minimal residual disease after long-term imatinib therapy. Achievement of these deeper molecular responses (MR4.5 and undetectable BCR-ABL) after switching to nilotinib may enable a greater proportion of CML-CP patients to be eligible for future discontinuation studies. Cumulative rates of confirmed undetectable BCR-ABL by 24 mo will be presented as the confirmation assessments for several responders were not available at the time of this analysis. Disclosures: Hughes: Novartis Pharmaceuticals Corp: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Ariad: Consultancy; CSL: Research Funding. Lipton:Novartis: Consultancy, Research Funding, Speakers Bureau. Spector:Novarits: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy. Leber:Novartis: Advisory Board Other, Honoraria, Speakers Bureau. Schwarer:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Etienne:Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy; BMS: Consultancy, Speakers Bureau. Branford:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Research Funding; Ariad: Research Funding. Purkayastha:Novartis Pharmaceuticals Corp: Employment. Collins:Novartis Pharmaceuticals Corp: Employment. Szczudlo:Novartis Pharmaceuticals Corp: Employment. Cervantes:Novartis: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; BMS: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Teva Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Description: Background: Imatinib, nilotinib, and dasatinib are BCR-ABL tyrosine kinase inhibitors (TKIs), with different selectivity profiles, approved for the treatment of patients (pts) with Philadelphia positive chronic myeloid leukemia (Ph+ CML). Given the differences in their kinase selectivity profiles, the safety profiles of these agents also differ, particularly with regard to episodes of fluid retention. The incidence of pleural/pericardial effusions in resistant or intolerant CML pts who failed imatinib, or both imatinib and dasatinib, therapy was evaluated. Methods: The occurrence of pleural/pericardial effusions in resistant or intolerant CML pts following therapy with imatinib, or imatinib and dasatinib sequentially, was evaluated in 915 pts with Ph+ CML in chronic phase (CML-CP, 60%), accelerated phase (CML-AP, 23%), and blast crisis (CML-BC 17%) who entered the nilotinib compassionate use program between June 2006 and April 2008. At the time of medical review for compassionate use approval, safety information including the presence of or the history of pleural/pericardial effusions was collected along with dosing information for imatinib and dasatinib. Nearly all pts analyzed (94%) had not received nilotinib therapy prior to inclusion in the compassionate use program. Resistance and intolerance as well as CML phase were defined using similar criteria as previously reported in the nilotinib pivotal phase I/II study. Results: The median age was 52 years (range: 11 – 87 years); 22 pts (2%) were 18 years old or younger. Most pts (734; 80%) had received prior imatinib only (64% discontinued due to resistance, 20% with resistance and intolerance and 16% due to intolerance) and 170 pts received both imatinib and dasatinib (29% resistant; 17% with resistance and intolerance, 54% intolerant), with most dasatinib failures being due to toxicity. Information on past treatment is currently unavailable for 11 pts. Of pts who were pretreated with imatinib alone, less than 2% of pts (n = 11) had pleural and/or pericardial effusions reported. Among those pts pretreated with both imatinib and dasatinib, 51 pts (30%) had pleural and/or pericardial effusions, with 50 (98%) having pleural effusions, 10 of which were bilateral. Fifty-five percent of pts with pleural and/or pericardial effusions were in chronic phase. Of the pts with dasatinib-associated pleural/pericardial effusions; 11% were noted on daily doses 〉 140 mg, 29% on doses of 140 mg, 20% on doses of 100 mg, and 10% on doses of 〈 100 mg. There were 14 pts who developed pleural and/or pericardial effusions in which the dasatinib dose was not available. Of the 33 pts with pleural and/or pericardial effusions on daily 140 mg dasatinib, 16 pts (48%) discontinued dasatinib due to pleural effusion and 6 pts exhibited persistent pleural effusions despite dasatinib dose reductions. One pediatric patient (age 11 years) had a pleural effusion with once daily 80 mg dasatinib. Pleural/pericardial effusions occurred in all age groups: 〉50 years old – 6 pts, 51–60 years old – 10 pts; 61–70 years old – 13 pts; 71–80 years old – 16 pts and 〉81 years old – 4 pts (2 of unknown age). No pts who developed dasatinib-associated pleural/pericardial effusions had a history of pleural/pericardial effusions during imatinib therapy. Conclusions: This large dataset supports earlier reports that pleural/pericardial effusions are frequently reported among CML pts treated with dasatinib compared with imatinib. Furthermore, the occurrence of dasatinib-associated pleural/pericardial effusions may occur at any dose, even below the standard 140 mg/day dose and in some cases with doses less than 100 mg/day.

Description: Abstract 1115 Poster Board I-137 Introduction Nilotinib, a potent and highly selective BCR-ABL kinase inhibitor, is approved for the treatment of patients (pts) with Philadelphia chromosome-positive chronic myelogeneous leukemia (Ph+ CML) in chronic phase (CML-CP) or accelerated phase (CML-AP) who are resistant or intolerant to prior therapy, including imatinib. The ENACT study is a Phase IIIb, open-label, multicenter study that evaluated the efficacy and safety of nilotinib in adult pts with imatinib-resistant or intolerant CML in a clinical practice setting outside of a registration program. It is the largest single source of efficacy and safety information of any available tyrosine kinase inhibitor (TKI) in CML. Data from ENACT are used to characterize the patterns and management of adverse events (AEs) in nilotinib pts with imatinib-resistant or -intolerant CML-CP or -AP. Methods Pts received nilotinib 400 mg twice daily. Safety assessments included monitoring for all AEs and cardiac procedures. The first occurrence of the following AEs were selected on the basis of the following criteria: 1) the most frequently reported hematologic or biochemical laboratory abnormalities; or 2) identified by participating investigators as AEs of interest that may lead to study drug discontinuation: thrombocytopenia, neutropenia, hyperglycaemia, elevated lipase, elevated amylase, hyperbilirubinaemia, elevated alanine transaminase (ALT), and elevated aspartate transaminase (AST). There were no differences observed between the pattern of management between AEs suspected and regardless of study drug relationship as well as all grades vs. grade 3/4. For this reason this analysis covers management of grade 3/4 AEs suspected of study-drug relationship including duration and subsequent management. The following actions taken were reported by the treating physicians: study drug dose adjusted or temporarily interrupted, non-drug therapy given, no action taken, study drug permanently discontinued, concomitant medication taken or hospitalization/ prolonged hospitalization. More than one action was allowed to be selected. Results The AEs experienced by 1,603 pts (1,422 CP and 181 AP) were generally identified during nilotinib treatment and lasted for short durations. The number of the grade 3 and 4 AEs in CP and AP, median time from start of treatment and median duration are reported in Table. For all included AEs, the overall most common action taken for the first occurrence was dose adjustment or temporary interruption with the exception of hyperglycaemia which was most often managed by treatment with concomitant medications (8/11 of hyperglycaemia AEs in CP and 1/2 in AP). In the majority of the biochemical abnormalities other than hyperglycaemia there was no additional action taken. 49/308 (16%) events of thrombocytopenia in CP pts (9 in AP) were managed by non-drug therapy. 31/204 (15%) events of neutropenia in CP pts were managed by concomitant medication (6/33 events in AP). Permanent discontinuation of study drug was infrequently observed (number of pts in CP; AP): thrombocytopenia (25; 7), neutropenia (15; 2), hyperglycaemia (1; 0), elevated lipase (3; 0), elevated amylase (0; no pts), hyperbilirubinaemia (2; 0), elevated ALT (3; 0), and elevated AST (1; 0). Conclusions Based on a large cohort of 1,603 nilotinib pts with CML-CP and CML-AP, nilotinib is well-tolerated. Most study drug-related grade 3/4 AEs could be managed by temporary treatment interruption or dose adjustment, such that permanent discontinuation of study drug due to AEs was infrequent. The only events requiring concomitant medication administration or non-drug therapy were thrombocytopenia, neutropenia, hyperglycaemia and hyperbilirubinaemia. The AE profile observed was predictable and similar to that seen in registration trial. Disclosures le Coutre: Novartis: Honoraria, Research Funding; BMS: Honoraria. Ceglarek:Novartis Pharmaceuticals: Honoraria. Turkina:Novartis Pharmaceuticals: Honoraria. Kim:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. Shen:Novartis Pharmaceuticals: Honoraria. Smith:Novartis Pharmaceuticals: Honoraria. Rizzieri:Novartis Pharma: Honoraria, Research Funding, Speakers Bureau. Szczudlo:Novartis: Employment. Berton:Novartis Pharmaceuticals: Employment. Wang:Novartis Pharmaceuticals: Employment. Dial:Novartis Pharmaceuticals: Research Funding. Nicolini:Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Chemgenex: Honoraria, Speakers Bureau.

Description: Abstract 2201 Poster Board II-178 Introduction: Nilotinib, a potent and highly selective BCR-ABL tyrosine kinase inhibitor (TKI), is approved for the treatment of patients (pts) with Philadelphia chromosome-positive chronic myelogeneous leukemia (Ph+ CML) in chronic phase (CP) and accelerated phase (AP) who are resistant or intolerant to prior therapy, including imatinib. The ENACT study is a Phase IIIb, open-label, multicenter study that evaluated the efficacy and safety of nilotinib 400 mg twice daily in 1,422 pts with CP who were resistant and/or intolerant to imatinib. It is the largest single source of efficacy and safety information of any available TKI in CML. Study results are presented for all CP pts as well as 2 subpopulations: (1) 2nd-line pts who received imatinib as the only prior CML therapy with no prior exposure to other therapy including interferon (IFN), busulfan and ara-c; and (2) pts with 6- and 12-month suboptimal cytogenetic response (SoR) to prior imatinib therapy. Methods: In addition to all CP pts, ENACT study results are presented for 2 subpopulations, defined as follows. (1) Pts who received nilotinib as 2nd-line therapy received only imatinib (hydroxycarbamide was allowed) prior to nilotinib. Pts with any other therapy, including interferon, busulfan and ara-c were excluded. (2) Pts with 6- or 12-month cytogenetic SoR to imatinib were identified as: a) received imatinib as 1st-line therapy within 12 months of CML diagnosis; b) did not have imatinib resistance; and c) met ELN criteria for cytogenetic SoR (

Description: 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 switching to nilotinib (NIL) versus high-dose IM versus standard-dose IM for patients with suboptimal molecular response to IM as first-line 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 enrolled in RE-NICE study, and informed consents were obtained from all patients. In NIL arm, patients received 400 mg BID (800 mg/day) and in high-dose IM arm, patients received 800 mg/day administrated as 400 mg BID. Primary endpoint is to evaluate the cumulative MMR rates by 12 months, and secondary endpoints are to evaluate the cumulative MMR, MR4.0 and undetectable molecular residual disease (UMRD) rates during further 24 month follow-up. The efficacy of switching to NIL or high-dose IM were compared with that of the patients who maintained standard-dose of IM. Patients with standard-dose IM were selected with the same inclusion criteria and maintained standard-dose IM after enrollment period. To compare the efficacy among three groups, MMR rate, MR4.0 and undetectable molecular residual disease (UMRD) rates by 12 months were analyzed. Safety profiles also be assessed. 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 severe intolerance to treatment were allowed to crossover to the alternative treatment. Results With a data cut-off date of 15 Jul 2013, a total of 52 patients were randomized into NIL arm (n = 26) or high-dose IM arm (n = 26) and 16 patients were included in standard-dose IM group. With a median follow-up of 21 months (range, 1-36) in NIL arm and high-dose IM arm, all patients have maintained CCyR without progression to advanced disease, and progressive decrease in BCR-ABL1 transcript levels was observed in all patients. With a median follow-up of 12 months (range, 1-60), all patients in standard-dose IM group have maintained CCyR without progression to advanced disease. Cumulative incidence (CI) of MMR by 12 months showed no significant difference between NIL arm and high-dose IM arm (41.1% vs 28.8, P = 0.334). Only in NIL arm, 2 in 26 (8%) achieved confirmed MR4.0 and UMRD. By 12 months, 10 in 26 (39%), 7 in 26 (27%) and 3 in 16 (19%) patients achieved MMR, in NIL arm, high-dose IM arm and standard-dose IM group respectively. Overall, the patients treated with high-dose IM showed toxicities more frequently, such as leucopenia, anemia, Thrombocytopenia, edema, fatigue, dyspnea and decreased phosphate. In addition, 14 patients in high-dose IM arm have cross-over to NIL treatment due to lack of response (n=11) and intolerance (n=3), and the median duration of NIL treatment was 23 months (range, 2-36 months). Among them, 6 (43%) patients have achieved MMR with a median NIL treatment duration of 12 months (range, 0-18). Conclusions These results demonstrate that early switching to NIL or dose escalation of IM could be recommended, considering the results of standard dose of IM in suboptimal molecular responders. When the tolerability of treatment was considered for switching to NIL or high-dose IM, NIL may be preferred. Through further clinical investigation on a large patient population and longer period observation, the efficacy and safety of early intervention of suboptimal molecular response using NIL or dose escalation of IM will be needed. Updated data with longer follow-up duration will be presented in the meeting. Disclosures: No relevant conflicts of interest to declare.

Description: 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.

Description: Abstract 606FN2 Background: Recent studies have demonstrated that about 40% of very highly selected CML-CP pts treated with imatinib achieve durable CMR and may be able to cease therapy without disease recurrence. However, most CML pts don't achieve CMR on imatinib even with long-term therapy. Results from ENESTnd demonstrated that significantly more patients achieved MMR (≤ 0.1%IS), CMR4 (≤ 0.01%IS), and CMR4.5 (≤ 0.0032%IS) with nilotinib vs imatinib by 12, 18, and 24 months (mo). No pt in ENESTnd who achieved CMR4.5 has progressed to AP/BC. In this study we asked whether pts on long-term imatinib would be more likely to achieve undetectable BCR-ABL levels if they switched to nilotinib, allowing for participation in potential cessation studies in the future. Methods: This open label, 1:1 randomized, prospective, multi-center, phase 3 study enrolled 207 pts with CML-CP who had achieved a complete cytogenetic response (CCyR) but were still BCR-ABL positive by RQ-PCR after ≥ 24 mo on imatinib. CMR (primary endpoint) was defined as undetectable BCR-ABL by RQ-PCR where there was no detectable BCR-ABL with a sample sensitivity of ≥ 4.5-logs. CMR4 and CMR4.5 were defined as BCR-ABL levels of ≤ 0.01% and ≤ 0.0032% expressed on the International Scale (IS), respectively and included patients with undetectable BCR-ABL levels with high sample sensitivity (4 or 4.5 logs). Patients were randomized to nilotinib 400 mg BID vs continuing imatinib 400 or 600 mg daily (same dose as at study entry.) The randomization was stratified by prior use of IFN (none, ≤ 12 mo, 〉 12 mo) and prior duration of imatinib therapy (〉 36 mo or ≤ 36 mo). The primary endpoint was the rate of confirmed best cumulative CMR by 12 mo of study therapy with nilotinib or imatinib. Secondary objectives included the kinetics of CMR at different timepoints, duration of CMR, progression-free survival, and overall survival in both arms. During the study, RQ-PCR for BCR-ABL was performed at baseline (BL) and every 3 mo and expressed on the IS in national reference laboratories in Australia, Brazil, and Canada. For this report: BL, 6 mo, and 12 mo results were analyzed in a central laboratory in Australia. Assessment of the primary efficacy endpoint has not been completed for 2% of the randomized pts; unblinded data will be available for all pts and will be presented by treatment arm. Results: BL results were available for 205/207 randomized pts. Overall, 56% of pts had no prior IFN exposure, while 21% and 23% had IFN exposure of ≤ 12 mo or 〉 12 mo, respectively; 81% of pts had been on imatinib 〉 36 mos. At BL, 153 pts (74%) were known to be in MMR and 54 pts (26%) had 〈 MMR (including 2 pts with missing PCR samples); 53 pts (26%), and 20 pts (10%) had CMR4 or CMR4.5 (with detectable BCR-ABL) at BL, respectively. Overall, 67 pts (32%) had at least a half-log reduction in BCR-ABL levels from BL by 12 mo. Of the 52 pts (25%) known not to have MMR at BL, 24 pts (46%) achieved MMR or better by 12 mo in the study. To date, no pt experienced a loss of MMR or CCyR on study. By 12 mo, 50% of pts with a molecular assessment had CMR4 and 27% had CMR4.5. Of the 152 pts who did not have CMR4 at baseline, 30% had achieved CMR4 (unconfirmed) by 12 mo. Of the 185 pts who did not have CMR4.5 at baseline, 21% had achieved CMR4.5 (unconfirmed) by 12 mo. Undetectable levels of BCR-ABL transcripts (with a test sensitivity of ≥ 4.5 log), were achieved by 12 mo by 12% of pts who did not have undetectable BCR-ABL transcript levels at BL. By 12 mo, 20 (10%) pts discontinued study (none due to progression, 1 due to death). Grade 3/4 adverse events were uncommon. Conclusions: ENESTcmr is the first phase 3 randomized study in CML-CP pts to assess the achievement of CMR as the primary endpoint. Unblinded results from this ongoing study will be presented and will provide information on the ability of pts to achieve confirmed CMR on nilotinib vs imatinib following extended treatment with imatinib. These aggregate data demonstrate that 12% of pts achieved undetectable BCR-ABL levels by 12 months after study entry. This is in contrast to observations in previous trials where the increase in the proportion of pts with undetectable BCR-ABL levels over time is more gradual. Further follow-up will identify pts with sustained CMR over time, which may offer these pts an opportunity to discontinue therapy. Disclosures: Hughes: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lipton:Novartis Pharmaceuticals Canada Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees. Leber:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Spector:Novartis: Membership on an entity's Board of Directors or advisory committees. Cervantes:Novartis: Speakers Bureau; BMS: Speakers Bureau. Pasquini:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Schwarer:Novartis: Honoraria; BMS: Honoraria. Mahon:Novartis: Honoraria, Research Funding. Rea:BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Yeung:Novartis Pharmaceuticals: Research Funding; BMS Oncology: Research Funding. Kamel-Reid:Novartis: 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. Reynolds:Novartis: Employment, Equity Ownership. Williams:Novartis: Employment. Szczudlo:Novartis: Employment, Equity Ownership. Branford:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Research Funding; Ariad: Research Funding.

Description: Abstract 394 Background: The advent and approval of TKIs has dramatically improved the life expectancy of patients with CML. As treatment innovation has transformed CML into a chronically managed disease, we examined the impact of these changes on patients with CML in order to offer recommendations for healthcare providers (HCPs) to better support patients with CML. Method: 50 patients with CML from Brazil, France, Germany, Russia and Spain were included in this ethnographic investigation including: patients within 18 months of diagnosis and on frontline imatinib therapy (n = 20), patients with ongoing frontline treatment (〉 18 months to 7 years, n = 20), and patients who were switched to second- or third-line TKI therapies (n = 10). Patients in all 5 countries participated in a 2.5-hour in-home interview, and patients in Brazil and France completed 7-day photo journals and an optional telephone debrief interview. Patients were asked to discuss and write about their perceptions and experiences regarding such issues as adherence, disease knowledge, disease management, and their relationship with HCPs. Result: This global ethnographic investigation generated a 5-stage, patient-centered model emphasizing emotions and experiences throughout the diagnosis, treatment and management of their disease: crisis, hope, adaption, normalcy, and uncertainty. Depending upon their circumstances, these experiential stages were found to be abbreviated or prolonged and influenced by patients having differentiating levels of knowledge about their disease, comfort levels with the treatment and/or their HCPs, as well as different degrees of optimism about their treatment and long-term prognosis. In addition, the study results showed that patients cycle through the various stages of the model throughout the course of their disease. The crisis phase occurred at diagnosis and tended to resolve upon HCP reassurance of the availability of successful treatments. Hope followed crisis when patients were educated about their disease and its treatments and responded to initial therapy. Adaption involved patients adjusting to any physical changes wrought by the disease, treatments, and associated adverse events. As well, they began to psychologically come to terms with the long-term nature of their disease and develop their drug-taking routines and compliance pattern. As patients attained stability in their disease and adapted to changes, a ‘new’ normal returned and patients began to refocus their life away from the disease back to social, work, and family matters. The uncertainty stage was found to be associated with drug resistance, disease progression, newly occurring adverse events, or due to limitations around access to therapy because of public health regulations or personal financial issues. While uncertainty arose for multiple reasons and could occur at any time after patients had advanced through the 4 preceding phases, patients who went through stages of uncertainty most often cycled back to phases of adaption or normalcy once the issues were resolved. Conclusions: Here, we have identified 5 common patient experience stages and we provide recommendations based on patient research for the management of CML. This investigation suggests that HCPs can help patients move through the early stages of crisis and hope by providing reassurance, along with information and resources regarding drug efficacy and product differentiation, while explaining the importance of speed and depth of responses. Once in the adaption/normalcy stages, HCPs should set expectations for the risk/benefits of long-term chronic drug therapy and long-term disease monitoring and continue to support patient compliance and adherence programs while helping patients achieve and maintain a normal lifestyle. Disclosures: Guilhot: Novartis: Equity Ownership, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. Coombs:Novartis: Employment, Equity Ownership. Szczudlo:Novartis: Employment, Equity Ownership. Zernovak:Novartis: Employment, Equity Ownership. Macdonald:Novartis: Consultancy. Shapiro:Novartis: Consultancy.