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Low-dose dasatinib is safe and effective in patients with chronic myeloid leukemia in chronic phase (CML-CP). No randomized trials have compared the outcome with standard-dose dasatinib. This study aims to compare the outcome of patients with CML-CP treated with frontline dasatinib 50 versus 100 mg/day. We analyzed 233 patients with newly diagnosed CML-CP treated with low-dose dasatinib (N = 83) or standard-dose dasatinib (N = 150). Propensity score analysis with 1:1 matching was performed and identified 77 patients in each cohort without significant baseline differences. Response rates were reported as the cumulative incidences of complete cytogenetic response, major molecular response (MMR), molecular response (MR)4, and MR4.5. Failure-free survival (FFS), event-free survival (EFS), transformation-free survival (TFS), and overall survival (OS) were also compared. Patients on low-dose dasatinib with suboptimal response by European LeukemiaNet (ELN) 2013 criteria had the option to increase the dose to 100 mg/day. The overall median follow-up time was 60 months. The 3-year MMR rates were 92% and 84% for low-dose and standard-dose dasatinib, respectively (p = .23). Dasatinib 50 mg/day induced higher cumulative incidence of MR4 (77% vs. 66%; p = .04) and MR4.5 (77% vs. 62%; p = .02) at 3 years. The 4-year FFS, EFS and OS rates were 89% versus 77% (p = .04), 95% versus 92% (p = .06), and 97% versus 96% (p = .78) with low-dose and standard-dose dasatinib, respectively. The rate of any grade pleural effusion was 5% with dasatinib 50 mg/day compared to 21% with 100 mg/day. Dasatinib 50 mg/day is at least as effective as 100 mg/day with a better safety profile and drug exposure.

Background: Tyrosine kinase inhibitors (TKI) improve survival in patients with chronic myeloid leukemia in chronic phase (CML-CP), who meet molecular milestones at specific timepoints. The European LeukemiaNet (ELN) revised the recommendations of molecular response for the guidance of TKI switch in patients with suboptimal response or failure irrespective of TKI therapy. The aims of this study are to assess the impact of molecular response on survival in patients with second generation TKIs and to define optimal milestones that correlate with best outcome. Methods: Patients with newly diagnosed CML-CP enrolled on clinical trials of frontline second generation TKI therapy were analyzed. We evaluated the impact of molecular response at 3 months (BCR-ABL1 >10% and ≤10% on the international scale [IS]), 6 months (BCR-ABL1 >10%, >1-10%, and ≤1% [IS]), and 12 months (BCR-ABL1 >1%, >0.1-1%, and ≤0.1% [IS]) of TKI therapy. Overall survival was calculated from the start of TKI therapy until death from any cause at any time. Landmark analysis was performed to assess the impact of molecular response at each time points among patients on frontline second-generation TKIs. Univariate and backward multivariate Cox regression was performed to identify prognostic factors for survival after variable selections by a p value cutoff of 0.200 by univariate analysis. Results: Between 2000 and 2020, 298 consecutive patients were treated and included in the analysis: 150 patients received dasatinib 100 mg/day, and 148 received nilotinib 800 mg/day (Table 1). Overall, the median follow-up was 114 months (range, 0.3-172.8); dasatinib 100 mg/day, 120 months; nilotinib 800 mg/day, 114 months (P At 3 months of TKI therapy, we identified 12 (4%) patients with 3-month BCR-ABL1 >10% among 274 evaluable patients. Among 11 evaluable patients with 3-month BCR-ABL1 >10%, none achieved 6-month BCR-ABL1 ≤1% while on the same second-generation TKI; 9 (82%) had 6-month BCR-ABL1 between 1% and 10%; and 2 (18%) had 6-month BCR-ABL1 >10% (P 10% and ≤10%, respectively (P10% (IS) (P At 6 months of TKI therapy, we identified 4 (2%) patients and 24 (9%) patients with 6-month BCR-ABL1 >10% and BCR-ABL1 >1-10% among 264 evaluable patients, respectively. Among 22 evaluable patients with 6-month BCR-ABL1 >1%, 6 (27%) achieved 12-month BCR-ABL1 ≤0.1%; 11 (50%) 12-month BCR-ABL1 >0.1-1%; and 5 (23%) 12-month BCR-ABL1 >1%. The 9-year survival rates were 50%, 71%, and 93% for patients with 6-month BCR-ABL1 >10%, >1-10%, and ≤1%, respectively (P1-10%, P=0.002; HR, 5.059; 95% CI, 1.837-13.922: 6-month BCR-ABL1 ≤1% vs. >10%, P At 12 months of TKI therapy, we identified 5 (2%) patients with 12-month BCR-ABL1 >1% among 248 evaluable patients. Among 3 evaluable patients with BCR-ABL1 >1%, one each achieved 18-month BCR-ABL1 ≤0.1%, >0.1-1%, and >1%, respectively. The 9-year survival rates, 40%, 90%, and 93% for patients with 12-month BCR-ABL1 >1%, >0.1-1%, and ≤0.1%, respectively (P=0.019) (Figure 3). The 12-month landmark multivariate analysis identified age and 12-month BCR-ABL1 >1% (12-month BCR-ABL1 ≤0.1% vs. >0.1-1%, P=0.184; HR, 1.944, 95% CI, 0.730-5.181; 12-month BCR-ABL1 ≤0.1% vs. >1%, P Conclusion: Frontline second-generation TKI therapy achieves optimal response defined by the revised ELN recommendations. However, patients with warning categories at 3-month and 6-month on second-generation TKI therapy have worse survival. We therefore propose to switch TKI therapy in patients who do not achieve 3-month BCR-ABL1≤10% and 6- to 12-month BCR-ABL1 ≤1% on frontline second-generation TKI therapy. These patients should be considered for ponatinib or novel TKI therapy under development. Lack of achievement of 12-month major molecular response was not associated with negative outcome. Disclosures Sasaki: Otsuka: Honoraria; Pfizer Japan: Consultancy; Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy. Kantarjian:Pfizer: Honoraria, Research Funding; Novartis: Research Funding; Astex: Research Funding; Agios: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; Ariad: Research Funding; Cyclacel: Research Funding; Jazz Pharma: Research Funding; AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; BMS: Research Funding; Takeda: Honoraria. Issa:Celegene: Research Funding; Syndax: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Garcia-Manero:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; H3 Biomedicine: Research Funding; Amphivena Therapeutics: Research Funding; Onconova: Research Funding; Jazz Pharmaceuticals: Consultancy; Novartis: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding. Kadia:Cellenkos: Research Funding; Pfizer: Honoraria, Research Funding; Cyclacel: Research Funding; Incyte: Research Funding; Amgen: Research Funding; Novartis: Honoraria; BMS: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Pulmotec: Research Funding; Astellas: Research Funding; Celgene: Research Funding; Astra Zeneca: Research Funding; Ascentage: Research Funding. Yilmaz:Pint Pharma: Honoraria; Pfizer: Research Funding; Daicho Sankyo: Research Funding. DiNardo:Jazz: Honoraria; MedImmune: Honoraria; ImmuneOnc: Honoraria; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Novartis: Consultancy; Syros: Honoraria; Calithera: Research Funding. Pemmaraju:Celgene: Honoraria; Novartis: Honoraria, Research Funding; DAVA Oncology: Honoraria; Incyte Corporation: Honoraria; Roche Diagnostics: Honoraria; Daiichi Sankyo: Research Funding; Affymetrix: Other: Grant Support, Research Funding; Stemline Therapeutics: Honoraria, Research Funding; Cellectis: Research Funding; LFB Biotechnologies: Honoraria; AbbVie: Honoraria, Research Funding; Samus Therapeutics: Research Funding; MustangBio: Honoraria; Plexxikon: Research Funding; SagerStrong Foundation: Other: Grant Support; Blueprint Medicines: Honoraria; Pacylex Pharmaceuticals: Consultancy. Cortes:Merus: Research Funding; Sun Pharma: Research Funding; Telios: Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Immunogen: Research Funding; Bristol-Myers Squibb: Research Funding; BiolineRx: Consultancy, Research Funding; Arog: Research Funding; Amphivena Therapeutics: Research Funding; Astellas: Research Funding; Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Jabbour:Genentech: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding.

Background: Low-dose dasatinib was shown to be safe and effective in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). There is no randomized clinical trials to compare the outcome with the standard-dose dasatinib. The aim of this study is to compare responses and outcome of patients with newly diagnosed CML-CP treated with frontline dasatinib 50 mg/day with those who received standard-dose dasatinib 100 mg/day. Method: We analyzed 233 patients with newly diagnosed CML-CP who were treated with low-dose dasatinib 50 mg/day (N=83) or standard-dose dasatinib 100 mg/day (N=150). Responses criteria were previously defined. Failure-free survival (FFS) was calculated from the start date of therapy to the dates of treatment discontinuation for any reason except of treatment-free remission; event-free survival (EFS), to the date of any of the events while on study as defined in the IRIS study; transformation-free survival (TFS), to the date of transformation to accelerated or blastic phases or death during study; overall survival (OS), to the date of death from any cause at any time or date of last follow-up. Patients on low-dose dasatinib who had suboptimal response by European LeukemiaNet criteria had an option to increase the dose to 100 mg/day. Propensity score analysis with 1:1 matching was performed with the nearest neighbor matching method using calipers of width equal to 0.2. Multiple imputation was performed to minimize the bias. Propensity scores were calculated with logistic regression from baseline covariates including age, spleen size by examination, white blood cell count, hemoglobin, platelet count, percentage of basophils, percentage of blasts in peripheral blood and bone marrow, the presence of clonal evolution, and Sokal risk classification to minimize difference. Results: The overall median follow-up was 84 months: 24 months and 120 months for low-dose and standard-dose, respectively. Propensity score matching identified 77 patients in each cohort without significant baseline difference (Table 1). The 12-month major molecular response (MMR) rates were 82% and 76% for low-dose and standard-dose groups, respectively (P=0.136). The cumulative incidence of molecular response (MR)4, MR4.5, and complete molecular response (CMR) rates within 1 year were higher in the low-dose dasatinib group compared with the standard-dose group (63% and 43%, 53% and 37%, and 24% and 11% for each)(P Conclusions: The low-dose dasatinib is at least as effective as standard-dose dasatinib with better drug exposure, resulting in better outcome. Disclosures Sasaki: Otsuka: Honoraria; Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Pfizer Japan: Consultancy. Jabbour:Adaptive Biotechnologies: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding. Yilmaz:Daicho Sankyo: Research Funding; Pfizer: Research Funding; Pint Pharma: Honoraria. Bose:Promedior, Inc.: Research Funding; NS Pharma: Research Funding; Celgene Corporation: Honoraria, Research Funding; Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Blueprint Medicines Corporation: Honoraria, Research Funding; Kartos Therapeutics: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Constellation Pharmaceuticals: Research Funding; Astellas Pharmaceuticals: Research Funding; Pfizer, Inc.: Research Funding. Thompson:Adaptive Biotechnologies: Consultancy, Research Funding; AbbVie: Research Funding; Pharmacyclics: Research Funding; Janssen-Cilag: Honoraria; Genentech: Consultancy. Alvarado:Tolero Pharmaceuticals: Research Funding; MEI Pharma: Research Funding; FibroGen: Research Funding; BerGenBio ASA: Research Funding; Jazz Pharmaceuticals: Research Funding; Sun Pharma: Research Funding; Astex Pharmaceuticals: Research Funding; Daiichi-Sankyo: Research Funding. Jain:TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Aprea Therapeutics: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Cellectis: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics: Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Garcia-Manero:Celgene: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Research Funding; Amphivena Therapeutics: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Onconova: Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Research Funding; H3 Biomedicine: Research Funding. Burger:BeiGene, Gilead, TG Therapeutics, and Pharmacyclics LLC, an AbbVie Company: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Gilead, Janssen, Novartis, TG Therapeutics, and Pharmacyclics LLC, an AbbVie Company: Other: Travel/accomodations/expenses, Speakers Bureau. Borthakur:BioTherix: Consultancy; Treadwell Therapeutics: Consultancy; Nkarta Therapeutics: Consultancy; BioLine Rx: Research Funding; Cyclacel: Research Funding; Novartis: Research Funding; Curio Science LLC: Consultancy; FTC Therapeutics: Consultancy; Argenx: Consultancy; PTC Therapeutics: Consultancy; BioLine Rx: Consultancy; BMS: Research Funding; AstraZeneca: Research Funding; Polaris: Research Funding; Xbiotech USA: Research Funding; Oncoceutics: Research Funding; Incyte: Research Funding; PTC Therapeutics: Research Funding; GSK: Research Funding; Jannsen: Research Funding; Abbvie: Research Funding. Pemmaraju:Pacylex Pharmaceuticals: Consultancy; Blueprint Medicines: Honoraria; Plexxikon: Research Funding; Stemline Therapeutics: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; DAVA Oncology: Honoraria; Samus Therapeutics: Research Funding; SagerStrong Foundation: Other: Grant Support; Affymetrix: Other: Grant Support, Research Funding; MustangBio: Honoraria; Incyte Corporation: Honoraria; Celgene: Honoraria; Daiichi Sankyo: Research Funding; LFB Biotechnologies: Honoraria; Novartis: Honoraria, Research Funding; Cellectis: Research Funding; Roche Diagnostics: Honoraria. Cortes:Daiichi Sankyo: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sun Pharma: Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Telios: Research Funding; Astellas: Research Funding; Amphivena Therapeutics: Research Funding; Arog: Research Funding; BiolineRx: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Immunogen: Research Funding; Merus: Research Funding. Kantarjian:Aptitute Health: Honoraria; BioAscend: Honoraria; Adaptive biotechnologies: Honoraria; BMS: Research Funding; Ascentage: Research Funding; Novartis: Honoraria, Research Funding; Jazz: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oxford Biomedical: Honoraria; Janssen: Honoraria; Sanofi: Research Funding; Pfizer: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Delta Fly: Honoraria; Daiichi-Sankyo: Honoraria, Research Funding; Immunogen: Research Funding.

Background Dasatinib, a potent Bcr-Abl tyrosine kinase inhibitor, is approved for the treatment of chronic-phase chronic myeloid leukemia (CML-CP) in the frontline and salvage settings. Notable side effects include pleural effusions and myelosuppression. Dasatinib at 50 mg daily has previously been reported to be active and better tolerated than the approved 100-mg daily dose. The aim of this study was to update the long-term follow-up results of dasatinib at 50 mg daily as frontline therapy for CML-CP. Methods Eighty-three patients with newly diagnosed CML-CP received dasatinib at 50 mg daily. Eligibility and response criteria were standards used in previous protocols. Results After a minimum follow-up of 12 months, 81 patients were evaluable. Two patients came off the study in less than 3 months. The rates of BCR-ABL1 transcript levels (International Standard) at ≤10% and ≤1% at 3 months were 96% and 77%, respectively. The cumulative rates for a complete cytogenetic response by 6 and 12 months were 77% and 95%, respectively. The cumulative rates for a major molecular response, a molecular response with a 4.0-log reduction, and a molecular response with a 4.5-log reduction by 12 months were 81%, 55%, and 49%, respectively. Twenty-one patients (25%) had treatment interruptions for a median of 13 days (range, 4-64 days). Five patients (6%) developed pleural effusions; 4 of these patients (80%) required a dose reduction. Two patients (2%) failed to achieve any cytogenetic or molecular response and were taken off the study. At a median follow-up of 24 months, none of the patients had disease transformation to an accelerated or blastic phase. The 2-year event-free and overall survival rates were 100%. Conclusions These updated results continue to support 50 mg of dasatinib daily as an effective and safe dose for early CML-CP.

We aimed to describe the impact of time to response on the outcomes of 75 patients with accelerated-phase chronic myeloid leukemia (CML-AP) at diagnosis. Patients had at least 1 feature of AP: blasts ≥15% (n = 2), basophils ≥20% (n = 19), platelets

Background: Low-dose dasatinib was shown to be safe and effective in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). There is no randomized clinical trials to compare the outcome with the standard-dose dasatinib. The aim of this study is to compare responses and outcome of patients with newly diagnosed CML-CP treated with frontline dasatinib 50 mg/day with those who received standard-dose dasatinib 100 mg/day. Method: We analyzed 233 patients with newly diagnosed CML-CP who were treated with low-dose dasatinib 50 mg/day (N=83) or standard-dose dasatinib 100 mg/day (N=150). Responses criteria were previously defined. Failure-free survival (FFS) was calculated from the start date of therapy to the dates of treatment discontinuation for any reason except of treatment-free remission; event-free survival (EFS), to the date of any of the events while on study as defined in the IRIS study; transformation-free survival (TFS), to the date of transformation to accelerated or blast phases during study; overall survival (OS), to the date of death from any cause at any time or date of last follow-up. Patients on low-dose dasatinib who had suboptimal response by European LeukemiaNet criteria had an option to increase the dose to 100 mg/day. Propensity score analysis with 1:1 matching was performed with the nearest neighbor matching method using calipers of width equal to 0.2. Multiple imputation was performed to minimize the bias. Propensity scores were calculated with logistic regression from baseline covariates including age, spleen size by examination, white blood cell count, hemoglobin, platelet count, percentage of basophils, percentage of blasts in peripheral blood and bone marrow, the presence of clonal evolution, and Sokal risk classification to minimize difference. Results: Propensity score matching identified 77 patients in each cohort without significant baseline difference (Table 1). The overall median follow-up was 60 months: 48 months and 131 months for low-dose and standard-dose, respectively. The 12-month major molecular response (MMR) rates were 82% and 75% for low-dose and standard-dose groups, respectively (P=0.229). The cumulative incidence of molecular response (MR)4, MR4.5, and complete molecular response (CMR) rates within 1 year were higher in the low-dose dasatinib group compared with the standard-dose group (63% and 43%, 53% and 36%, and 46% and 33% for each)(P=0.009; P=0.031; P=0.060). The incidence of pleural effusion was 6% and 21% in the low-dose and standard-dose, respectively (P=0.016). The 4-year FFS rates were 89% and 77% in the low-dose dasatinib and standard-dose dasatinib, respectively (P=0.041) (Figure 1). The 4-year TFS rates were 100% and 100%, respectively (P=1.000); the 4-year EFS rates were 95% and 92%, respectively (P=0.556); the 4-year OS rates were 97% and 96%, respectively (P=0.781). Conclusions: The low-dose dasatinib is as effective as standard-dose dasatinib with less intolerance, resulting in favorable outcome. Figure 1 Figure 1. Disclosures Sasaki: Novartis: Consultancy, Research Funding; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Issa: Syndax Pharmaceuticals: Research Funding; Novartis: Consultancy, Research Funding; Kura Oncology: Consultancy, Research Funding. Yilmaz: Pfizer: Research Funding; Daiichi-Sankyo: Research Funding. Ferrajoli: Janssen: Other: Advisory Board ; AstraZeneca: Other: Advisory Board, Research Funding; BeiGene: Other: Advisory Board, Research Funding. Bose: Incyte Corporation: Honoraria, Research Funding; Pfizer: Research Funding; Astellas: Research Funding; Constellation Pharmaceuticals: Research Funding; Blueprint Medicines: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Sierra Oncology: Honoraria; Kartos Therapeutics: Honoraria, Research Funding; Novartis: Honoraria; NS Pharma: Research Funding; BMS: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Promedior: Research Funding. Thompson: Janssen: Consultancy, Honoraria; AbbVie: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Gilead: Other: Institution: Advisory/Consultancy, Honoraria; Genentech: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Amgen: Other: Institution: Honoraria, Research Grant/Funding; Adaptive Biotechnologies: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding, Expert Testimony; Pharmacyclics: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding. Alvarado: Sun Pharma: Consultancy, Research Funding; Jazz Pharmaceuticals: Research Funding; FibroGen: Research Funding; BerGenBio: Research Funding; CytomX Therapeutics: Consultancy; MEI Pharma: Research Funding; Daiichi-Sankyo: Research Funding; Astex Pharmaceuticals: Research Funding. Jain: ADC Therapeutics: Honoraria, Research Funding; Cellectis: Honoraria, Research Funding; Janssen: Honoraria; Aprea Therapeutics: Research Funding; Pfizer: Research Funding; Beigene: Honoraria; Precision Biosciences: Honoraria, Research Funding; Servier: Honoraria, Research Funding; Fate Therapeutics: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Incyte: Research Funding; TG Therapeutics: Honoraria; Adaptive Biotechnologies: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Pharmacyclics: Research Funding. Takahashi: GSK: Consultancy; Novartis: Consultancy; Symbio Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy. Borthakur: GSK: Consultancy; Astex: Research Funding; Protagonist: Consultancy; University of Texas MD Anderson Cancer Center: Current Employment; ArgenX: Membership on an entity's Board of Directors or advisory committees; Ryvu: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Pemmaraju: HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Roche Diagnostics: Consultancy; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; LFB Biotechnologies: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy; CareDx, Inc.: Consultancy; Incyte: Consultancy; Daiichi Sankyo, Inc.: Other, Research Funding; Springer Science + Business Media: Other; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Aptitude Health: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Samus: Other, Research Funding; Plexxicon: Other, Research Funding; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; MustangBio: Consultancy, Other; Sager Strong Foundation: Other; Celgene Corporation: Consultancy; Affymetrix: Consultancy, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Cortes: Sun Pharma: Consultancy, Research Funding; Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Kantarjian: Precision Biosciences: Honoraria; Immunogen: Research Funding; Jazz: Research Funding; Taiho Pharmaceutical Canada: Honoraria; Ascentage: Research Funding; Pfizer: Honoraria, Research Funding; Astra Zeneca: Honoraria; Daiichi-Sankyo: Research Funding; BMS: Research Funding; AbbVie: Honoraria, Research Funding; Astellas Health: Honoraria; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Aptitude Health: Honoraria; NOVA Research: Honoraria; KAHR Medical Ltd: Honoraria; Ipsen Pharmaceuticals: Honoraria.

Clonal chromosomal abnormalities in Philadelphia chromosome-negative (CCA/Ph-) metaphases emerge as patients with chronic phase chronic myeloid leukemia (CP-CML) are treated with tyrosine kinase inhibitors (TKIs). We assessed the characteristics and prognostic impact of 598 patients with CP-CML treated on clinical trials with various TKIs. CCA/Ph- occurred in 58 patients (10%); the most common were -Y in 25 (43%) and trisomy 8 in 7 patients (12%). Response to TKI therapy was similar for patients with CCA/Ph- and those without additional chromosomal abnormalities (ACAs). We further categorized CCA/Ph- into those in which -Y was the only clonal abnormality, and all others. We found that patients with non -Y CCA/Ph- had worse failure-free survival (FFS), event-free survival (EFS), transformation-free survival (TFS), and overall survival (OS) compared with those without ACAs with the following 5-year rates: FFS (52% vs 70%, P = .02), EFS (68% vs 86%, P = .02), TFS (76% vs 94%, P < .01), and OS (79% vs 94%, P = .03). In a multivariate analysis, non -Y CCA/Ph- increased the risk of transformation or death when baseline characteristics were considered with a hazard ratio of 2.81 (95% confidence interval, 1.15-6.89; P = .02). However, this prognostic impact was not statistically significant when achieving BCR-ABL

BACKGROUND Outcomes in patients with chronic myeloid leukemia in blast phase (CML-BP) are historically dismal. Herein, the authors sought to analyze the characteristics, prognostic factors, and survival outcomes in patients with CML-BP in the tyrosine kinase inhibitor (TKI) era. METHODS A total of 477 patients with CML-BP were treated with a TKI at some point during the course of their CML. Cox proportional hazard models identified characteristics that were predictive of survival. Overall survival and failure-free survival were assessed. Optimal cutoff points for specific parameters were identified using classification and regression tree (CART) analysis. RESULTS The median age of the patients was 53 years (range, 16-84 years) and 64% were male. Approximately 80% of patients initially were diagnosed in the chronic phase of CML at a median of 41 months (range, 0.7-298 months) before transformation to CML-BP. De novo CML-BP occurred in 71 patients. Approximately 72% of patients received TKI therapy before CML-BP. The initial therapy for CML-BP included a TKI alone (35%), a TKI with chemotherapy (46%), and non-TKI therapies (19%). The median overall survival was 12 months and the median failure-free survival was 5 months. In multivariate analysis, myeloid immunophenotype, prior TKI, age ≥58 years, lactate dehydrogenase level ≥1227 IU/L, platelet count

BACKGROUND Both dasatinib and nilotinib are approved frontline therapy for chronic myeloid leukemia in chronic phase (CML-CP) based on randomized trials compared with imatinib. However, no head-to-head comparison of dasatinib and nilotinib has been conducted in patients with newly diagnosed CML-CP. METHODS The authors conducted a propensity score (PS) matched comparison of patients with CML-CP who received frontline therapy with either dasatinib (N = 102) or nilotinib (N = 104) under the respective phase 2 trials conducted in parallel. RESULTS PS matching resulted in 87 patients from each trial being matched for pretreatment characteristics. The 3-month BCR-ABL1/ABL1 ratio

This study assessed the relevance of 2013 European LeukaemiaNet (ELN) response categories on patients treated with common frontline tyrosine kinase inhibitors (TKI) in chronic myeloid leukaemia in chronic phase (CML-CP). Four hundred and eighty-seven patients treated with imatinib (400 mg; IM 400, n = 70; 800 mg; IM800, n = 201), dasatinib (n = 107) or nilotinib (n = 109) were analysed. Intention to treat (ITT) analysis indicated that the proportion of patients falling into optimal, warning and failure ELN categories were 89%, 6%, 6% at 3 months, 78%, 17% and 6% at 6 months, and 75%, 13% and 13% at 12 months, respectively. Rates of optimal response at 3 months were 75% for IM400, 90% for IM800, 89% for dasatinib and 97% for nilotinib; 41%, 80%, 86% and 89% at 6 months; and 47%, 77%, 76% and 87% at 12 months, respectively. Patients achieving optimal response had longer eventfree (EFS), failurefree (FFS), transformationfree (TFS) and overall survival (OS) compared to warning and failure responses at all-time points. Treatment with imatinib 800, dasatinib or nilotinib predicted for achieving an optimal response. Optimal response predicted for significantly longer EFS, FFS, TFS and OS at 3, 6 and 12 months, irrespective of the TKI modality used. ELN response categories reliably predicted outcomes in CML patients receiving commonly used TKIs.

Context Low-dose dasatinib was shown to be safe and effective in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). There are no randomized clinical trials to compare the outcome with the standard-dose dasatinib. Objective The aim of this study is to compare responses and outcome of patients with newly diagnosed CML-CP treated with frontline dasatinib 50 mg/day with those who received standard-dose dasatinib 100 mg/day. Design Propensity score analysis with 1:1 matching was performed with the nearest neighbor-matching method using calipers of width equal to 0.2. Setting MD Anderson Cancer Center. Patients or other participants We analyzed 233 patients with newly diagnosed CML-CP who were treated with low-dose dasatinib 50 mg/day (N=83) or standard-dose dasatinib 100 mg/day (N=150). Interventions Patients on low-dose dasatinib who had suboptimal response by European LeukemiaNet criteria had an option to increase the dose to 100 mg/day. Main outcome measures Responses criteria were previously defined. Failure-free survival (FFS) was calculated from the start date of therapy to the dates of treatment discontinuation for any reason except of treatment-free remission; event-free survival (EFS), to the date of any of the events while on study as defined in the IRIS study; transformation-free survival (TFS), to the date of transformation to advanced stage or death during study; overall survival (OS), to the date of death from any cause at any time or date of last follow-up. Results The overall median follow-up was 84 months: 24 months and 120 months for low-dose and standard-dose, respectively. Propensity score matching identified 77 patients in each cohort without significant baseline difference. The 12-month MMR rates were 82% and 76% for low-dose and standard-dose groups, respectively. The cumulative incidence of MR4, MR4.5, CMR rates within 1 year were higher in the low-dose dasatinib group compared with the standard-dose group (63% and 43%, 53% and 37%, and 24% and 11% for each). The 2-year FFS rates were 96% and 84%, respectively (P=0.011). The TFS, EFS, and OS rates were similar. Conclusions The low-dose dasatinib is at least as good as standard-dose dasatinib with better safety profile, resulting in better outcome.

Ruxolitinib is a potent and specific JAK1/JAK2 inhibitor recently approved for the treatment of myelofibrosis.We conducted a single-center phase I/II clinical study testing 3 dose levels (50 mg b.i.d. [n = 4], 100 mg b.i.d. [n = 5], and 200 mg b.i.d. [n = 18]). We enrolled 27 patients older than 14 years with relapsed or refractory acute myeloid leukemia (n = 26) or acute lymphoid leukemia (n = 1).The median age was 66 (range, 25-88) years. Thirteen patients were evaluable for dose-limiting toxicities. The most common Grade 3 or 4 nonhematologic event was infection (n = 26 events; most frequently pneumonia; 15 of 26; 58%). One patient with multiple relapses after 7 lines of therapy had a CRp at a ruxolitinib dose of 200 mg b.i.d.In this cohort of heavily pretreated patients with relapsed or refractory acute leukemias, ruxolitinib was overall reasonably well tolerated, with 1 patient achieving CRp.

Kinase domain (KD) mutations of ABL1 represent the most common resistance mechanism to tyrosine kinase inhibitors (TKI) in CML. Besides T315I, mutations in codon 255 are highly resistant mutations in vitro to all TKI. We aimed to study the incidence, prognosis, and response to treatment in patients with E255K/V. We evaluated 976 patients by sequencing of BCR–ABL1 fusion transcript for ABL1 KD mutations. We identified KD mutations in 381 (39%) patients, including E255K/V in 48 (13% of all mutations). At mutation detection, 14 patients (29%) were in chronic phase (CP), 12 (25%) in accelerated phase (AP), and 22 (46%) in blast phase (BP). 9/14 CP patients responded to treatment (best response complete hematologic response—CHR-4; complete cytogenetic response—CCyR-1; major molecular response—MMR-4); only 4/12 AP patients (CHR 3; MMR 1) and 7/22 BP patients responded (CCyR 2; MMR 2; partial cytogenetic response—PCyR-3). After a median follow-up of 65 months from mutation detection, 36 patients (75%) died: 9/14 (64%) in CP, 9/12 (75%) in AP, and 18/22 (82%) in BP (p = 0.003); median overall survival was 12 months. Patients with E255K/V mutation have a poor prognosis, regardless of the stage of the disease at detection.

INTRODUCTION The introduction of 20 years ago of imatinib, the first tyrosine kinase inhibitor (TKI), has drastically improved the survival of patients (pts) with Chronic Phase (CP) Chronic Myeloid Leukemia (CML), with a life expectancy similar to that of the general population. First used in patients after interferon (IFN) failure, imatinib and other TKIs have become standard frontline therapy. This analysis was done to investigate a 20-year outcome of Imatinib in pts Interferon-alpha failure. METHODS The long term outcome of 154 patients treated at our Institution with imatinib 400 mg after interferon failure from 1999-2000 was analyzed. RESULTS The median age was 44 (16 to 79yrs). 16 pts (11%) had prior malignancies 6 (38%) breast cancer, 3 (19%) skin cancer, 2 (12%) each prostate cancer and lymphoma, and 1 patient (6%) each lung cancer, colon cancer, and hairy cell leukemia. At the time of this analysis, 26 pts (17%) remained on imatinib of whom 22 pts (85%) had decreased their dosage. The median dose at last follow-up (FU) was 400mg (100-400mg). 128 pts (83%) discontinued imatinib permanently. Among them, 47 pts (37 %) changed to second generation TKIs, including 27 pts (58%) to dasatinib, 13 pts (28%) to nilotinib, and 7 (15%) to bosutinib.28 (60 %) received therapy with only 2 TKIs, and 19 (41%) received more than two TKIs. 81 pts (64%) did not receive a second TKI. Of these, 29 (36%) died, 23 (29%) were lost to follow up, 4 pts (12%) transformed to blast phase, 6 (8%) had stem cell transplant, 6 (8%) received farnesyltransferase inhibitor, 2 (3%) hyper-CVAD, 2 (3%) gemtuzumab ozogamicin, 1 (2%) homoharringtonine, 1(2%) with decitabine, and 7 (9%) had elective treatment discontinuation. All these 7 pts have remained treatment-free with a median follow up after discontinuation of 11.8 months. At baseline 13.6% had cardiac/vascular comorbidities and none had renal comorbidities. At 5-years, 8.4% had cardiac/vascular adverse events (AEs) and 1.2% had renal AEs. At last follow up, 13.4% had developed cardiac/vascular AEs and 3.8% renal AEs. 12 pts (8%) acquired second cancers after the start of imatinib. Of those, 2 pts each (16%) had esophageal, prostate, breast, and pancreatic cancers, and one each glioblastoma, basal cell cancer, lung cancer, and melanoma each had 1 patient (6%). At the time of this report, intention to treat (ITT) responses are available for 63 patients. The median FU for these pts was 232 months, with a median overall survival (OS) of 51%. At three months, the ITT responses were: 35% for MCyR, 13% for CCyR. At 6 months they were 54% MCyR, 25% CCyR, and 2% each for MR4, MR4.5, and CMR (undetectable transcripts with ≥100,000 copies ABL). At one year they were 73% MCyR, 39% CCyR, and 3% for MMR, MR4, and MR4.5, respectively. At 18 months, responses were 67% MCyR, 38% CCyR, 5% for MMR, MR4, and MR4.5, respectively, and 2% for CMR. At three years, best responses included 71% MCyR, 49% CCyR, 40% MMR, 24% MR4 and MR4.5, and 13% CMR. At five years best responses were 83% MCyR, 70% CCyR, 43% MMR, 23% MR4, 19% MR4.5, and 11% CMR. At ten years, best responses were 66% for MCyR and CCyR, 63% for MMR, 46% for MR4, 41% for MR4.5, and 12% for CMR. Lastly, at fifteen years, best responses were 72% for MCyR and CCyR, 66% for MMR, and 59% for MR4 and MR4.5, and 34% for CMR. The overall best response rates (at any time) for these 63 pts was 87% for MCyR, 79% for CCyR, 62% for MMR, 51% for MR4 and MR4.5, and 33% for CMR (Table). The median duration of sustained MR4.5 for 21 pts was 139 months, and only 3 pts (15%) lost it while on therapy. The one year, five years, and nineteen years survival outcomes are: Overall Survival (OS) 98%, 89%, and 50%, respectively; Failure free survival (FFS) 68%, 31%, and 20%, respectively; Event Free Survival (EFS) 86%, 53%, and 40%, respectively. Treatment Free Survival (TFS), 90%, 81%, and 70%, respectively. CONCLUSION These results represent the longest follow-up of imatinib therapy available to date and demonstrate the long-term benefit of TKIs even in the setting of IFN failure. Figure Disclosures Kantarjian: Ariad: Research Funding; Pfizer: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Takeda: Honoraria; Amgen: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Astex: Research Funding; BMS: Research Funding; Cyclacel: Research Funding; AbbVie: Honoraria, Research Funding; Immunogen: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Jazz Pharma: Research Funding. Borthakur:Incyte: Research Funding; Oncoceutics, Inc.: Research Funding; Bayer Healthcare AG: Research Funding; NKarta: Consultancy; AbbVie: Research Funding; AstraZeneca: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclacel: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Eli Lilly and Co.: Research Funding; Agensys: Research Funding; Merck: Research Funding; Cantargia AB: Research Funding; Cantargia AB: Research Funding; Merck: Research Funding; Oncoceutics: Research Funding; Novartis: Research Funding; Janssen: Research Funding; BMS: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; BioTheryX: Membership on an entity's Board of Directors or advisory committees; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Arvinas: Research Funding; GSK: Research Funding; Eisai: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Xbiotech USA: Research Funding; Polaris: Research Funding; Strategia Therapeutics: Research Funding; Arvinas: Research Funding; PTC Therapeutics: Consultancy. Verstovsek:Genetech: Research Funding; CTI BioPharma Corp: Research Funding; Promedior: Research Funding; Sierra Oncology: Research Funding; Ital Pharma: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Pragmatist: Consultancy; Protaganist Therapeutics: Research Funding; Incyte: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Constellation: Consultancy; Novartis: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding. Ravandi:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Selvita: Research Funding; Menarini Ricerche: Research Funding; Cyclacel LTD: Research Funding; Macrogenix: Consultancy, Research Funding; Xencor: Consultancy, Research Funding. Cortes:Pfizer: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Sun Pharma: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria. Kadia:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioline RX: Research Funding; Celgene: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; AbbVie: Consultancy, Research Funding. Wierda:Cyclcel: Research Funding; Sunesis: Research Funding; Xencor: Research Funding; Janssen: Research Funding; Oncternal Therapeutics Inc.: Research Funding; KITE pharma: Research Funding; Juno Therapeutics: Research Funding; Miragen: Research Funding; Loxo Oncology Inc.: Research Funding; GSK/Novartis: Research Funding; Gilead Sciences: Research Funding; Acerta Pharma Inc: Research Funding; Pharmacyclics LLC: Research Funding; Genentech: Research Funding; AbbVie: Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Jabbour:Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding.

7052 Background: Dasatinib, a potent BCR-ABL tyrosine kinase inhibitor (TKI), is approved for the treatment of chronic phase CML (CML-CP) in the frontline and salvage settings. Notable side effects include pleural effusions and myelosuppression. We previously reported dasatinib 50 mg daily to be active and better tolerated than the approved 100 mg daily dose (CANCER. 2018 Jul 1;124(13):2740-2747). We present an update on the efficacy and toxicity profile of lower dose dasatinib 50 mg orally daily in patients with early CML-CP. Methods: All patients presenting to our institution in early CML-CP were eligible to participate. Prior TKI therapy for up to 1 month was allowed. Responses were assessed according to the European LeukemiaNet guidelines (Baccarani et al. Blood 2013 122.872:884). Results: From March 2016 to March 2018, 81 patients have been enrolled. Median age is 47 years (20-84). Patients categorized by Sokal risk are: low 53; intermediate 22 and high 6. Median follow-up is 18 months (9-31). Cumulative response rates over time are shown below: At 3 months, 96% patients achieved early molecular response ( BCR-ABL PCR ≤10%). Median time to CCyR was 4.6 months, MMR 6.0 months, MR4.0 11.4 months and MR4.5 12.2 months. Eighteen patients had treatment interruption: pleural effusion 4 (possibly related 3, unrelated 1 due to pneumonia); gastrointestinal bleed 2; thrombocytopenia 3; transaminitis 2; renal dysfunction 1; asthma exacerbation 1; pneumonitis 1; lower extremity edema 1; myalgias 1, and pregnancy 2. Four patients had dose reductions: pleural effusion 3; myalgias 1. Four patients had dasatinib dose increased to 100mg: lack of CCyR at 6 months, 3; lack of MMR at 12 months, 1. Four patients are off study: no response 2, pneumonitis 1, and insurance 1. None of the patients have transformed or died. Conclusions: These updated results continue to support dasatinib 50 mg daily as an effective and safe dose for early CML-CP. Clinical trial information: NCT02689440. [Table: see text]

Patients received 5-azacytidine (AZA) 75 mg/m(2) intravenously daily for 7 days and sorafenib 400 mg orally twice daily continuously; cycles were repeated at ~1-month intervals. Forty-three acute myeloid leukemia (AML) patients with a median age of 64 years (range, 24-87 years) were enrolled; 37 were evaluable for response. FMS-like tyrosine kinase-3 (FLT3)-internal tandem duplication (ITD) mutation was detected in 40 (93%) patients, with a median allelic ratio of 0.32 (range, 0.009-0.93). They had received a median of 2 prior treatment regimens (range, 0-7); 9 had failed prior therapy with a FLT3 kinase inhibitor. The response rate was 46%, including 10 (27%) complete response with incomplete count recovery (CRi), 6 (16%) complete responses (CR), and 1 (3%) partial response. The median time to achieve CR/CRi was 2 cycles (range, 1-4), and the median duration of CR/CRi was 2.3 months (range, 1-14.3 months). Sixty-four percent of patients achieved adequate (defined as >85%) FLT3 inhibition during their first cycle of therapy. The degree of FLT3 inhibition correlated with plasma sorafenib concentrations. FLT3 ligand levels did not rise to levels seen in prior studies of patients receiving cytotoxic chemotherapy. The combination of AZA and sorafenib is effective for patients with relapsed AML and FLT-3-ITD. This trial was registered at clinicaltrials.gov as #NCT01254890.

OBJECTIVES Nilotinib is a potent, second generation inhibitor of BCR-ABL tyrosine kinase (TKI) and represent a standard of care for patients with chronic myeloid leukemia (CML), including accelerated phase (AP-CML). In 2005, we initiated a phase 2 study of nilotinib 400 mg twice daily as a frontline therapy in patients with AP-CML, and herein present the efficacy and safety data after a median follow-up of 68.4 months (range, 0.3-124.8). METHODS This was a prospective, single institution, phase 2 study in patients of age ≥18 years with a newly diagnosed, untreated AP-CML (except for Response criteria are standard. Fisher exact test and χ2 were used for analysis of categorical variables; and survival probabilities were estimated using the Kaplan-Meier method. Time to events (e.g., overall survival, event free survival) was calculated from the date of treatment to the date of an event or to last follow-up as previously reported (Cortes et al, 2010). RESULTS Twenty two patients of a median age of 53.7 years (range, 26-79.7) were enrolled. Table 1 summarizes clinical characteristics of all patients. The median treatment duration was 47.3 months (range; 0.3-124.4), and the median follow-up 68.4 months (range, 0.3-124.8). All patients discontinued study as of January 2017 due to planned study closure; but 11 patients (50%) continued on nilotinib off protocol at data cut-off (400 mg BID [3]; 300 mg BID [2]; and 200 mg BID [6]). Median time to treatment discontinuation in the remaining 11 patients was 12.9 months (range, 0.3-112); reason for discontinuation was: inadequate response [3], toxicity [2], non-compliance/financial [4]; elective discontinuation after sustained MR4.5 >2 years [1]; and death due to stroke [1]. Sixteen patients (73%) achieved complete hematologic response (CHR). Overall rates of CCyR, MMR, MR4.5 and CMR (undetectable transcripts with at least 100,000 ABL copies) were 73%, 73%, 55%, and 41%, respectively. Median times to CCyR, MMR, and MR4.5 were 2.9 months (range, 2.7-6.4), 5.7 months (range, 2.7-99.2) and 6.0 months (range, 2.7-36), respectively. Seven patients (32%) achieved sustained MR4.5 >2 years. In total, 4 patients lost their best achieved response (CHR [1], CCyR [2] and MR4.5 [1]) while on study. All events were associated with acquired ABL domain mutation; Y253H [2], T315I [1], and F359I [1] with a median time to detection of 16.7 months (range, 7-40). During the study conduct, one patient progressed to blast phase after 2 months on nilotinib. Two patients died while on study, one due to stroke and one due to unrelated medical condition, after being on therapy for 3 and 0.4 months, respectively. One patient electively discontinued nilotinib after being in sustained MR4.5 for 107 months, and remains in MR4.5 after 6 months off therapy. Estimated overall survival and event free survival at 5 years were 84% and 70%, respectively (Figures 1a & 1b). On univariate analysis, age >55 years was associated with lower rate of MMR (p = 0.034; HR 0.34; 95% CI 0.12-0.92); MR4 (p = 0.013; HR 0.25; 95% CI 0.08-0.75); and MR4.5 (p = 0.01; HR 0.15; 95% CI 0.04-0.63). Overall survival was inferior in patients older than 55 years (p = 0.014; HR 2.4; 95% CI 2.36-not estimated); and in those with > 1 AP-CML defining abnormality (p = 0.018; HR 9.53; 95% CI 0.98-92). The most frequent non-hematologic adverse events (AEs) were hyperbilirubinemia (63% of patients), rash (63%), hypertension (59%), and transaminitis (50%). Grade ≥3 AEs observed in more than one patient were hyperbilirubinemia (n=2), and transaminitis (=2). Two patients developed arterio-thrombotic AEs: stroke and myocardial infarction (one each). Hematologic AEs included (all grades; grade ≥3): anemia (36%; 9%), thrombocytopenia (32%; 14%) and neutropenia (14%; 9%). Two patients (9%) discontinued therapy due to nilotinib related AE, one for G3 peripheral neuropathy and one for G3 hyperbilirubinemia with G2 thrombocytopenia. CONCLUSION Nilotinib is safe and highly effective in patients with AP-CML, and induces fast and durable responses. More than 50% of patients can achieve MR4.5. Clinical trial.gov: NCT00129740. Disclosures Cortes: novartis: Research Funding. O'Brien:Pfizer: Consultancy, Research Funding; Janssen: Consultancy; Aptose Biosciences Inc.: Consultancy; Kite Pharma: Research Funding; Regeneron: Research Funding; Vaniam Group LLC: Consultancy; Amgen: Consultancy; Pharmacyclics: Consultancy, Research Funding; Celgene: Consultancy; Alexion: Consultancy; Abbvie: Consultancy; GlaxoSmithKline: Consultancy; Acerta: Research Funding; Gilead: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Astellas: Consultancy; TG Therapeutics: Consultancy, Research Funding. Konopleva:Stemline Therapeutics: Research Funding; Immunogen: Research Funding; abbvie: Research Funding; cellectis: Research Funding. Verstovsek:Incyte: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Kadia:Celgene: Research Funding; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Abbvie: Consultancy; BMS: Research Funding; Novartis: Consultancy; Takeda: Consultancy; Celgene: Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Abbvie: Consultancy; Takeda: Consultancy; Amgen: Consultancy, Research Funding. Ravandi:Macrogenix: Honoraria, Research Funding; Orsenix: Honoraria; Orsenix: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Xencor: Research Funding; Sunesis: Honoraria; Bristol-Myers Squibb: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Jazz: Honoraria; Abbvie: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Macrogenix: Honoraria, Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau; Jazz: Honoraria; Sunesis: Honoraria; Xencor: Research Funding; Seattle Genetics: Research Funding.

Summary Background Several tyrosine kinase inhibitors (TKIs) are available for treatment of patients with chronic myeloid leukaemia in chronic phase (CML-CP). We analysed long-term molecular and cytogenetic response and survival outcomes for four TKI modalities used as frontline therapy for CML-CP. Methods In a retrospective cohort analysis, we included data from patients with CML-CP treated in prospective clinical trials with frontline TKI modalities at a single institution between July 31, 2000, and Sept 10, 2013. The main aim of the study was to determine whether achievement of complete cytogenetic response or major molecular response had similar prognostic implications irrespective of the frontline TKI modality used. We analysed each TKI modality for response assessment and analysed survival endpoints (event-free, failure-free, transformation-free, and overall survival) with the Kaplan-Meier method. Univariate and multivariate analyses were done with Cox proportional hazard regression. Findings Our analysis included 482 patients who were treated with imatinib 400 mg daily (n=68), imatinib 800 mg daily (n=200), dasatinib 50 mg twice daily or 100 mg daily (n=106), or nilotinib 400 mg twice daily (n=108). More patients receiving imatinib 800 mg or second-generation TKIs (ie, dasatinib or nilotinib) achieved complete cytogenetic response (58 [87%] of 67 for imatinib 400 mg vs 180 [90%] of 199 for imatinib 800 mg, vs 100 [96%] of 104 for dasatinib vs 99 [93%] of 107 for nilotinib), major molecular response (51 [76%] vs 171 [86%] vs 93 [90%] vs 97 [91%]), and 4·5 log or higher reduction in BCR-ABL transcripts (MR 4·5 response 38 [57%] vs 148 [74%] vs 76 [71%] vs 76 [71%]). This finding was consistent over time (3–60 months). 5-year event free survival significantly differed between the imatinib 400 mg group and the other TKI groups (imatinib 800 mg p=0·029, dasatinib p=0·003, nilotinib p=0·031). There was no significant difference in 5-year failure-free survival (p=0·32, p=0·075, p=0·332), transformation-free survival (p=0·053, p=0·038, p=0·493), or overall survival (p=0·563, p=0·162, p=0·981). Multivariate analysis showed that therapy with imatinib 800 mg (HR 0·51, 95% CI 0·29–0·88, p=0·016), dasatinib (0·28, 0·12–0·66, p=0·004), or nilotinib (0·42, 0·20–0·89, p=0·024) predicted for better event-free survival compared with imatinib 400 mg, but that failure-free, transformation-free, and overall survival were similar irrespective of the TKI used. 28 (41%) patients receiving imatinib 400 mg, 85 (43%) receiving imatinib 800 mg, 23 (21%) receiving dasatinib, and 27 (25%) receiving nilotinib discontinued treatment for any reason. Interpretation Treatment with imatinib 800 mg or the second-generation TKIs dasatinib or nilotinib resulted in superior and deeper responses than did standard-dose imatinib, which were maintained after 5 years of follow-up. Results with imatinib 800 mg were similar to those with second-generation TKIs, although more patients discontinued therapy. Funding MD Anderson Cancer Center, National Cancer Institute.

Introduction: TKIs have changed the natural history of CML with a markedly reduced risk of transformation to CML-BP. However, some patients (pts) become resistant to therapy and progress and a few pts present with CML-BP at diagnosis. In this study, we have identified the clinical characteristics, prognostic factors and outcome of pts with CML-BP from a single center cohort of pts treated with a TKI at some point during the course of their disease. Methods: We analyzed all CML pts diagnosed with CML-BP (defined as ≥30% blasts or extramedullary disease) from 07/1997 to 07/2015. Among a total of 498 pts included with CML-BP, 302 presented to MDACC already in BP (of whom 72 had BP at the time of initial diagnosis, in many instances prior to referral to MDACC); 84 presented in accelerated phase (AP) and later progressed, and 112 presented in chronic phase (CP) and progressed to BP. All pts were enrolled in clinical trials with different TKI/non-TKI based therapies. Clinical characteristics were collected at the time of initial presentation to MDACC in BP. Failure free survival (FFS) and overall survival (OS) were defined from the time of initial presentation to MDACC to treatment failure/death, respectively. Results: Median age for all 498 pts was 52 years (range, 2 to 84); 63% were male and 64% were Caucasian. Median time from initial diagnosis to BP was 36 months (0.4 to 298 months) for all pts excluding the 72 pts who were already in BP at diagnosis; median time from AP to BP (n=160) was 14 months (0.3-161). Immunophenotype was myeloid in 67%, lymphoid in 29%, mixed lineage in 3%, biphenotypic in 1% and megakaryocytic in 0.2%. Sixty-one percent of pts had additional chromosomal abnormalities besides the Ph chromosome, including double Philadelphia (17%), iso17q (7%), trisomy 8 (16%), chromosome 3 aberration (11%), del7q (8%), and trisomy 19 or 21 (4% each). Six percent of pts had a variant Ph. BCR-ABL mutation screening was performed in 174 pts at the time of BP, with mutations identified in 68 (39%), most commonly T315I (n=24) and E255K (n=13). Extramedullary (EMD) BP was detected in 26% pts, the most common being CNS involvement in 39% pts with EMD. Eighty-four percent had received one or more TKI by the time of transformation. The median OS was 12 months (10 months for myeloid and 17 months for lymphoid) and median FFS was 5 months. In univariate analysis, factors significantly associated with inferior OS were older age, high bone marrow blast %, female gender, lower hemoglobin, higher LDH, presence of trisomy 19 or chromosome 3 aberrations, prior TKI treatments, myeloid phenotype and prior AP (Figure-1 A-C). Recursive partitioning analysis revealed that age ≥56 years and LDH ≥888 were associated with increased risk of death. In multivariate analysis (MVA), adjusting for the above variables, age ≥ 56 yrs (HR=1.73, p Conclusions: Despite progress in therapy for CML, those who transform to CML-BP have a dismal outcome, particularly if previously treated with TKI. Patients with age ≥ 56, LDH ≥ 888 and those pts with myeloid phenotype had the worst outcomes. Better treatment options are needed for this small but poor prognosis subset of patients. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Konopleva:Calithera: Research Funding; Cellectis: Research Funding. Wierda:Acerta: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Novartis: Research Funding; Abbvie: Research Funding. Daver:Ariad: Research Funding; Sunesis: Consultancy, Research Funding; Otsuka: Consultancy, Honoraria; Kiromic: Research Funding; Pfizer: Consultancy, Research Funding; BMS: Research Funding; Karyopharm: Honoraria, Research Funding. O'Brien:Janssen: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

Introduction: The Philadelphia chromosome (Ph+) is a hallmark of CML and is also present in a subset of patients with acute lymphoblastic leukemia (ALL). Lymphoid blast phase (CML-BP) and Ph+ ALL almost always affect B cell lineage. In this report, we present the clinical characteristics of the rare subset of patients with Ph+ ALL or CML-BP with T-cell lymphoid phenotype. Methods: We reviewed the institutional database for all patients with blast phase CML (n=498) and de novo T-ALL (n=150) diagnosed since 07/1997. All clinical characteristics at the time of the diagnosis of BP or Ph+ ALL were collected. Seven patients with Ph+ T-cell lymphoid leukemia were identified. Results: Among the total of 498 CML-BP patients, 5 patients had T-cell lymphoid CML-BP (0.01%); in addition 2 patients with de novo Ph+ T-ALL were identified among 150 patients with T-ALL seen during the same time period (1.3%). Median age of the seven patients was 57 years (range 31-72 years); 71% were male. Among patients with CML-BP, all were in BP at the time they were referred to MDACC (one had progressed from an initial diagnosis in CP, 1 from accelerated phase, and 3 were in BP at initial diagnosis). Only 2 patients with CML-BP received prior TKI therapy; the 2 patients with T-ALL were previously untreated at the time of referral. Immunophenotype included 2 cortical, 3 early T-cell and 2 early T-cell precursor; 2 patients were negative and one was dim positive for TdT (summarized in Table-1). Extramedullary disease at initial presentation was seen in all patients [2 with lymphadenopathy alone, 2 with mediastinal involvement (one also with lymphadenopathy and the other with splenomegaly and lymphadenopathy), 2 with pleural effusion (1 with lymphadenopathy and another with splenomegaly) and 1 patient with splenomegaly alone]. None had CNS involvement at initial presentation, but one patient developed CNS involvement at first relapse. One patient had variant Ph+ and 2 had complex karyotype. Three patients had lymphoblastic lymphoma and 4 patients had T-ALL. Five patients died (3 from disease progression, one from complications of SCT, and one from intestinal obstruction and sepsis) and 2 are alive (25 and 49 months from BP diagnosis). The median survival for all patients was 13 months (range 1-49 months). Five patients received hyper-CVAD based therapy as an induction regimen: 3 of them received hyper-CVAD alone - one achieved CR then underwent a SCT but died due to complications of SCT, another achieved PR and was given imatinib followed by dasatinib which he did not tolerate; he was subsequently lost to follow up; and one patient had no response. The other 2 patients received hyper-CVAD with dasatinib - one achieved PR, then underwent allo-SCT and achieved CR but later had a CNS relapse and progressed; the other patient developed nodal progression 9 months after achieving CR with HCVAD-dasatinib which was later found to represent metastatic prostate cancer in the lymph nodes with no T-ALL recurrence and is currently on dasatinib with major molecular response. Two patients never received any TKI therapy and progressed on chemotherapy alone. Two patients received nelarabine as first salvage - one as a single agent (no response) and another with dasatinib (with PR). Conclusions: Ph+ T-cell lymphoid leukemias are very rare and have clinical features similar to those of de novo T-ALL. Induction with a combination of HCVAD and TKIs may achieve prolonged remission in some patients. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. O'Brien:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

INTRODUCTION: Ponatinib is a pan-tyrosine kinase inhibitor (TKI) with proven efficacy in multi-refractory CML patients (pts) who have failed other TKIs and approved in all CML stages after failure to other TKIs and for pts with T315I mutation. Despite excellent response rates, resistance or intolerance may develop in some cases. Treatment options in these pts are limited and the outcomes have not been described. METHODS: We conducted a retrospective review of the outcomes of pts with refractory chronic (CP) and accelerated (AP) phase CML who discontinued ponatinib in the salvage setting. Pts were assessed for the cause of ponatinib discontinuation, therapies (Rxs) received after discontinuation, response to such Rx, and survival post-ponatinib discontinuation. RESULTS: Among 55 pts treated (32 treated in CP, 23 in AP), 36 (65 %) have discontinued ponatinib at the time of this analysis. Nineteen pts were either lost to follow up (F/U) or died on Rx and excluded from this analysis. Of the 36 pts analyzed, 19 were in CP and 17 in AP at initiation of ponatinib. Pts had received a median of 4 Rxs (2-6) prior to ponatinib. Median age at discontinuation was 67 yrs (22-94). Median duration on ponatinib Rx was 17 mo (1-61). Of 19 CP pts, 5 discontinued due to toxicity (pancreatitis = 2, stroke = 1, headache = 1, thrombocytopenia = 1), 13 for lack of response, 1 per pt choice. At discontinuation, 14 were still in CP [complete cytogenetic response (CCyR) = 3, no/minor CyR (NR/mCyR) = 10, major molecular response (MMR) = 1]; 3 had progressed to AP, and 2 to blast phase (BP). Subsequent therapy for those still in CP included stem cell transplant (SCT) = 4, supportive care only (NT) = 3, dasatinib = 2, omacetaxine = 2, and bosutinib + decitabine (DAC), nilotinib, and imatinib (1 each); the 3 pts that progressed to AP received dasatinib + DAC, low-dose Ara-C (LDAC), and NT = 1 each, respectively; and BP pts received Hyper - CVAD + dasatinib followed by SCT = 1, ponatinib + LDAC = 1. Of the 3 CP pts in CCyR, 1 died from sepsis 1 mo after discontinuing ponatinib due to thrombocytopenia; 1 pt received SCT and died in MMR 11 mo post SCT; 1 developed 7q- /Ph- on ponatinib and received SCT (MMR at 47 mo F/U). The CP pt in MMR discontinued ponatinib after a stroke and lost MMR 38 mo later (still in CCyR off Rx). Two CP pts improved to CCyR after SCT (1 died in 8 mos; 1 in MMR at 25 mo). Thirteen pts (CP 9, AP 3, BP 2; all non-SCT Rx) did not improve their responses post ponatinib (remained in NR/mCyR). The Median survival (OS) post ponatinib discontinuation of the 19 CP pts was 26 mo [Fig 1]. Twelve pts have died: 5 disease related (CP 2, BP 2, AP 1), 4 cause unknown (CP 3, AP 1), 3 from sepsis (CP 2, AP 1). Of 17 AP pts who discontinued, 15 stopped due to poor response and 2 for toxicity (stroke = 1, nausea = 1). At discontinuation, 14 were still in AP [NR/mCyR = 13, partial CyR (PCyR) = 1], 3 had progressed to BP. Subsequent therapy included NT = 5, dasatinib = 4, dasatinib + DAC = 2, SCT = 2, hydroxyurea = 1 for those still in AP, and SCT = 1, BIDFA = 1, mitoxantrone + etoposide + ponatinib = 1 for those in BP. The pt with PCyR at discontinuation died 3 mos after discontinuation of heart failure. Three pts (AP = 2, BP = 1) received SCT: 1 BP pt achieved MMR but died 12 mos post SCT of unknown cause; 1 AP pt maintains MMR 63 mos after SCT; the other AP pt did not respond and relapsed in AP, then received Rx with dasatinib + DAC and died of progressive disease 5 mos later. The remaining 14 pts (AP 12, BP 2; all non-SCT Rx) did not improve their responses post ponatinib (remained in NR/mCyR). The OS post ponatinib discontinuation (17 AP) was 9 mo [Fig 1]. Twelve pts have died: sepsis 3 (AP 3); progression 4 (AP 3, BP1), unidentified 5 (BP 1, AP 4); other 1 (BP 1). The OS for all 36 pts was 16 mos [Fig 2]; OS by stage at discontinuation was 31mo in CP, 9 mo in AP, 13 mo in BP [Fig 3]. The 12-mo survival probabilities for individual post-discontinuation Rx cohorts were: TKI 74%, SCT 56%, supportive 30%, other 50%. The OS for pts who stopped ponatinib because of toxicity vs resistance was 60 mo and 11 mo respectively. CONCLUSIONS: Long term outcomes of pts with ponatinib failure are poor with estimated 1-year OS and EFS rates of 54% and 40% respectively. Lack of response to ponatinib, after failing other TKIs, predicts a considerable risk for subsequent Rx failure. New Rx options are required for this small subset of patients. Figure 1 OS post ponatinib by stage at start of ponatinib Figure 1. OS post ponatinib by stage at start of ponatinib Figure 2 OS after failure for pts treated in CP or AP Figure 2. OS after failure for pts treated in CP or AP Figure 3 OS post ponatinib by stage at the time of ponatinib dc Figure 3. OS post ponatinib by stage at the time of ponatinib dc Disclosures Kantarjian: Amgen: Research Funding; ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. Daver:Otsuka: Consultancy, Honoraria; Sunesis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Karyopharm: Honoraria, Research Funding; Kiromic: Research Funding; BMS: Research Funding; Ariad: Research Funding. Kadia:BMS: Research Funding; Novartis: Honoraria. Ravandi:BMS: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. Jain:Pfizer: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Infinity: Research Funding; BMS: Research Funding; Servier: Consultancy, Honoraria; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Abbvie: Research Funding; Novartis: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Novimmune: Consultancy, Honoraria; Seattle Genetics: Research Funding; Celgene: Research Funding. Burger:Gilead: Research Funding; Portola: Consultancy; Roche: Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Other: Travel, Accommodations, Expenses; Pharmacyclics, LLC, an AbbVie Company: Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

To evaluate if pretreatment FLT3-ITD allele burden is associated with an impact on the response to the combination of sorafenib and azacytidine. Methods: We retrospectively analyzed the clinical records for 56 patients with FLT3-ITD treated with azacytidine and sorafenib between 2009 and 2013. Results: Among the patient, 34 (54%) were male, 15 (24%) had secondary AML and 7 (11%) had therapy-related AML. The median age prior to treatment with azacytidine plus sorafenib was 64 years (range, 20-87), with the median age at initial diagnosis of 63 years (range, 19-86 years). Eastern Cooperative Oncology Group performance status was 2 in 19 patients (31%). The median number of prior therapies received was 2 (range, 0-9); 12 patients were elderly (aged 61 years) without prior therapy who were deemed unfit to receive standard cytotoxic chemotherapy. The median white blood count was 8.9 10 (range, 7.5-13.1 10) and the median bone marrow blast percentage was 56% (range, 0-99%). The median FLT3-ITD allelic burden was 0.73 (range, 0.34-0.93) Median time from diagnosis to treatment with sorafenib and azacytidine was 5.5 months (range, 3 days -27months); cytogenetics was unfavorable in 8 patients (13%), normal karyotype in 30 (48%), and miscellaneous in 24 (39%). Eight (14%) patients achieved a complete response (CR) with 7 patients (13%) achieving CR without platelet recovery (CRp) and 10 (18%) achieving CR without peripheral blood count recovery (CRi); 1 patient (1%) had partial response (PR). The overall response rate was 46%. The OS at 3 months and 12 months were 45% and 24%, respectively. FLT-3 ITD allele burden had no significant impact on overall survival (OS) [HR 0.93, 95% CI (0.79-1.10); p1⁄40.433]. The variables with significant and independent impact on OS were achieving CR/CRp/CRi [HR 0.183, 95% CI (0.77-0.435); p 1⁄4 0.000], and ECOG 2[HR 3.78, 95% CI (1.782-7.843)]. The only variable with a significant impact on the overall response rate was blast percentage [OR 1.025 (1.007-1.043); p 1⁄4 0.007]. FLT3-ITD allele burden had no impact on response rate [OR 0.63 (0.21-1.83) p 1⁄4 0.394]. Conclusion: The FLT3-ITD allele burden in patients with relapsed, refractory, or high-risk untreated AML does not have an impact on the response rate or survival.

e18542Background: Dasatinib produces higher and faster responses compared to imatinib. We report the long-term follow-up of the first phase II trial of dasatinib frontline therapy for pts with CML-...

7057Background: TKI discontinuation for CML pts may be considered for those who achieve the deepest molecular responses as qualified by MR4.5 and complete molecular response for ≥ 2 years (susMR4.5...

Background Additional chromosomal abnormalities (ACAs) in the Philadelphia chromosome (Ph)-negative metaphases that emerge as patients with chronic myeloid leukemia (CML) are treated with tyrosine kinase inhibitors (TKIs) have been reported during treatment with imatinib. It has been suggested that these might be associated with an inferior outcome and in rare instances lead to the emergence of a new malignant clone resulting in myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) (Jabbour et. al, Blood 2007). This phenomenon has not been well characterized when other TKIs are used. We conducted a retrospective analysis of patients treated on imatinib, dasatinib, nilotinib, and ponatinib frontline trials to assess the frequency and prognostic impact of ACAs appearing during the treatment after achieving cytogenetic response. Patients and Methods A total of 524 patients with CML were evaluated with a median age at diagnosis of 48 years (range 15 to 86). These included 236 patients treated with imatinib, 125 with nilotinib, 118 with dasatinib and 45 with ponatinib. All the patients were treated in clinical trials approved by the institutional board review and signed an informed consent in accordance with institutional guidelines and in accordance with the declaration of Helsenki. Conventional cytogenetic analysis was done in bone marrow cells using standard G-banding technique at baseline, every 3 months during the first year, then every 6-12 months. Clonal ACAs were identified as abnormalities present in ≥2/20 metaphases or, if only one metaphase, present in ≥2 consecutive assessments. Results After a median follow-up of 83.8 months (range 0.3-176.6 months) 13% (72/524) patients had ACAs, of which 7% (41/524) were clonal. ACAs were seen in 11% (27/236) of patients on imatinib compared to 11% (13/118, p=0.9) on dasatinib, 19 % (24/125, p= 0.04) on nilotinib, and 17% (8/45, p=0.2) on ponatinib. Six patients had both clonal evolution (CE) and ACAs at different times. The median number of metaphases containing ACAs was 5/20 (range 1 to 20) with an average of 7/20. Most appeared within the first year of the start of the TKI (median 6 months, range 3-72 months); they first appeared after 12 months of therapy in 21 of the 72 (29%) patients. ACAs were transient and were detected in 2 or less time points in 52 of the 72 (72%) cases. The most common clonal ACAs were - Y (13/41) and +8 (4/41). The rates of cytogenetic and molecular responses were similar for patients with and without clonal ACAs (CCyR: 88% vs 91%; p=0.55) (MMR: 78% vs 86%, p=0.20). Having clonal ACAs did not affect the rate of deep molecular response either (MR4.5 71% vs 67%; p =0.65). There was no significant difference in EFS and OS (5y EFS 73% vs 86%; p=0.19) (5y OS 77% vs 93%; p=0.06) although there was a trend for lower rates for both. Responses and clinical outcomes were similar between different TKIs for patients with and without clonal ACAs. One patient with -7 treated with ponatinib developed MDS. Monosomy 7 appeared 9 months from the start of treatment in 9/20 metaphases and persisted. He was taken off ponatinib because of pancytopenia. He subsequently received bosutinib, achieved and maintained a CCyR. A high-risk MDS was documented approximately 1 year after appearance of the -7 clone. He was started on decitabine and achieved a partial cytogenetic response for MDS. Another patient in the imatinib cohort with -7 developed secondary AML (CCyR for CML) and died from a multiple organ failure after allogeneic stem cell transplant from a one antigen-mismatched unrelated donor. There was a third patient with -7 that later had CE and developed Ph+ CML blast phase. Conclusion ACAs are rare and mostly transient events that appear during the treatment of CML with TKIs. These changes do not affect responses or clinical outcomes, independent of what TKI is used. A small subset of patients with -7 may develop AML or MDS warranting close monitoring of patients with changes that are reminiscent of those diseases. Molecular analysis after appearance of ACAs could help identify mutations driving the Ph-clone into AML or MDS. Disclosures Pemmaraju: Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Cortes:BerGenBio AS: Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Teva: Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.

Background: Aside from the possibility of treatment discontinuation, the prognostic significance of deep molecular responses regarding survival endpoints in pts with CP-CML treated with TKI remains controversial. Achievement of complete cytogenetic response (CCyR) correlates with improved overall survival (OS). Among pts with CCyR, achievement of major molecular response (MMR) correlates with improved event-free survival (EFS). We have previously shown that among pts in sustained CCyR, those who achieve deeper molecular responses at 18 or 24 months may have longer EFS and failure-free survival (FFS) but not transformation-free survival (TFS) or OS. In this analysis, we sought to determine whether the achievement of a MR4.5 might correlate with improved long-term outcome in CP-CML pts who achieve CCyR after frontline TKI therapy. Methods: Pts with CP-CML treated with front line TKI, including imatinib 400 mg daily (IM400), imatinib 800 mg daily (IM800), nilotinib (NILO), or dasatinib (DASA), were included in the analysis. Landmark analyses were conducted at various time points to identify the association between achieving MR4.5 and various survival outcomes. Since the benefit of achieving CCyR is well established, only pts who were in CCyR were considered at each time point. The probabilities of OS, EFS, FFS and TFS were estimated using the Kaplan-Meier method and Cox proportional hazards regression models were fit to assess the association between OS, EFS, FFS, TFS and response. All outcomes were measured from the date treatment was started. OS was measured until death from any cause; TFS until death or transformation to accelerated (AP) or blast phase (BP) during study; EFS until loss of complete hematologic response or major cytogenetic response, transformation to AP or BP, or death from any cause; FFS until any event (as per EFS definition), failure (as defined by the ELN criteria), loss of CCyR, discontinuation or change of therapy for any reason. Results: The study population consisted of 478 pts. 59% of them were males and 9% had high Sokal score at diagnosis. 71 pts received IM400, 204 IM800, 105 NILO, and 98 DASA. Median follow-up is 106 (4-177) months (163 for IM400, 133 for IM800, 61 for NILO and 71 for DASA). The overall cumulative rate of CCyR was 92% (85% for IM400, 90% for IM800, 99% for NILO, and 97% for DASA). The overall cumulative rate of MR4.5 was 73% (56%, 74%, 80% and 78%, respectively for the 4 treatment cohorts). Among pts with CCyR, corresponding rates of MR4.5 were 79% overall and 66%, 81%, 83% and 80%, respectively, for the 4 treatment cohorts. For the entire population, the 5-year OS was 92.7%, TFS 86.0%, EFS 80.7%, and FFS 69.1%. In pts who were in CCyR at 12, 18, 24, 30, 36 or 48 months after initiation of TKI therapy there was no significant difference in terms of EFS, FFS, TFS or OS between pts who achieved a MR4.5 and those who did not (Table). Conclusion: Our analysis suggests that the achievement of MR4.5 does not provide a meaningful improvement in EFS, FFS, TFS, or OS for CP-CML pts who have achieved CCyR after being treated with frontline TKI. While obtaining a MR4.5 may enable the option of TKI discontinuation, our results suggest that failure to do so should not be considered failure or suboptimal response and thus should not prompt a change in TKI in pts who are in CCyR. Change of therapy to achieve MR4.5 with the goal of treatment discontinuation should be considered only within clinical trials. Table 1. Cox proportional hazards models for EFS, FFS, TFS, and OS at various time points. Time point EFS FFS TFS OS HR 95% CI p-value HR 95% CI p-value HR 95% CI p-value HR 95% CI p-value 12 months 0.82 0.42-1.61 0.57 0.94 0.58-1.53 0.81 0.99 0.46-2.12 0.98 1.06 0.47-2.39 0.89 18 months 0.96 0.51-1.82 0.9 0.75 0.45-1.25 0.27 1.34 0.69-2.81 0.36 1.41 0.68-2.94 0.35 24 months 0.85 0.44-1.65 0.63 0.8 0.49-1.33 0.39 0.9 0.41-2.01 0.8 0.99 0.43-2.25 0.97 30 months 0.75 0.35-1.62 0.47 0.64 0.36-1.15 0.14 0.82 0.34-1.96 0.65 0.98 0.40-2.39 0.97 36 months 0.98 0.46-2.09 0.96 0.55 0.30-1.02 0.06 1.11 0.47-2.65 0.81 1.24 0.52-2.95 0.63 48 months 0.86 0.35-2.10 0.73 0.7 0.35-1.40 0.31 0.84 0.29-2.43 0.75 0.86 0.30-2.48 0.78 Disclosures Pemmaraju: Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Cortes:Pfizer: Consultancy, Research Funding; ARIAD Pharmaceuticals Inc.: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Teva: Consultancy, Research Funding.

Background: Dasatinib (DAS) and nilotinib (NIL) are standard frontline therapy for chronic myeloid leukemia, chronic phase (CML-CP) based on randomized trials compared to imatinib. However, DAS and NIL have not been compared directly. The purpose of this study is to analyze efficacy, long-term outcome and toxicity of DAS and NIL as a front line therapy in newly diagnosed CML-CP. Method: Newly diagnosed patients (pts) with CML-CP, who received front-line therapy by either one of the phase II trials conducted almost in parallel (DAS: NCT00254423, N = 102 and NIL: NCT00129740, N = 104) are matched with caliper matching by the propensity score (PS) to adjust pre-treatment confounding factors. DAS was given orally by either 50mg twice daily (N = 30) or 100mg daily (N = 77). NIL was given 400mg orally twice daily. Toxicity was recorded according to the CTCAE ver. 4.0. Result: PS matching resulted in 87 pts from each trial to be matched for pre-treatment characteristics including age, Sokal score, lab, and organ function (Table). The median observation duration was 50.9 months (95% CI: 40.1-61.7) vs. 43.0 months (95% CI: 35.3-50.7) (DAS vs. NIL, P = 0.56). Response rate at 3, 6, and 12 months as well as cumulative (best) response are shown in Table. There were no significant differences in measures of response throughout the study period except for a higher rate of complete molecular response at 6 months with NIL (NIL vs. DAS, 11% vs. 3%, P = 0.04). However, at 12 months, this difference was not retained; there was also no difference in the rate of optimal response at 3 months. There was no statistical difference in cumulative response between 2 groups. No statistical difference was observed between 2 groups in any of the survival endpoints at 3 years (overall, event-free, failure-free, and transformation-free survival). Treatment discontinuation was observed in 16 (18%) vs. 17 (19%) pts with (DAS vs. NIL, P = 0.82). Reason for the discontinuation was; 1) toxicity (8 vs. 8, P = 1.00), 2) resistance (5 vs. 8, P = 0.39), and 3) financial (4 vs. 1, P = 0.37) (all presented as DAS vs. NIL, respectively). Adverse event (AE) was observed in 40 (46%) vs. 42 (48%) pts (DAS vs. NIL, P = 0.76), whereas grate 3 or more AE was observed in 19 (22%) vs. 15 (17%) pts (DAS vs. NIL, P = 0.44). Conclusion: In PS matched cohort of newly diagnosed CML-CP pts, the outcome observed with both treatment options (DAS and NIL) is excellent with no clear difference in response or long-term survival endpoints. Incidence of clinically significant AEs was similar between DAS and NIL. Table 1. Pre-treatment patient characteristics and treatment outcome in matched cohort. Variable DAS group(N = 87) NIL group (N = 87) P –value Median age 49 (19-79) 47 (17-80) 0.87 Age ³ 65, N (%) 6 (7) 6 (7) 1.00 Sokal Score Group 0.78 Low (%) 69 (79) 66 (76) Intermediate (%) 14 (16) 15 (17) High (%) 4 (5) 6 (7) WBC, x103/µL 23.9 (0.8-193.0) 39.8 (1.4-342.5) 0.51 HGB, g/dL 11.9 (8.8-16.2) 12.4 (8.9-15.8) 0.65 PLT, x103/µL 337 (86.0-1906.0) 322 (73.0-1356.0) 0.92 BM blast % 2.0 (0.0-6.0) 2.0 (0.0-7.0) 0.53 BM blast > 5 % (%) 3 (4) 3 (4) 1.00 ALB, mg/dL 4.4 (3.7-5.5) 4.4 (3.3-5.5) 0.79 LDH, IU/L 894(393-3648) 1097 (252-3467) 0.37 Cre , mg/dL 0.9 (0.6-1.3) 0.9 (0.6-1.3) 0.27 Tbil , mg/dL 0.4 (0.2-3.4) 0.4 (0.1-1.3) 0.54 AST, IU/L 32 (14-121) 36 (12-101) 0.65 ALT, IU/L 25 (12-154) 27 (11-84) 0.94 BCR-ABL (IS), % 14.1 (0.04-35.4) 14.1 (0.01-35.4) 0.68 Transcript type (%) 0.74 b2a2 32 (37) 34 (39) b3a2 32 (37) 37 (43) b3a3 1 (1) 0 (0) b2a2 and b3a2 21 (24) 15 (17) e1a2 1 (1) 1 (1) Previous use of imatinib ( grade 2 19 (22) 15 (17) 0.44 Disclosures O'Brien: Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding. Cortes:Ariad: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Consultancy, Research Funding.

7089 Background: In 2013 ELN proposed new response categories applicable to TKI frontline therapy for CML. We analyzed the outcome by ELN category of patients (pts) on different TKI as frontline th...

7024 Background: The tyrosine kinase inhibitor imatinib is standard therapy for patients with chronic myeloid leukemia in chronic phase (CML-CP). It has been suggested that higher-dose imatinib (HD-IM) may offer faster and deeper responses. The purpose of this study was to assess long-term follow-up data of patients treated with HD-IM (minimum follow-up 8 years). Methods: Patients with newly diagnosed CML-CP received daily imatinib 400 mg (IM400; 70 patients) or 800 mg (IM800; 201 patients) in consecutive clinical trials. Patients were assessed for cytogenetic and molecular response, overall survival (OS), event-free survival (EFS), transformation-free survival (TFS), and failure-free survival (FFS). Results: The 271 patients’ median follow-up time was 118 months. The median age was 48.3 years (range, 15.1-84.8 years). Sokal risk scores, rates of best response, FFS, TFS, EFS, and OS are given in Table 1. The response rates at 3, 6, and 12 months in IM800 patients were significantly higher than those of th...

Background A potential mechanism of resistance to FLT3 kinase inhibitors is high levels of FLT3 ligand (FL) which is commonly seen after treatment with myelosuppressive chemotherapy. We hypothesized that combining sorafenib with a less myelosuppressive agent, such as 5-azacytidine (AZA), may lead to higher and more durable responses. Furthermore, differentiation of leukemic blasts has been reported with both agents. Methods Patients were eligible if they had relapsed or refractory AML, were 18 years of age or older, and had adequate performance status (ECOG 2 2) and organ function. Patients older than 60 without prior therapy were also eligible if they were unsuitable to receive chemotherapy or refused it. Presence of FLT3-ITD was not a requirement but these patients were sought for participation in the study. Treatment regimen included AZA 75 mg/m2 daily for 7 days together with sorafenib 400 mg twice daily for 28 days; cycles were repeated in approximately 4 to 5-week intervals. Dose adjustments of both agents, and delay of AZA, based on toxicity were allowed. Plasma samples were collected on Day 1 and Day 10 of each cycle. Results Overall, 57 patients with AML with a median age of 65 years (range, 21-87) were enrolled. They included 27 (47%) patients with normal cytogenetics, 12 (21%) with chromosome 5/7 or complex cytogenetic abnormalities, 15 (26%) with other miscellaneous abnormalities; 3 (5%) had insufficient metaphases. Prior to the initiation of treatment, FLT3-ITD was detected in 53/57 (93%) patients with a median allelic ratio of 0.348 (range, 0.009 – 0.934). They had received a median of 2 prior treatments (range, 0 -7) including 13 previously untreated patients. Twenty (35%) patients had received ≥3 prior regimens and 12 had failed prior therapy with FLT3 kinase inhibitors (6 with AC220, 2 with PKC412, and 9 with sorafenib, either as monotherapy or with chemotherapy or plerixafor); 4 patients had failed 2 prior FLT3 inhibitors. The overall CR/CRi/PR rate among the 57 patients is 44%, including 16 (28%) with CRi and 8 (14%) with CR and 1 (2%) with PR. The response rate among the previously untreated patients was 62% and among relapsed patients 39%. Patients have received a median of 3 (range, 1 - 27) treatment cycles with the median number of cycles to response among the responders being 2 (range, 1 – 4) and the median time to achieving response, 2.1 months (range, 0.8 – 4.6 months). The median duration of CR/CRi Is 2.4 months (range, 0.8 – 24.8 months). Seven patients have proceeded to allogeneic stem cell transplant. The most common study drug-related adverse events were rash and fatigue with no deaths attributable to study medications. One patient developed grade 3 cardiomyopathy. With a median follow-up of 8.6 months (range, 6.1 – 26.9), 13 patients remain alive, 5 still in remission. The median overall survival of the 57 patients was 6.3 months, and 12.4 months in the 25 responding patients. Mean FL levels at cycle 2, day 0 and cycle 2, day 10 were 27 pg/mL and 54 pg/mL, respectively, which is significantly lower than those seen previously in studies of FLT3 kinase inhibitor plus chemotherapy. Conclusions Combination of AZA and Sorafenib is effective for the treatment of patients with AML and FLT3-ITD. FL levels are significantly lower during the course of therapy with this combination compared to previously reported levels after chemotherapy. Disclosures: Ravandi: Celgene: Consultancy, Research Funding.

7090 Background: Development of OCA has been reported among pts receiving imatinib as initial therapy for CML. Little is known about OCA development in CML pts treated with frontline 2nd generation TKI (dasatinib, nilotinib). Methods: OCA is defined as cytogenetic abnormality in non-Philadelphia chromosome positive clones as pts respond to TKI. Among pts treated with frontline dasatinib (n=99) or nilotinib (n=117), on parallel prospective single-arm phase II protocols at MDACC, 30 OCA ptswere identified, chronic (n=25) or accelerated phase (AP) (n=5). Results: 11 (11%) pts treated with dasatinib and 19 (16%) with nilotinib developed OCA; median follow-up 30 mo (range 0-71). Difference in OCA incidence with dasatinib and nilotinib was not statistically significant. At start of therapy, median age (years) of OCA pts was 53 (41-71) with dasatinib and 52 (37-82) with nilotinib, compared to those pts without OCA: 48 (18-83) with dasatinib and 49 (17-87) with nilotinib. Most common OCA was abnormality of chromosome 7 with 6 occurrences in 5 pts (1 pt with both inv(7) and +7) (inversion (n=1), 2 different translocations (n=2), deletions (n=2), and additions (n=1)). No pts developed trisomy 8 (historically most common OCA in imatinib-treated pts). Median time to first OCA: 9 mo (range 3-58) for all pts (12 mo (range 3-58) for dasatinib group and 9 mo (3-48) for nilotinib group). OCA disappeared spontaneously in 25 pts during follow-up. Outcomes for OCA versus non-OCA group (Table). For AP pts: 3/6 (50%) in dasatinib group and 2/17 (12%) in nilotinib group developed OCA. None of the OCA pts has developed AML or MDS. Conclusions: OCA is observed in 10-15% of pts receiving initial therapy with 2nd generation TKI. At median follow-up of 30 mo, occurrence of OCA confers no adverse impact on outcomes when compared to non-OCA pts treated with 2nd generation TKI and has not resulted in other hematologic disorders. [Table: see text]

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

4939 Background: High dose cytarabine containing regimens are still considered standard options for pts (pts) with AML relapsing after a first complete remission (CR1) lasting more than 12 months. No standard options exist for pts relapsing after shorter remission duration or with primary refractory disease. We conducted a phase II study assessing the efficacy and safety of twice daily fludarabine and cytarabine (BID FA) in pts with R/R AML, high-risk MDS and CML-BP. Pts and Methods: 147 pts with de Novo AML, R/R AML, intermediate-2 and high-risk MDS, and CML-BP, with a performance status of 3 or less, as well as normal organ functions were eligible. Pts were scheduled to receive fludarabine 15 mg/m2 intravenously (IV) q12 hrs on days 1 to 5 as well as cytarabine at the dose of 0. 5 g/m2IV over 2 hrs q12 hrs on days 1 to 5. GO was administered at the dose of 3 mg/m2 IV on day 1 for the first 70 pts enrolled. Courses were repeated every 4 to 6 weeks for a maximum of 7 courses. Pts with CML-BP were allowed to receive concomitant tyrosine kinase inhibitors. Four pts with AML who had FLT3 mutation were allowed to receive BID FA and sorafenib. Results: A total of 147 pts were treated. The median age was 63 years (range, 20 to 85 years). 131 (89%) had AML, 7 (5%) had high-risk MDS, and 9 (6%) had CML-BP. Of the 131 AML pts, 17 (12%) were de novo AML, 50 (38%) were in first salvage: first CR duration (CRD1) of less than 12 months in 39 pts (29%), and more than 12 months in 11 (9%) pts. Cytogenetic studies showed diploid karyotype in 52 pts (35%) and unfavorable chromosomal abnormalities involving chromosomes 5 and 7 in 30 pts (20%). 128 pts (87%) had a PS ≥1. Sixty-four pts (44%) had failed previous intensive chemotherapy, while 21 (14%) had failed targeted and hypomethylating agents. Forty-three (29%) pts had failed both. Overall, 34 pts (23%) achieved a complete remission (CR) and 8 (6%) achieved a CR without platelet recovery (CRp), for an overall response rate (ORR) of 29%. 6 pts received reinduction therapy, of which 3 achieved a CR. The CR rates for AML pts with frontline therapy, with relapsed AML with CRD1 ≥12 months, relapsed AML with CRD1< 12 months, and R/R AML beyond first salvage were 47%, 64%, 21%, and 14%, respectively. In CML-BP, 2 (22%) of 9 pts had objective responses (1 CR, 1 CRp). 1 of the 7 pts with MDS responded ([Table 1][1]). The treatment was well tolerated with only 7 of the pts experiencing grade 3 and 4 toxicities including mainly skin rash and increased liver enzymes. The overall 4-week mortality rate was 13%. With a median follow-up of 24 months (range, 10 to 33), 20 patients (14%) remained alive. The overall 6-month survival rate was 44%. The median overall survival (OS) and event free survival (EFS) were 5 months (range, 0. 1 to 33) and 1 month (range, 0. 1 to 33), respectively. The median CR/CRp duration was 12 months. Median OS for pts with de novo AML, a CRD1≥12 months, pts with CRD1

Abstract 3617 Background: Outcomes in the treatment of AML remain overall poor. Novel targeted approaches to therapy are warranted. Ruxolitinib is a potent JAK1 and JAK2 inhibitor recently approved in the US for treatment of intermediate or high-risk myelofibrosis (MF), including primary MF, post-polycythemia MF, and post-essential thrombocytopenia MF and is being actively investigated as treatment for pts with acute leukemia. Objectives: To determine safety, maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of ruxolitinib in treatment of relapsed/refractory acute leukemia pts (AML or ALL). Methods: We conducted a single-center prospective phase I clinical trial (n=27) in which 3 different dose levels were tested (mg, oral, BID): 50 (n=4), 100 (n=5), 200 (n=18) as continuous daily dosing. One cycle of therapy was defined as 28 days. Inclusion criteria: Age >14 years, relapsed/refractory AML or ALL, adequate organ function (ALT and/or AST ≤1.5x upper limit of normal and serum creatinine ≤2.5mg/dL, ECOG PS 0–2, at least 2 weeks from prior leukemia therapy with exception of hydroxyurea. Toxicities were defined with CTCAE criteria, v4.0. Results: A total of 27 pts with acute leukemias were enrolled. All but one pt had AML (one pt with B-ALL). Median age at diagnosis was 66 years (range 25–88 years). 14 pts (52%) were male. 11 pts (41%) were PS=2 at enrollment. 5 pts had splenomegaly at baseline (range 4–21 cm). Baseline median laboratory parameters included: Hb (g/dL)= 9.2 (7.9–10.9), platelet (109/L)=22(3–271), WBC (109/L) =4(0.3–42.8), Blast % (PB)=23(0–97), Blast % (BM)=56 (1–99). The pt with only 1% BM blasts prior to starting therapy had persistent AML represented by extramedullary disease requiring further treatment. Baseline cytogenetics: diploid (n=9), Trisomy 8 (n=1), −5/-7/both (n=8), abnormal 11q (n=1), miscellaneous (n=8). Baseline molecular mutations: JAK2V617F (n=5), NRAS (n=3), MPL (n=1), FLT3-ITD (n=1), NPM1 (n=1), CEBPA (n=1), IDH2 (n=1), DNMT3a (n=1). Majority of pts (23 pts, 85%) were treated in salvage 2 (S2) or beyond: S2-S3 (n=11), ≥S4 (n=12). 7 pts had a prior non-leukemia malignancy (mantle cell lymphoma, breast, colon, lung, prostate, melanoma, T-cell lymphoma), all 7 of whom required prior chemotherapy, radiation, or surgery. 16 pts had prior diagnosis of either MPN or MDS. Median number of treatment cycles on protocol was 2 (range 1–4). Among 27 pts enrolled, 12 pts were found to be evaluable for DLT-assessment, responses below in Table. Only one pt required a dose reduction during study period (during cycle 3, from 200mg BID to 150mg BID in setting of drug-related Grade 3 thrombocytopenia). Most common Grade ≥3 non-hematologic event was infection (n=17)(most commonly pneumonia (n=9); most commonly occurring at 200mg po BID dosing level (8/17, 47%), followed by stroke (n=2), cerebral edema (n=1), fatigue (n=1), mucositis (n=1), elevation of alkaline phosphatase (n=1). 1 pt had CRp at 200mg po BID dosing (68 year old AML pt, received 6 prior AML therapies, Trisomy 8-positive, JAK2 mutation negative; achieved CRp after 2 cycles and was on study for total of 3 cycles). Among the 5 JAK2-positive pts, 4 were evaluable for response; median number of cycles was 1(range 1–3) and no CR/CRp were noted among this group. Conclusion: In this heavily pre-treated cohort of acute leukemia pts, 1 CRp was noted at highest dosing level (200mg po BID), in a relapsed/refractory AML pt, however this response was short (1 cycle). Most common grade ≥3 non-hematologic event during study period was infection, with pneumonia being most commonly reported. Disclosures: Off Label Use: Ruxolitinib off label investigational drug. Cortes:Incyte: Research Funding. Ravandi:Incyte: Research Funding. Verstovsek:Incyte: Research Funding.

Abstract 1519 Background: The outcome of patients (pts) with acute myeloid leukemia (AML) and FLT3-ITD mutation is poor, particularly in the relapse setting. Sorafenib is a potent inhibitor of FLT3 kinase with reported clinical activity as a single agent (Metzelder S, Blood, 2009), and in combination with chemotherapy (Ravandi F, JCO, 2010). A potential mechanism of resistance to FLT3 kinase inhibitors is high levels of FLT3 ligand (FL) as seen after myelosuppressive chemotherapy. We hypothesized that combining sorafenib with a less myelosuppressive agent, such as 5-azacytidine (AZA), may lead to higher and more durable responses than cytotoxic chemotherapy. Furthermore, both drugs have demonstrated a potential for inducing differentiation in AML cells, thereby providing further rationale for the combination. Methods: Pts were eligible if they had relapsed or refractory AML, were 18 years of age or older, and had adequate performance status (ECOG ≤ 2) and organ function. Older pts without prior therapy were also eligible, if they were deemed unsuitable to receive chemotherapy. Presence of FLT3-ITD was not a requirement but these pts were targeted for enrollment. Treatment regimen included AZA 75 mg/m2 daily for 7 days together with sorafenib 400 mg twice daily for 28 days; cycles were repeated in approximately 4 to 5-week intervals. Overall responses were assessed after the completion of at least one cycle of therapy and at the time of the best peripheral blood and bone marrow response. Plasma samples were collected on approximately Day 1 and Day 10 of each cycle. To assess the degree of FLT3 inhibition, the plasma inhibitory activity (PIA) assay was performed using the Molm-14 cell line (Levis M, Blood, 2006). Plasma FL concentrations were measured using an ELISA kit (R&D Systems). Results: 43 pts with AML with a median age of 64 years (range, 24–87) were enrolled. They included 19 (44%) pts with diploid cytogenetics, 11 (26%) with chromosome 5/7 or complex cytogenetic abnormalities, and 13 (30%) with miscellaneous abnormalities. Prior to the initiation of treatment, FLT3-ITD was detected in 40/43 (93%) pts with a median allelic ratio of 0.28 (range, 0 – 0.93). They had received a median of 2 prior treatments (range, 0–7). 16 (37%) pts had received ≥3 prior regimens and 9 had failed therapy with FLT3 kinase inhibitors (5 with AC220, 1 with PKC412, and 6 with sorafenib, either as monotherapy or with chemotherapy or plerixafor); 3 had failed 2 prior FLT3 inhibitors. 6 pts were inevaluable as they discontinued therapy before response assessment at one month and 3 are too early for response assessment. The overall CR/CRi/PR rate among the 34 evaluable pts is 44%, including 10 (29%) with CRi and 4 (12%) with CR and 1 (3%) with PR (in this pt, bone marrow blast declined from 51% to 6% with normalization of blood counts). Overall, pts have received a median of 3 (range, 1–9) treatment cycles with the median number of cycles to response among the responders being 2 (range, 1 – 4) and the median time to achieving response, 2.1 months (range, 0.9 – 4.6 months). The median duration of CR/CRi Is 2.3 months (range, 1 – 12.2+ months). Six pts have proceeded to allogeneic stem cell transplant. The most common study drug-related adverse events were rash and fatigue with no deaths attributable to study medications. One pt developed grade 3 cardiomyopathy suspected to be related to the study regimen. Of the 34 pts included in the clinical analysis, there were 22 pts from whom plasma samples spanning at least one cycle of therapy were available. Among them, 64% achieved FLT3 inhibition to a targeted level of less than 15% of baseline during their first cycle of therapy. Median survival in pts who achieved this degree of inhibition was 238 days, while median survival in pts who did not reach this level was 154 days (p=0.13). Mean FL levels at cycle 1, day 1 and cycle 1, day 10 were 9 pg/mL and 17 pg/mL, respectively. Mean FL levels at cycle 2, day 0 and cycle 2, day 10 were 27 pg/mL and 54 pg/mL, respectively. Conclusions: Combination of AZA and Sorafenib is effective for the treatment of older pts and pts with relapsed and refractory AML and FLT3-ITD mutation. While not statistically significant, there was a trend toward improved survival in pts with adequate FLT3 inhibition during cycle 1. FL levels did not rise to the levels seen in pts receiving cytotoxic chemotherapy. Disclosures: Ravandi: Bayer/Onyx: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Off Label Use: Off-label use of sorafenib and 5-azacytidine in patients with acute myeloid leukemia. Levis:Astellas Pharma: Consultancy; Plexxikon: Consultancy; Symphogen: Consultancy. Garcia-Manero:Celgene: Research Funding. Andreeff:Hoffmann-La Roche: Research Funding; Karyopharm Therapeutics: Unrestricted gift, Unrestricted gift Other. Cortes:Celgene: Research Funding.

24 Background: Outcome of patients with relapsed acute myeloid leukemia (AML) with FLT3-ITD mutation is poor. Elevated FLT3 ligand levels (FL) secondary to cytotoxic chemotherapy is a putative mechanism of resistance to the FLT3 kinase inhibitors. We hypothesized that FL levels will be lower when combining sorafenib with less intensive therapy such as 5-Azacytidine (5-Aza). This study was conducted to evaluate the efficacy and tolerability of the combination of sorafenib and 5-Aza in patients with refractory or relapsed AML with FLT3-ITD mutation. Methods: Patients were eligible if they had relapsed or refractory AML and were 18 years of age or older. They received 5-Aza 75 mg/m2 IV daily x 7 days and sorafenib 400 mg PO BID continuously; cycles were repeated in approximately one month intervals. Results: 38 patients with AML with a median age of 60 years (range, 24-87) were enrolled. 4 were inevaluable as they never received therapy or discontinued it before response assessment. FLT-3-ITD was detected in 30 (88%) patients. They had received a median of 2 prior treatments (range, 0-6); 13 (38%) had received ≥ 3 prior regimens and 8 had failed prior FLT3 kinase inhibitor. Response rate was 41%, including 6 (17%) with CRi, 4 (12) with CRp, 3 (9%) with CR, and 1(3%) PR. The median time to achieving CR/CRi was 2 cycles (Range, 1-6) and the median duration of CR/CRi was 3 months (Range, 1–12). Conclusions: Combination of 5-Aza and sorafenib is effective for patients with relapsed AML with FLT-3-ITD mutation.