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Aims: Treatment of acute myeloid leukemia (AML) requires significant healthcare resource utilization (HRU), including lengthy hospitalizations. In a phase 3 study (NCT01696084), CPX-351 (Vyxeos) sh...

The need for new therapies for medically less fit adults with acute myeloid leukemia (AML) is unquestioned.[1][1] CPX-351, a liposomal formulation of cytarabine and daunorubicin,[2][2] may be an attractive option. In patients with relapsed/refractory leukemia, in whom CPX-351 was administered on

CPX-351, a dual-drug liposomal encapsulation of cytarabine and daunorubicin at a synergistic 5:1 molar drug ratio, achieved superior efficacy compared with conventional chemotherapy in older adults with newly diagnosed, high-risk/secondary acute myeloid leukemia (AML) in phase 2 and 3 studies. Prior to CPX-351 commercialization, an expanded access program (EAP) provided CPX-351 access for this population in the United States. In this phase 4, single-arm, open-label study (NCT02533115), 52 patients were treated with CPX-351 for 1-2 induction cycles and ≤4 consolidation cycles. The primary endpoint was safety. The most common serious adverse events were febrile neutropenia (19%), pneumonia (10%), and infection (8%). The 30- and 60-d mortality rates were 0% and 6%, respectively. Remission was achieved by 44% of patients; 90% of patients were alive at study completion. Overall, these results support outcomes from prior studies and the use of CPX-351 in older adults with newly diagnosed, high-risk/secondary AML.

CPX-351 is a dual-drug liposomal encapsulation of cytarabine/daunorubicin. In a phase 3 study (ClinicalTrials.gov Identifier: NCT01696084), patients aged 60-75 years with newly diagnosed, high-risk/secondary AML received 1-2 induction cycles with CPX-351 or 7 + 3 chemotherapy; those achieving complete remission (including with incomplete platelet or neutrophil recovery) could receive up to 2 consolidation cycles with CPX-351 or 5 + 2 chemotherapy, respectively. In this exploratory analysis of the subgroup of patients who received consolidation, median overall survival was prolonged among patients receiving CPX-351 induction/consolidation versus 7 + 3/5 + 2 (25.43 vs. 8.53 months; HR = 0.44 [95% CI: 0.25-0.77]). The safety profile of CPX-351 consolidation was consistent with that of the overall study. Outpatient administration of CPX-351 consolidation occurred in 51%-61% of patients and did not diminish overall survival. These findings suggest consolidation with CPX-351 in this patient population contributed to the prolonged overall survival versus 7 + 3/5 + 2, building upon findings from the overall study population, and provide evidence that, with careful monitoring, some patients can successfully receive CPX-351 as outpatients.

Purpose CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin that delivers a synergistic 5:1 drug ratio into leukemia cells to a greater extent than normal bone marrow cells. Prior clinical studies demonstrated a sustained drug ratio and exposure in vivo and prolonged survival versus standard-of-care cytarabine plus daunorubicin chemotherapy (7+3 regimen) in older patients with newly diagnosed secondary acute myeloid leukemia (sAML). Patients and Methods In this open-label, randomized, phase III trial, 309 patients age 60 to 75 years with newly diagnosed high-risk/sAML received one to two induction cycles of CPX-351 or 7+3 followed by consolidation therapy with a similar regimen. The primary end point was overall survival. Results CPX-351 significantly improved median overall survival versus 7+3 (9.56 v 5.95 months; hazard ratio, 0.69; 95% CI, 0.52 to 0.90; one-sided P = .003). Overall remission rate was also significantly higher with CPX-351 versus 7+3 (47.7% v 33.3%; two-sided P = .016). Improved outcomes were observed across age-groups and AML subtypes. The incidences of nonhematologic adverse events were comparable between arms, despite a longer treatment phase and prolonged time to neutrophil and platelet count recovery with CPX-351. Early mortality rates with CPX-351 and 7+3 were 5.9% and 10.6% (two-sided P = .149) through day 30 and 13.7% and 21.2% (two-sided P = .097) through day 60. Conclusion CPX-351 treatment is associated with significantly longer survival compared with conventional 7+3 in older adults with newly diagnosed sAML. The safety profile of CPX-351 was similar to that of conventional 7+3 therapy.

Purpose Acute myeloid leukemia (AML) disproportionately affects older adults; the prognosis in this subpopulation is generally poor, with variable use of inpatient chemotherapy. This study characterizes treatment patterns, hospitalizations, and outcomes among older patients with AML. Methods Using the Centers for Medicare & Medicaid Services' 2010–2012 100% Limited Data Set (LDS), data from all hospital claims from fee-for-service Medicare beneficiaries between 60 and 75 years of age with newly diagnosed AML and ≥1 hospitalization were analyzed. Findings Among 3700 identified patients with AML, 1979 (53.5%) received chemotherapy. Hospitalization rates were highest initially and then declined over time, irrespective of chemotherapy use. The mean length of initial hospital stay was longer in patients receiving chemotherapy. Intensive care unit admissions occurred in 33% of initial hospitalizations. Factors associated with receiving chemotherapy included younger age, fewer comorbidities, and the absence of prior hematologic disorders. Chemotherapy was associated with significantly increased survival compared with no chemotherapy (P Implications AML in older patients is associated with frequent hospitalizations and intensive care unit admissions. New treatment options with more favorable risk-to-benefit profiles are needed in this population.

7042 Background: CPX-351, a liposomal encapsulation of cytarabine (C) and daunorubicin (D) at a synergistic ratio, is approved as Vyxeos in the US and EU for adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes. In a phase 3 study, CPX-351 significantly improved OS and remission rates vs 7+3 in patients (pts) aged 60-75 y with newly diagnosed high-risk/sAML. Some studies suggest a high baseline blast percentage may portend a worse prognosis in AML. This post hoc analysis of phase 3 data assessed outcomes by baseline BM blast percentage. Methods: Pts diagnosed with AML per 2008 WHO criteria (≥20% blasts in peripheral blood or BM) were randomized 1:1 to receive ≤2 inductions of CPX-351 (100 units/m2 [C 100 mg/m2 + D 44 mg/m2] on Days 1, 3, 5 [2nd induction: Days 1, 3]) or 7+3 (C 100 mg/m2/d continuously for 7 d [2nd induction: 5 d] + D 60 mg/m2 on Days 1-3 [2nd induction: Days 1-2]). Pts achieving complete remission (CR) or CR with incomplete platelet or neutrophil recovery (CRi) could receive ≤2 consolidations. Results: CPX-351 had longer median OS and higher remission rates vs 7+3 irrespective of baseline BM blast percentage; median OS was worse in higher blast groups for both treatments (Table). The incidence of grade ≥3 TEAEs was >80% for both arms; febrile neutropenia was the most common. Conclusions: Improved outcomes were observed with CPX-351 vs 7+3 irrespective of baseline BM blast percentage in older adults with newly diagnosed high-risk/sAML. Clinical trial information: NCT01696084. [Table: see text]

Background: CPX-351 (Vyxeos®) is a dual-drug liposomal encapsulation of cytarabine and daunorubicin at a synergistic ratio. In a large randomized, open-label, multicenter, phase 3 study (NCT01696084) of CPX-351 versus conventional cytarabine/daunorubicin chemotherapy (7+3 regimen) in patients (pts) aged 60-75 years with newly diagnosed, high-risk/secondary AML, CPX-351 significantly improved overall survival (OS) and remission rates (Lancet JE, et al. J Clin Oncol. 2018). CPX-351 was approved by the US FDA in 2017 for the treatment of adults with newly diagnosed therapy-related AML or AML-MRC and is currently under review by the EMA. The WHO 2016 AML-MRC designation applies to AML pts who meet any of the following criteria: 1) a history of myelodysplastic syndrome (MDS) or myelodysplastic/myeloproliferative neoplasm (MDS/MPN), 2) an MDS-related cytogenetic abnormality, or 3) multilineage dysplasia in >50% of ≥2 cell lineages in the absence of NPM1 or biallelic CEBPA mutations. Pts with AML-MRC typically face a poor prognosis, with inferior outcomes in response to standard induction chemotherapy. A subgroup analysis of the phase 3 study was performed to specifically compare the efficacy and safety of CPX-351 versus 7+3 in pts with AML-MRC. Methods: Pts enrolled in the phase 3 study who met the WHO 2008 AML-MRC classification were included in this subgroup analysis; however, pts with a history of MPN other than CMML or combined MDS/MPN and pts with only morphologic evidence of multilineage dysplasia were excluded from the phase 3 study. Pts were randomized 1:1 to receive up to 2 inductions with CPX-351 (100 units/m2 [cytarabine 100 mg/m2 + daunorubicin 44 mg/m2] on Days 1, 3, and 5 [2nd induction: Days 1 and 3]) or 7+3 (cytarabine 100 mg/m2/day continuously for 7 days [2nd induction: 5 days] + daunorubicin 60 mg/m2 on Days 1-3 [2nd induction: Days 1-2]). Pts achieving complete remission (CR) or CR with incomplete platelet or neutrophil recovery (CRi) could receive up to 2 consolidations with CPX-351 (65 units/m2 [cytarabine 65 mg/m2 + daunorubicin 29 mg/m2] on Days 1 and 3) or 5+2 (as in 2nd induction). Pts could receive hematopoietic cell transplantation (HCT) at the discretion of their treating physician. Results: The study enrolled 309 pts, 246 of whom met the criteria for AML-MRC (CPX-351: n = 123; 7+3: n = 123). Of these 246 pts, 59.0% had antecedent MDS, 9.3% had antecedent CMML, and 31.7% had de novo AML with MDS karyotype. Baseline characteristics were similar between treatment arms (median age 68 years; 64.6% male; 11.0% with ECOG status of 2). A second induction cycle was received by 33.3% of pts in the CPX-351 arm and 37.8% of pts in the 7+3 arm. Among pts with AML-MRC, CPX-351 was associated with a significant OS benefit versus 7+3 (median: 9.07 vs 5.95 months; HR = 0.70 [95% CI: 0.53-0.93]). CPX-351 was also associated with higher rates of CR+CRi (48.0% vs 32.5%; OR = 1.83 [95% CI: 1.09-3.09]), CR (37.4% vs 24.4%; OR = 1.80 [95% CI: 1.02-3.17]), and HCT (33.3% vs 24.4%; OR = 1.53 [95% CI: 0.86-2.74]). Among pts who received HCT, median OS was longer with CPX-351 versus 7+3 when calculated from the date of randomization (not reached vs 15.21 months; HR = 0.50 [95% CI: 0.26-0.99]) or date of HCT (not reached vs 10.68 months; HR = 0.48 [95% CI: 0.24-0.96]). Early mortality rates in the CPX-351 and 7+3 arms, respectively, were 4.9% and 8.9% at Day 30 and 13.8% and 20.3% at Day 60. The treatment-emergent adverse event (TEAE) profile of CPX-351 in pts with AML-MRC was consistent with the overall study population and generally comparable between treatment arms (Table). Two pts treated with CPX-351 and 1 treated with 7+3 discontinued treatment due to a TEAE (cardiac failure [CPX-351], cardiomyopathy [CPX-351], and ejection fraction decreased [7+3]). Grade 5 TEAEs occurred in 8.9% and 14.3% of pts treated with CPX-351 and 7+3, respectively; those occurring in >1 pt in a treatment arm included sepsis (2.4% and 0.8%), disease progression (1.6% and 3.4%), multi-organ failure (0.8% and 1.7%), and respiratory failure (0.8% and 1.7%). Conclusions: In this subgroup analysis, CPX-351 improved OS and remission rates compared with 7+3 in older adults with AML-MRC, while maintaining a similar safety profile. Importantly, CPX-351 is the first agent to be associated with prolonged OS compared with standard-of-care chemotherapy (7+3 regimen) in adults with newly diagnosed AML-MRC, which supported FDA approval in this population. Disclosures Ryan: AbbVie: Equity Ownership; University of Rochester: Patents & Royalties. Uy:Curis: Consultancy; GlycoMimetics: Consultancy. Cortes:Astellas Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Arog: Research Funding; Pfizer: Consultancy, Research Funding. Ritchie:Bristol-Myers Squibb: Research Funding; Incyte: Consultancy, Speakers Bureau; NS Pharma: Research Funding; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Astellas Pharma: Research Funding; Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; Pfizer: Consultancy, Research Funding; ARIAD Pharmaceuticals: Speakers Bureau. Stuart:Sunesis Pharmaceuticals: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Agios: Research Funding; Astellas: Research Funding; Bayer AG: Research Funding; Celator/Jazz Pharmaceuticals: Research Funding; Incyte: Research Funding. Strickland:Sunesis Pharmaceuticals: Consultancy, Research Funding; Tolero Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Baxalta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas Pharma: Consultancy. Bixby:GlycoMimetics: Research Funding. Kolitz:Magellan Health: Consultancy, Honoraria. Schiller:bluebird bio: Research Funding; Astellas Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding. Wieduwilt:Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Shire: Research Funding; Reata Pharmaceuticals: Equity Ownership; Leadiant: Research Funding; Amgen: Research Funding; Merck: Research Funding. Ryan:Jazz Pharmaceuticals: Employment, Other: Stock and stock options. Chiarella:Celator/Jazz Pharmaceuticals: Employment, Equity Ownership. Louie:Celator/Jazz Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties.

Background: Outcomes for the treatment of AML with conventional induction chemotherapy (eg, 7+3 cytarabine/daunorubicin regimen) are poor for older adults and those with high-risk/secondary AML. CPX-351 (Vyxeos®), a dual-drug liposomal encapsulation of cytarabine and daunorubicin in a synergistic ratio, was approved by the US FDA in 2017 for the treatment of adults with newly diagnosed, therapy-related AML or AML with myelodysplasia-related changes and is currently under review by the EMA. A large randomized, open-label, multicenter, phase 3 study (ClinicalTrials.gov #NCT01696084) evaluated the efficacy and safety of CPX-351 versus conventional 7+3 chemotherapy in adults aged 60-75 y with newly diagnosed, high-risk/secondary AML (Lancet JE, et al. J Clin Oncol. 2018). In this study, CPX-351 significantly improved median overall survival (OS; primary endpoint) versus 7+3 (9.56 vs 5.95 mo; HR = 0.69 [95% CI: 0.52-0.90]; 1-sided P = 0.003), as well as event-free survival (EFS; 2.53 vs 1.31 mo; HR = 0.74 [95% CI: 0.58-0.96]; 2-sided P = 0.021). CPX-351 was also associated with higher rates of complete remission (CR; 37.3% vs 25.6%; 2-sided P = 0.040) and CR or CR with incomplete platelet or neutrophil recovery (CR+CRi; 47.7% vs 33.3%; 2-sided P = 0.016) versus 7+3, which likely contributed to the higher rate of patients undergoing hematopoietic cell transplantation (HCT) with CPX-351 (34.0% vs 25.0%; 2-sided P = 0.098). HCT is a potentially curative therapy, and the higher rate of HCT observed in the CPX-351 arm could therefore have an impact on long-term survival outcomes. To better understand the contribution of HCT and treatment with CPX-351 versus 7+3 to survival, exploratory analyses using a time-dependent proportional hazards model were performed to evaluate survival in patients who underwent HCT and assess the impact of treatment with CPX-351 versus 7+3 on survival independent of HCT status. Methods: Patients were randomized 1:1 to receive up to 2 induction cycles with CPX-351 (100 units/m2 [cytarabine 100 mg/m2 + daunorubicin 44 mg/m2] on Days 1, 3, and 5 [2nd induction: Days 1 and 3]) or 7+3 (cytarabine 100 mg/m2/d continuously for 7 d [2nd induction: 5 d] + daunorubicin 60 mg/m2 on Days 1-3 [2nd induction: Days 1-2]). Patients achieving CR or CRi could receive up to 2 consolidations with CPX-351 (65 units/m2 [cytarabine 65 mg/m2 + daunorubicin 29 mg/m2] on Days 1 and 3) or 5+2 (as in 2nd induction). Patients could receive HCT at the discretion of the treating physician. Results: A total of 309 patients were enrolled in the study (CPX-351: n = 153; 7+3: n = 156), and baseline characteristics were balanced between arms. A total of 52 (34.0%) patients in the CPX-351 arm and 39 (25.0%) in the 7+3 arm underwent HCT; most were 60-69 y of age (CPX-351: 69.2%; 7+3: 84.6%), had ECOG performance status ≤1 (CPX-351: 92.3%; 7+3: 94.9%), and were in CR (CPX-351: 57.7%; 7+3: 48.7%) or CRi (CPX-351: 19.2%; 7+3: 12.8%). Median time to HCT from first study dose was similar with CPX-351 (114.5 d) and 7+3 (113.0 d). Similar to the primary endpoint analysis, median OS landmarked from the time of HCT was significantly improved with CPX-351 versus 7+3 (not reached vs 10.25 mo; HR = 0.46 [95% CI: 0.24-0.89]). Further, in the current exploratory analyses in which HCT was treated as a time-dependent covariate, the HRs remained strongly in favor of CPX-351 versus 7+3 for OS (HR = 0.71) and EFS (HR = 0.74), with the upper bounds of the 95% CIs below 1.0 (Table). These results suggest CPX-351 may be associated with prolonged OS and EFS that is independent of HCT. The adverse event profile of CPX-351 was generally consistent with the known safety profile of conventional 7+3. Grade 3-5 adverse events reported in ≥10% of patients in the CPX-351 or 7+3 cohorts included febrile neutropenia (68.0% vs 70.9%), pneumonia (19.6% vs 14.6%), and hypoxia (13.1% vs 15.2%). Early mortality rates with CPX-351 and 7+3, respectively, were 5.9% and 10.6% at Day 30 and 13.7% and 21.2% at Day 60. Conclusions: Treatment with CPX-351 was associated with significantly longer median OS and EFS, as well as a higher proportion of patients achieving remission and undergoing HCT, compared with conventional 7+3 chemotherapy in this population of older patients with newly diagnosed, high-risk/secondary AML. Further, while it is expected that HCT had a positive impact on survival in this study, exploratory analyses suggest that CPX-351 produced positive OS and EFS outcomes independent of HCT. Disclosures Lin: Jazz Pharmaceuticals: Honoraria. Cortes:Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Arog: Research Funding. Ritchie:NS Pharma: Research Funding; Bristol-Myers Squibb: Research Funding; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; ARIAD Pharmaceuticals: Speakers Bureau; Astellas Pharma: Research Funding; Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; Pfizer: Consultancy, Research Funding. Stuart:Sunesis Pharmaceuticals: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Agios: Research Funding; Astellas: Research Funding; Bayer AG: Research Funding; Celator/Jazz Pharmaceuticals: Research Funding; Incyte: Research Funding. Strickland:Tolero Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Baxalta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas Pharma: Consultancy; Sunesis Pharmaceuticals: Consultancy, Research Funding. Bixby:GlycoMimetics: Research Funding. Kolitz:Magellan Health: Consultancy, Honoraria. Schiller:bluebird bio: Research Funding; Astellas Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding. Wieduwilt:Leadiant: Research Funding; Reata Pharmaceuticals: Equity Ownership; Merck: Research Funding; Shire: Research Funding; Amgen: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees. Ryan:University of Rochester: Patents & Royalties; AbbVie: Equity Ownership. Ryan:Jazz Pharmaceuticals: Employment, Other: Stock and stock options. Chiarella:Celator/Jazz Pharmaceuticals: Employment, Equity Ownership. Louie:Jazz Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties. Uy:GlycoMimetics: Consultancy; Curis: Consultancy.

Background: CPX-351 (Vyxeos®) is a dual-drug liposomal encapsulation of cytarabine and daunorubicin at a synergistic ratio. In a large randomized, open-label, multicenter, phase 3 study of CPX-351 versus conventional cytarabine/daunorubicin chemotherapy (7+3 regimen) in adults aged 60-75 years with newly diagnosed high-risk/sAML, patients treated with CPX-351 had significantly longer survival times and higher remission rates (Lancet JE, et al. J Clin Oncol. 2018). Based on these results, CPX-351 was approved by the US FDA in 2017 for the treatment of adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes (AML-MRC). This abstract reports the results of an EAP study that provided expanded access to CPX-351 for older patients who met the eligibility criteria for the phase 3 study and collected additional data on safety and efficacy. Methods: In this phase 4, single-arm, open-label EAP, patients were between 60-75 years of age and had confirmed high-risk/sAML (therapy-related AML [tAML], AML with a history of myelodysplasia [MDS] or chronic myelomonocytic leukemia [CMML], or de novo AML with MDS karyotype). Patients could receive up to 2 cycles of induction with CPX-351 100 units/m2 (cytarabine 100 mg/m2 + daunorubicin 44 mg/m2) on Days 1, 3, and 5 (2nd induction: Days 1 and 3). Patients with complete remission (CR) or CR with incomplete platelet or neutrophil recovery (CRi) could receive up to 4 cycles of consolidation with CPX-351 65 units/m2 (cytarabine 65 mg/m2 + daunorubicin 28.6 mg/m2) on Days 1 and 3. The primary endpoint was safety, and the secondary endpoint was the rate of CR+CRi. Results: Overall, 52 patients received ≥1 dose of CPX-351 and were included in the safety analysis. Among these patients, the median age was 70 years (range: 55-75) and 23% had an Eastern Cooperative Oncology Group score of 2. Median time since diagnosis was 0.30 months (range: 0.03-36.14) months. Patients with AML-MRC accounted for 77% of the safety analysis population, including those with antecedent MDS with prior hypomethylating agent (HMA) treatment (25%), antecedent MDS without prior HMA treatment (21%), antecedent CMML (8%), and de novo AML with MDS karyotype (23%); 23% of patients had tAML. All patients received 1 induction cycle and 25% received 2 induction cycles; 17%, 8%, 4%, and 2% of patients received 1, 2, 3, and 4 consolidation cycles, respectively. CR+CRi was achieved in 23 patients (44% [95% CI: 31%, 59%]), including 15 with CR (29% [95% CI: 17%, 43%]) and 8 with CRi (15% [95% CI: 7%, 28%]; Table). The median time to remission was 37 days (range: 15-72). At the end of the study, 47 (90%) of patients were still alive and 11 (21%) patients received transplant. All patients were alive at Day 30, and the mortality rate at Day 60 was 6%. The safety profile observed in this EAP study was consistent with that of the phase 3, randomized study (Table). Treatment-emergent adverse events (TEAEs) of any grade occurred in 96% of patients, including 44% of patients with an TEAE deemed related to treatment; the only treatment-related AE that occurred in >10% of patients was febrile neutropenia (31%). Only 2 patients (4%) discontinued treatment due to an AE (ejection fraction decrease and intercranial hemorrhage [n = 1 each]). Five patients (10%) had grade 5 AEs during the study, including disease progression, multiple organ dysfunction syndrome, acute respiratory distress syndrome, aspiration, and intracranial hemorrhage (n = 1 each). Conclusions: The data from this EAP study were consistent with results from the randomized, phase 3 study. The safety profile in the EAP study was similar to that observed in the phase 3 study and there was a similar CR+CRi rate (44% vs 48%, respectively) in this high-risk/sAML population. Disclosures Roboz: Sandoz: Consultancy; Cellectis: Research Funding; Argenx: Consultancy; Bayer: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Aphivena Therapeutics: Consultancy; Sandoz: Consultancy; AbbVie: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy; Novartis: Consultancy; Celgene Corporation: Consultancy; Celltrion: Consultancy; Jazz Pharmaceuticals: Consultancy; Roche/Genentech: Consultancy; Eisai: Consultancy; Otsuka: Consultancy; Astex Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; Janssen Pharmaceuticals: Consultancy; Janssen Pharmaceuticals: Consultancy; Eisai: Consultancy; Otsuka: Consultancy; Orsenix: Consultancy; Celltrion: Consultancy; AbbVie: Consultancy; Daiichi Sankyo: Consultancy; Aphivena Therapeutics: Consultancy; Bayer: Consultancy; Argenx: Consultancy; Jazz Pharmaceuticals: Consultancy; Astex Pharmaceuticals: Consultancy; Cellectis: Research Funding; Orsenix: Consultancy; Pfizer: Consultancy. Rubenstein:Alexion: Consultancy, Honoraria, Speakers Bureau; Cyclacel: Other: Travel support; Astex: Other: Travel support. Schiller:Celator/Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding. An:Jazz Pharmaceuticals: Employment. Mancino:Jazz Pharmaceuticals: Employment. Chiarella:Celator/Jazz Pharmaceuticals: Employment, Equity Ownership. Louie:Celator/Jazz Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties. Lin:Jazz Pharmaceuticals: Honoraria.

7040Background: CPX-351, a liposomal encapsulation of cytarabine (C) and daunorubicin (D) at a synergistic ratio, is approved in the US for treatment of adults with newly diagnosed therapy-related ...

e18507 Background: FLT3+ AML patients (pts; 20%-30% of AML pts) often have rapid post-induction relapse, highlighting the need for therapies that improve the bridge to SCT. CPX-351 is a liposomal formulation that delivers a synergistic 5:1 molar ratio of cytarabine (C) and daunorubicin (D). CPX-351 demonstrated efficacy versus 7+3 in a randomized, open-label, controlled phase III trial in pts aged 60-75 years with newly diagnosed, high-risk AML; our analysis investigated outcomes in the subset of FLT3+ pts. Methods: Pts were randomized 1:1 to induction with 1-2 cycles of CPX-351 (100 u/m2 [C 100 mg/m2 + D 44 mg/m2] on Days 1, 3, and 5 [2nd induction: Days 1 and 3]) or 7+3 (C 100 mg/m2/day x 7 days [2nd induction: x 5 days] + D 60 mg/m2on Days 1, 2, and 3 [2nd induction: Days 1 and 2]). Pts with complete remission (CR) or CR with incomplete platelet or neutrophil recovery (CRi) could receive up to 2 consolidation cycles. Results: Of the pts who had FLT3 mutations assessed and received study treatment, 22/138 (16%) pts in the CPX-351 arm and 20/136 (15%) pts in the 7+3 arm had baseline FLT3 mutations. AML subtypes in FLT3+ pts were: tAML (19%); AML after MDS with (38%) or without (10%) prior hypomethylating agents; AML after CMMoL (12%); and de novo AML with MDS karyotype (21%). In FLT3+ pts, median OS was longer with CPX-351 (10.25 mo) versus 7+3 (4.55 mo; HR = 0.57 [95% CI: 0.24, 1.33]; P= 0.093) and the rate of CR+CRi was higher (68% vs 25%). A greater number of FLT3+ pts treated with CPX-351 were able to undergo SCT (n = 10/22 [45%]; 4 pts were alive as of this analysis, after a median post-SCT follow up of 692 days [range: 96-769]) compared with 7+3 (n = 2/20 [10%]; neither pt still alive). The on-study safety profile of CPX-351 in FLT3+ pts was comparable to 7+3 and consistent with the overall study population. Serious adverse events were experienced by 7 (32%) FLT3+ pts in the CPX-351 arm and 10 (50%) in the 7+3 arm. Conclusions: CPX-351 demonstrated numerical improvement in median OS in older pts with newly diagnosed, FLT3+ high-risk AML and allowed more pts to undergo SCT. The analysis was limited by small number of pts. Clinical trial information: NCT01696084.

7036 Background: The CPX-351 liposomal formulation delivers a synergistic 5:1 molar ratio of cytarabine (C) and daunorubicin (D) preferentially to leukemia cells. CPX-351 has demonstrated significantly improved overall survival (OS) versus 7+3 in a randomized, open-label, phase III study in patients (pts) aged 60-75 years with newly diagnosed, high-risk AML. In contrast to 7+3, which includes C continuous infusion, CPX-351 is administered as a 90-minute infusion and has the potential to be given in the outpatient setting. The current analysis of the phase III trial assessed the setting of consolidation therapy. Methods: Pts were randomized 1:1 to 1-2 induction cycles of CPX-351 or 7+3; pts with complete remission (CR) or CR with incomplete platelet or neutrophil recovery (CRi) could receive up to 2 consolidation cycles (CPX-351: 65 u/m2 [C 65 mg/m2 + D 28.6 mg/m2] on Days 1 and 3; 7+3: C 100 mg/m2/day x 5 days + D 60 mg/m2 on Days 1 and 2). Site of administration was not protocol defined. Results: Few pts received induction as outpatient therapy (CPX-351 n = 3/153 and 7+3 n = 1/151 in each cycle). 49/153 CPX-351 pts and 32/151 7+3 pts received consolidation, with a substantial proportion of pts receiving CPX-351 as outpatients (consolidation 1: 51%; consolidation 2: 61%). CPX-351 consolidation was associated with substantial improvement in median OS versus 7+3 irrespective of inpatient/outpatient status (Table). Median OS was not diminished with CPX-351 administration in the outpatient versus inpatient setting (consolidation 1: 25.43 and 14.72, respectively; consolidation 2: 26.32 and not reached). Conclusions: Some pts can successfully receive CPX-351 consolidation as outpatients without diminished efficacy, potentially reducing hospitalizations associated with treatment administration. Clinical trial information: NCT01696084. [Table: see text]

7035 Background: tAML may occur as a late complication of cytotoxic therapy and is associated with a poor prognosis. CPX-351 is a liposomal formulation that delivers a synergistic 5:1 molar ratio of cytarabine (C) and daunorubicin (D). In a randomized, open-label, controlled phase III trial in patients (pts) aged 60-75 years with newly diagnosed, secondary AML (tAML or after MDS), CPX-351 significantly improved OS versus 7+3. The current analysis of this phase III study evaluated outcomes in the subgroup of pts with tAML. Methods: Pts were randomized 1:1 to induction with 1-2 cycles of CPX-351 (100 u/m2 [C 100 mg/m2 + D 44 mg/m2] on Days 1, 3, and 5 [2nd induction: Days 1 and 3]) or 7+3 (C 100 mg/m2/day x 7 days [2nd induction: x 5 days] + D 60 mg/m2on Days 1, 2, and 3 [2nd induction: Days 1 and 2]). Pts with complete remission (CR) or CR with incomplete platelet or neutrophil recovery (CRi) could receive up to 2 cycles of consolidation therapy. The study was not powered for this subgroup analysis. Results: 304 pts were enrolled and received study treatment, including 62 (20%) pts with tAML; demographics of tAML pts were similar between study arms. Pts with tAML had typically received prior non-anthracycline chemotherapy alone (25%), radiation alone (25%), or non-anthracycline chemotherapy + radiation (32%). CPX-351 was associated with an OS benefit versus 7+3 in older tAML pts and numerically longer event-free survival (EFS) and remission duration (Table). A greater proportion of tAML pts achieved CR+CRi (47% vs 36%, respectively) and proceeded to stem cell transplantation (37% vs 27%) with CPX-351. The safety profile of CPX-351 was comparable to that of 7+3. Conclusions: CPX-351 is associated with improved outcomes in older pts with newly diagnosed tAML. Outcomes in the tAML subgroup mirrored the overall study population, indicating CPX-351 may represent a new therapeutic option for this difficult to treat population. Clinical trial information: NCT01696084. [Table: see text]

Introduction Intensive induction chemotherapy for acute myeloid leukemia (AML) in patients aged 60 years or older has lower remission rates with increased induction mortality compared with younger patients. CPX-351 (Vyxeos) is a liposomal formulation of cytarabine and daunorubicin encapsulated at a 5:1 molar ratio. Previously reported results from a phase III, randomized, open-label study of CPX-351 versus 7+3 (cytarabine and daunorubicin) in newly diagnosed older patients with secondary AML suggested superior survival in those randomized to CPX-351. We conducted an exploratory analysis of patients who received allogeneic hematopoietic cell transplantation (HCT) after induction treatment, to determine the effect of HCT on outcome by arm, as few patients in this age range can be cured with chemotherapy alone. Methods This phase III trial was a randomized, open-label, parallel-arm, standard therapy-controlled study. Eligible patients were aged 60 to 75 years with newly diagnosed secondary AML defined as having a history of prior cytotoxic treatment, antecedent myelodysplastic syndrome (MDS) (± prior treatment with hypomethylating agents), or AML with World Health Organization-defined MDS-related cytogenetic abnormalities. Patients were randomized 1:1 to CPX-351 induction (100 units/m2 [100 mg/m2 cytarabine + 44 mg daunorubicin mg/m2] on days 1, 3, and 5 [first induction only]) or 7+3 induction (cytarabine 100 mg/m2/day x 7 days plus daunorubicin 60 mg/m2 on days 1, 2, and 3 [first induction] or x 5 days [reinduction/consolidation] plus daunorubicin 60 mg/m2 on days 1 and 2). The distribution of overall survival (OS) after HCT in each treatment arm was estimated using the Kaplan-Meier method, and Cox regression hazard ratio and OS rates, along with corresponding confidence intervals, are reported. Results Three hundred and nine (309) patients were enrolled from December 2012 to November 2014 at 39 US and Canadian sites, with 153 patients randomized to the CPX-351 arm and 156 to the 7+3 arm. Patients in either arm responding to induction with a complete response (CR) or a CR with incomplete platelet or neutrophil recovery (n=125) were considered for allogeneic HCT when possible. In total, 91 patients were transplanted: 52 (34%) from the CPX-351 arm and 39 (25%) from the 7+3 arm. Patient and AML characteristics were similar according to randomized arm, including percentage of patients in each arm that underwent transplant in CR/CRi status (Table); however, the CPX-351 arm contained a higher percentage of older patients (age ≥ 70) who were transplanted (CPX-351, 31%; 7+3, 15%). Mortality at 100 days after transplant was 9.6% for patients in the CPX-351 arm and 20.5% in the 7+3 arm patients. Causes of death Conclusions An exploratory analysis from this phase III study demonstrated that CPX-351, compared with standard cytarabine and daunorubicin, resulted in better outcomes after allogeneic HCT in older patients with high-risk AML, including 53% fewer deaths within 100 days of transplant. These results suggest that CPX-351 may provide an effective bridge to successful transplant for a very poor-risk subgroup of AML patients. Support: Celator Pharmaceuticals, Inc., a subsidiary of Jazz Pharmaceuticals plc. Disclosures Uy: Boehringer Ingelheim: Consultancy; Glycomimetics: Consultancy. Cortes:ARIAD: Consultancy, Research Funding; Bristol-Myers Squib: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Ritchie:Astellas Pharma: Research Funding; Ariad: Speakers Bureau; Celgene: Consultancy, Other: Travel, Accomodations, Expenses, Speakers Bureau; Pfizer: Consultancy, Research Funding; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; NS Pharma: Research Funding; Bristol-Meyers Squibb: Research Funding. Stuart:Celator: Research Funding; Incyte: Research Funding; Astellas: Research Funding; Sunesis: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding; Agios: Research Funding; Bayer: Research Funding. Strickland:Alexion Pharmaceuticals: Consultancy; Ambit: Consultancy; Baxalta: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Sunesis Pharmaceuticals: Consultancy, Research Funding; Abbvie: Research Funding; Astellas Pharma: Research Funding; Celator: Research Funding; Cyclacel: Research Funding; GlaxoSmithKline: Research Funding; Karyopharm Therapeutica: Research Funding; Sanofi: Research Funding. Hogge:Sanofi: Consultancy; Roche: Other: Travel, Accomodations, Expenses. Stone:Sunesis Pharmaceuticals: Consultancy; Xenetic Biosciences: Consultancy; Agios: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celator: Consultancy; Roche: Consultancy; Seattle Genetics: Consultancy; Juno Therapeutics: Consultancy; Jansen: Consultancy; Merck: Consultancy; ONO: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy. Kolitz:Gliead Sciences: Consultancy; Pharmacyclics: Consultancy; Seattle Genetics: Consultancy. Schiller:Celator: Research Funding. Ryan:AbbVie: Equity Ownership; U of Rochester: Patents & Royalties. Chiarella:Celator Pharmaceuticals, Inc., a subsidiary of Jazz Pharmaceuticals plc.: Employment, Equity Ownership. Louie:Celator Pharmaceuticals, Inc., a subsidiary of Jazz Pharmaceuticals plc.: Employment, Equity Ownership. Medeiros:MEI Pharma: Research Funding; Merck/Schering Plough: Research Funding; Celgene: Consultancy, Other: Travel, Accomodations, Expenses, Research Funding; ARIAD: Consultancy; Celator: Other: Travel, Accomodations, Expenses, Research Funding; Roche/Genentech: Consultancy, Research Funding; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Amgen: Consultancy.

Introduction: Acute myeloid leukemia (AML) is a rare but difficult to treat form of leukemia, with 17.5 new cases per 100,000 per year among individuals ≥65 years of age and an estimated 5-year survival of 6.6% despite current treatment options (SEER; accessed 7/21/2016 at seer.cancer.gov). Chemotherapy can increase survival, but older adults may not receive intensive chemotherapy due to the uncertain risk-benefit associated with current treatment options (i.e., decreased effectiveness and tolerability with increased age) (Medeiros et al. Ann Hematol 2015. 94:1127-1138; Walters et al. Clin Adv Hematol Oncol. 2013;11(9):571-7). The goal of this study is to characterize treatment patterns, healthcare resource use and outcomes among treated and untreated older patients who were newly diagnosed with AML. Methods: We used the Center for Medicare and Medicaid Services (CMS) 100% Limited Data Set, which contains demographic information and all hospital claims for Fee-for-Service (FFS) Medicare beneficiaries. Included patients were 65-75 years old, newly-diagnosed with AML and had to have ≥ one hospitalization with an AML diagnosis (International Classification of Disease-9th Revision-Clinical Modification [ICD-9-CM] code 205.0) between 1/1/2010 and 12/31/2012 and inpatient and outpatient coverage ≥ 6 months before and ≥ 12 months after the first AML diagnosis. We identified high risk patients with prior Myelodysplastic Syndrome (MDS; ICD-9 code 238.7) or Myeloproliferative Neoplasm (MPN; ICD-9 codes: 205.1, 238.4, 289.89 or 289.9) and used Charlson Comorbidity Index (CCI) to measure patient health status at diagnosis. Outcomes included: hospitalization rates as number of hospitalizations per patient per month; hospitalization length-of-stay (LOS); and ICU admissions. Hospitalizations where chemotherapy was administered were identified using a combination of ICD-9 diagnosis and procedure codes, HCPCS codes, revenue center codes and MS-DRGs. Patients with at least one hospitalization where chemotherapy was administered were considered as treated with chemotherapy. We compared chemotherapy treated and untreated patient characteristics using two-tailed t-tests and conducted unadjusted analyses of overall survival (OS) and hospitalization rates for treated patients and, separately, for those who were not chemotherapy-treated. We used logistic regression, controlling for age, gender, health status (CCI), prior MDS/MPN, and prior cancer to estimate the odds of receiving chemotherapy, and 6- and 12- month survival. Results: A total 3,700 patients met all study inclusion requirements, of which 53.5% (1,979) were treated with chemotherapy. Univariate analyses demonstrated that chemotherapy-treated patients were younger (mean age [SD]: 70.1 [2.93] vs. 70.9 [2.97]; P In multivariate analyses, older patients were less likely to receive chemotherapy: those ages 72-75 had 0.52 times the odds of receiving treatment (vs. ages 65-68; P < 0.0001). Chemotherapy had a significant and positive effect on 6- and 12-month OS compared to untreated group: Odds Ratio (OR) 6-month: 2.92; 12-month: 2.32; both P < 0.0001. Key limitations associated with this retrospective database analysis include our inability to differentiate the use of hypomethylating agents from more intensive chemotherapy treatment. We also could not determine chemotherapy dosing or directly assess patient frailty. However, our analysis was based on a large sample of older AML patients from diverse geographic areas in the U.S. Conclusions: AML in older patients is associated with low treatment rates, frequent hospitalizations and ICU admissions. Chemotherapy treatment is associated with increased overall survival. New treatment options with a more favorable risk:benefit are needed in older patients with newly diagnosed AML. Support: Jazz Pharmaceuticals Figure Figure. Disclosures Sacks: Jazz Pharmaceuticals: Other: Naomi Sacks is an employee of Precision for Value which received funding from Jazz Pharmaceuticals for data access, study design, and analysis.; Precision for Value: Employment. Cyr:Precision for Value: Employment; Jazz Pharmaceuticals: Other: Phil Cyr is an employee of Precision for Value which received funding from Jazz Pharmaceuticals for data access, study design, and analysis. . Liu:Jazz Pharmaceuticals: Other: Yanmei Liu is an employee of Precision for Value which received funding from Jazz Pharmaceuticals for data access, study design, and analysis.; Precision for Value: Employment. Miller:Celator Pharmaceuticals: Other: Derek Miller is a former employee of Celator (recently acquired by Jazz) Pharmaceuticals.; Jazz Pharmaceuticals: Consultancy. Chiarella:Jazz Pharmaceuticals: Employment, Equity Ownership. Louie:Celator Pharmaceuticals, Inc., a subsidiary of Jazz Pharmaceuticals plc.: Employment, Equity Ownership.

Introduction CPX-351 (Vyxeos), a liposomal formulation of cytarabine and daunorubicin encapsulated at a 5:1 molar ratio, has shown enhanced efficacy compared with standard induction in older adults with high-risk AML in phase II clinical trials. Presented here are pre-specified secondary subgroup results from a phase III randomized, open-label study of CPX-351 versus 7+3 (cytarabine plus daunorubicin) in newly diagnosed patients with high-risk features, focusing on efficacy results stratified by age group. Methods Eligible patients were aged 60 to 75 years and had secondary AML, either therapy-related or an antecedent myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia, or AML with World Health Organization-defined MDS-related cytogenetic abnormalities. Patients were randomized 1:1 to receive CPX-351 induction (100 units/m2 [100 mg/m2 cytarabine + 44 mg daunorubicin mg/m2] on days 1, 3, and 5 [first induction only]) or 7+3 induction (cytarabine 100 mg/m2/day x 7 days plus daunorubicin 60 mg/m2 on days 1, 2, and 3 [first induction] or x 5 days [reinduction/consolidation] plus daunorubicin 60 mg/m2 on days 1 and 2). A dynamic allocation procedure was performed to stratify patients by age group (60-69 or 70-75 years) for each arm of the study. The distribution of overall survival (OS) by treatment arm was estimated using the method of Kaplan-Meier. Efficacy for each age group was reported in terms of median OS in months and percentage of patients with a morphologic complete remission (CR) or CR with incomplete platelet or neutrophil recovery (CRi) according to International Working Group criteria. Results Three hundred and nine patients were enrolled from December 2012 to November 2014 at 39 US and Canadian sites, with 153 patients randomized to the CPX-351 arm and 156 to the 7+3 arm. Among patients aged 60-69 years, there were 96 patients in the CPX-351 arm and 102 in the 7+3 arm; for patients aged 70-75 years, there were 57 and 54 patients in each arm, respectively. Demographic data for these age subgroups were similar between the CPX-351 and 7+3 arms of the study. The CR+CRi rates for patients aged 60-69 years were 50.0% for patients in the CPX-351 arm and 36.3% in the 7+3 arm, with an odds ratio (OR) of 1.76 (95% confidence interval [CI], 1.00-3.10); for patients aged 70-75 years, the rates of CR+CRi were 43.9% and 27.8%, respectively, with an OR of 2.03 (95% CI, 0.92-4.49). Kaplan-Meier curves for OS by age group are shown in the Figure. Median OS in months for patients aged 60-69 years was 9.63 in the CPX-351 arm and 6.87 in the 7+3 arm, with a hazard ratio of 0.68 (95% CI, 0.49-0.95); for patients aged 70-75 years these were 8.87 for the CPX-351 arm and 5.62 for the 7+3 arm, with a hazard ratio of 0.55 (95% CI, 0.36-0.84). The allogeneic hematopoietic cell transplant (HCT) rate in patients aged 60-69 years was 37.5% in the CPX-351 arm and 32.4% in the 7+3 arm, with an OR of 1.25 (95% CI, 0.70-2.25). For patients aged 70-75 years, the allogeneic HCT rates were 28.1% and 11.1%, respectively, with an OR of 3.12 (95% CI, 1.12-8.72). Incidence of grade 3-5 adverse events were virtually equal (92% vs 91%) and were similar in frequency and severity in both arms. The most common grade 3-5 nonhematologic adverse events (>10% overall) were febrile neutropenia (CPX-351: 68%; 7+3: 71%), pneumonia (CPX-351: 20%; 7+3: 15%), and hypoxia (CPX-351: 13%; 7+3: 15%). Conclusions This subgroup analysis of patients aged 60-69 and 70-75 years with untreated secondary AML demonstrated that CPX-351 treatment had substantially greater median OS and higher CR+CRi rates than standard 7+3 (cytarabine and daunorubicin) in both age groups. In addition, somewhat more patients in each age group in the CPX-351 arm received allogeneic HCT compared with the 7+3 arm, with the greatest difference in the older age group. Future studies with larger patient groups are warranted. Support: Celator Pharmaceuticals, Inc., a subsidiary of Jazz Pharmaceuticals plc. Disclosures Medeiros: Agios: Consultancy, Research Funding; Amgen: Consultancy; ARIAD: Consultancy; Celgene: Consultancy, Other: Travel, Accomodations, Expenses, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Roche/Genentech: Consultancy, Research Funding; Celator: Other: Travel, Accomodations, Expenses, Research Funding; MEI Pharma: Research Funding; Merck/Schering Plough: Research Funding. Lancet:Celgene: Consultancy, Research Funding; Quantum First: Consultancy; Kalo Bios: Consultancy; Pfizer: Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy; ERYtech: Consultancy; Biopath Holdings: Consultancy; Karyopharm: Consultancy; Boehringer-Ingelheim: Consultancy; Seattle Genetics: Consultancy; Baxalta: Consultancy; Amgen: Consultancy. Cortes:ARIAD: Consultancy, Research Funding; Bristol-Myers Squib: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Ritchie:Celgene: Consultancy, Other: Travel, Accomodations, Expenses, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Ariad: Speakers Bureau; Pfizer: Consultancy, Research Funding; Astellas Pharma: Research Funding; Bristol-Meyers Squibb: Research Funding; NS Pharma: Research Funding. Stuart:Astellas: Research Funding; Incyte: Research Funding; Agios: Research Funding; Sunesis: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding; Bayer: Research Funding; Celator: Research Funding. Strickland:Sunesis Pharmaceuticals: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy, Research Funding; Celator: Research Funding; Astellas Pharma: Research Funding; Alexion Pharmaceuticals: Consultancy; Sanofi: Research Funding; CTI Biopharma: Consultancy; Karyopharm Therapeutica: Research Funding; Baxalta: Consultancy; Daiichi Sankyo: Consultancy; Ambit: Consultancy; Abbvie: Research Funding; Cyclacel: Research Funding; GlaxoSmithKline: Research Funding. Hogge:Sanofi: Consultancy; Roche: Other: Travel, Accomodations, Expenses. Stone:ONO: Consultancy; Xenetic Biosciences: Consultancy; Seattle Genetics: Consultancy; Amgen: Consultancy; Agios: Consultancy; Karyopharm: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Juno Therapeutics: Consultancy; Celator: Consultancy; Roche: Consultancy; Sunesis Pharmaceuticals: Consultancy; Merck: Consultancy; Pfizer: Consultancy; Jansen: Consultancy. Kolitz:Gliead Sciences: Consultancy; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy. Schiller:Celator: Research Funding. Ryan:AbbVie: Equity Ownership; U of Rochester: Patents & Royalties. Chiarella:Celator Pharmaceuticals, Inc., a subsidiary of Jazz Pharmaceuticals plc.: Employment, Equity Ownership. Louie:Celator Pharmaceuticals, Inc., a subsidiary of Jazz Pharmaceuticals plc.: Employment, Equity Ownership. Uy:Glycomimetics: Consultancy; Boehringer Ingelheim: Consultancy.

7000Background: Older patients with secondary AML have poor outcomes following first-line cytarabine and anthracycline-based treatment. CPX-351 is a liposomal formulation of cytarabine and daunorubicin encapsulated at a 5:1 molar ratio with enhanced efficacy among poor risk AML patients. We report final results from a randomized open-label study of first-line CPX-351 in patients with high-risk sAML (NCT01696084). Methods: Patients 60-75 years of age with untreated AML with a history of prior cytotoxic treatment, antecedent MDS or CMML (+/- prior hypomethylator treatment), or AML with WHO-defined MDS-related cytogenetic abnormalities were eligible. 300 patients were to be randomized 1:1 to CPX-351 (100 units/m2, days 1, 3, 5) or 7+3 (cytarabine 100 mg/m2/day x 7 days, daunorubicin 60 mg/m2 days 1, 2, 3) induction therapy. Endpoints included: overall (OS, 1o) and event free survival (EFS) assessed by stratified log rank analysis, independent blinded assessment of CR+CRi, and 60-day mortality. Patient enroll...

Introduction: CPX-351 is a liposomal formulation of a synergistic 5:1 molar ratio of cytarabine and daunorubicin for the treatment for Acute Myeloid Leukemia (AML). CPX-351 possesses important pharmacologic differences that favorably impact efficacy and safety and may confer certain benefits related to health care resource use (HRU). CPX-351 has been granted fast track approval by the FDA, based on Phase 2 clinical trial (Study 204) results (Lancet, et al., Blood. 2014;123(21):3239-3246). Study 204 was analyzed to develop directional data regarding the impact of CPX-351 on HRU in relation to its clinical benefit. Materials and Methods: Baseline characteristics from Study 204 were checked to confirm balanced patient demographics and AML risk factors. Study treatment (CPX-351 vs. 7+3), and its administration (number of inductions and consolidations) and setting (inpatient vs. outpatient) were viewed in the context of patient outcomes (response, 60-day mortality, and transplant). Time spent within and outside the hospital, free of an event (starting from randomization until documentation of persistent disease, start of transplant, relapse, or death, whichever occurred first) were calculated and compared by treatment arm. An intent-to-treat (ITT) analysis was performed so that the experience for 10 patients who crossover to CPX-351 were attributed to 7+3. Statistical significance was assessed using a one-tailed t-test. All results are unadjusted for potential confounders and the study was not powered to showed statistical significant difference of HRU. Results: 85 patients were randomized to CPX-351 and 41 to the 7+3 control arm. The two study arms were balanced for age, sex, race, AML type (de novo vs. secondary AML), performance status, and cytogenetic risk. The prospectively defined survival analysis of the secondary AML subgroup showed significant improvement in the CPX-351 arm (HR=0.51, p=0.04). 60-day mortality was also markedly improved following CPX-351 (4.7% vs. 14.6%). CPX-351 patients were more likely to have only one induction (80% vs. 70.7%; p = 0.13) and more likely to respond to induction (66.7% vs. 51.2%; p = 0.07). Among responders, CPX-351 patients were more likely to achieve remission with one induction only (82.1% vs. 72.4%; p = 0.15). A total of 52 patients who responded to induction went on to receive consolidation (CPX-351: n=37; 7+3: n=15). A much larger proportion of responding CPX-351 patients received consolidation in the outpatient setting (40.5% vs. 13.3%; p = 0.02), and had only one induction (86.5%; vs. 66.7%). Nearly all CPX-351 transplanted patients were responders compared with control (13CR/14 (92.9%) vs. 5CR/7 (71.4%); p =0.1). The number of hospital admissions and total days spent in hospital are key contributors to HRU. CPX-351 patients had fewer hospital admissions per patient compared to 7+3 (mean 1.51 vs. 1.76, p < 0.05). CPX-351 induction in all patients was associated with more days in hospital (median 35 vs. 28 days) than 7+3. However, among responding patients total days in hospital for induction plus consolidation was similar (median 42 vs. 43 days) with fewer days of hospitalization required for consolidation in the CPX-351 arm (median 4 vs. 11 days). Although CPX-351 was associated with longer hospitalization for induction among all patients it was also associated with greater time spent outside of the hospital after completion of AML treatment (median: 129 vs. 76 days). Discussion: CPX-351 is associated with better clinical outcomes, including, lower early death rates, higher response rates, and improved overall survival in specific patient subsets. This report provides the first evidence that number of hospitalizations per patient, a key driver of hospital costs, is significantly less for CPX-351 and that overall days in hospital is similar for CPX-351 and 7+3 among responding patients, with many CPX-351 patients receiving consolidation as outpatients. In addition, CPX-351 improves the duration and proportion of time spent as an outpatient following completion of AML treatment. A more robust analysis of HRU is planned for the Phase 3 trial. Disclosures Lancet: Seattle Genetics: Consultancy; Kalo-Bios: Consultancy; Amgen: Consultancy; Celgene: Consultancy, Research Funding; Pfizer: Consultancy; Boehringer-Ingelheim: Consultancy. Cyr:Celator Pharmaceuticals: Consultancy. Chiarella:Celator Pharmaceuticals: Employment, Equity Ownership. Louie:Celator Pharmaceuticals, Inc.: Employment, Equity Ownership. Cortes:Teva: Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; BerGenBio AS: Research Funding; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.

Abstract 3626 Background: CPX-351 is a liposomal formulation of cytarabine (Ara-C) and daunorubicin (DNR) in a 5:1 molar ratio designed to maximize anti-tumor synergy. CPX-351 accumulates within bone marrow with preferential uptake of liposomes by leukemia cells followed by intracellular release of encapsulated drug. A Phase 2b study randomized untreated older patients with AML 2:1 to CPX-351 or standard 7+3. At entry patients were stratified by age, cytogenetics, and presence or absence of antecedent hematologic disorder (AHD)/prior cytotoxic treatment that evolved into AML (sAML) into a high-risk group (age ≥70 or adverse cytogenetics or sAML) or standard-risk group (age 60–69 and non-adverse cytogenetics and de novo AML). The standard-risk group was relatively homogeneous, while the high-risk group gathered together patients with one, two or all three risk factors. Response after CPX-351 was increased in all patients (66.7% vs. 51.2%). Patients with secondary AML had coherent improvement in survival (HR=0.40, p=0.01), EFS (HR=0.51, p=0.04), and CR + CRi rate (57.6% vs. 31.6%). This report presents the results of uni/multivariate analyses for survival and event free survival. Methods: Untreated de novo or sAML patients, aged 60–75, PS= 0–2, serum creatinine < 2.0 mg/dL, total bilirubin < 2.0 mg/dL, ALT/AST < 3 × ULN, and LVEF ≥50% were eligible. Patients with history of treatment for their AHD were eligible. Patients received up to 2 induction and 2 consolidation courses of CPX-351 (100 u/m2; D 1, 3, 5) or 7+3 (Ara-C= 100 mg/m2/d and DNR= 60 mg/m2). Consolidation with hematopoietic stem cell transplantation (HSCT) was permitted. The primary endpoint was CR + CRi rate. Event free survival was calculated from randomization to the date of documentation of persistent leukemia after induction, relapse after achievement of response, or death, whichever occurred first. Allogeneic transplants were permitted for post remission treatment. The association between baseline characteristics and survival was assessed by univariate and multivariate Cox regression analyses. Response was included as a time-dependent variable. The multivariate model used stepwise selection to identify prognostic factors after accounting for potential treatment effects. Results: Significant factors affecting overall survival (OS) in the univariate analysis included: response (p=0.01), ≥2 risk factors (p=0.013), secondary AML (p=0.021), and adverse cytogenetics (p=0.038). After accounting for treatment, response (p=0.003) and ≥2 risk factors (p=0.005) were strongly associated with OS in the multivariate model. Response and 60-day deaths were similar in both study arms for patients with 0 or 1 risk factor. Patients with 2 or 3 risk factors treated with CPX-351 had rates of response and 60-day death rates that were similar to those with only 0 or 1 risk factor. Control arm patients with multiple risk factors did much worse, with fewer CRs, no CRi's, and a substantially higher rate of early deaths. Conclusions: CPX-351 is highly active in every subgroup of older patients with newly diagnosed AML. This analysis demonstrates that CPX-351 minimizes the loss of response and increase in 60-day mortality that occurs with 7+3 treatment among patients with secondary AML and adverse cytogenetics. The relative benefit of CPX-351 is greatest among patients with ≥ 2 risk factors. Disclosures: Lancet: Celator Pharmaceuticals: Research Funding. Cortes:Celator Pharmaceuticals: Research Funding. Kovacsovics:Celator Pharmaceuticals: Research Funding. Hogge:Celator Pharmaceuticals: Research Funding. Kolitz:Celator Pharmaceuticals: Research Funding. Hoering:Celator Pharmaceuticals: Consultancy. Chiarella:Celator Pharmaceuticals: Employment. Louie:Celator Pharmaceuticals: Employment. Feldman:Celator Pharmaceuticals: Research Funding.

6601 Background: A Phase 2b study randomized untreated elderly AML pts to CPX-351 or 7+3. CPX-351 improved leukemia clearance (88% v 71%, Cr < 2.0 mg/dL, total bilirubin 2; D 1, 3, 5; 90 min infusion) or 7+3 (cytarabine=100 mg/m2 and daunorubicin=60 mg/m2). Consolidation with stem cell transplantation (SCT) was permitted. The 1o endpoint was CR+CRi rate. The 7+3 control arm had only a single CRi among 21 responders. The CPX-351 arm had 15 CRi (27%) and 41 CR (73%) allowing a CR v CRi comparison to be made. Results: CR and CRi pts were balanced by age, race, and PS. The CRi group had more males (87% v 51%), more baseline WBC>20K (27% v 15%), and more adverse karyotype (40% v 27%) and sAML (47% v 29%). A smaller proportion of CRi pts received post-remission chemotherapy (47% v 73%) but had similar rates of SCT (13% v 20%). Most CRi pts had delayed platelet recovery (80%). By 1-year more CRi pts had relapsed (54% v 39%) and more had died (54% v 34%). Contributing causes included: relapsed AML (7 CRi v 10 CR pts), complications post SCT (1 CRi v 1 CR pt), chemotherapy complications (0 CRi v 2 CR pts) and unknown causes (0 CRi v 1 CR pt). The survival curves were not significantly different (p=0.39). Conclusions: More CRi patients had adverse karyotype and sAML and most (53%) received no post remission chemotherapy. Survival was not significantly different compared to CR patients but was markedly better than that of non-responders. These data suggest that CRi following CPX-351 provides clinically meaningful benefit, a finding that needs to be confirmed in a larger randomized study.

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Background: CPX-351 is a liposomal formulation that co-encapsulates Cyt and Daun enabling delivery of both drugs at a synergistic 5:1 molar ratio. A Phase I study in advanced AML patients demonstrated substantial efficacy with complete remissions (CRs) and acceptable safety. The MTD was 101 units/m2. One unit of CPX-351 contains 1 mg Cyt and 0.44mg of Daun. Here we examine the PK of CPX-351 as a function of dose, inter-patient variability and patient characteristics in order to identify potential PD relationships. Methods: 35 male and female patients with advanced hematologic malignancies were included in the PK portion of this Phase I trial and received 24, 32, 43, 57, 76, 101, or 134 units/m2 of CPX-351 by IV infusion over 90 minutes on Days 1, 3, and 5. Validated LC/MS/MS assays were used for determination of total plasma Cyt and Daun. PK parameters [Cmax, AUC, t1/2, Vss, CL, Cmax/Dose, AUC/Dose] were determined on Days 1 and 5. Results: Mean Cyt and Daun PK parameters are presented in the [table below][1]. No significant differences were observed in t1/2, Vss, CL, Cmax/Dose, or AUC/Dose among dose groups on either study day, although some drug accumulation was observed from day 1 to day 5. Cyt and Daun PK parameters were not correlated with patient gender, age or race. Incidence of non-hematologic toxicity increased with dose and systemic exposure. CRs were observed in patients receiving doses of 32-134 units/m2 of CPX-351. The responses at 101 units/m2 and above appear to be more durable. The Cyt:Daun molar ratio remained near 5:1 for up to 48 hours on both study days for all dose levels. Conclusions: Cyt and Daun delivered in CPX-351 exhibited linear single dose and multiple dose PK and low inter-patient variability in plasma concentrations within dose groups. CPX-351 provides predictable, extended systemic exposure of elevated Cyt:Daun concentrations near a 5:1 molar ratio. The 100 unit/m2 dose is undergoing testing in Phase II studies. ![Figure][2] Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1292. doi:10.1158/1538-7445.AM2011-1292 [1]: #F1 [2]: pending:yes

1033 Poster Board I-55 CPX-351 is a liposomal formulation that encapsulates cytarabine and daunorubicin at a 5:1 molar ratio that is consistently synergistic and avoids antagonism across multiple leukemic and solid tumor cell lines, in vitro. In preclinical observations CPX-351 has been shown to accumulate in bone marrow where it is preferentially taken up by leukemia cells. A recently completed Phase 1 study recommended that 90-minute infusions of 101 u/m2 be given on Days 1, 3, and 5 (1 u = 1 mg cytarabine + 0.44 mg daunorubicin). The results suggested that liposomal encapsulation of this chemotherapy doublet might change the safety profile by reducing non-hematologic toxicities including alopecia, gastrointestinal toxicities (such as mucositis), and hepatic toxicity, while retaining hematopoietic cytotoxicity as evidenced by a high proportion of aplasia achieved and a significant number of complete remissions. A Phase 2 randomized study was initiated comparing CPX-351 with conventional cytarabine + daunorubicin (“7 + 3” regimen) in AML patients aged 60-75. This report summarizes safety data for the first 45 patients. Materials and Methods: Patients with de novo or therapy-related AML or AML evolved from an antecedent hematologic disorder, ECOG PS of 0-2, SCr 50% by echo or MUGA were eligible. Patients are randomized 2:1 to receive CPX-351 (100u/m2 Day 1, 3, and 5 by 90 minute infusion) or to “7 + 3” (cytarabine 100mg/m2/d for 7 days by continuous IV infusion and daunorubicin 45-60mg/m2 Day 1, 2 and 3 by IV push). Results: As of Aug. 1, 2009, 45 of the 80 patients enrolled to date have been randomized (31 to CPX-351 and 14 to “7 + 3” Control), treated and completed follow-up sufficient to capture safety data for at least the first induction course. Among this group of 45 patients one or more SAE events, as defined in the protocol, were reported in 15/31 (42%) CPX-351 patients and 5/14 (29%) Control patients. Deaths during induction were infrequently reported in both arms of the study [1 (3%) vs. 1 (7%)]. One patient in each arm of the study died of sepsis related events on Days 20 and 19, respectively. One post-induction death occurred in a patient in the CPX-351 arm who died on Day 83 of an intracranial bleed, 24 days after start of consolidation therapy. Cytopenia-related events associated with treatment of leukemia accounted for the majority of the SAEs in both arms of the study, including 11 of the 15 (73%) SAEs in the CPX-351 arm and 3 of 5 (60%) SAEs in the control arm. These SAEs consisted of fever and febrile neutropenia (13% vs.14%), sepsis (3% vs. 7%), pneumonia (3% vs. 0), major bleeding episodes (3% vs. 0) and a number of minor infections and anemia. Data for all adverse events are available for 41 patients and events occurring in 10 or more patients are presented in the table below. Skin rash was more common with CPX-351 and rigors/chills were more common with “7 + 3”. The majority of other adverse events were similar (±15%) in the two groups. | Adverse Event (all grades) | CPX-351 | 7+3 | |:--------------------------:| ------- | --- | - | | n=29 | n=12 | | Fever/Feb. Neutropenia | 23 | 79% | 9 | 75% | | Rash | 22 | 76% | 6 | 50% | | Diarrhea | 17 | 59% | 6 | 50% | | Nausea | 13 | 45% | 4 | 33% | | Stomatitis | 12 | 41% | 5 | 42% | | Fatigue | 11 | 38% | 4 | 33% | | Constipation | 10 | 34% | 4 | 33% | | Anorexia | 9 | 31% | 4 | 33% | | Rigors/Chills | 7 | 24% | 5 | 42% | | Epistaxis | 8 | 28% | 2 | 17% | Title: Most Frequent Adverse Events by Patient Discussion/Conclusion: In this study, induction mortality to date with CPX-351 is low (3%). The overall toxicity of CPX-351 appears comparable to that due to 7 + 3. As observed in the Phase 1 study of CPX-351, grade 3/4 GI adverse events were distinctly uncommon. No adverse events unique to CPX-351 were observed. CPX-351 exhibits an acceptable safety profile for use in older, newly diagnosed AML patients. Disclosures: Chiarella: Celator Pharmaceuticals: Employment. Louie: Celator Pharmaceuticals: Employment.