ALBERT

Description: 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.

Description: 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.

Description: 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

Description: 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

Description: 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.

Description: Abstract 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 〈 2.0 mg/dL, total bilirubin 〈 2.0 mg/dL, ALT/AST 〈 3 x ULN, and cardiac ejection fraction 〉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. 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.