The control of the branching in polyglycidols as semibranched alternatives to traditional polyglycidols is presented. The relative abundance of dendritic carbons is lowered by five-fold compared to hyperbranched polyglycidols. It is the first example of tailoring the branching in polyglycidol and creating protein-glycidol bioconjugates as alternatives to pegylated biostructures.

Simple planar measurement is an efficient method that correlates well with the more time-consuming volumetric method. The major risk factor for tumor growth is nodular enhancement on a baseline scan, a finding that warrants annual MRI beginning 2 years postoperatively. Younger age and larger preoperative size minimally increased risk of growth.

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Background: Patients (pts) with secondary acute myeloid leukemia (s-AML) have poor long-term outcomes following standard induction chemotherapy with 7+3. In 2017, a liposomal cytarabine and daunorubicin formulation (CPX-351) was FDA approved for upfront treatment of s-AML based on a pivotal phase 3 trial demonstrating improved overall survival in pts aged 60-75 years old (Lancet J et al; JCO 2018). Although CPX-351 treatment was subsequently approved for s-AML regardless of age, data in younger pts < 60 years who were not eligible for the pivotal trial is lacking. We sought to address this unanswered question by retrospective review of clinical experience since FDA approval at 6 large academic centers. Methods: Medical records were retrospectively reviewed at Roswell Park Comprehensive Cancer Center, Memorial Sloan Kettering Cancer Center, Moffitt Cancer Center, Allegheny Health Network, University of Alabama Comprehensive Cancer Center, and Levine Cancer Institute to identify pts aged 18-59 years old with untreated s-AML defined as antecedent MDS or CMML, prior cytotoxic therapy, or AML with WHO defined myelodysplasia related changes (AML-MRC) treated with CPX-351 as induction therapy. Demographics, disease-specific variables, and outcomes were collected in accordance with the IRB approved protocol. Responses were defined per 2003 International Working Group (IWG) criteria. Demographic and baseline characteristics, treatment response, overall survival and adverse events were analyzed using descriptive statistics. Overall survival was estimated using Kaplan-Meier (KM) analysis. Results: Sixty-six pts with confirmed s-AML received CPX-351 therapy. Median age was 54.9 years (range 23 - 59), 37 were male (56%). The majority (65%, N=43) had AML-MRC, 23 (35%) had antecedent MDS, and 14 (21%) had treatment-related AML (t-AML). Sixteen pts had received prior hypomethylating therapy. Thirty pts had a complex karyotype (46%), and 10 patients were found to have a normal karyotype (15%). The most common molecular event was TP53 mutation observed in 19 pts (30%), followed by FLT3-ITD identified in 5 pts (8%). At the time of analysis, response assessments were available for 62 pts. Overall response rate (CR/CRi) was 43.5% with 19 CR (30.6%), 8 CRi (12.9%). Seven pts (11.3%) had PR, 2 pts (3.2%) with MLFS and the remainder (N=26, 42%) were non-responders (Table 1). Thirty-one pts have received an allogenic stem cell transplant. Of the 19 pts with TP53 mutation eligible for response assessment, 6 pts (31.5%) achieved CR, 2 pts (10.5%) had a PR, 1 pt (5.2%) had MLFS and the remaining 10 pts (52.6%) were primary refractory. In contrast, 21 (48.8%) of 43 TP53 wild-type pts achieved CR/CRi. The most common adverse event was infection (80%, 24/30) with 4 clinically significant bleeding events. Thirty-day mortality was 9.1%, with 60-day mortality of 16.7%. Overall survival in all evaluable pts (N=66) was 5.2 months (range 0.5 - 15.3 months) (Figure 1), with median follow up of 6.2 months. Conclusions: This multi-institutional retrospective analysis demonstrates lower response rates (CR/CRi 43.5%) and shorter overall survival (5.2 mos) following CPX-351 therapy in young pts (<60) as compared to phase 3 results in older (60-75 years old) (Table 1). Potential explanations for this discrepancy include short follow up, small sample size, retrospective analysis, and high proportions of young pts with complex karyotype and TP53 mutant AML. Historically, patients < 65 years old with s-AML have had a reported overall survival of approximately 7 months. Further prospective investigation of CPX-351 vs 7+3 vs other approaches in younger pts with s-AML is clearly warranted. Figure 1 Figure 1. Disclosures Przespolewski: Jazz: Research Funding. Goldberg: Pfizer: Research Funding; Prelude Therapeutics: Research Funding; Aptose: Consultancy, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Aprea: Research Funding; Arog: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Honoraria; Celularity: Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees. Talati: Astellas: Speakers Bureau; Jazz: Speakers Bureau; Pfizer: Honoraria; BMS: Honoraria; AbbVie: Honoraria. Fazal: Takeda: Consultancy, Honoraria, Speakers Bureau; Stemline Therapeutics: Consultancy, Honoraria, Speakers Bureau; Taiho Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Sanofi Genzyme: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Karyopharm Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Janssen Oncology: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Glaxo Smith Kline: Consultancy, Honoraria, Speakers Bureau; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau; AMGEN: Consultancy, Honoraria, Speakers Bureau; Agios: Consultancy, Honoraria, Speakers Bureau. Vachhani: Incyte: Consultancy, Speakers Bureau; Pfizer: Consultancy; Blueprint Medicines: Consultancy; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham: Current Employment; Jazz Pharmaceuticals: Consultancy; Novartis: Consultancy; Abbvie: Consultancy; Seattle Genetics: Research Funding; Astellas Pharma: Speakers Bureau; CTI BioPharma Corp: Consultancy; Agios: Consultancy. Griffiths: Genentech: Research Funding; Boston Biomedical: Consultancy; Taiho Oncology: Consultancy, Honoraria; Novartis: Honoraria; Takeda Oncology: Consultancy, Honoraria; Astex Pharmaceuticals: Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Apellis Pharmaceuticals: Research Funding; Alexion Pharmaceuticals: Consultancy, Research Funding. Thompson: Novartis/ Bristol-Myers Squibb: Research Funding. Sweet: Gilead: Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wang: Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Mana Therapeutics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Advisory Board; Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; Genentech: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Other: Advisory board; DAVA Oncology: Consultancy, Speakers Bureau; Rafael Pharmaceuticals: Other: Data safety monitoring committee; Gilead: Consultancy, Honoraria, Other: Advisory board; Daiichi Sankyo: Consultancy, Honoraria, Other: Advisory board; PTC Therapeutics: Consultancy, Honoraria, Other: Advisory board; Genentech: Consultancy; MacroGenics: Consultancy.

Background: Liposomal daunorubicin/cytarabine (CPX-351) and hypomethylating agent+venetoclax (HMA+V) have shown survival advantage as frontline therapies for older and biologically adverse AML. Although HMA+V is approved for chemotherapy ineligible pts, there is increased use of the combination in older fit pts. with biologically adverse AML. However, clinical outcomes between the two treatments have not been compared and will have a major clinical impact. Our aim was to compare CPX-351 vs HMA+V as upfront treatment for newly diagnosed AML using a multi-center retrospective study. Methods: This is a multicenter retrospective study drawing from 4 large U.S. academic medical centers (Weill Cornell, Northwestern, Moffitt, Memorial Sloan Kettering). Eligibility included pts who received either CPX-351 or HMA+V as frontline therapy for AML. Response was determined using ELN 2017 guidelines. To evaluate the association between treatment type and categorical factors of interest, and the primary outcome variable of treatment response, the chi-square test or Fisher's exact test was used. For the outcome variable of bone marrow response status, multivariable logistic regression analysis was performed. For the relapse free survival (RFS) and overall survival (OS) outcomes, Kaplan-Meier survival analysis was performed, and the log-rank test was employed to compare between categories of treatment-type and prognostic factors of interest. Multivariable cox proportional hazards regression analysis was performed to assess the independent effect of treatment and demographic/prognostic factors of interest on outcomes of RFS/OS. Results: Our study included 211 CPX-351 and 226 HMA+V treated pts. 11 pts were excluded due to missing age or ELN risk. Pt. characteristics and univariate analyses are summarized in Table 1 and 2. Overall CR+CRi rates, median RFS and OS for CPX-351 vs. HMA+V were 57.8% vs. 56.6%, 32.5 vs. 14.1 months (p=0.11) and 17.3 vs. 11.1 months (p=0.007). In multivariable analysis, after adjusting for age, ELN risk, prior myeloid malignancy, and prior HMA therapy, there was no difference between CPX-351 vs. HMA+V in CR+CRi (HR 1.32, p=0.23, 95% CI 0.8-2.1) and RFS (HR 0.92, p=0.75, CI 0.59-1.46). There was a significant difference favoring CPX-351 for OS (HR 0.74, p=0.04, CI 0.55-0.99). When analyses were restricted to pts aged 60-75 years (n= 152 CPX-351, n= 100 HMA+V), rates of CR+CRi were 59.2% vs. 54.0% (p=0.41), and median RFS and OS for CPX-351 vs. HMA+V treated pts was 32.5 vs. 13.3 months (p= 0.80) and OS 17.1 vs. 10.3 months (p=0.12). Multivariable analysis after adjusting for above variables showed no difference in CR+CRi, RFS and OS between CPX-351 vs. HMA+V (CR+CRi: HR 1.28, p=0.55, 95% CI 0.77-2.27, RFS: HR 0.70, p=0.17, CI 0.42-1.17 and OS: HR 0.80, p=0.20, CI 0.57-1.12). Multivariable subgroup analyses demonstrated significant advantage favoring CPX-351 for RFS in TP53 mutated pts (HR 0.37, 95% C.I. 0.14-0.96, p=0.04). Subgroup analyses for OS are summarized in Figure 2. Among patients where minimal residual disease (MRD) data was available (n=93 CPX-351, n=133 HMA+V), MRD negativity by flow was 34.4% (n=32) and 39.1%(n=52) for CPX-351 and HMA+V pts, respectively (p=0.47). Among pts aged 60-75 years, 47.7% and 19% of patients underwent HSCT in CPX-351 and HMA+V groups (p<0.001). Because HSCT was a significant predictor for RFS and OS (p<0.001), we conducted multivariable analysis in pts aged 60-75 years who did not receive a transplant and found no difference in OS (HR 0.99, p=0.96, 95% CI 0.68-1.43). There was no difference in RFS and OS post-transplant between CPX-351 and HMA+V groups (OS: 64 vs NA months, p=0.69). RFS could not be inferred statistically due to small number of patients transplanted in the HMA+V group. Our study will be further expanded to include additional centers and comorbidity analyses. Conclusion: Our analysis demonstrated significant difference in OS favoring CPX-351 in the overall cohort and in several clinical subgroups, while no difference in CR+CRi and RFS was seen. The survival advantage in the CPX-351 group may be due to higher HSCT rates in CPX-351 treated pts. Among pts that did not proceed to HSCT, there was no difference in CR+CRi, RFS and OS between the treatment groups. We suspect that greater HSCT rates in the CPX-351 cohort were due to fewer comorbidities among CPX-351-treated pts or other biases, and comorbidity analyses are pending and will be reported. Figure 1 Figure 1. Disclosures Ritchie: Bristol Myers Squibb: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria; NS Pharma: Research Funding; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria; Protaganist: Consultancy, Honoraria; Astellas: Consultancy, Research Funding; Incyte: Consultancy, Honoraria, Speakers Bureau; ARIAD Pharmaceuticals: Ended employment in the past 24 months, Speakers Bureau; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Celgene/BMS: Consultancy, Other: travel support, Speakers Bureau. Lee: Pin Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Innate: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees. Goldberg: Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Arog: Research Funding; Aprea: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Prelude Therapeutics: Research Funding; Aptose: Consultancy, Research Funding; DAVA Oncology: Honoraria; Celularity: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dinner: Pfizer: Consultancy, Honoraria; Kite/Gilead: Consultancy, Honoraria. Sweet: AROG: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Roboz: Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Glaxo SmithKline: Consultancy; Jazz: Consultancy; Astex: Consultancy; Blueprint Medicines: Consultancy; Mesoblast: Consultancy; Astellas: Consultancy; AstraZeneca: Consultancy; Pfizer: Consultancy; Bayer: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; Daiichi Sankyo: Consultancy; Janssen: Consultancy; Jasper Therapeutics: Consultancy; Roche/Genentech: Consultancy; Helsinn: Consultancy; Amgen: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Agios: Consultancy; Actinium: Consultancy; AbbVie: Consultancy; Janssen: Research Funding. Desai: Agios: Consultancy; Kura Oncology: Consultancy; Takeda: Consultancy; Astex: Research Funding; Bristol Myers Squibb: Consultancy; Janssen R&D: Research Funding.