Abstract: CPX-351 and venetoclax and azacitidine (ven/aza) are both indicated as initial therapy for acute myeloid leukemia (AML) in older adults. In the absence of prospective randomized comparisons of these regimens, we used retrospective observational data to evaluate various outcomes for patients with newly diagnosed AML receiving either CPX-351 (n = 217) or ven/aza (n = 439). This study used both a nationwide electronic health record (EHR)-derived de-identified database and the University of Pennsylvania EHR. Our study includes 217 patients who received CPX-351 and 439 who received ven/aza. Paitents receiving ven/aza were older, more likely to be treated in the community, and more likely to have a diagnosis of de novo acute myeloid leukemia. Other baseline covariates were not statistically significantly different between the groups. Median overall survival (OS) for all patients was 12 months and did not differ based on therapy (13 months for CPX-351 vs 11 months for ven/aza; hazard ratio, 0.88; 95% confidence interval, 0.71-1.08; P = .22). OS was similar across multiple sensitivity analyses. Regarding safety outcomes, early mortality was similar (10% vs 13% at 60 days). However, documented infections were higher with CPX-351 as were rates of febrile neutropenia. Hospital length of stay, including any admission before the next cycle of therapy, was more than twice as long for CPX-351. In this large multicenter real-world dataset, there was no statistically significant difference in OS. Prospective randomized studies with careful attention to side effects, quality of life, and impact on transplant outcomes are needed in these populations.

Abstract: Introduction Increasingly clinicians face the choice between CPX-351 (NCT01696084) and venetoclax and azacitadine (ven/aza, NCT02993523) in front-line acute myeloid leukemia (AML), especially for frailer older adults with comorbidities. Given no prospective data, we examined retrospective observational survival outcomes for patients with newly diagnosed AML receiving either CPX-351 or ven/aza as initial therapy. Methods After local Institutional Review Board approval, we included patients from both the University of Pennsylvania ("HUP", n=111) and the Flatiron Health electronic health record (EHR) derived, de-identified database with a first incident AML diagnosed between January 2017 and 2021, and with documented receipt of CPX-351 or venetoclax and azacitadine as initial therapy (n=548). Given a total of 219 patients received CPX-351 and 440 received ven/aza, there was 90% power to detect a hazard ratio (HR) of 0.77 or smaller with alpha 0.05. Overall Survival (OS) was analyzed by the Kaplan-Meier method and compared between arms using the log-rank test. Pre-planned sensitivity analyses included restriction and multiple imputation (MI) to address missingness with inverse-probability of treatment weighting (IPTW) to balance baseline covariates with treatment effect estimates from each imputed dataset combined via Rubin's rules. Results For all patients, baseline covariates showed patients receiving ven/aza were older (75 vs 65 years old median age), more likely to have Medicare (29% vs 20%), have de-novo AML vs secondary or therapy-related disease (52% vs 29%) and be treated in the community rather than an academic center (66% vs 52%). All other baseline covariates-including ELN cytogenetic risk groups, high risk mutations (TP53, ASXL1, RUNX1), FLT3, IDH, HCT-comorbidity index-were not statistically significant different between groups (table 1). Missing values in the HUP dataset was & lt;5% for all baseline covariates; Flatiron dataset missing values ranged from 0-56% for covariates (e.g., sex and baseline LDH respectively). Median OS (mOS) was 12 months for all patients and 13 months for CPX-351 versus 11 months for ven/aza (HR 0.87, 95% CI 0.70-1.07, p-value 0.184, Fig 1a). There was no clear subset with improved OS with CPX-351 vs ven/aza (Fig 1b); in multi-variate analysis controlling for all covariates with univariate p-value & lt; 0.20 induction choice did not affect overall survival (limited to complete cases n=133, HR 0.63, p-value 0.73). Restricting to only the population eligible for CPX-351 pivotal trial, there was no significant difference in OS (CPX-351 n=160 mOS=10, ven/aza n=181 mOS=12 HR 0.86 p-value 0.33). After MI and IPTW, survival remained similar with HR 0.95 p-value 0.77 (Fig 1c). Adjusting further for variables with absolute standardized difference & gt;10% after MI and IPTW (baseline HCT-comorbidity index, race and insurance status), multivariable Cox model gave similar results (HR 0.93, p-value 0.70). Regarding safety outcomes, early mortality was similar. However, documented diagnosed infections were higher in CPX-351 patients and within the HUP cohort, rates of febrile neutropenia and culture positive infection were also higher (Fig 1d). Length of stay, including any admission prior to next cycle of therapy, was more than twice as long for CPX-351 in the HUP cohort. Additional analyses, including detailed assessment of baseline covariates, multivariate analysis with transplant as a time-varying dependent covariate, event free survival, disease free survival also available for presentation. Conclusion In this multi-center real word dataset with over 600 patients, there was no statistically significant difference in overall survival between induction with CPX-351 and ven/aza. This large retrospective dataset is limited by missingness in covariates, risk of misclassification bias and lack of power for formal equivalence testing. However, a consistent lack of superiority for CPX-351 or ven/aza within a robust, manual chart-review of an academic institution, a large national real world database and combined analyses of these cohorts supports clinical equipoise. Given the apparent lack of a large survival benefit further work is needed. Prospective studies to confirm similar effectiveness with careful attention to side effects, quality of life and impact on transplant outcomes may help clinicians decide between these therapies. Figure 1 Figure 1. Disclosures Perl: Syndax: Consultancy; Loxo: Consultancy; Forma: Consultancy; AbbVie: Consultancy, Research Funding; Roche: Consultancy; Actinium: Consultancy; Genentech: Consultancy; Astellas: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Fujifilm: Research Funding; BMS/Celgene: Consultancy; Arog: Research Funding; Onconova: Consultancy; Sumitomo Dainippon: Consultancy. Luger: Syros: Honoraria; Agios: Honoraria; Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria; Brystol Myers Squibb: Honoraria; Acceleron: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Onconova: Research Funding; Celgene: Research Funding; Biosight: Research Funding; Hoffman LaRoche: Research Funding; Kura: Research Funding. Frey: Kite Pharma: Consultancy; Novartis: Research Funding; Sana Biotechnology: Consultancy; Syndax Pharmaceuticals: Consultancy. Gill: Interius Biotherapeutics: Current holder of stock options in a privately-held company, Research Funding; Carisma Therapeutics: Current holder of stock options in a privately-held company, Research Funding; Novartis: Other: licensed intellectual property, Research Funding. Hexner: Blueprint medicines: Membership on an entity's Board of Directors or advisory committees, Research Funding; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Tmunity Therapeutics: Research Funding. Porter: American Society for Transplantation and Cellular Therapy: Honoraria; ASH: Membership on an entity's Board of Directors or advisory committees; DeCart: Membership on an entity's Board of Directors or advisory committees; Genentech: Current Employment, Current equity holder in publicly-traded company; Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Unity: Patents & Royalties; Wiley and Sons Publishing: Honoraria. Stadtmauer: Oncopeptides: Consultancy; Amgen: Consultancy; BMS Celgene: Consultancy; GSK: Consultancy; Janssen: Consultancy; AbbVie: Consultancy, Research Funding. Maillard: Regeneron: Research Funding. Margolis: Pfizer: Consultancy; Leo: Consultancy; Sanofi: Consultancy; National Eczema Association: Membership on an entity's Board of Directors or advisory committees. Pratz: Abbvie: Consultancy, Honoraria, Research Funding; Agios: Consultancy; BMS: Consultancy, Honoraria; Novartis: Consultancy; Astellas: Consultancy, Honoraria, Research Funding; Cellgene: Consultancy, Honoraria; Millenium: Research Funding; University of Pennsylvania: Current Employment.

Abstract: Introduction Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) patients are at risk of invasive fungal infection (IFI) due to prolonged neutropenia related to the underlying diseases and the induction chemotherapy required to treat them. The risk of IFI specifically in AML or MDS patients treated with hypomethylating agents (HMA) has not been fully elucidated, with previous publications reporting various prophylaxis practices and IFI incidences from 3.3% to 14.4%. We sought to characterize the incidence of IFI in patients with MDS and AML who received azacitidine (AZA) or decitabine (DAC) at our institution. Methods A retrospective cohort study was performed to evaluate the incidence of IFI in adults receiving between 10/1/10 and 10/1/17. Patients were included if they received at least two cycles of either drug and were diagnosed with AML, MDS with a revised international prognostic scoring system (R-IPSS) score of at least 3.5, or chronic myelomonocytic leukemia (CMML) categorized as intermediate 2 or higher risk using CMML-specific prognostic scoring system (CPSS). Patients were excluded if they received mold-active antifungal prophylaxis at any time during HMA therapy prior to the development of an IFI, or if they received mold-active antifungal treatment when starting a HMA. The primary endpoint was the incidence of IFI, defined as proven, probable, or possible using the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group criteria (EORTC). Results Six hundred and fifty-one consecutive patients were screened, and 203 patients met inclusion criteria. The three most common reasons for exclusion were incomplete data (n=158), receipt of fewer than two cycles of a HMA (n=138), and receipt of mold-active antifungal treatment at the time of HMA initiation or mold-active antifungal prophylaxis at any point during HMA therapy (n=86). Six patients had two distinct episodes of HMA therapy separated by either an allogeneic stem cell transplant or a treatment other than HMA; thus 209 episodes of treatment occurred amongst 203 patients. Overall, the study population was elderly with the median age of 69, and 59% of the patients were male. Fifty-one percent of patients had AML, while 49% had MDS or CMML; 72% received AZA. The median number of cycles of HMA utilized was five. Most patients were treatment-naïve (59% AML and 87% MDS had no prior therapy). A significant portion of the group (25.8%) was neutropenic on cycle 1 day 1 (C1D1) of HMA. Other pertinent baseline characteristics of the study population are displayed in Table 1. We identified 20 cases of IFI, with an overall incidence of 9.6%. Most IFI were possible cases according to the EORTC criteria (13/20, 65%), but there were 3 culture-proven cases. The possible cases all met the host criterion of neutropenia and 12 of 13 met the clinical criterion of lower respiratory tract infection based on imaging. Organisms isolated on culture included Aspergillus spp., Fusarium spp., and Scedosporium spp. A diagnosis of IFI was made at a median of 3 cycles of HMA, with the majority (85%) diagnosed within the first four cycles. Among the 20 cases of IFI, 12 were diagnosed while receiving AZA and 8 were receiving DAC. More than half of the patients who developed IFI were neutropenic on C1D1. These patients had a significantly higher risk of IFI compared to non-neutropenic patients (20.4% vs. 5.8%, p=0.0051). When other baseline characteristics were analyzed, patients with therapy-related MDS (t-MDS) compared to de novo MDS were more likely to have an IFI (20.8% vs. 5.1%, p=0.0314). Patients with de novo AML also had a higher incidence of IFI compared to AML from an antecedent MDS/MPN (15.4% vs. 2.4%), however this did not reach statistical significance (p=0.07). Additional comparisons are described in Table 2. Conclusion IFI occurred in 9.6% of patients treated with HMA, but was observed in 20.4% of those who were neutropenic on C1D1 of HMA. Another potential risk factor identified was t-MDS versus de novo MDS. Prospective evaluation of mold-active antifungal prophylaxis in patients with MDS or AML who are neutropenic at the start of HMA therapy is warranted. Disclosures Frey: Novartis: Consultancy; Servier Consultancy: Consultancy. Perl:Arog: Consultancy; NewLink Genetics: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees; Actinium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Porter:Kite Pharma: Other: Advisory board; Novartis: Other: Advisory board, Patents & Royalties, Research Funding; Genentech: Other: Spouse employment.

Abstract: Introduction: Older patients with high-risk myeloid malignancies are now eligible for either induction chemotherapy (IC) or novel treatment strategies including liposomal cytarabine and daunorubicin (Vyxeos) or hypomethylating agent (HMA)/venetoclax. Vyxeos and HMA/venetoclax may be associated with less early mortality, but no trials have demonstrated significantly less mortality compared to IC. In this context, we need a better tool to determine a patient's risk of early mortality by strategy in order to inform therapy selection for older patients. The current methods to assess a patient's fitness for IC are the Eastern Cooperative Oncology Group (ECOG) or Karnofsky Performance Status (KPS) assessments, clinician subjective evaluations [i.e. gestalt (CG)], and often age itself ( 〉 75-80 years). None of these include objective measures of fitness. The Fried frailty phenotype (FP) uses both subjective (exhaustion and activity level) and objective measures (weight loss, gait speed, and grip strength) of frailty to categorize patients into fit, pre-frail, and frail. We hypothesized that FP would correlate with early mortality in this population and could be used to guide initial treatment selection. Methods: From September, 2018 to June, 2019 we prospectively enrolled 30 patients age 60 years or older with newly diagnosed, untreated acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) on an ongoing institutional review board approved clinical trial. We performed FP, CG, hematopoietic cell transplantation-comorbidity index (HCT-CI), and ECOG assessments on all patients prior to initiation of any therapy for their high grade myeloid disease. The primary endpoints were 60 and 100-day mortality. Results: Median patient age and follow up were 70.9 (range 61-82) years and 111 days, respectively. Patients had high-risk disease features as shown in Table 1, with the vast majority of AML patients being adverse risk by European Leukemia Network criteria and all MDS patients being high or very high-risk by the Revised International Prognostic Scoring System. The most common molecular mutations were TP53, ASXL1, RUNX1, IDH1/2, FLT3, and DNMT3A. IC consisting of either 7+3 or Vyxeos was used in 11 patients, HMA alone or in combination in 16, targeted therapy with enasidenib alone in 1, and best supportive care (BSC) in 2 (Table 1). Four patients who were frail by FP received IC (3 with Vyxeos). By FP assessments, 17% of patients were fit (score 0), 33% were pre-frail (score 1-2), and 50% were frail (score 3-5). In contrast, CG categorized 37% of patients as fit, 30% as pre-frail, and 33% as frail. Seven of 15 frail patients by FP were categorized as pre-frail or fit by CG. FP and ECOG scores also differed with 7 patients having low-risk ECOG scores of 0-1 and a high-risk FP of ≥3 (frail). For entire cohort, 60- and 100-day mortality rates were 15% and 25%, respectively. Frail patients by FP had 60-day and 100-day mortality rates of 32% and 51%, respectively, which was significantly worse than fit and pre-frail patients, all of whom were alive at 100 days (Figure 1/2, p=.016). Of the 6 out of 15 FP frail patients who died, 1 received a HMA alone, 3 HMA with venetoclax, and 2 BSC. In patients with ECOG scores of 0-1 or those categorized as fit by CG, 100-day mortalities were 8% and 10%, respectively. Mortality for patients with HCT-CI scores of 1-2 was unexpectedly higher (34% at both 60 days and 100 days) than for patients with higher risk HCT-CI scores ≥3 (13% and 29%, respectively). Conclusion: In newly diagnosed older patients with advanced myeloid neoplasms, being frail by FP was associated with increased 60 and 100-day mortality, owing to high mortality rates with HMA based therapies. While HCT-CI scores have been significantly associated with mortality after allogeneic transplantation, we observed that these scores were not linearly associated with survival or mortality in newly diagnosed AML and high/very-high risk MDS patients. By ECOG and CG, even the low risk groups contained patient deaths, suggesting that these standard metrics may not capture certain at-risk patients. CG tended to down grade frailty scores, categorizing patients as fitter than they were by FP. As such, FP may be a useful tool to predict early mortality. Further research is warranted to determine whether mortality differs by treatment within a given FP category, which may support the use of FP to select initial therapy. Disclosures Frey: Novartis: . Gill:Novartis: Research Funding; Tmunity Therapeutics: Research Funding; Carisma Therapeutics: Research Funding; Amphivena: Consultancy; Aro: Consultancy; Intellia: Consultancy; Sensei Bio: Consultancy; Carisma Therapeutics: Equity Ownership. Perl:Bayer: Research Funding; BioMed Valley Discoveries: Research Funding; FujiFilm: Research Funding; Novartis: Honoraria, Other: Advisory board, Non-financial support included travel costs for advisory board meetings as well as a medical writing company that assisted with manuscript preparation/submission and slide deck assembly for academic meeting presentations of the data., Research Funding; Jazz: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.; NewLink Genetics: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.; Takeda: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.; Astellas: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings as well as a medical writing company that assisted with manuscript preparation/submission and slide deck assembly for academic meeting presentations of trial data., Research Funding; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Non-financial support included travel costs for advisory board meetings.; Daiichi Sankyo: Consultancy, Honoraria, Other, Research Funding; Arog: Consultancy, Other: Non-financial support included travel costs for advisory board meetings.; AbbVie: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.; Actinium Pharmaceuticals: Consultancy, Honoraria, Other: Clinical Advisory Board member, Research Funding. Maillard:Genentech: Consultancy; Regeneron: Consultancy. Pratz:Millenium/Takeda: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees, Research Funding. Porter:Kite: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Glenmark Pharm: Membership on an entity's Board of Directors or advisory committees; Immunovative: Membership on an entity's Board of Directors or advisory committees; American Board of Internal Medicine: Membership on an entity's Board of Directors or advisory committees; Wiley and Sons: Honoraria; Genentech: Employment. Carroll:Astellas Pharmaceuticals: Research Funding; Incyte: Research Funding; Janssen Pharmaceuticals: Consultancy. Luger:Seattle Genetics: Research Funding; Biosight: Research Funding; Ariad: Research Funding; Agios: Honoraria; Genetech: Research Funding; Daichi Sankyo: Honoraria; Onconova: Research Funding; Kura: Research Funding; Jazz: Honoraria; Celgene: Research Funding; Cyslacel: Research Funding; Pfizer: Honoraria.