Background: CPX-351 (Vyxeos®; daunorubicin and cytarabine liposome for injection) is a treatment for adults with newly diagnosed AML with myelodysplasia-related changes or therapy-related AML. Intensive induction chemotherapy causes marked symptom burden, quality of life (QOL) impairment, and psychological distress, but data on the patient experience with CPX-351 are lacking. We aimed to compare the patient experience of physician-chosen CPX-351 to standard induction regimens using validated patient-reported outcome (PRO) measures collected prospectively in a randomized clinical trial. Methods: This was an exploratory analysis of a US, multi-site supportive care trial in AML (NCT02975869). PRO assessments were collected at baseline, 2 weeks later (when studies show patients feel their worst during a typical induction hospitalization), and then at 1, 3, and 6 months. PROs assessed the following patient experience domains: symptoms (Edmonton Symptom Assessment Scale [ESAS]), QOL (FACT-Leukemia and FACT-TOI), anxiety (HADS-A), depression (HADS-D), and post-traumatic stress (PTSD Checklist). All analyses were adjusted for baseline PROs, patient age, receipt of additional targeted therapy, and supportive care interventions. Analysis of covariance models were used to find adjusted 2-week PRO scores by treatment, and logistic regression models were used to find adjusted odds ratios (aOR) for dichotomous PROs at 2 weeks. Linear mixed effects models were used to estimate adjusted mean between-group differences in PROs across the 6-month study period (reported as B). Given the exploratory nature of this study, we defined a 2-sided P value of <0.20 as hypothesis-generating, consistent with standard approaches to exploratory analysis, and not to imply significance. Results: Across 4 sites, we enrolled 109 patients with newly diagnosed AML. Thirty-five (32%) received CPX-351 and 74 (68%) received a standard regimen (72 received 7+3, 1 received FLAG, and 1 received MEC). Baseline sociodemographic characteristics and PROs were similar across groups. Mean age was 67 years (SD: 6.8) in the CPX-351 group and 65.2 (SD: 8.9) in the standard group. Most patients were white (>90%) and partnered (>70%). At 2 weeks, those receiving CPX-351 had better PRO scores (adjusted means) for symptoms (ESAS total score: 25.89 vs 31.73; P = 0.11) and depression (HADS-D: 5.17 vs 7.0; P = 0.08); CPX-351 was favored on all other PROs, including quality of life (FACT-Leu: 118.02 vs 112.56; P = 0.44), anxiety (HADS-A: 4.51 vs 5.27; P = 0.465), and PTSD symptoms (PTSD-checklist: 27.08 vs 28.16; P = 0.6). At 2 weeks, patients receiving CPX-351 were less likely to have worsening ESAS total symptoms (45.7% vs 54.1%; aOR = 0.52; P = 0.172), physical symptoms (45.7% vs 63.5%; aOR = 0.41; P = 0.064), and clinically significant depression symptoms (27.3% vs 37.7%; aOR = 0.48; P = 0.159), but no difference in clinically significant anxiety symptoms (28.9% vs 30.3%; aOR = 0.62; P = 0.392). In longitudinal analyses, those receiving CPX-351 had better QOL (FACT-TOI: B = 6.41; P = 0.173), lower anxiety (B = −1.47; P = 0.153), less depression symptoms (B = −1.58; P = 0.09), and less leukemia symptoms (B = 3.67; P = 0.16), but no differences in total symptom burden (ESAS: B = −0.06; P = 0.988) or in PTSD symptoms (PTSD Checklist: B = 2.23; P = 0.354). While patients receiving CPX-351 had a longer index hospitalization length of stay compared to standard induction (mean of 44.3 vs 39 days; P = 0.072), they also had fewer hospitalizations during the 6-month follow-up period (2.82 vs 3.55; P = 0.158). Furthermore, the total number of days hospitalized after the index admission was lower for those receiving CPX-351 (17.71 vs 22.27 days; P = 0.199). Patients receiving CPX-351 had an average of 94.08 days alive and out of the hospital, while those receiving standard induction had 91.85 days (P = 0.849). Conclusions: This exploratory analysis supports the observation that patients receiving CPX-351 may have an overall better patient experience during induction treatment, as measured by validated PROs assessing symptoms, QOL, mood, and PTSD. Our ability to draw more definitive conclusions is limited by sample size and the fact that treatment with CPX-351 is only indicated for certain AML subtypes, resulting in a non-random allocation to treatment groups and potential differences in clinical outcomes. Disclosures Leblanc: AstraZeneca: Research Funding; Agios, AbbVie, and Bristol Myers Squibb/Celgene: Speakers Bureau; UpToDate: Patents & Royalties: Royalties; American Cancer Society, BMS, Duke University, NINR/NIH, Jazz Pharmaceuticals, Seattle Genetics: Research Funding; AbbVie, Agios, Amgen, AstraZeneca, CareVive, BMS/Celgene, Daiichi-Sankyo, Flatiron, Helsinn, Heron, Otsuka, Medtronic, Pfizer, Seattle Genetics, Welvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Morris:Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Hooks:Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. El-Jawahri:Jazz Pharmaceuticals: Research Funding.