The Impact of Hematopoietic Cell Transplantation on Survival: An Exploratory Analysis of a Phase 3 Study of CPX-351 Versus 7+3 in Older Patients with Newly Diagnosed, High-Risk/Secondary AML
Authors: Lin Tara L , Cortes Jorge E. , Newell Laura F. , Ritchie Ellen K. , Stuart Robert K. , Strickland Stephen A. , Hogge Donna , Solomon Scott R , Stone Richard M. , Bixby Dale L. , Kolitz Jonathan E. , Schiller Gary J. , Wieduwilt Matthew J. , Ryan Daniel H. , Ryan Robert , Chiarella Michael , Louie Arthur C. , Uy Geoffrey L. 
Published: October 2019

Abstract
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.