VYXEOS® – A Novel First Line Treatment for High Risk Acute Myeloid Leukemia

SUMMARY: The American Cancer Society estimates that in 2016, 19,950 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 10,430 patients will die of the disease. Acute Myeloid Leukemia in general is a disease of the elderly and the average age of a patient with AML is about 66 years. AML can be considered as a group of heterogeneous diseases with different clinical behavior and outcomes. In general, only 40% of patients younger than 60 years of age survive more than 5 years and 5 year survival for those who relapse after achieving a complete remission (CR) is dismal. Treatment with conventional chemotherapy regimens in elderly patients with secondary AML (sAML) have resulted in poor outcomes. Even though rapid development of new agents against genetic and epigenetic targets is underway, modifications and reformulations of conventional chemotherapy have demonstrated improved outcomes in patients with AML.

CPX-351 (VYXEOS®) is a liposomal formulation of a fixed combination of Cytarabine and Daunorubicin in a 5:1 molar ratio, developed using a platform known as “CombiPlex”. In vitro studies have demonstrated that this ratio maximizes synergy with the lowest level of antagonism and results in preferential uptake of the drug into leukemic cells. In a randomized, open label phase II trial involving patients with or without secondary AML (sAML), CPX-351 improved the composite CR (CRc) rate (Complete Remission and CR with incomplete blood count recovery – CRi) when compared to conventional induction chemotherapy with Daunorubicin and Cytarabine. Those patients with a higher rate of CRc (CR + CRi) had a statistically significant 6 month survival benefit. In another study of AML patients in first relapse, CPX-351 improved median Overall Survival (OS) in poor-risk patients when compared to investigator’s choice of salvage regimens.

On the basis of these studies, the authors conducted a randomized, open-label, phase III trial of first-line CPX-351 in patients with high-risk sAML. Enrolled patients (N=309) were stratified based on AML type (therapy-related AML, AML with a history of MDS with and without prior Hypo Methylating Agent therapy, AML with a history of CMML, or de novo AML with MDS karyotype) and age (60-69 yrs or 70-75yrs). Patients were randomized in a 1:1 ratio to receive either CPX-351 (N=153) 100 units/m2, days 1, 3, 5 or the standard 7+3 (Cytarabine 100 mg/m2/day x 7 days, Daunorubicin 60 mg/m2 days 1, 2, 3) induction therapy (N=156). Both treatment groups were well balanced. The primary end point was Overall Survival (OS) and secondary endpoints included Event Free Survival (EFS), independent blinded assessment of CR+CRi, and 60-day mortality.

The final analysis began after a minimum follow up of 13.7 months. Patients in the CPX-351 group had a significant improvement in Overall Survival compared with standard treatment (HR=0.69; P=0.005; median OS, 9.56 versus 5.95 months). Additionally, there was a significant improvement in Event Free Survival for the CPX-351 group compared to standard therapy (HR=0.74; P=0.021), as well as CR+CRi response (47.7% versus 33.3%; P=0.016) and 60-day mortality (13.7% versus 21.2%). The Complete Remission rates alone were 37.3% and 25.6%, in favor of CPX-351 (P=0.04). Grade 3-5 Adverse Events were similar in frequency and severity in both arms (92% versus 91%) and similar numbers of patients underwent transplantation in both treatment groups.

The authors concluded that treatment with CPX-351 (VYXEOS®) significantly improved Overall Survival, Event Free Survival and Response Rates, without an increase in 60-day mortality or Adverse Events, in elderly patients with high risk secondary AML, when compared with standard induction therapy. CPX-351 reduced the risk of death by 31%. Final results of a phase III randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high risk (secondary) AML. Lancet JE, Uy GL, Cortes JE, et al. J Clin Oncol 34, 2016 (suppl; abstr 7000).