On August 3, 2017, a liposome-encapsulated combination of daunorubicin and cytarabine (Vyxeos) was approved for treatment of adults with newly diagnosed therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes.^1,2 This is the first U.S. Food and Drug Administration–approved treatment specifically for patients with therapy-related AML or AML with myelodysplasia-related changes.

Supporting Efficacy Data

Approval was based on improved overall survival with the liposome-encapsulated combination of daunorubicin and cytarabine in an open-label phase III study in which 309 patients aged 60 to 75 years were randomized to receive the liposome-encapsulated combination (n = 153) or a standard (7+3) daunorubicin/cytarabine combination (n = 156). Patients had to have a left-ventricular ejection fraction of ≥ 50% and a lifetime cumulative anthracycline exposure < 368 mg/m² of daunorubicin (or its equivalent). Patients could receive up to two cycles of induction and two cycles of consolidation; a second induction was highly recommended for patients who did not achieve response and was mandatory for patients achieving > 50% reduction in percent blasts. Postremission therapy with hematopoietic stem cell transplantation (HSCT) was permitted either in place of or after consolidation chemotherapy.

Among all patients, the median age was 68 years; 61% were male; 88% had an Eastern Cooperative Oncology Group performance status of 0 or 1; 20% had therapy-related AML, 54% had AML with an antecedent hematologic disorder, and 25% had de novo AML with myelodysplasia-related cytogenetic abnormalities; and 34% had previous treatment with a hypomethylating agent for myelodysplastic syndrome.

All patients in the liposome-encapsulated combination group and 97% in the control group received at least one cycle of induction, with 32% and 21% receiving at least one cycle of consolidation. The rate of HSCT in first complete response was 20% vs 12%; the overall rate of HSCT (induction failure, first complete response, or as salvage after relapse) was 34% vs 25%.

Median overall survival was 9.6 months in the liposome-encapsulated combination group vs 5.9 months in the control group (hazard ratio [HR] = 0.69, P = .005). Complete response rates were 38% vs 26% (P = .036).

How It Works

Daunorubicin and cytarabine is a liposomal formulation of daunorubicin and cytarabine at a fixed 1:5 molar ratio. This formulation has been shown to have synergistic effects in killing leukemia cells in vitro and in murine models. Daunorubicin has antimitotic and cytotoxic activity achieved by forming complexes with DNA, thus inhibiting topoisomerase II activity, inhibiting DNA polymerase activity, affecting the regulation of gene expression, and producing DNA-damaging free radicals. Cytarabine is a cell-cycle phase-specific antineoplastic agent; it affects cells only during the S phase of cell division and acts primarily via inhibition of DNA polymerase. Animal models indicate that the liposomes enter and persist in the bone marrow and are taken up intact by bone marrow cells. In leukemia-bearing mice, the liposomes are taken up by leukemia cells to a greater extent than by normal bone marrow cells. After cellular internalization, liposomes undergo degradation, releasing cytarabine and daunorubicin into the intracellular environment.

How It Is Used

A full course of the liposome-encapsulated combination consists of one or two cycles of induction and up to two cycles of consolidation. Prior to initiating induction, cardiac, liver, and renal function should be assessed. Prophylactic antiemetics should be given before treatment. 

The dose for the first cycle of induction is daunorubicin at 44 mg/m² and cytarabine at 100 mg/m² liposome via 90-minute infusion on days 1, 3, and 5. For patients without remission with the first induction cycle, a second induction cycle may be administered 2 to 5 weeks after the first if there was no unacceptable toxicity; the dose for the second induction cycle is the same as the first cycle and is given on days 1 and 3. The patient’s prior cumulative anthracycline exposure should be calculated before each cycle.

The first consolidation cycle should be given at 5 to 8 weeks after the start of the last induction cycle. The consolidation dose is daunorubicin at 29 mg/m² and cytarabine at 65 mg/m² liposome via 90-minute infusion on days 1 and 3. Cardiac function, complete blood cell counts, and liver and renal function tests should be assessed before each consolidation cycle. Consolidation should not be started until the absolute neutrophil count recovers to > 0.5 Gi/L and the platelet count recovers to > 50 Gi/L in the absence of unacceptable toxicity. The second consolidation cycle should be started at 5 to 8 weeks after the start of the first cycle in patients without disease progression or unacceptable toxicity.

For hypersensitivity reactions of any grade, infusion should be interrupted immediately and symptoms managed. For mild symptoms, once they resolve, infusion should be reinitiated at half the prior infusion rate; premedication with antihistamines and/or corticosteroids should be considered for subsequent doses. For moderate symptoms, infusion should not be restarted; for subsequent doses, patients should be premedicated with antihistamines and/or corticosteroids prior to initiating infusion at the same rate. For severe/life-threatening symptoms, treatment with the liposome-encapsulated combination of daunorubicin and cytarabine should be permanently discontinued.

The liposome-encapsulated combination of daunorubicin and cytarabine should be permanently discontinued in patients who exhibit impaired cardiac function, unless the benefit of continuing treatment outweighs the risk.

Safety Profile

The most common adverse events of any grade during induction in the liposome-encapsulated combination of daunorubicin and cytarabine group in the phase III study were hemorrhage (70% vs 49% in the control group), febrile neutropenia (68% vs 68%), rash (54% vs 36%), and edema (51% vs 60%); others with an incidence > 25% in the liposome-encapsulated combination of daunorubicin and cytarabine group consisted of nausea, mucositis, diarrhea, constipation, musculoskeletal pain, fatigue, abdominal pain, dyspnea, headache, cough, decreased appetite, arrhythmia, pneumonia, bacteremia, chills, sleep disorders, and vomiting. The most common grade ≥ 3 adverse events were febrile neutropenia (66% vs 68%), bacteremia (excluding sepsis; 23% vs 21%), and pneumonia (excluding fungal; 20% vs 17%) All patients developed severe neutropenia, thrombocytopenia, and anemia.

The most common serious adverse events in ≥ 5% of the liposome-encapsulated combination of daunorubicin and cytarabine group were dyspnea, myocardial toxicity, sepsis, pneumonia, febrile neutropenia, bacteremia, and hemorrhage. Adverse events led to treatment discontinuation in 18% of patients (13% in the control group), with causes including prolonged cytopenias, infection, cardiotoxicity, respiratory failure, hemorrhage (gastrointestinal and central nervous system [CNS]), renal insufficiency, colitis, and generalized medical deterioration.

Nine patients (6%) in each group had a fatal adverse event on or within 30 days after treatment that was not in the setting of progressive disease; those in the liposome-encapsulated combination of daunorubicin and cytarabine group included infection, CNS hemorrhage, and respiratory failure. All-cause 30-day mortality was 6% in the liposome-encapsulated combination of daunorubicin and cytarabine group vs 11% in the control group; 60-day mortality was 14% vs 21%.

The liposome-encapsulated combination of daunorubicin and cytarabine has a boxed warning against interchange with other daunorubicin- and/or cytarabine-containing products. The liposome-encapsulated combination of daunorubicin and cytarabine has different dosage recommendations than daunorubicin hydrochloride injection, cytarabine injection, daunorubicin citrate liposome injection, and cytarabine liposome injection. The drug name and dose must be verified prior to preparation and administration to avoid dosing errors.

The liposome-encapsulated combination of daunorubicin and cytarabine carries warnings/precautions for serious/fatal hemorrhagic events with associated prolonged thrombocytopenia, cardiotoxicity, severe/life-threatening hypersensitivity reactions, local tissue necrosis at the site of drug extravasation, and embryofetal toxicity. Blood cell counts should be monitored regularly until recovery. ■

REFERENCES

1. U.S. Food and Drug Administration: FDA approves liposome-encapsulated combination of daunorubicin-cytarabine for adults with some types of poor prognosis AML. Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm569950.htm. Accessed November 28, 2017.

2. Vyxeos (daunorubicin and cytarabine) liposome for injection prescribing information, Jazz Pharmaceuticals, August 2017. Available at http://pp.jazzpharma.com/pi/vyxeos.en.USPI.pdf. Accessed November 28, 2017.