Introduction
Vyxeos (daunorubicin and cytarabine) liposome for injection is a fixed-combination chemotherapy agent specifically designed for the treatment of adults with newly diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC). This innovative formulation represents a significant advancement in AML treatment by encapsulating two established chemotherapeutic agents in a liposomal delivery system that enhances drug targeting to leukemia cells while potentially reducing systemic toxicity.
Mechanism of Action
Vyxeos combines two antineoplastic agents with complementary mechanisms of action:
- Cytarabine: A pyrimidine analog that incorporates into DNA during the S-phase of cell division, inhibiting DNA polymerase and ultimately causing chain termination and impaired DNA synthesis
- Daunorubicin: An anthracycline that intercalates between DNA base pairs, inhibiting topoisomerase II and generating free radicals that cause DNA strand breaks and membrane damage
The liposomal encapsulation allows for prolonged circulation time and enhanced delivery to bone marrow and leukemic cells. The fixed 1:5 molar ratio (daunorubicin:cytarabine) was optimized in preclinical models to demonstrate synergistic antileukemic activity.
Indications
Vyxeos is FDA-approved for:
- Treatment of adults with newly diagnosed therapy-related acute myeloid leukemia (t-AML)
- Treatment of adults with acute myeloid leukemia with myelodysplasia-related changes (AML-MRC)
Dosage and Administration
Standard dosing: Vyxeos is supplied as a liposomal combination containing 44 mg daunorubicin and 100 mg cytarabine per vial. The recommended dose is based on the daunorubicin component:- Induction: 44 mg/m² daunorubicin and 100 mg/m² cytarabine (as Vyxeos) intravenously over 90 minutes on days 1, 3, and 5 of the first induction cycle
- Consolidation: For patients who achieve complete remission or complete remission with incomplete recovery, administer 29 mg/m² daunorubicin and 65 mg/m² cytarabine (as Vyxeos) intravenously over 90 minutes on days 1 and 3 of each consolidation cycle
- Renal impairment: No dosage adjustment recommended for mild to moderate impairment (CrCl ≥30 mL/min). Use with caution in severe impairment.
- Hepatic impairment: No dosage adjustment recommended for mild impairment (total bilirubin ≤ULN and AST >ULN, or total bilirubin >1.0 to 1.5 × ULN). Avoid use in moderate to severe impairment.
- Elderly: No specific dosage adjustment recommended based on age alone
Pharmacokinetics
Absorption: Administered intravenously only; complete bioavailability Distribution: Liposomal encapsulation alters distribution profile. Steady-state volume of distribution approximately 3.9 L/m². Daunorubicin and cytarabine remain predominantly encapsulated during circulation Metabolism:- Daunorubicin: Hepatic metabolism to active metabolite daunorubicinol via carbonyl reductase and aldo-keto reductase
- Cytarabine: Deaminated to inactive uracil arabinoside (ara-U) primarily in liver, plasma, and granulocytes
- Daunorubicin: Terminal half-life approximately 31.5 hours; primarily biliary excretion
- Cytarabine: Terminal half-life approximately 232 hours; primarily renal excretion (≤10% unchanged)
Contraindications
- History of serious hypersensitivity reaction to daunorubicin, cytarabine, or any component of the formulation
- Patients with known hypersensitivity to copper or products containing copper
Warnings and Precautions
Myelosuppression: Severe and fatal myelosuppression occurs with Vyxeos. Monitor blood counts regularly until recovery Hemorrhage: Serious and fatal hemorrhagic events have been reported Infections: Serious and fatal infections, including sepsis and pneumonia, may occur Cardiotoxicity: Anthracycline class warning for myocardial damage and arrhythmias. Assess cardiac function before and during treatment Hypersensitivity reactions: Infusion reactions may occur; monitor during administration Tissue damage: Extravasation can cause severe local tissue damage. Ensure proper intravenous access before administration Embryo-fetal toxicity: Can cause fetal harm. Advise patients of reproductive potential to use effective contraceptionDrug Interactions
Strong CYP3A4 inhibitors: May increase daunorubicin exposure. Avoid concomitant use or consider dosage reduction P-glycoprotein inhibitors: May increase daunorubicin exposure. Monitor for increased toxicity Live vaccines: Avoid administration during treatment due to immunosuppression Other myelosuppressive drugs: May enhance myelosuppressive effects; monitor closelyAdverse Effects
Most common adverse reactions (≥30%):- Hemorrhage (91%)
- Fever (83%)
- Rash (52%)
- Edema (51%)
- Nausea (49%)
- Mucosal inflammation (48%)
- Diarrhea (43%)
- Constipation (40%)
- Musculoskeletal pain (39%)
- Fatigue (37%)
- Abdominal pain (36%)
- Dyspnea (35%)
- Headache (35%)
- Vomiting (34%)
- Decreased appetite (33%)
- Arrhythmia (32%)
- Pneumonia (31%)
- Sleep disorders (31%)
- Hemorrhage (45%)
- Fever (35%)
- Infection (32%)
- Respiratory failure (16%)
- Gastroenteritis (14%)
- Arrhythmia (13%)
- Edema (13%)
- Pneumonia (11%)
- Sepsis (10%)
Monitoring Parameters
Before initiation:- Complete blood count with differential
- Comprehensive metabolic panel (including hepatic and renal function)
- Cardiac assessment (LVEF by echocardiogram or MUGA scan)
- Pregnancy test in women of reproductive potential
- Daily CBC during induction and until recovery
- Liver and renal function weekly
- Cardiac function monitoring before each cycle
- Signs/symptoms of infection, bleeding, or hypersensitivity
- Monitoring for extravasation during infusion
- Long-term cardiac monitoring due to anthracycline component
- Secondary malignancy surveillance
Patient Education
- Report signs of infection (fever, chills) immediately
- Watch for bleeding or bruising tendencies
- Report chest pain, palpitations, or shortness of breath
- Use effective contraception during treatment and for several months after
- Avoid vaccination with live vaccines during treatment
- Maintain good oral hygiene to reduce risk of mucositis
- Report nausea, vomiting, or diarrhea for appropriate management
- Understand that hair loss is likely during treatment
- Arrange for assistance with daily activities during treatment period
- Keep all scheduled follow-up appointments for monitoring
References
1. Lancet JE, Uy GL, Cortes JE, et al. CPX-351 (cytarabine and daunorubicin) Liposome for Injection Versus Conventional Cytarabine Plus Daunorubicin in Older Patients With Newly Diagnosed Secondary Acute Myeloid Leukemia. J Clin Oncol. 2018;36(26):2684-2692. 2. Vyxeos [package insert]. Palo Alto, CA: Jazz Pharmaceuticals, Inc.; 2021. 3. Lancet JE, Cortes JE, Hogge DE, et al. Phase 2 trial of CPX-351, a fixed 5:1 molar ratio of cytarabine/daunorubicin, vs cytarabine/daunorubicin in older adults with untreated AML. Blood. 2014;123(21):3239-3246. 4. FDA Approval: Vyxeos (daunorubicin and cytarabine) liposome for injection. August 2017. 5. NCCN Clinical Practice Guidelines in Oncology: Acute Myeloid Leukemia. Version 3.2022.