Liposomal Daunorubicin-Cytarabine (Vyxeos®) Management

Written by: Anna Howard, PharmD, BCOP, Billings Clinic
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Description: The purpose of this PQI is to discuss the option of using liposomal daunorubicin-cytarabine for patients with newly diagnosed therapy-related Acute Myeloid Leukemia (AML) or AML with myelodysplasia-related changes (AML-MRC).¹

Background: Liposomal daunorubicin-cytarabine is a combination of daunorubicin and cytarabine in a fixed molar ratio of 1:5 (44mg daunorubicin and 100mg cytarabine) encapsulated together in liposomes.¹ Daunorubicin and cytarabine are commonly used together in the “7+3” regimen for AML induction. However, in the “7+3” regimen, the drugs are mixed and administered separately. Daunorubicin is given as a bolus on days 1 through 3 and cytarabine is administered as a continuous infusion on days 1 through 7. Liposomal daunorubicin-cytarabine, in contrast, while including the same core medications, is administered as 90-minute infusion days 1, 3, and 5 or days 1 and 3 (depending on whether used for induction or consolidation). In a randomized clinical study in patients 60 to 75 years of age with newly-diagnosed therapy-related AML (t-AML) or AML-MRC observed all-cause day-30 mortality was 6% in the liposomal daunorubicin-cytarabine arm and 11% in the control arm utilizing standard 7+3 combination. During the first 60 days of the study, 14% (21/153) of patients died in the liposomal daunorubicin-cytarabine arm vs. 21% (32/151) of patients in the 7+3 treatment group.¹ Animal studies have shown that the pharmacokinetics are changed due to the liposomal formulation of daunorubicin/cytarabine^1,2

• Liposomes persist in the bone marrow
• Liposomes favor uptake into leukemia cells more than normal bone marrow cells
• Once intracellular, liposomes degrade and release daunorubicin and cytarabine to intracellular environment
• Half-life of daunorubicin and cytarabine is significantly longer in liposomal daunorubicin-cytarabine compared to non-liposomal formulations of each drug

PQI Process:

• Patient eligibility
  • Confirmation of t-AML or AML-MRC
  • Anthracycline eligibility:¹
    • Calculate patient’s previous lifetime anthracycline dose. If approaching or over recommended lifetime maximum, consider alternative therapy. Liposomal daunorubicin-cytarabine is not recommended for patients who have reached maximum lifetime anthracycline dose
    • Evaluate baseline echocardiogram for signs of cardiac dysfunction. If patient exhibits significant cardiac dysfunction at baseline, discuss risks/benefits of continuing this therapy vs. choosing alternative. Re-evaluate echocardiogram prior to consolidation with liposomal daunorubicin-cytarabine and as clinically necessary
  • Consolidation with liposomal daunorubicin-cytarabine is only preferred if given in induction³
• Premedications¹
  • Follow institutional practice for moderate emetic risk IV chemotherapy
• Preparation¹
  • Calculate the volume of reconstituted Liposomal daunorubicin-cytarabine required based on daunorubicin dose: [volume required (mL) = daunorubicin dose (mg/m²) X BSA (m²) ÷ 2.2 (mg/mL)]
  • Review PI for complete admixture details which must be followed to increase homogeneity of product

• Compatible with NS or D5W
• Resulting product will be a purple, opaque, homogeneous dispersion with no visible particulates

• Dosing¹
  • Dose adjustments:
    • Renal: not required. Not studied in severe renal impairment or end-stage renal disease
    • Hepatic: not required. Not studied in patients with bilirubin >2.92 mg/dL
  • Induction:
    • 44mg/m² daunorubicin + 100mg/m² cytarabine IV infusion over 90 minutes on Days 1, 3, and 5
  • Second induction (administered 2 to 5 weeks after first induction, if remission is not achieved with first induction cycle):
    • 44mg/m² daunorubicin + 100mg/m² cytarabine IV infusion over 90 minutes on Days 1 and 3
  • First consolidation cycle (administered 5 to 8 weeks after start of last induction cycle) and second consolidation cycle (administered 5 to 8 weeks after start of first consolidation cycle):
    • 29 mg/m² daunorubicin + 65mg/m² cytarabine IV infusion over 90 minutes on Days 1 and 3
    • Do not administer consolidation until neutrophils and platelets have recovered to 5 Gi/L and 50 Gi/L respectively¹
  • Administration
    • May be administered as outpatient in an infusion center if patient is clinically stable^4,5
    • Due to risk for tissue necrosis from extravasation, only administer through central line¹
    • Review the PI regarding specifics surrounding infusion filtration¹
  • Adverse events
    • Some common events include (>25%): hemorrhagic events, febrile neutropenia, rash, edema, nausea, mucositis, diarrhea, constipation, musculoskeletal pain, fatigue, abdominal pain, dyspnea, headache, cough, arrhythmia, pneumonia
    • Differences in adverse events compared to standard 7+3 regimen^1,2
      • Prolonged high-grade cytopenias in absence of active leukemia (lasting past cycle day 42) were more frequent in liposomal daunorubicin-cytarabine than 7+3 regimen
      • Prolonged neutropenia in liposomal daunorubicin-cytarabine vs. 7+3 regimen (neutrophils < 0.5 Gi/L): 17% vs 3% (induction), 10% vs 3% (consolidation)
      • Prolonged thrombocytopenia (Platelets < 50 Gi/L): 28% vs 12% (induction), 25% vs 16% (consolidation)
      • Hemorrhage: In an observed clinical study, fatal treatment-emergent CNS hemorrhage not in the setting of progressive disease occurred in liposomal daunorubicin-cytarabine (2%) vs 7+3 (0.7%)
        • Grade 3 or higher hemorrhagic events from severe thrombocytopenia in liposomal daunorubicin-cytarabine (12%) vs 7+3 (8%)
      • Grade 5 infection related events: 7.2 % liposomal daunorubicin-cytarabine vs 2.6% 7+3. Rates of febrile neutropenia: 68.0% vs 70.9%²
    • Copper Overload Risk¹
      • When reconstituted for infusion, contains 5 mg/mL copper gluconate, of which 14% is elemental copper

• If a patient has a history of Wilson’s disease or other copper-related metabolic disorder, evaluate risk/benefit
  • Monitor total serum copper, serum nonceruloplasmin bound copper, 24-hour urine copper levels and serial neuropsychological examinations in this patient population
  • If signs or symptoms of acute copper toxicity develop, discontinue

Patient Centered Activities:

• Patient monitoring¹
  • May cause severe neutropenia, anemia, and thrombocytopenia. Monitor blood counts during therapy
  • Monitor liver function
    • Daunorubicin is metabolized by the liver. No dose adjustments are recommended by manufacturer at this time but has not been studied in patients with total bilirubin greater than 3mg/dL
  • Monitor cardiac function due to daunorubicin
  • Monitor daunorubicin lifetime cumulative dose from liposomal daunorubicin-cytarabine and other therapies
• Patient education
  • Monitor and educate patient for signs and symptoms for:

• Heart failure
• Infection
• Bleeding
• Rash
• GI side effects: Nausea, Vomiting, Diarrhea, Abdominal pain, Colitis

Supplemental Information

• Billing Information
  • Permanent, product specific HCPCS J-code: J9153
  • Dosage: Injection, liposomal, 1 mg daunorubicin and 2.27 mg cytarabine
  • Billing unit per dose: 1
  • Billing unit per vial: 44 units
  • See manufacturer website for further billing information including NTAP designation

References:

1. Daunorubicin and cytarabine liposome for injection (Vyxeos®) [Package insert]. Jazz Pharmaceuticals, Inc, Palo Alto, CA; July 2019.
2. 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. JCO 2018;36(26):2684-2692.
3. National Comprehensive Cancer Network. Acute Myeloid Leukemia (Version 3.2020). https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed April 21, 2020.
4. Kubal TE, Salamanca C, Komrokji RS, et al. Safety and feasibility of outpatient induction chemotherapy with CPX-351 in selected older patients with newly diagnosed AML. J Clin Oncol. 2018:36(15)(suppl):e19013.
5. Deutsch YE, Presutto JT, Brahim A, et al. 3559 Safety and feasibility of outpatient liposomal daunorubicin and cytarabine (Vyxeos) induction and management in patients with secondary AML. Paper presented at: American Society of Hematology Annual Meeting; December 1-4, 2018; San Diego, CA.

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