Written by: Anna Howard, PharmD, BCOP, Billings Clinic
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The purpose of this PQI is to discuss the option of using liposomal daunorubicin-cytarabine for patients with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes (AML-MRC).1
Background
Vyxeos 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. Vyxeos, 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 t-AML or AML-MRC observed all-cause day-30 mortality was 6% in the Vyxeos 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 Vyxeos 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 Vyxeos compared to non-liposomal formulations of each drug
PQI Process:
- Patient eligibility
- Confirmation of therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC)
- Anthracycline eligibility:1
- Calculate patient’s previous lifetime anthracycline dose. If approaching or over recommended lifetime maximum, consider alternative therapy. Vyxeos 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 Vyxeos and as clinically necessary.
- Consolidation with Vyxeos is only preferred if given in induction3
- Premedications:1
- Follow institutional practice for moderate emetic risk IV chemotherapy
- Preparation:1
- Calculate the volume of reconstituted VYXEOS required based on daunorubicin dose:
[volume required (mL) = daunorubicin dose (mg/m2) X BSA (m2) ÷ 2.2 (mg/mL)]
- Review Vyxeos PI for complete admixture details which must be followed to increase homogeneity of final product
- Vyxeos is compatible with NS or D5W
- Resulting product will be a deep purple, opaque, homogeneous dispersion with no visible particulates
- Dosing:1
- 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 >3 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 respectively.1
- Dose adjustments:
- Administration:
- May be administered as outpatient in an infusion center if patient is clinically stable4,5
- 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 Vyxeos than 7+3 regimen
- Prolonged neutropenia in Vyxeos 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 Vyxeos (2%) vs 7+3 (0.7%)
- Grade 3 or higher hemorrhagic events from severe thrombocytopenia in Vyxeos (12%) vs 7+3 (8%)
- Grade 5 infection related events= 7.2 % Vyxeos vs 2.6% 7+3. Rates of febrile neutropenia: 68.0% vs 70.9%2
- Copper Overload Risk:1
- When reconstituted for infusion, Vyxeos 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 of using Vyxeos
- 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 Vyxeos
Patient Centered Activities:
- Patient monitoring:1
- Vyxeos 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 Vyxeos 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 Vyxeos 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
- Monitor and educate patient for signs and symptoms for:
Supplemental Information
- Billing Information
- Permanent, product specific HCPCS J-code for Vyxeos: 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:
Daunorubicin and cytarabine liposome for injection (Vyxeos®) [Package insert]. Jazz Pharmaceuticals, Inc, Palo Alto, CA; July 2019.
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.
National Comprehensive Cancer Network. Acute Myeloid Leukemia (Version 3.2020). https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed April 21, 2020.
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.
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.
