Daunorubicin-Cytarabine Liposome (Vyxeos)

Number: 0921

Policy

1. Criteria for Initial Approval

   Aetna considers daunorubicin-cytarabine liposome (Vyxeos) medically necessary for the treatment of members with therapy-related acute myeloid leukemia (t-AML), AML with antecedent myelodysplastic syndrome/chronic myelomonocytic leukemia (MDS/CMML), or AML with cytogenetic changes that are consistent with MDS (AML-MRC) who meet any of the following criteria: 

   1. Induction therapy

      1. Member is less than 60 years of age and who is induction eligible without core binding factor (CBF) abnormalities; or
      2. Member is 60 years of age and older and is a candidate for intensive remission induction therapy. 
         

   2. Re-induction therapy

      1. Member is less than 60 years of age with significant residual disease without a hypocellular marrow and without core binding factor (CBF) abnormalities, or
      2. Member is 60 yeas of age and older with residual disease. 
         

   3. Post-induction therapy

      Member is 60 years of age and older with complete response to previous intensive therapy and able to receive conventional consolidation.

   4. Consolidation therapy

      Member is less than 60 years of age with treatment-related disease other than core binding factor (CBF) and/or unfavorable cytogenetics and/or molecular abnormalities.

   Aetna considers all other indications as experimental and investigational.

2. Continuation of Therapy

   Aetna considers continuation of daunorubicin-cytarabine liposome (Vyxeos) therapy medically necessary for an indication outlined in Section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Dosage and Administration

Vyxeos is available for injection in a single-dose vial containing 44 mg daunorubicin and 100 mg cytarabine encapsulated together in liposomes, forming a lyophilized cake. Vials are to be reconstituted for intravenous infusion.

The following are FDA-approved labeled dosage and administration recommendations: 

A full course consists of 1-2 cycles of Induction, and up to 2 cycles of Consolidation:

• Induction cycle: Vyxeos (daunorubicin 44 mg/m² and cytarabine 100 mg/m²) liposome via intravenous infusion over 90 minutes on days 1, 3, and 5. For persons who do not achieve remission with the first induction cycle, a second induction cycle may be administered on days 1 and 3, with the same dose, 2 to 5 weeks after the first cycle, if there was no unacceptable toxicity with Vyxeos.
• Consolidation: Vyxeos (daunorubicin 29 mg/m² and cytarabine 65 mg/m²) liposome via intravenous infusion over 90 minutes on days 1 and 3. Administer the first consolidation cycle 5 to 8 weeks after the start of the last induction. Administer the second consolidation cycle 5 to 8 weeks after the start of the first consolidation cycle in persons who do not show disease progression or unacceptable toxicity.

For additional information, consult the Full Prescribing Information (Jazz 2021b).

Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Vyxeos is indicated for the treatment of newly-diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC) in adults and pediatric patients 1 year and older.

Compendial Uses

• Therapy-related Acute Myeloid Leukemia (t-AML)
• AML with antecedent Myelodysplastic Syndrome (MDS)/Chronic Myelomonocytic Leukemia (CMML)
• AML with cytogenetic changes that are consistent with MDS (AML-MRC)

Vyxeos is a liposomal combination of daunorubicin, an anthracycline topoisomerase inhibitor, and cytarabine, a nucleoside metabolic inhibitor. Daunorubicin has antimitotic and cytotoxic activity, which is achieved by forming complexes with DNA, inhibiting topoisomerase II activity, inhibiting DNA polymerase activity, affecting regulation of gene expression, and producing DNA-damaging free radicals. Cytarabine is a cell cycle phase-specific antineoplastic agent, affecting cells only during the S-phase of cell division. Cytarabine acts primarily through inhibition of DNA polymerase. Based on animal data, the liposomes enter and persist in the bone marrow, where they 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 within the intracellular environment (Jazz, 2021b).

Warnings and Precautions

• Vyxeos has different dosage recommendations than daunorubicin hydrochloride injection, cytarabine injection, daunorubicin citrate liposome injection, and cytarabine liposome injection. Verify drug
  name and dose prior to preparation and administration to avoid dosing errors.
• Serious or fatal hemorrhagic events with associated prolonged thrombocytopenia have occurred. Monitor blood counts regularly until recovery. 
• Cardiotoxicity: Vyxeos treatment is not recommended in patients with cardiac function that is less than normal. Discontinue in patients with impaired cardiac function unless the benefit of continuing treatment outweighs the risk. 
• If severe or life-threatening hypersensitivity reaction occurs, discontinue, according to standard of care, and monitor until signs and symptoms resolve. 
• Daunorubicin has been associated with local tissue necrosis at the site of drug extravasation. Administer with care.
• Embryo-Fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. 

The most common adverse reactions (incidence ≥ 25%) were hemorrhagic events, febrile neutropenia, rash, edema, nausea, mucositis, diarrhea, constipation, musculoskeletal pain, fatigue, abdominal pain, dyspnea, headache, cough, decreased appetite, arrhythmia, pneumonia, bacteremia, chills, sleep disorders, and vomiting (Jazz Pharmaceuticals, 2019).

Acute Myeloid Leukemia (AML)

Acute myeloid leukemia (AML) is a rapidly progressing cancer that forms in the bone marrow and results in an increased number of white blood cells in the bloodstream. Therapy-related acute myeloid leukemia (t-AML) is found in persons who are exposed to cytotoxic agents and/or ionizing radiation therapy (Larson, 2017; Shiffer and Gurbuxani, 2017). The definition of AML with myelodysplasia-related changes (AML-MRC)  includes criteria for AML (≥ 20 percent blasts in the peripheral blood or bone marrow) and absence of a history of prior cytotoxic therapy for an unrelated disease, and with one or more of the following characteristics:

1. AML that has evolved from previously documented myelodysplastic syndrome (MDS),
2. AML that contains MDS-related cytogenetic abnormalities, and/or
3. AML that demonstrates multilineage dysplasia (Dunphy, 2017; Schiffer and Gurbuxani, 2022).

Patients with newly diagnosed t-AML or AML-MRC have very low life expectancies (FDA, 2017).

On August 3, 2017, the U.S. Food and Drug Administration approved Vyxeos, a liposomal combination of daunorubicin, an anthracycline topoisomerase inhibitor, and cytarabine, a nucleoside metabolic inhibitor, for the treatment of adults with newly-diagnosed therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC), which are two types of AML having a poor prognosis. The 1:5 molar ratio of daunorubicin:cytarabine has been shown to have synergistic effects at killing leukemia cells in vitro and in murine models (FDA, 2017).

FDA approval was based on data from Study 1 (NCT01696084), a randomized (1:1), multicenter, open-label, active-controlled trial comparing Vyxeos to a standard combination of daunorubicin and cytarabine (7+3) in 309 patients 60-75 years of age with newly-diagnosed t-AML or AML-MRC. Vyxeos demonstrated an estimated median overall survival of 9.6 months compared with 5.9 months for the 7+3 control (hazard ratio 0.69; 95% CI: 0.52, 0.90; p=0.005). The conclusion was that Vyxeos demonstrated superiority in overall survival compared with the 7+3 control (FDA, 2017).

Inclusion criteria included pathological diagnosis of AML according to WHO criteria (with at least 20% blasts in the peripheral blood or bone marrow), t-AML must have had documentation of history of prior cytotoxic therapy or ionizing radiotherapy for an unrelated disease, MDSAML must have had bone marrow documentation of prior MDS, de novo AML must have had cytogenetics with abnormalities per WHO, and a cardiac ejection fraction ≥ 50% by echocardiography or MUGA. Patients with second malignancies in remission were eligible if there was clinical evidence of disease stability for a period of greater than 6 months off cytotoxic chemotherapy, documented by imaging, tumor marker studies, etc., at screening. Patients maintained on long-term non-chemotherapy treatment, e.g., hormonal therapy, were eligible.  However, except for CMMoL, patients with history of myeloproliferative neoplasms (MPN) (defined as a history of essential thrombocytosis or polycythemia vera, or idiopathic myelofibrosis prior to the diagnosis of AML) or combined MDS/MPN, patients with prior cumulative anthracycline exposure of greater than 368 mg/m2 daunorubicin (or equivalent), and heart failure  NYHA Class III or IV were excluded from the study (not an all-inclusive list) (Jazz, 2017).

On June 28, 2018, the Committee for Medicinal Products for Human Use adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Vyxeos, intended for the treatment of acute myeloid leukemia (AML). "The pivotal study showed similar outcome across age subgroups (60–69 years and 70–75 years), although it excluded patients aged less than 60 years. Most patients that receive the standard treatment need to be fit for intensive chemotherapy, and therefore, patients’ performance status and their suitability to receive the treatment is based on clinical judgement and the physician's decision". Accoring to Tzogani and colleagues (2020), "for patients aged less than 60 years with high‐risk AML scheduled to receive the standard 7+3, Vyxeos seems an optimized formulation that is likely to be superior to 7 + 3 given the results in patients aged more than 60 years from the pivotal study. It appears there are no differences in disease biology for treatment‐related AML or AML with myelodysplasia‐related changes between adult age subgroups. Prognosis is very poor, and these subtypes of AML represent an unmet medical need irrespective of age" (Tzogani et al, 2020).

On March 30, 2021, the U.S. Food and Drug Administration (FDA) approved a revised label for Vyxeos (daunorubicin and cytarabine) to include a new indication to treat newly-diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC) in pediatric patients aged one year and older. The approval for this indication was based on safety data from two single-arm trials: AAML 1421 and CPX-MA-1201. Additionally, the effectiveness of Vyxeos for this indication was supported from study CPX351-301 in adult patients (Jazz, 2021a).

Lancet and associates (2021) stated that daunorubicin and cytarabine are used as standard induction chemotherapy for patients with AML.  CPX-351 is a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio.  Primary analysis of the phase-III clinical trial in adults aged 60 to 75 years with newly diagnosed high-risk or secondary AML provided support for approval of CPX-351 by the FDA and European Medicines Agency (EMA).  These researchers described the prospectively planned final 5-year follow-up results of the randomized, open-label, multi-center, phase-III clinical trial carried out in 39 academic and regional cancer centers in the U.S. and Canada.  Eligible patients were aged 60 to 75 years and had a pathological diagnosis of AML according to World Health Organization (WHO) 2008 criteria, no previous induction therapy for AML, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.  Patients were randomly assigned 1:1 (stratified by age and AML subtype) to receive up to 2 induction cycles of CPX-351 (100 units/m2 administered as a 90-min intravenous infusion on days 1, 3, and 5; on days 1 and 3 for the 2nd induction) or standard chemotherapy (cytarabine 100 mg/m2 per day continuous intravenous infusion for 7 days plus intravenous daunorubicin 60 mg/m2 on days 1, 2, and 3 [7+3]; cytarabine for 5 days and daunorubicin on days 1 and 2 for the 2nd induction [5+2]).  Patients with complete remission (CR) or complete remission with incomplete neutrophil or platelet recovery (CRi) could receive up to 2 cycles of consolidation therapy with CPX-351 (65 units/m2 90-min infusion on days 1 and 3) or chemotherapy (5+2, same dosage as in the 2nd induction cycle).  The primary outcome was overall survival (OS) analyzed in all randomly assigned patients.  No additional adverse events (AEs) were collected with long-term follow-up, except data for deaths.  Between December 20, 2012, and November 11, 2014, a total of 309 patients with newly diagnosed high-risk or secondary AML were enrolled and randomly assigned to receive CPX-351 (153 patients) or 7+3 (156 patients).  At a median follow-up of 60.91 months (inter-quartile range [IQR] 60.06 to 62.98) in the CPX-351 group and 59.93 months (59.73 to 60.50) in the 7+3 group, median OS was 9.33 months (95 % CI: 6.37 to 11.86) with CPX-351 and 5.95 months (4.99 to 7.75) with 7+3 (hazard ratio [HR] 0.70, 95 % CI: 0.55 to 0.91); 5-year OS was 18 % (95 % CI: 12 % to 25 %) in the CPX-351 group and 8 % (4 % to 13 %) in the 7+3 group.  The most common cause of death in both groups was progressive leukemia (70 [56 %] of 124 deaths in the CPX-351 group and 74 [53% ] of 140 deaths in the 7+3 group); 6 (5 %) of 124 deaths in the CPX-351 group and 7 (5 %) of 140 deaths in the 7+3 group were considered related to study treatment.  The authors concluded that after 5 years of follow-up, the improved OS with CPX-351 versus 7+3 was maintained, which supported the previous evidence that CPX-351 could contribute to long-term remission and improved OS in patients aged 60 to 75 years with newly diagnosed high-risk or secondary AML.

Cortes and colleagues (2021) noted that CPX-351 (Vyxeos) is approved by the FDA for the treatment of adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes.  In a phase-III clinical trial that examined 309 patients aged 60 to 75 years with newly diagnosed high-risk/secondary AML, CPX-351 significantly improved median OS versus conventional 7 + 3 chemotherapy (cytarabine continuous infusion for 7 days plus daunorubicin for 3 days), with a comparable safety profile.  A Quality-adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis of the phase-III clinical trial was carried out to compare survival quality between patients receiving CPX-351 versus conventional 7 + 3 after 5 years of follow-up.  Patients were randomized 1:1 between December 20, 2012 and November 11, 2014 to receive induction with CPX-351 or 7 + 3.  Survival time for each patient was partitioned into 3 health states: TOX (time with any grade 3 or 4 toxicity or prior to remission), TWiST (time in remission without relapse or grade 3 or 4 toxicity), and REL (time after relapse).  Within each treatment arm, Q-TWiST was calculated by adding the mean time spent in each health state weighted by its respective quality-of-life (QOL), represented by health utility.  The relative Q-TWiST gain, calculated as the difference in Q-TWiST between treatment arms divided by the mean survival of the 7 + 3 control arm, was determined in order to examine results in the context of other Q-TWiST analyses.  The relative Q-TWiST gain with CPX-351 versus 7 + 3 was 53.6 % in the base case scenario and 39.8 % among responding patients.  Across various sensitivity analyses, the relative Q-TWiST gains for CPX-351 ranged from 48.0 % to 57.6 %, remaining well above the standard clinically important difference threshold of 15 % for oncology.  The authors concluded that this post-hoc analysis demonstrated that CPX-351 improved quality-adjusted survival, further supporting the clinical benefit in patients with newly diagnosed high-risk/secondary AML.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
Other CPT codes related to the CPB:
96413 - 96417	Chemotherapy administration, intravenous infusion technique
HCPCS codes covered if selection criteria are met:
J9153	Injection, liposomal, 1 mg daunorubicin and 2.27 mg cytarabine
ICD-10 codes covered if selection criteria are met:
C92.00 - C92.50	Acute myelomonocytic leukemia
C92.60 - C92.62	Acute myeloid leukemia with 11q23-abnormality
C92.A0 - C92.A2	Acute myeloid leukemia with multilineage dysplasia
C93.10 - C93.12	Chronic myelomonocytic leukemia
D46.0 - D46.Z, D46.9	Myelodysplastic syndromes

The above policy is based on the following references: