Vyxeos (Daunorubicin-Cytarabine) Liposome

Number: 0921

Policy

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

   1. Induction therapy, and
       
      1. Member is 60 years of age and older and a candidate for intensive remission induction therapy, or
         
   2. Re-induction therapy, and
       
      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, or
         
   3. Post-remission therapy, and 
       
      1. Member is less than 60 years of age with treatment-related disease without CBF abnormalities, unfavorable cytogenetics, or molecular abnormalities, or
      2. Member is 60 years of age and older with complete response to previous intensive therapy.
         
         
2. Aenta considers continuation of Vyxeos (daunorubicin-cytarabine) liposome medically necessary for members with acute myeloid leukemia, myelodysplastic syndrome, or chronic myelomonocytic leukemia who met initial selection criteria and have not experienced disease progression or an unacceptable toxicity from therapy.
   
   

3. Aetna considers Vyxeos (daunorubicin-cytarabine) liposome experimental and investigational for all other indications.

Dosing Recommendations

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. For additional information, consult the Full Prescribing Information (Jazz Pharmaceuticals, 2017):

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 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.

Background

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: (i) AML that has evolved from previously documented myelodysplastic syndrome (MDS), (ii) AML that contains MDS-related cytogenetic abnormalities, and/or (iii) AML that demonstrates multilineage dysplasia (Dunphy, 2017; Schiffer and Gurbuxani, 2017). 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).

Per prescribing information, common side effects (≥ 25%) include hemorrhage 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. The prescribing information also includes a boxed warning not to interchange Vyxeos with other daunorubicin- and/or cytarabine-containing products due to Vyxeos has different dosage recommendations than daunorubicin hydrochloride injection, cytarabine injection, daunorubicin citrate liposome injection, and cytarabine liposome injection (FDA, 2017).

National Comprehensive Cancer Network (NCCN)

The National Comprehensive Cancer Network Drugs and Biologics Compendium (NCCN, 2019) include the following recommendations for Vyxeos:

• For treatment induction for patients with therapy-related AML, antecedent MDS/CMML, or cytogenetic changes that are consistent with MDS (AML-MRC)
   
  • in patients age <60 years without core binding factor (CBF) abnormalities (category 2B)
  • in patients age ≥60 years in candidates for intensive remission induction therapy (category 1)
     
• For re-induction (preferred if given in induction) after standard-dose cytarabine induction for patients with therapy-related AML or patients with antecedent MDS/CMML or cytogenetic changes that are consistent with MDS (AML-MRC)
   
  • for patients age <60 years with significant residual disease without a hypocellular marrow and without core binding factor (CBF) abnormalities ( category 2A)
  • for patients age ≥60 years with residual disease (category 2A)
     
• For post-remission therapy (preferred if given in induction) for patients with therapy-related AML or patients with antecedent MDS/CMML or cytogenetic changes that are consistent with MDS (AML-MRC)
   
  • for patients age <60 yearswith treatment-related disease other than core binding factor (CBF) and/or unfavorable cytogenetics and/or molecular abnormalities (category 2A)
  • for patients age ≥60 years with complete response to previous intensive therapy (category 2A).
    

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: