Vyxeos (Daunorubicin-Cytarabine) Liposome

Number: 0921

Policy

1. Aetna considers Vyxeos (daunorubicin-cytarabine) liposome medically necessary for the treatment of adults with cytotoxic 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 less than 60 years of age without core binding factor (CBF) abnormalities, or
      2. Member is 60 years of age and older and candidate for intensive remission induction therapy with unfavorable cytogenetic/molecular markers, antecendent hematologic disorder, or therapy-related AML, or
   2. Re-induction after standard-dose cytarabine induction therapy, and
       
      1. Member is less than 60 years of age with significant residual disease without a hypocellular marrow and without 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 without CBF abnormalities, treatment-related disease, poor-risk cytogenetics, and/or molecular abnormalities, or
      2. Member is 60 years of age and older with complete response to previous intensive therapy.

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

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).

The National Comprehensive Cancer Network (NCCN) Drugs and Biologics Compendium (2018) include the following recommendations for Vyxeos:

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

Appendix

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.

Recommended dosing per FDA-approved labeling are as follows (FDA, 2017):

• Calculate the lifetime cumulative anthracycline daunorubicin exposure prior to each cycle of Vyxeos, as Vyxeos is not recommended in patients whose lifetime exposure has reached the maximum cumulative limit. (Total cumulative doses of non-liposomal daunorubicin greater than 550 mg/m2 have been associated with an increased incidence of drug-induced congestive heart failure. The tolerable limit appears lower (400 mg/m2) in patients who received radiation therapy to the mediastinum) Note that the clinical study only included patients with prior lifetime cumulative anthracycline exposure less than 368 mg/m2 daunorubicin.
• Calculate the Vyxeos dose based on daunorubicin and patient’s BSA.
• Calculate the number of vials of Vyxeos based on the daunorubicin dose.
• Calculate the volume of reconstituted Vyxeos required using the following formula: [volume required (mL) = dose of daunorubicin (mg/m2) X patient’s BSA (m2) ÷2.2 (mg/mL)].
• 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 patients 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 patients who do not show disease progression or unacceptable toxicity.

Recommended dosing per NCCN guidelines on "Acute myeloid leukemia" (version 2.2018):

• Induction therapy -
   
  • Adults less than 60 years of age, and 60 years of age and older when criteria met: cytarabine 100 mg/m2 and daunorubicin 44 mg/m2 IV over 90 minutes on days 1, 3, and 5.
     
• Re-induction after standard-dose cytarabine induction therapy -
   
  • Adults less than 60 years of age and 60 years of age and older when criteria met: cytarabine 100 mg/m2 and daunorubicin 44 mg/m2 IV over 90 minutes on days 1 and 3.
     
• Post-remission therapy -
   
  • Adults less than 60 years of age, and 60 years of age and older when criteria met: cytarabine 65 mg/m2 and daunorubicin 29 mg/m2 IV over 90 minutes on days 1 and 3.
     
    

The above policy is based on the following references: