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Transcript

((Dr. Abbas))

Hello, I’m Dr Jonathan Abbas. I’m the director of the acute leukemia and blood cancer program with Tennessee Oncology in Nashville, Tennessee. I specialize in hematologic malignancies, specifically acute leukemia, and my center treats over a hundred patients a year with aggressive chemotherapy for AML many of whom have sAML, including t-AML and AML-MRC.

CPX-351 (or VYXEOS) is a liposomal combination of a synergistic ratio of daunorubicin and cytarabine and is the only treatment recommended in the NCCN Guidelines® for induction in patients ≥60 years of age with t-AML or antecedent MDS/CMML or AML-MRC being a category 1 recommendation.

The 1:5 molar ratio of daunorubicin to cytarabine has been shown to have synergistic effects at killing leukemia cells in vitro and in murine models.

VYXEOS was approved by the FDA based on the results of a large Phase 3 trial in newly-diagnosed patients with t-AML or AML-MRC.

Patients could receive up to 2 cycles of induction and 2 cycles of consolidation in each arm. A second induction was highly recommended for patients who did not achieve a response and was mandatory for patients achieving >50% reduction in percent blasts.

VYXEOS is the first chemotherapy to demonstrate superior overall survival versus 7+3 in adults with newly-diagnosed t-AML or AML-MRC.

The Phase 3 multicenter, open-label, randomized study of VYXEOS versus 7+3 included 309 patients with newly-diagnosed t-AML or AML-MRC, aged 60 to 75 years.

Primary endpoint was OS.

Patient and disease characteristics were similar across both the VYXEOS and 7+3 treatment study arms.

Overall survival is more than double at 5 years with VYXEOS at 18% versus 8% with 7+3, based on KM estimate.

The reported adverse reactions for VYXEOS in the Phase 3 trial were generally consistent with the known safety profile of cytarabine and daunorubicin therapy.

VYXEOS was associated with lower 30- and 60-day mortality rates compared to treatment with 7+3.

  • 6% of patients in both the VYXEOS arm and the control arm had a fatal adverse reaction on treatment or within 30 days of therapy that was not in the setting of progressive disease. Overall, all-cause 30-day mortality was 6% in the VYXEOS arm and 11% in the control arm
  • During the first 60 days of the study, 14% of patients in the VYXEOS arm and 21% of patients in the 7+3 arm died
  • Fatal adverse reactions in the VYXEOS arm included infection, CNS hemorrhage, and respiratory failure

 

For years we have known that sAML is one of the most challenging types of AML to treat because so few of the diseases actually go into a remission.

Historically we’ve always used 7+3 as our induction due to the lack of superiority of any regimen in a randomized clinical trial, and this is why the study with VYXEOS is so significant because now we see not only improved overall survival but we also see a higher percentage of patients achieving that first remission, which opens the door for the potential curative stem cell transplant.

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INDICATION

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.

IMPORTANT SAFETY INFORMATION

WARNING: DO NOT INTERCHANGE WITH OTHER DAUNORUBICIN AND/OR CYTARABINE-CONTAINING PRODUCTS

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.

Contraindications

VYXEOS is contraindicated in patients with a history of serious hypersensitivity reactions to cytarabine, daunorubicin, or any component of the formulation.

Warnings and Precautions

Hemorrhage

Serious or fatal hemorrhage events, including fatal CNS hemorrhages, associated with prolonged thrombocytopenia, have occurred with VYXEOS. The overall incidence (grade 1-5) of hemorrhagic events was 74% in the VYXEOS arm and 56% in the control arm. The most frequently reported hemorrhagic event was epistaxis (36% in VYXEOS arm and 18% in control arm). Grade 3 or greater events occurred in 12% of VYXEOS-treated patients and in 8% of patients in the control arm. Fatal treatment-emergent CNS hemorrhage not in the setting of progressive disease occurred in 2% of patients in the VYXEOS arm and in 0.7% of patients in the control arm. Monitor blood counts regularly and administer platelet transfusion support as required.

Cardiotoxicity

VYXEOS contains daunorubicin, which has a known risk of cardiotoxicity. This risk may be increased in patients with prior anthracycline therapy, preexisting cardiac disease, previous radiotherapy to the mediastinum, or concomitant use of cardiotoxic drugs. Assess cardiac function prior to VYXEOS treatment and repeat prior to consolidation and as clinically required. Discontinue VYXEOS in patients with impaired cardiac function unless the benefit of initiating or continuing treatment outweighs the risk. VYXEOS is not recommended in patients with cardiac function that is less than normal.

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. Calculate the lifetime cumulative anthracycline exposure prior to each cycle of VYXEOS. VYXEOS is not recommended in patients whose lifetime anthracycline exposure has reached the maximum cumulative limit.

Hypersensitivity Reactions

Serious or fatal hypersensitivity reactions, including anaphylactic reactions, have been reported with daunorubicin and cytarabine. Monitor patients for hypersensitivity reactions. If a mild or moderate hypersensitivity reaction occurs, interrupt or slow the rate of infusion with VYXEOS and manage symptoms. If a severe or life-threatening hypersensitivity reaction occurs, discontinue VYXEOS permanently, treat the symptoms, and monitor until symptoms resolve.

Copper Overload

VYXEOS contains copper. Consult with a hepatologist and nephrologist with expertise in managing acute copper toxicity in patients with Wilson’s disease treated with VYXEOS. Monitor total serum copper, serum non-ceruloplasmin-bound copper, 24-hour urine copper levels, and serial neuropsychological examinations during VYXEOS treatment in patients with Wilson’s disease or other copper-related metabolic disorders. Use only if the benefits outweigh the risks. Discontinue in patients with signs or symptoms of acute copper toxicity.

Tissue Necrosis

Daunorubicin has been associated with severe local tissue necrosis at the site of drug extravasation. Administer VYXEOS by the intravenous route only. Confirm patency of intravenous access before administration. Do not administer by intramuscular or subcutaneous route.

Embryo-Fetal Toxicity

VYXEOS can cause embryo-fetal harm when administered to a pregnant woman. Patients should avoid becoming pregnant while taking VYXEOS. If VYXEOS is used during pregnancy or if the patient becomes pregnant while taking VYXEOS, apprise the patient of the potential risk to a fetus. Advise females and males of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of VYXEOS.

MOST COMMON ADVERSE REACTIONS

The most common adverse reactions (incidence ≥25%) are hemorrhagic events (74%), febrile neutropenia (70%), rash (56%), edema (55%), nausea (49%), mucositis (48%), diarrhea (48%), constipation (42%), musculoskeletal pain (43%), fatigue (39%), abdominal pain (36%), dyspnea (36%), headache (35%), cough (35%), decreased appetite (33%), arrhythmia (31%), pneumonia (31%), bacteremia (29%), chills (27%), sleep disorders (26%), and vomiting (25%).

Please see full Prescribing Information, including BOXED Warning.

INDICATION

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.

Important Safety Information

WARNING: DO NOT INTERCHANGE WITH OTHER DAUNORUBICIN AND/OR CYTARABINE-CONTAINING PRODUCTS

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.