FDA Approves a Revised Indication for Daunorubicin/Cytarabine for the Treatment of Pediatric AML

March 31, 2021
Sara Karlovitch

The FDA has revised the approval of daunorubicin and cytarabine to add 2 new indications for the treatment of newly diagnosed therapy-related acute myeloid leukemia or for AML with myelodysplasia-related changes in pediatric patients aged 1 year and older.

The FDA has revised the approval of daunorubicin and cytarabine (Vyxeos) to add 2 new indications for the treatment of newly diagnosed therapy-related acute myeloid leukemia (t-AML) or for AML with myelodysplasia-related changes (AML-MRC) in pediatric patients aged 1 year and older, according to a press release by Jazz Pharmaceuticals.1

The drug is a liposomal combination of daunorubicin, an anthracycline topoisomerase inhibitor, and cytarabine, a nucleoside metabolic inhibitory. 1

The expanded approval is based on data from 2 single-arm studies, AAML1421 (NCT02642965) and CPX-MA-1201 (NCT01943682). Both studies were used to establish the efficacy and safety of the combination.1

In AAML1421, 38 participants received intratumoral (IT) or intravenous (IV) cytarabine on day 0 then again at day 28-30, or up to 7 days prior to the start of course 2 and the combination of daunorubicin-cytarabine intravenously over 90 minutes on days 1, 3, and 5. Patients without evidence of central nervous system (CNS) disease received no further CNS-directed therapies. However, patients with evidence of CNS2 received an additional 4-6 doses of cytarabine given IT or IV twice weekly starting 48 hours after the third dose of the combination until CNS is clear. Patients who met the criteria were able to move onto course 2, where participants received filgrastim on days 1-5 and again on day 15 until blood count recovery. Patients then received a fludarabine phosphate IV over 30 minutes and high-dose cytarabine IV over 1-3 hours once daily on days 1-5. After the study was complete, patients were followed-up with periodically for 12 months then yearly for 5 years. 

The primary outcome of the study was the number of participants with dose-limiting toxicities (DLTs), and the percentage of responders. Secondary outcomes included liposome-encapsulated daunorubicin clearance. In order to participate, patients must be between 1 and 21 years old, verified AML at original diagnosis and recurrent disease with less than or equal to 5% blasts in bone marrow or recurrent disease with an absolute blast count greater than 1000 per microliter in the peripheral blood. Patients who have received daunorubicin equivalents or receiving another investigational drug were excluded.

The study found that 1 in 6 patients experienced DLTs. There was only one incidence of grade 3 cardiac toxicity. The most common AEs were fever/neutropenia (45%), and rash (40%). According to the study, there were no toxic mortality. Of the 38 patients, 70% achieved best response after cycle 1.2

In CPX-351, 27 participants received a single course of cytarabine and daunorubicin on days 1, 3, and 5. Primary outcomes of the study included dose limiting toxicities, number of participants with DLTs in order to determine maximum tolerated dose, and pharmacokinetics. Secondary outcomes included tumor measurement by bone marrow biopsy, blood counts, and/or PET/CT scan.

In order to participate, patients must be between 1 and 21 years old in the dose exploration phase and 1 to 30 years at the time of enrollment into the expanded phase. Patients must also have a diagnosis of AML, acute lymphoblastic leukemia, or aggressive lymphoma. Patients with acute promyelocytic leukemia, down syndrome, Fanconi amenia, acute lymphoblastic leukemia with central nervous system leukemia, and Wilson’s disease are not eligible.

No safety profile differences based on age were found. 1

Common AEs of the combination is fever, rash, sores in the mouth or throat, diarrhea, constipation, muscle pain, tiredness, and others.1

According label for daunorubicin plus cytarabine, more than 25% of patients may experience bleeding events, fever, rash, swelling, nausea, sores in the mouth or throat, diarrhea, constipation, muscle pain, tiredness, stomach pain, difficulty breathing, headache, cough, decreased appetite, irregular heartbeat, pneumonia, blood infection, chills, sleep disorders and vomiting.

"The expansion of the Vyxeos label to include children is a welcome and necessary advancement in support of some of our most vulnerable patients," said Edward Anders Kolb, MD, director of the Center for Cancer and Blood Disorders at Nemours/Alfred I. DuPont Hospital for Children and chair of myeloid disease committee at COG, in a press release.

REFERENCE:
1. Jazz Pharmaceuticals announces FDA approval of additional indication for Vyxeos® (daunorubicin and cytarabine) for the treatment of secondary acute myeloid leukemia in pediatric patients. News Release. Jazz Pharmaceuticals. March 30, 2021. Accessed March 30, 2021. https://bit.ly/31Awlnu
2. Copper, T., Absalon, M., Alonzo, T. et al. AAML 1421, a phase I/II study of CPX-351 followed by fludarabine, cytarabine, and G-CSF (FLAG) for children with relapsed acute myeloid leukemia (AML): A Report from the Children’s Oncology Group. J Clin Oncol. 2019; 37(suppl 15); 10003-10003. doi: 10.1200/JCO.2019.37.15_suppl.10003