The FDA has approved daunorubicin and cytarabine (Vyxeos®, Jazz Pharmaceuticals) for pediatric patients one year and older with newly diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes.
"Effective regimens are needed for children with relapsed acute myeloid leukemia (AML)," wrote Todd Cooper, DO, of Seattle Children's Hospital, and colleagues, in their May publication in the Journal of Clinical Oncology of AAML1421 (NCT02642965), one of the studies on which the approval was based. "AAML1421 sought to determine the recommended phase II dose of CPX-351 and the response rate after up to two cycles of therapy."
The approval was supported by safety data from two clinical trials, AAML1421 and CPX-MA-1201 (NCT01943682). AAML1421, a phase 1/2 study conducted by the Children's Oncology Group, enrolled 38 patients ages one to 21 years with AML in first relapse. CPX-MA-1201, a phase 1 study conducted by Cincinnati Children's Hospital, enrolled 27 patients ages one to 19 years with relapsed/refractory hematologic malignancies. These studies established safety and pharmacokinetics in children and young adults; according to AAML1421, toxicities of grade ≥3 during cycle 1 included fever/neutropenia (45%), infection (47%), and rash (40%), and there was no toxic mortality. Evidence of efficacy was provided by study CPX351-301 (NCT01696084) in adult patients.
Patients in AAML1421 were treated with different doses of daunorubicin/cytarabine to determine the recommended phase II dose; this was determined to be 135 units/m2 on days 1, 3, and 5. CPX-MA-1201 also tested different doses on days 1, 3, and 5 to determine the safer dose for children.
According to the prescribing information, adverse events occurring in at least 25% of patients included 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.
"Toxicity was manageable, and protocol therapy was effective," concluded Dr. Cooper and colleagues. "Response rates are superior to prior published North American cooperative group clinical trials for children with AML in first relapse."
The recommended induction dosage of daunorubicin/cytarabine is 44 mg/m2 daunorubicin and 100 mg/m2 cytarabine liposome via intravenous infusion over 90 minutes on days 1, 3, and 5 and on days 1 and 3 for subsequent cycles of induction, if needed. The recommended consolidation dosage is 29 mg/m2 daunorubicin and 65 mg/m2 cytarabine liposome via intravenous infusion over 90 minutes on days 1 and 3.
For More Information
Cooper TM, Absalon MJ, Alonzo TA, et al (2020). Phase I/II study of CPX-351 followed by fludarabine, cytarabine, and granulocyte-colony stimulating factor for children with relapsed acute myeloid leukemia: a report from the children's oncology group. J Clin Oncol, 38(19):2170-2177. DOI:10.1200/JCO.19.03306
Clinicaltrials.gov (2021). Liposome-encapsulated daunorubicin-cytarabine, fludarabine phosphate, cytarabine, and filgrastim in treating younger patients with relapsed or refractory acute myeloid leukemia. NLM identifier: NCT02642965.
Cision PR Newswire (2021). Jazz Pharmaceuticals announces FDA approval of additional indication for Vyxeos® (daunorubicin and cytarabine) for the treatment of secondary acute myeloid leukemia in pediatric patients. Available at: https://www.prnewswire.com/news-releases/jazz-pharmaceuticals-announces-fda-approval-of-additional-indication-for-vyxeos-daunorubicin-and-cytarabine-for-the-treatment-of-secondary-acute-myeloid-leukemia-in-pediatric-patients-301259059.html
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