Background: CPX-351 (Vyxeos®) is a liposomal nanoparticle of cytarabine and daunorubicin in a 5:1 molar ratio currently FDA approved for treatment of adults with newly-diagnosed therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes. The agent also has potent activity against acute lymphoblastic leukemia (ALL) in murine xenograft models [H. Carol et al. Pediatr Blood Cancer 2015;62: 65-71]. We conducted the first phase I/pilot study to evaluate the safety and describe the efficacy of CPX-351 in children and adolescents with relapsed or refractory (R/R) acute leukemia (NCT01943682).

Methods: In the Dose Exploration Phase participants age 12 months to 21 years were eligible to receive a single course of CPX-351 administered once daily on Days 1, 3, and 5. Enrollment was initiated at the recommended dose for study in adults (Dose Level 1: 100 Units/m2/dose= cytarabine 100 mg/m2 and daunorubicin 44 mg/m2 per dose) with provisions to explore either a single dose escalation to 134 Units/m2/dose (Dose Level 2) or de-escalation to 67 Units/m2/dose. Response was determined after Day 28. The upper age for eligibility was increased to 30 years and an additional 18 subjects were enrolled into the Expanded Phase of the study.

Results: Nine children and adolescents with R/R AML (n=6) or ALL (n=3) were enrolled and evaluable for toxicity in the Dose Exploration Phase. All 9 experienced Grade 3 or 4 hematologic toxicity including 8 with fever with neutropenia or infection. Dose Limiting Toxicity (DLT) was not observed in the 4 patients enrolled at Level 1 but Grade 3 pain/headache lasting greater than 48 hours did occur in 2 of the 5 patients treated at Dose Level 2. One patient with AML was unevaluable for response in this phase due to removal from protocol therapy to receive bone marrow transplantation while in aplasia. All others were evaluable for response. One patient with ALL had stable disease, 2 with AML achieved a complete remission (CR), and 1 with AML achieved a CR in blood and marrow but developed low level disease in the cerebral spinal fluid (CSF).

One patient with mixed phenotype acute leukemia and 17 with R/R AML were subsequently enrolled into the Expanded Phase of the study to receive CPX-351 at Dose Level 1. CPX-351 treatment was well tolerated in this population with a similar toxicity profile observed in the Dose Exploration Phase. Dose limiting prolonged aplasia occurred in one patient but no other DLTs were observed. The response has yet to be determined in one patient. To date, seven patients with AML (41%) achieved a CR or complete remission with incomplete blood recovery (CRi). Another patient achieved a CR in marrow but with low level disease detected in the CSF similar to the patient described in the Dose Exploration phase. The remaining 9 patients failed to achieve a clinical response. Pharmacokinetic (PK) parameters of total cytarabine and daunorubicin were analyzed for 21 of these pediatric patients and the results were similar to those observed in adults. However, due to the small sample size of each age group, these interim PK results will need to be validated as data in pediatric patients become available from future clinical studies.

Conclusions: CPX-351 100 Units/m2/dose on Days 1, 3, and 5 was well tolerated in this pediatric population and has promising activity in children and young adults with R/R AML. Additional CNS directed therapy is recommended for pediatric patients at high risk for failure in the CNS.


Phillips:Novartis AG: Consultancy. An:Jazz Pharmaceuticals: Employment.

Author notes


Asterisk with author names denotes non-ASH members.

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