Background and Significance: Secondary myeloid neoplasms (SMN) in children and adolescents are rare malignancies with dismal prognosis, lacking unified treatment approaches. SMN encompass therapy-related myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) and MDS/AML arising from bone marrow failure and germline predisposition syndromes. While hematopoietic stem cell transplantation (HSCT) remains the only curative option, outcomes remain poor with historical survival rates up to 45%. CPX-351 (Vyxeos®) is a liposomal formulation of cytarabine and daunorubicin in a fixed 5:1 molar ratio. CPX-351 demonstrated superior efficacy compared to standard chemotherapy in adult secondary AML, leading to FDA approval in 2017. The liposomal encapsulation preferentially accumulates in bone marrow and leukemic cells while potentially reducing systemic toxicity. There are no standardized treatment approaches for pediatric SMN and standard AML-type chemotherapy is associated with severe toxicity. Our institutional experience with CPX-351 in 7 pediatric patients with newly diagnosed SMN, all attaining complete morphologic remission with acceptable toxicity (Blood Adv 2022, PMID: 34710216), provided rationale for this study.

Study Design and Methods: This single-center, single-arm pilot study (ClinicalTrials.gov: NCT05656248) evaluates CPX-351 safety, tolerability, and efficacy in patients <22 years with SMN at St. Jude Children's Research Hospital. The study population includes patients with treatment-related MDS/AML (previously treated with chemotherapy/radiation) and secondary MDS/AML arising from inherited bone marrow failure syndromes (e.g. severe congenital neutropenia, Shwachman-Diamond syndrome and others) or germline predisposition syndromes involving mutations in GATA2, RUNX1, ERCC6L2, NF1, ETV6, TP53, and others). Patients with higher-risk MDS (5-20% blasts) are reviewed at interdisciplinary conference to determine eligibility for HSCT; if a decision is made that cytoreductive therapy is warranted, patients are offered enrollment on the trial. Additional inclusion criteria include adequate renal, hepatic, and cardiac function, adequate performance status, and cumulative doxorubicin-equivalent dose <400/500mg/m² (without/with cardioprotection). Key exclusion criteria include de novo AML, JMML, constitutional trisomy 21, telomere biology disorders, Fanconi anemia, other DNA repair disorders, Wilson disease, and cumulative anthracycline exposure beyond standard safety limits.

Treatment consists of CPX-351 100 units/m² (cytarabine 100mg/m² + daunorubicin 44mg/m²) on days 1, 3, and 5 of cycle 1. Cycle 2 administration depends on response: patients achieving complete remission (CR) with incomplete recovery (CRi) with measurable residual disease (MRD) <0.1% receive reduced-dose cycle of CPX-351 if HSCT is delayed (65mg/m² cytarabine + 29mg/m² daunorubicin), while patients with persistent disease receive standard dosing (if cumulative anthracycline exposure permits). If HSCT cannot be performed within 3-4 weeks after cycle 2, interim therapy options include additional FLT3 inhibitors for those patients with activating FLT3 mutations, or venetoclax alone or in combination. Response is assessed by bone marrow examination on Day 22 of each cycle with blast enumeration and MRD via flow cytometry (0.1% sensitivity).

The primary endpoint is evaluated using Simon's two-stage minimax design (n=25), with 80% power to detect a composite CR/CRi rate ≥70%. Tolerability monitoring employs a three-stage design with 88.8% power to declare the therapy tolerable success (defined as completing 2 cycles without grade 4-5 non-hematologic toxicity) when the true tolerability success rate is 70%. Secondary endpoints include characterization of toxicity (including respiratory and cardiac), biological correlates of response, and 3-year overall and event-free survival of patients who received 1 or 2 courses of CPX-351 followed by HSCT. Exploratory objectives include analysis of pharmacogenomic response scores and bulk/single-cell genomic studies.The trial opened in January 2023, with 24 of 25 planned patients enrolled as of July 2025 (15 male). Ages at enrollment range from 4 to 19 years, with diverse racial representation (10 white, 3 multiracial, 2 black, 1 Asian, 1 Pacific Islander, 7 unreported). No stopping rules have been triggered, and recruitment has proceeded without major protocol modifications.

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2025
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