CPX-351 in Down syndrome-associated Myeloid Leukemia: Results and Prognostic Factors from the Phase 3 ML-DS 2018 Trial Open Access

• CPX-351 (66U/m2) in children with ML-DS resulted in significantly lower EFS compared to standard induction

• Positive MRD by error-corrected GATA1 NGS, trisomy 8, complex karyotype and TP53 mutations was associated with increased relapse risk

Myeloid leukemia in children with Down Syndrome (ML-DS) is associated with an excellent prognosis but high treatment-related toxicity and mortality. The ML-DS 2018 trial aimed to maintain the excellent event-free survival achieved in the previous ML-DS 2006 trial while further reducing treatment intensity. Children aged 6 months to 6 years with ML-DS were eligible. Intensity-reduced induction and reinduction therapy with cytarabine, idarubicin ± etoposide of the ML-DS 2006 trial was replaced with CPX-351 (66 U/m² on three days in course 1 and two days in course 2). Risk stratification was based on flow cytometric measurable residual disease after first induction. High-risk patients received high-dose cytarabine (3 g/m²/12h) in consolidation; standard-risk patients received 1 g/m²/12h. Thirty-five patients were enrolled until the trial was halted due to an unexpectedly high relapse rate. A per protocol interim analysis revealed a significantly lower 24-month event-free survival compared to the ML-DS 2006 trial (69% vs. 90%, P<.001). In contrast to previous studies, most relapsed patients responded to salvage therapy, resulting in a comparable 24-month overall survival of 88% (vs. 92% in ML-DS 2006, P=.612). CPX-351 demonstrated a favorable toxicity profile with no treatment-related mortality. Positive measurable residual disease by error-corrected GATA1 next-generation sequencing, as well as the presence of trisomy 8 or a complex karyotype, were associated with an increased risk of relapse. In conclusion, replacing intensity-reduced induction therapy with CPX-351 in ML-DS resulted in significantly lower event-free survival, highlighting the need for dose optimization to balance efficacy and toxicity in this sensitive patient population. EudraCT: 2018-002988-25