CPX-351 in Down syndrome-associated myeloid leukemia: results and prognostic factors from the phase 3 ML-DS 2018 trial.

Myeloid leukemia of Down syndrome (ML-DS) is associated with an excellent prognosis but high treatment-related toxicity and mortality. The Phase 3 Clinical Trial for CPX-351 in ML-DS 2018 aimed to maintain the excellent event-free survival (EFS) achieved in the previous ML-DS 2006 trial while reducing the treatment intensity. Intensity-reduced induction and reinduction therapy with cytarabine and idarubicin with or without etoposide was replaced with CPX-351 (66 U/m2 on 3 days in course 1 and on 2 days in course 2). Risk stratification was based on flow cytometric measurable residual disease (MRD) after first induction. High-risk patients received high-dose cytarabine (3 g/m2 per 12 hour) in consolidation; standard-risk patients received cytarabine at a dose of 1 g/m2 per 12 hour. A total of 35 patients were enrolled until the trial was halted because of an unexpectedly high relapse rate. A per-protocol interim analysis revealed a significantly lower 24-month EFS when compared with the ML-DS 2006 trial (69% vs 90%; P< .001). In contrast with previous studies, most patients who relapsed responded to salvage therapy, leading to a comparable 24-month overall survival of 88% (vs 92%; P = .612). CPX-351 demonstrated a favorable toxicity profile with no treatment-related mortality. Positive MRD by error-corrected GATA1 next-generation sequencing, the presence of trisomy 8 or a complex karyotype were associated with an increased risk for relapse. In conclusion, replacing intensity-reduced induction therapy with CPX-351 in ML-DS led to a significantly lower EFS, highlighting the need for dose optimization to balance the efficacy and toxicity in this sensitive patient population. This trial was registered at https://www.clinicaltrialsregister.eu as EudraCT #2018-002988-25.