Venetoclax and azacytidine in childhood primary advanced myelodysplastic syndromes, refractory/relapsed acute myeloid leukemia and therapy-related myeloid neoplasms

Pediatric refractory/relapsed acute myeloid leukemia (r/r-AML), myelodysplastic syndromes with excess blasts (MDSEB), and therapy-related MDS/AML (t-MDS/AML) remain a clinical challenge due to high rate of treatment failure. Venetoclax plus azacytidine (ven/aza) has transformed adult myeloid neoplasm treatment, but pediatric data are limited and heterogeneous. This AIEOP retrospective, multicenter study analyzed 50 patients (M/F=1.8/1; median age 11 years) with r/r-AML (n=32), MDS-EB (n=10), or t-MDS/AML (n=8) treated with ven/aza. Responses were defined as complete (CR), partial (PR), or non-response (NR) based on bone marrow (BM) blast evaluation. Adverse events (AEs) were graded per CTCAE v5.0; outcomes were evaluated with Kaplan-Meier and Cox-regression analysis. Patients received a median of 2 cycles (range, 1-7). Grade ≥3 AEs occurred in 34% of patients. Overall, 30 patients (60%) achieved CR (24 MRD-negative), 9 (18%) PR, and 11 (22%) NR. CR were 58%, 57% and 100% in KMT2A-AML, FLT3-ITD-AML (ven/aza+FLT3-inhibitors) and UBTF-TD myeloid neoplasms, respectively. In 10 MDS-EB, 7 CR and 2 PR were recorded. In 8 t-MDS/AML, we observed 5 CR and 2 PR. Thirty-three patients (66%) underwent hematopoietic cell transplantation (HCT), after a median of 97 days (range: 33-933) from ven/aza start. Median follow-up was 389 days (range 36-1405). Two-year event-free survival (EFS) was 54.5% (CI:46.7-62.3), being 75.8% in transplanted patients, and 77.2% in those achieving CR. CR and HCT were associated with better EFS. Ven/aza shows substantial activity and manageable toxicity in pediatric high-risk myeloid diseases, especially as a bridge to HCT and in specific molecular subgroups, supporting future, prospective, genetically-guided studies.