Gemtuzumab Ozogamicin Improves Event-Free Survival and Reduces Relapse in Pediatric KMT2A-Rearranged AML: Results From the Phase III Children's Oncology Group Trial AAML0531

Abstract

Purpose: We investigated the impact of the CD33-targeted agent gemtuzumab ozogamicin (GO) on survival in pediatric patients with KMT2A-rearranged (KMT2A-r) acute myeloid leukemia (AML) enrolled in the Children's Oncology Group trial AAML0531 (NCT01407757).

Methods: Patients with KMT2A-r AML were identified and clinical characteristics described. Five-year overall survival (OS), event-free survival (EFS), disease-free survival (DFS), and relapse risk (RR) were determined overall and for higher-risk versus not high-risk translocation partners. GO's impact on response was determined and outcomes based on consolidation approach (hematopoietic stem cell transplant [HSCT] v chemotherapy) described.

Results: Two hundred fifteen (21%) of 1,022 patients enrolled had KMT2A-r AML. Five-year EFS and OS from study entry were 38% and 58%, respectively. EFS was superior with GO treatment (EFS 48% with GO v 29% without, P = .003), although OS was comparable (63% v 53%, P = .054). For patients with KMT2A-r AML who achieved complete remission, GO was associated with lower RR (40% GO v 66% patients who did not receive GO [No-GO], P = .001) and improved 5-year DFS (GO 57% v No-GO 33%, P = .002). GO benefit was observed in both higher-risk and not high-risk KMT2A-r subsets. For patients who underwent HSCT, prior GO exposure was associated with decreased relapse (5-year RR: 28% GO and HSCT v 73% No-GO and HSCT, P = .006). In multivariable analysis, GO was independently associated with improved EFS, improved DFS, and reduced RR.

Conclusion: GO added to conventional chemotherapy improved outcomes for KMT2A-r AML; consolidation with HSCT may further enhance outcomes. Future clinical trials should study CD33-targeted agents in combination with HSCT for pediatric KMT2A-r AML.

FIG 1.

Outcomes for patients with KMT2A-r versus KMT2A WT outcome by GO exposure. (A) Five-year EFS from study entry and (B) 5-year RR from CR. CR, complete remission; EFS, event-free survival; GO, gemtuzumab ozogamicin; KMT2A-r, KMT2A-rearranged; No-GO, not receiving GO; RR, relapse risk; WT, wild-type.

FIG 2.

EFS for patients with KMT2A-r acute myeloid leukemia. EFS from study entry for the entire study cohort (n = 215) and by specific translocation partners associated with higher-risk KMT2A-r AML (n = 70), non–high-risk KMT2A-r AML (n = 107), and other KMT2A-r subsets (n = 28). AML, acute myeloid leukemia; EFS, event-free survival; KMT2A-r, KMT2A-rearranged.

FIG 3.

Outcomes for patients with HR versus NHR patients with KMT2A-r AML by GO exposure. (A) EFS from study entry and (B) RR from CR. CR, complete remission; EFS, event-free survival; GO, gemtuzumab ozogamicin; HR, higher risk; KMT2A-r, KMT2A-rearranged; NHR, not high-risk; No-GO, did not receive GO; RR, relapse risk.

FIG 4.

Outcome for KMT2A-r acute myeloid leukemia by GO exposure and consolidation approach. (A) DFS by GO exposure for patients treated with GO and HSCT, (B) DFS by GO exposure for patients treated with chemotherapy only, and (C) RR by GO exposure and consolidation approach. DFS, disease-free survival; GO, gemtuzumab ozogamicin; HSCT, hematopoietic stem cell transplant; KMT2A-r, KMT2A-rearranged; No-GO, did not receive GO; RR, relapse risk.

FIG A1.

CONSORT diagram of the study population. DS, Down syndrome; GO, gemtuzumab ozogamicin; HSCT, hematopoietic stem cell transplant; KMT2A-r, KMT2A-rearranged; No-GO, did not receive GO; WT, wild type.

FIG A2.

CD33 expression in KMT2A-r AML. (A) Distribution of patients with KMT2A-r AML in AAML0531-defined CD33 expression quartiles. (B) Median CD33 MFI for KMT2A-r versus KMT2A-WT and for HR versus NHR KMT2A-r AML. AML, acute myeloid leukemia; HR, higher risk; KMT2A-r, KMT2A-rearranged; MFI, mean fluorescence intensity; NHR, non–high-risk; WT, wild-type.