Measurable Residual Disease and Fusion Partner Independently Predict Survival and Relapse Risk in Childhood <i>KMT2A</i>-Rearranged Acute Myeloid Leukemia: A Study by the International Berlin-Frankfurt-Münster Study Group
Romy E. van Weelderen, Kim Klein, Christine J. Harrison, Yilin Jiang, Jonas Abrahamsson, Nira Arad‐Cohen, Emmanuelle Bart–Delabesse, Barbara Buldini, Barbara De Moerloose, Michael Dworzak, Sarah Elitzur, José María Fernández Navarro, Robert B. Gerbing, Bianca F. Goemans, Hester A. de Groot‐Kruseman, Erin Guest, Sy Ha, Henrik Hasle, Charikleia Kelaïdi, Hélène Lapillonne, Guy Leverger, Franco Locatelli, Riccardo Masetti, Takako Miyamura, Ulrika Norén‐Nyström, Sophia Polychronopoulou, Mareike Rasche, Jeffrey E. Rubnitz, Jan Starý, Anne Tierens, Daisuke Tomizawa, C. Michel Zwaan, Gertjan J.L. Kaspers
Abstract
PURPOSE A previous study by the International Berlin-Frankfurt-Münster Study Group (I-BFM-SG) on childhood KMT2A-rearranged ( KMT2A-r) AML demonstrated the prognostic value of the fusion partner. This I-BFM-SG study investigated the value of flow cytometry-based measurable residual disease (flow-MRD) and evaluated the benefit of allogeneic stem-cell transplantation (allo-SCT) in first complete remission (CR1) in this disease. METHODS A total of 1,130 children with KMT2A-r AML, diagnosed between January 2005 and December 2016, were assigned to high-risk (n = 402; 35.6%) or non–high-risk (n = 728; 64.4%) fusion partner-based groups. Flow-MRD levels at both end of induction 1 (EOI1) and 2 (EOI2) were available for 456 patients and were considered negative (<0.1%) or positive (≥0.1%). End points were 5-year event-free survival (EFS), cumulative incidence of relapse (CIR), and overall survival (OS). RESULTS The high-risk group had inferior EFS (30.3% high risk v 54.0% non-high risk; P < .0001), CIR (59.7% v 35.2%; P < .0001), and OS (49.2% v 70.5%; P < .0001). EOI2 MRD negativity was associated with superior EFS (n = 413; 47.6% MRD negativity v n = 43; 16.3% MRD positivity; P < .0001) and OS (n = 413; 66.0% v n = 43; 27.9%; P < .0001), and showed a trend toward lower CIR (n = 392; 46.1% v n = 26; 65.4%; P = .016). Similar results were obtained for patients with EOI2 MRD negativity within both risk groups, except that within the non–high-risk group, CIR was comparable with that of patients with EOI2 MRD positivity. Allo-SCT in CR1 only reduced CIR (hazard ratio, 0.5 [95% CI, 0.4 to 0.8]; P = .00096) within the high-risk group but did not improve OS. In multivariable analyses, EOI2 MRD positivity and high-risk group were independently associated with inferior EFS, CIR, and OS. CONCLUSION EOI2 flow-MRD is an independent prognostic factor and should be included as risk stratification factor in childhood KMT2A-r AML. Treatment approaches other than allo-SCT in CR1 are needed to improve prognosis.