title: Integrated use of minimal residual disease classification and IKZF1 alteration status accurately predicts 79% of relapses in pediatric acute lymphoblastic leukemia.
abstract: Response to therapy as determined by minimal residual disease (MRD) is currently used for stratification in treatment protocols for pediatric acute lymphoblastic leukemia (ALL). However, the large MRD-based medium risk group (MRD-M; 50-60% of the patients) harbors many relapses. We analyzed MRD in 131 uniformly treated precursor-B-ALL patients and evaluated whether combined MRD and IKZF1 (Ikaros zinc finger-1) alteration status can improve risk stratification. We confirmed the strong prognostic significance of MRD classification, which was independent of IKZF1 alterations. Notably, 8 of the 11 relapsed cases in the large MRD-M group (n=81; 62%) harbored an IKZF1 alteration. Integration of both MRD and IKZF1 status resulted in a favorable outcome group (n=104; 5 relapses) and a poor outcome group (n=27; 19 relapses), and showed a stronger prognostic value than each of the established risk factors alone (hazard ratio (95%CI): 24.98 (8.29-75.31)). Importantly, whereas MRD and IKZF1 status alone identified only 46 and 54% of the relapses, respectively, their integrated use allowed prediction of 79% of all the relapses with 93% specificity. Because of the unprecedented sensitivity in upfront relapse prediction, the combined parameters have high potential for future risk stratification, particularly for patients originally classified as non-high risk, such as the large group of MRD-M patients.
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, Radboud University Centre of Oncology and Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Waanders
authors.forename: V H J
authors.initials: VH
authors.lastname: van der Velden
authors.forename: C E
authors.initials: CE
authors.lastname: van der Schoot
authors.forename: F N
authors.initials: FN
authors.lastname: van Leeuwen
authors.forename: S V
authors.initials: SV
authors.lastname: van Reijmersdal
authors.forename: V
authors.initials: V
authors.lastname: de Haas
authors.forename: A J
authors.initials: AJ
authors.lastname: Veerman
authors.forename: A Geurts
authors.initials: AG
authors.lastname: van Kessel
authors.forename: P M
authors.initials: PM
authors.lastname: Hoogerbrugge
authors.forename: R P
authors.initials: RP
authors.lastname: Kuiper
authors.forename: J J M
authors.initials: JJ
authors.lastname: van Dongen
mesh_terms: D002648:Child; D015321:Gene Rearrangement; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics*; D053208:Kaplan-Meier Estimate; D009154:Mutation; D018365:Neoplasm, Residual / Q000473:pathology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000401:mortality / Q000473:pathology*; D011237:Predictive Value of Tests; D012008:Recurrence; D018570:Risk Assessment; D012680:Sensitivity and Specificity
chemical_list: C497239:IKZF1 protein, human; D051740:Ikaros Transcription Factor