Conflict of interest: Nothing to declare.
Ikaros (IKZF1) alterations and minimal residual disease at day 15 assessed by flow cytometry predict prognosis of childhood BCR/ABL-negative acute lymphoblastic leukemia†
Article first published online: 19 SEP 2012
Copyright © 2012 Wiley Periodicals, Inc.
Pediatric Blood & Cancer
Volume 60, Issue 3, pages 420–427, March 2013
How to Cite
Volejnikova, J., Mejstrikova, E., Dörge, P., Meissner, B., Zimmermannova, O., Svojgr, K., Stanulla, M., Cario, G., Schrappe, M., Stary, J., Hrusak, O., Trka, J. and Fronkova, E. (2013), Ikaros (IKZF1) alterations and minimal residual disease at day 15 assessed by flow cytometry predict prognosis of childhood BCR/ABL-negative acute lymphoblastic leukemia. Pediatr. Blood Cancer, 60: 420–427. doi: 10.1002/pbc.24299
- Issue published online: 15 JAN 2013
- Article first published online: 19 SEP 2012
- Manuscript Accepted: 6 AUG 2012
- Manuscript Received: 7 MAR 2012
- Czech Ministry of Health. Grant Number: NT 12397-4
- German Federal Ministry of Education and Research (BMBF; NGFN project number 01GS0442)
- Deutsche Krebshilfe
- Madeleine Schickedanz Kinderkrebs-Stiftung
- Charles University Prague. Grant Number: GAUK 363011
- GAČR Centre of Excellence. Grant Number: P302/12/G101
- acute lymphoblastic leukemia (ALL);
- minimal residual disease (MRD)
Recently, several studies have demonstrated a negative prognostic impact of Ikaros (IKZF1) gene alterations in acute lymphoblastic leukemia (ALL). However, controversies still exist regarding the impact of IKZF1 in current treatment protocols.
We simultaneously detected IKZF1 gene deletions by multiplex ligation-dependent probe amplification and gene expression of IKZF1 isoforms in 206 children with BCR/ABL-negative ALL treated with ALL IC-BFM 2002 protocol, in which risk stratification was not based on minimal residual disease (MRD), and validated the results on a cohort of 189 patients treated with MRD-directed ALL-BFM 2000 protocol.
Deletion of IKZF1 was present in 14 of 206 (7%) ALL IC patients. Interestingly, gene expression did not completely correlate with the deletion status in either cohort. Deletions were not always reflected in the gene expression of dominant-negative isoforms, and conversely, 7 of 395 (2%) non-deleted cases overexpressed dominant-negative isoform Ik6. IKZF1 deletions significantly affected event-free survival (EFS) of the ALL IC cohort (41 ± 14% vs. 86 ± 3%, P < 0.0001). Regarding IKZF1 isoforms, only Ik6 overexpression had negative prognostic impact (EFS 50 ± 16% vs. 85 ± 3%, P = 0.003). In multivariate analysis, which included ALL IC risk criteria, flow-cytometric MRD and IKZF1 alterations, day 15 MRD and IKZF1 deletion status displayed an independent prognostic impact.
We show that MRD-directed treatment diminishes prognostic impact of IKZF1 alterations. However, IKZF1 status alone or combined with day 15 flow cytometry can significantly improve risk stratification within BFM protocols at centers that do not perform antigen-receptor-based MRD monitoring. Pediatr Blood Cancer 2013; 60: 420–427. © 2012 Wiley Periodicals, Inc.