The Prognostic Effect of IKZF1 Deletions in ETV6::RUNX1 and High Hyperdiploid Childhood Acute Lymphoblastic Leukemia
Anna Østergaard,
Amir Enshaei,
Rob Pieters,
Ajay Vora,
Martin A. Horstmann,
Gabriele Escherich,
Bertil Johansson,
Mats Heyman,
Kjeld Schmiegelow,
Peter M. Hoogerbrugge,
Monique L. den Boer,
Roland P. Kuiper,
Anthony V. Moorman,
Judith M. Boer,
Frank N. van Leeuwen
Affiliations
Anna Østergaard
1 Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
Amir Enshaei
3 Leukaemia Research Cytogenetics Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
Rob Pieters
1 Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
Ajay Vora
4 Department of Haematology, Great Ormond Street Hospital, London, United Kingdom
Martin A. Horstmann
5 Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Gabriele Escherich
5 Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Bertil Johansson
7 Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Sweden
Mats Heyman
9 Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
Kjeld Schmiegelow
11 Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Institute of Clinical Medicine, Faculty of Medicine, University of Copenhagen, Denmark
Peter M. Hoogerbrugge
1 Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
Monique L. den Boer
1 Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
Roland P. Kuiper
1 Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
Anthony V. Moorman
3 Leukaemia Research Cytogenetics Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
Judith M. Boer
1 Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
Frank N. van Leeuwen
1 Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
IKZF1 deletions are an established prognostic factor in childhood acute lymphoblastic leukemia (ALL). However, their relevance in patients with good risk genetics, namely ETV6::RUNX1 and high hyperdiploid (HeH), ALL remains unclear. We assessed the prognostic impact of IKZF1 deletions in 939 ETV6::RUNX1 and 968 HeH ALL patients by evaluating data from 16 trials from 9 study groups. Only 3% of ETV6::RUNX1 cases (n = 26) were IKZF1-deleted; this adversely affected survival combining all trials (5-year event-free survival [EFS], 79% versus 92%; P = 0.02). No relapses occurred among the 14 patients with an IKZF1 deletion treated on a minimal residual disease (MRD)-guided protocols. Nine percent of HeH cases (n = 85) had an IKZF1 deletion; this adversely affected survival in all trials (5-year EFS, 76% versus 89%; P = 0.006) and in MRD-guided protocols (73% versus 88%; P = 0.004). HeH cases with an IKZF1 deletion had significantly higher end of induction MRD values (P = 0.03). Multivariate Cox regression showed that IKZF1 deletions negatively affected survival independent of sex, age, and white blood cell count at diagnosis in HeH ALL (hazard ratio of relapse rate [95% confidence interval]: 2.48 [1.32-4.66]). There was no evidence to suggest that IKZF1 deletions affected outcome in the small number of ETV6::RUNX1 cases in MRD-guided protocols but that they are related to higher MRD values, higher relapse, and lower survival rates in HeH ALL. Future trials are needed to study whether stratifying by MRD is adequate for HeH patients or additional risk stratification is necessary.
