Refining risk stratification in paediatric B-acute lymphoblastic leukaemia: Combining IKZF1plus and Day 15 MRD
Hsi-Che Liu1, Ying-Jung Huang2, Tang-Her Jaing3,4
1Department of Hematology-Oncology, MacKay Children's Hospital and MacKay Medical College, Taipei, Taiwan.
Insights
IKZF1 deletion, particularly the IKZF1plus subtype, serves as a significant high-risk marker in pediatric acute lymphoblastic leukemia (B-ALL). Its presence, especially with early measurable residual disease, predicts poorer outcomes and identifies a high-relapse subgroup.
Area of Science:
- Hematology
- Pediatric Oncology
- Molecular Diagnostics
Background:
- Paediatric acute lymphoblastic leukaemia (ALL) requires accurate risk stratification for optimal treatment.
- Minimal/measurable residual disease (MRD) is a key prognostic factor in B-ALL management.
- The role of IKZF1 deletion as an independent prognostic marker needs further elucidation.
Purpose of the Study:
- To investigate the utility of IKZF1 deletion as an additional high-risk marker in paediatric B-ALL.
- To evaluate the prognostic impact of IKZF1 status combined with MRD in the TPOG-ALL-2013 protocol.
- To identify specific patient subgroups with adverse outcomes based on IKZF1 status and MRD.
Main Methods:
- Analysis of 412 newly diagnosed paediatric B-ALL patients (aged 1-18) within the TPOG-ALL-2013 protocol.
- Determination of IKZF1 deletion status using multiplex ligation-dependent probe amplification (MLPA).
- Definition of IKZF1plus as co-occurring deletions (CDKN2A, CDKN2B, PAX5, PAR1) without ERG deletions.
Main Results:
- IKZF1 deletion (14.6%) and IKZF1plus (7.8%) independently predicted poorer outcomes in B-ALL.
- IKZF1plus was associated with significantly lower 5-year event-free survival (53.9%) compared to IKZF1 deletion alone (83.8%) and wild-type (91.3%).
- Patients with IKZF1plus and Day 15 MRD ≥0.01% showed the worst event-free, relapse-free, and overall survival rates.
Conclusions:
- IKZF1plus deletion is a potent independent predictor of adverse outcomes in paediatric B-ALL.
- Combining IKZF1plus assessment with Day 15 MRD positivity identifies a high-risk Philadelphia-negative B-ALL subgroup with a 50% relapse risk.
- Integrating IKZF1plus status into risk stratification may help minimize overtreatment in paediatric ALL.
Abstract:
This study investigates the potential utility of IKZF1 deletion as an additional high-risk marker for paediatric acute lymphoblastic leukaemia (ALL). The prognostic impact of IKZF1 status, in conjunction with minimal/measurable residual disease (MRD), was evaluated within the MRD-guided TPOG-ALL-2013 protocol using 412 newly diagnosed B-ALL patients aged 1-18. IKZF1 status was determined using multiplex ligation-dependent probe amplification. IKZF1 deletions, when co-occurring with CDKN2A, CDKN2B, PAX5 or PAR1 region deletions in the absence of ERG deletions, were termed IKZF1plus. Both IKZF1 deletion (14.6%) and IKZF1plus (7.8%) independently predicted poorer outcomes in B-ALL. IKZF1plus was observed in 4.1% of Philadelphia-negative ALL, with a significantly lower 5-year event-free survival (53.9%) compared to IKZF1 deletion alone (83.8%) and wild-type IKZF1 (91.3%) (p < 0.0001). Among patients with Day 15 MRD ≥0.01%, provisional high-risk patients with IKZF1plus exhibited the worst outcomes in event-free survival (42.0%), relapse-free survival (48.0%) and overall survival (72.7%) compared to other groups (p < 0.0001). Integration of IKZF1plus and positive Day 15 MRD identified a subgroup of Philadelphia-negative B-ALL with a 50% risk of relapse. This study highlights the importance of assessing IKZF1plus alongside Day 15 MRD positivity to identify patients at increased risk of adverse outcomes, potentially minimizing overtreatment.
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