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Published on: November 26, 2018
Prognostic value of rare IKZF1 deletion in childhood B-cell precursor acute lymphoblastic leukemia: an international
J M Boer1, A van der Veer1, D Rizopoulos2
1Department of Pediatric Oncology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
Insights
Rare IKZF1 deletions in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) indicate a poor prognosis. All variants of these deletions are linked to unfavorable outcomes, impacting event-free survival in young patients.
Area of Science:
- Pediatric Oncology
- Hematologic Malignancies
- Molecular Genetics
Background:
- IKZF1 deletions are present in approximately 15% of pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cases.
- Known IKZF1 deletions (exons 4-7, 1-8) are associated with poor prognosis, but the impact of other rare variants is understudied.
Purpose of the Study:
- To investigate the prognostic value of rare IKZF1 deletion variants in pediatric BCP-ALL.
- To compare the outcomes associated with rare IKZF1 deletions to established deletion types and wild-type controls.
Main Methods:
- International multicenter study utilizing a case-control design.
- Matching of 134 rare IKZF1-deleted cases with three wild-type controls based on cytogenetics, treatment, risk stratification, WBC count, and age.
- Matched pair Cox regression analysis to calculate hazard ratios for event-free survival.
Main Results:
- All rare IKZF1 deletions collectively showed a poor prognosis (P<0.001) across all risk stratification arms.
- Specific rare variants DEL 2-7 (P=0.03), DEL 2-8 (P=0.002), and DEL-Other (P<0.001) were associated with the most unfavorable event-free survival.
- The prognostic impact of rare IKZF1 deletions was equal to or worse than major deletion variants (DEL 4-7, DEL 1-8).
Conclusions:
- All variants of rare IKZF1 deletions are associated with an unfavorable prognosis in pediatric BCP-ALL.
- These findings highlight the importance of identifying and characterizing all IKZF1 deletion types for risk stratification and treatment decisions.
Abstract:
Deletions in IKZF1 are found in ~15% of children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). There is strong evidence for the poor prognosis of IKZF1 deletions affecting exons 4-7 and exons 1-8, but evidence for the remaining 33% of cases harboring other variants of IKZF1 deletions is lacking. In an international multicenter study we analyzed the prognostic value of these rare variants in a case-control design. Each IKZF1-deleted case was matched to three IKZF1 wild-type controls based on cytogenetic subtype, treatment protocol, risk stratification arm, white blood cell count and age. Hazard ratios for the prognostic impact of rare IKZF1 deletions on event-free survival were calculated by matched pair Cox regression. Matched pair analysis for all 134 cases with rare IKZF1 deletions together revealed a poor prognosis (P<0.001) that was evident in each risk stratification arm. Rare variant types with the most unfavorable event-free survival were DEL 2-7 (P=0.03), DEL 2-8 (P=0.002) and DEL-Other (P<0.001). The prognosis of each type of rare variant was equal or worse compared with the well-known major DEL 4-7 and DEL 1-8 IKZF1 deletion variants. We therefore conclude that all variants of rare IKZF1 deletions are associated with an unfavorable prognosis in pediatric BCP-ALL.
