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Published on: October 11, 2018
IKZF1 status as a prognostic feature in BCR-ABL1-positive childhood ALL
Arian van der Veer1, Marketa Zaliova, Federica Mottadelli
1Department of Pediatric Oncology, Erasmus University Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands;
Insights
IKZF1 deletions indicate a poor prognosis in childhood BCR-ABL1-positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL), even with imatinib treatment. Patients without IKZF1 deletions may benefit from imatinib, potentially avoiding stem-cell transplantation.
Area of Science:
- Pediatric Oncology
- Hematologic Malignancies
- Molecular Genetics
Background:
- Childhood BCR-ABL1-positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL) frequently exhibits IKZF1 deletions.
- These deletions are associated with unfavorable outcomes in BCP-ALL patients.
Purpose of the Study:
- To evaluate the prognostic significance of IKZF1 deletions in childhood BCR-ABL1-positive BCP-ALL.
- To assess the impact of IKZF1 deletions on outcomes before and after the introduction of imatinib therapy.
Main Methods:
- Analysis of two patient cohorts: pre-tyrosine kinase inhibitor (pre-TKI) and European Study for Philadelphia-Acute Lymphoblastic Leukemia (EsPhALL) treated with imatinib.
- Detection of IKZF1 deletions using molecular methods.
- Comparison of disease-free survival (DFS) between patients with and without IKZF1 deletions.
Main Results:
- IKZF1 deletions were detected in 66% of the 191 cases.
- In the pre-TKI cohort, IKZF1 deletions were linked to significantly lower 4-year DFS (30.0% vs 57.5%, P = .01).
- In the EsPhALL cohort, IKZF1 deletions were associated with poorer prognosis even in good-risk patients (4-year DFS 51.9% vs 78.6%, P = .03) and those on imatinib (4-year DFS 55.5% vs 75.0%, P = .05).
Conclusions:
- IKZF1 deletions confer a highly unfavorable prognosis in childhood BCR-ABL1-positive BCP-ALL, regardless of imatinib.
- Good-risk patients with wild-type IKZF1 show excellent response to imatinib, suggesting it may be a viable alternative to stem-cell transplantation for this subgroup.
Abstract:
Childhood BCR-ABL1-positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has an unfavorable outcome and shows high frequency of IKZF1 deletions. The prognostic value of IKZF1 deletions was evaluated in 2 cohorts of BCR-ABL1-positive BCP-ALL patients, before tyrosine kinase inhibitors (pre-TKI) and after introduction of imatinib (in the European Study for Philadelphia-Acute Lymphoblastic Leukemia [EsPhALL]). In 126/191 (66%) cases an IKZF1 deletion was detected. In the pre-TKI cohort, IKZF1-deleted patients had an unfavorable outcome compared with wild-type patients (4-year disease-free survival [DFS] of 30.0 ± 6.8% vs 57.5 ± 9.4%; P = .01). In the EsPhALL cohort, the IKZF1 deletions were associated with an unfavorable prognosis in patients stratified in the good-risk arm based on early clinical response (4-year DFS of 51.9 ± 8.8% for IKZF1-deleted vs 78.6 ± 13.9% for IKZF1 wild-type; P = .03), even when treated with imatinib (4-year DFS of 55.5 ± 9.5% for IKZF1-deleted vs 75.0 ± 21.7% for IKZF1 wild-type; P = .05). In conclusion, the highly unfavorable outcome for childhood BCR-ABL1-positive BCP-ALL with IKZF1 deletions, irrespective of imatinib exposure, underscores the need for alternative therapies. In contrast, good-risk patients with IKZF1 wild-type responded remarkably well to imatinib-containing regimens, providing a rationale to potentially avoid hematopoietic stem-cell transplantation in this subset of patients.
