IKZF1 status as a prognostic feature in BCR-ABL1–positive childhood ALL

Abstract

Key Points• IKZF1 deletions are predictive of an unfavorable outcome in childhood BCR-ABL1-positive ALL.• Good-risk BCR-ABL1-positive patients with wild-type IKZF1 have good outcomes when treated with imatinib.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 6.8% vs 57.5 6 9.4%; P 5 .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 6 8.8% for IKZF1-deleted vs 78.6 6 13.9% for IKZF1 wild-type; P 5 .03), even when treated with imatinib (4-year DFS of 55.5 6 9.5% for IKZF1-deleted vs 75.0 6 21.7% for IKZF1 wildtype; P 5 .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. (Blood. 2014;123(11):1691-1698

The genomic landscape of acute lymphoblastic leukemia in children and young adults

“…Despite this low mutational load, key pathways are mutated at high frequency across multiple subtypes of ALL, including: (1) 13 In contrast, alterations of IKZF2 (HELIOS) and IKZF3 (AIOLOS) are selectively associated with near haploid and low hypodiploid ALL, but are otherwise rare in non-hypodiploid ALL. 4 …”

Routine Cytogenetic Analysis of Chromosome Abnormalities in Acute Lymphoblastic Leukemia

“…Although the Ph chromosome in ALL is associated with a poor prognosis, treatment with tyrosine kinase inhibitors have improved the event free survival rates of ALL patients compared to patients treated with traditional chemotherapy and stem cell transplantation [17,18]. However, Phpositive ALL with IKZF1 deletions has an unfavourable outcome even with imatinib therapy compared to those with IKZF1 wild-type [19,20]. Gene expression profiling (GEP) has also identified 'BCR-ABL1-like' B-ALL which is found in 15% of childhood B-ALL.…”

Prognostic impact of IKZF1 deletions in association with vincristine–dexamethasone pulses during maintenance treatment of childhood acute lymphoblastic leukemia on trial ALL-BFM 95

“…1,2 In several studies, deletions of IKZF1-encoding IKAROS, a transcription factor important for lymphoid development and differentiation-have been associated with a poor treatment outcome in precursor B cell ALL. [3][4][5] Deletions of IKZF1 are observed in 10-15% of pediatric ALLs and affect either the entire IKZF1 gene or appear as focal deletions. [3][4][5] The most common of the latter ones (Δ4-7) includes the DNA-binding region and results in a dominant-negative isoform (Ik6), impairing cell differentiation in CD34+ lymphoid progenitor cells.…”

“…[3][4][5] Deletions of IKZF1 are observed in 10-15% of pediatric ALLs and affect either the entire IKZF1 gene or appear as focal deletions. [3][4][5] The most common of the latter ones (Δ4-7) includes the DNA-binding region and results in a dominant-negative isoform (Ik6), impairing cell differentiation in CD34+ lymphoid progenitor cells. [3][4][5] Recently, Clappier et al 6 from the EORTC Study Group suggested that patients with IKZF1-deleted ALL and intermediate-risk features-so-called average-risk (AR) patientstreated on the BFM-based EORTC protocol 58951 may benefit from intensification of conventional maintenance therapy by application of vincristine-glucocorticoid pulses.…”

“…[3][4][5] The most common of the latter ones (Δ4-7) includes the DNA-binding region and results in a dominant-negative isoform (Ik6), impairing cell differentiation in CD34+ lymphoid progenitor cells. [3][4][5] Recently, Clappier et al 6 from the EORTC Study Group suggested that patients with IKZF1-deleted ALL and intermediate-risk features-so-called average-risk (AR) patientstreated on the BFM-based EORTC protocol 58951 may benefit from intensification of conventional maintenance therapy by application of vincristine-glucocorticoid pulses. We previously reported that on ALL-BFM protocols IKZF1 status exerts additive value as a prognostic factor, especially in the intermediate-risk group, in which still the majority of relapses occur.…”