Prognostic value of genetic alterations in children with first bone marrow relapse of childhood B-cell precursor acute lymphoblastic leukemia

Abstract

Despite risk-adapted treatment, survival of children with relapse of acute lymphoblastic leukemia (ALL) remains poor compared with that of patients with initial diagnosis of ALL. Leukemia-associated genetic alterations may provide novel prognostic factors to refine present relapse treatment strategies. Therefore, we investigated the clinical relevance of 13 recurrent genetic alterations in 204 children treated uniformly for relapsed B-cell precursor ALL according to the ALL-REZ BFM 2002 protocol. The most common alterations were deletions of CDKN2A/2B, IKZF1, PAX5, ETV6, fusion of ETV6-RUNX1 and deletions and/or mutations of TP53. Multivariate analysis identified IKZF1 deletion and TP53 alteration as independent predictors of inferior outcome (P ¼ 0.002 and P ¼ 0.001). Next, we investigated how both alterations can improve the established risk stratification in relapsed ALL. Intermediate-risk relapse patients with low minimal residual disease are currently considered to have a good prognosis. In this group, deletion of IKZF1 and alteration of TP53 identify patients with significantly inferior outcome (Po0.001). In high-risk relapse patients, deletion of IKZF1 is strongly predictive of a second relapse after stem cell transplantation (Po0.001). We conclude that IKZF1 and TP53 represent relevant prognostic factors that should be considered in future risk assessment of children with relapsed ALL to indicate treatment intensification or intervention.

What is the relevance of Ikaros gene deletions as a prognostic marker in pediatric Philadelphia-negative B-cell precursor acute lymphoblastic leukemia?

“…10,[20][21][22] We did not find statistically significant differences in the incidence of these genetic alterations in children positive or negative for IKZF1 deletions (Online Supplementary Table S3). Most of these genetic alterations occurred simultaneously in the same patients and are described in detail in Online Supplementary Table S2.…”

“…7,18,20 Patients positive for IKZF1 deletions were further analyzed by the more specific Salsa MLPA P202-A1 IKZF1 kit (MRC-Holland, Amsterdam, the Netherlands) to confirm and better define the extension of the alteration.…”

Prognostic significance of copy number alterations detected by multi‑link probe amplification of multiple genes in adult acute lymphoblastic leukemia

“…The proportion of IKZF1 gene deletions in these cases of ALL relapse was ~2-fold that reported previously in children newly diagnosed with ALL (33 vs. 14-19%). The common gene deletions identified in 142 cases of adolescent and adult ALL were CDKN2A/2B (42%), IKZF1 (35%), PAX5 (34%), RB1 (15%), BTG1 (10%), EBF1 (11%) and ETV6 (7%) (12). The majority of the patients with IKZF1 and CDKN2A/2B deletions also harbored other deletions.…”

“…In ~43% patients, no gene deletions were detected and patients with ≥3 types of gene deletions were observed in 10% of all patients. MLPA facilitated the screening of 204 children with ALL relapse (12). The common gene deletions included CDKN2B (37.7%), CDKN2A (37.3%), IKZF1 (33.3%), PAX5 (26.5%) and ETV6 (25%).…”

The role of Ikaros transcriptional factor in normal hematopoiesis and leukemogenesis: biological and clinical aspects

“…Наконец, группа немецких авторов детально изучи-ла прогностические факторы для первого костномоз-гового рецидива В-линейного ОЛЛ у детей [63]. С ис-пользованием метода MLPA была выявлена высокая частота делеций IKZF1 (33,3 %).…”