Poor Prognosis for IKZF1 Intra-Gene Deletions in Pediatric Ph− B-Cell Precursor Acute Lymphoblastic Leukemia,
Authors: Palmi Chiara , Silvestri Daniela , Longinotti Giulia , Vendramini Elena , Conter Valentino , Basso Giuseppe , Biondi Andrea , Valsecchi Maria Grazia , te Kronnie Geertruy , Cazzaniga Giovanni 
Published: October 2019

Abstract
Abstract 3518

Introduction.
In the AIEOP-BFM ALL 2000 study, the MRD-based risk groups stratification allowed to achieve more than 80% cure rate. However, relapse is still the most frequent adverse event, occurring mainly in the largest subgroup of non-high risk (HR) patients. This emphasizes the need for new prognostic markers for upfront identification of patients with a high risk of relapse. Recently, new genomic abnormalities of the CRLF2 and Ikaros (IKZF1) genes have been reported in the subset of BCP-ALL patients without known chromosomal aberrations. We recently analyzed the poor prognostic impact of P2RY8-CRLF2 fusion in a representative cohort of 464 non-DS Ph- BCP-ALL patients enrolled in Italy into AIEOP-BFM ALL2000 study from February 2003 to July 2005. Aim. In order to estimate the incidence and prognostic value of IKZF1 deletions, alone or in combination with CRLF2 alterations, we initiated the screening of the full cohort of patients. A pilot test of a subset of 154 non-DS, Ph-, BCP-ALL patients treated in Italy according to the AIEOP-BFM ALL 2000 protocol from February 2003 to June 2004 has been completed so far. Methods. Ig/TcR PCR-MRD and RT-PCR screening for known chromosomal translocation were routinely performed; P2RY8-CRLF2 fusion was detected by RT-PCR. Multiplex Ligation-dependent Probe Amplification (MLPA) (Salsa MLPA P335-A3 ALL-IKZF1 kit; MRC-Holland, Amsterdam, NL) was performed to identify IKZF1 deletions together with deletions in additional B-cell development genes. Patients positive for IKZF1 deletions were further analyzed by Salsa MLPA P202-A1 IKZF1 kit to confirm and better define the extension of the IKZF1 gene deletion. Results. IKZF1 deletions were detected in 22/154 cases (14.3%), in keeping with incidence data reported in the literature. In 9 cases (5.8%) the deletion was intra-genic, involving only some exons of the IKZF1 gene, while in 13 cases (8.4%) the deletion was encompassing the whole IKZF1 gene. Three out of 16 patients (18.8%) carried both IKZF1 and CRLF2 deletions. Overall, the 5-year Cumulative Incidence of Relapse (median follow-up: 5.8 years) was 23±9% for patients carrying IKZF1 deletions and 12.2±2.9% for patients who did not (p=0.22). Interestingly, out of 13 cases with complete deletion of IKZF1, only one case (1/13, 7.7%) relapsed, vs 4/9 cases (44.4%) positive for IKZF1 intra-gene deletion. Conclusions. IKZF1 intra-gene deletion, but not whole gene deletion, showed a tendency to be associated with poor prognosis in childhood BCP-ALL treated according to the AIEOP-BFM ALL 2000 protocol. Whether these results will be confirmed at the completeness of this study, the assessment of IKZF1 status might serve as a new stratification marker. It will be of particular interest to verify whether different IKZF1 deletions within non-HR patients by MRD will have a prognostic impact.

Disclosures:
No relevant conflicts of interest to declare.