Prognostic relevance of CD200/BTLA deletions in pediatric precursor-B cell acute lymphoblastic leukemia treated according to the EORTD-CLG 58951 protocol

Introduction: Despite the use of current risk classification in children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL), a substantial proportion of so-called standard risk patients will experience a hematological relapse. Detection of DNA copy number abnormalities in BCP-ALLs has revealed additional genetic alterations, some of which are associated with outcome and may be included in future stratification strategies. Materials and methods: Using array-comparative genomic hybridization in a selected cohort of 70 intermediate risk pediatric BCP-ALLs, we characterized a recurrent RAG-mediated deletion of the CD200 and BTLA genes in 10% of patients. A breakpoint-specific PCR assay was designed and used to screen an independent non-selected cohort of 1154 genetically well-characterized BCP-ALLs uniformly treated according to the BFM-based EORTC-58951 protocol. Results: CD200 / BTLA deletions were identified in 56 patients of the non-selected cohort (4.8%). Survival analysis revealed that CD200 / BTLA deletions are associated with an inferior 8-year event free survival (EFS) of 70.2% ± 1.2% for patients with the deletions versus 83.5% ± 6.4% for non-deleted cases (HR 2.02; 95% CI 1.23-3.32; p=0.005) in the complete cohort of 1154 BCP-ALL patients. We observed a strong association between CD200 / BTLA deletions and ETV6-RUNX1 positive leukemias (Table 1). The presence of ETV6-RUNX1 is a good prognostic marker in BCP-ALL and CD200 / BTLA deletions did not affect prognosis within this genetic subtype. However and most notably, CD200 / BTLA deletions were also identified in patients without any known genetic lesion, who are classified as having an intermediate outcome and belong to the intermediate-risk genetic group (defined in Table 1). Within this genetic group an inferior 8-year EFS rate of 33.3% (95% CI 7.8%-62.3%) was observed for patients with the deletions versus 76.2% (95% CI 71.0%-80.6%) for non-deleted cases (HR 4.00; 99% CI 1.34-11.93; p CD200 / BTLA deletions, after adjusting for the presence of IKZF1 deletions, gender, response to prephase treatment and CNS involvement. Discussion and conclusion: Altogether, these findings suggest that the prognostic value of CD200 / BTLA deletions is restricted to intermediate risk BCP-ALL cases that lack any of the currently known prognostic indicators and underscore the rationale for implementing additional genetic markers in future risk stratification strategies. Disclosures No relevant conflicts of interest to declare.