Prognostic Relevance of CD200/Btla Deletions in Pediatric Precursor-B Cell Acute Lymphoblastic Leukemia Treated According to the EORTC-CLG 58951 Protocol
Authors: Ghazavi Farzaneh , Lammens Tim , Clappier Emmanuelle , Suciu Stefan , Caye Aurélie , Zegrari Samira , Bakkus Marleen , Grardel Nathalie , Benoit Yves , Bertrand Yves , Minckes Odile , Costa Vitor , Ferster Alina , Mazingue Françoise , Plat Geneviève , Plouvier Emmanuel , Poirée Marilyne , Uyttebroeck Anne , Van der Werff Ten Bosch Jutte , Helsmoortel Hetty , Meul Magali , Van Roy Nadine , Philippé Jan , Speleman Frank , Cavé Hélène , Van Vlierberghe Pieter , De Moerloose Barbara 
Published: November 2019

Abstract
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 <0.001). Similarly, CD200/BTLA deleted cases were characterized by an inferior 8-year overall survival rate of 48.6% (95% CI 12.8-77.6%) versus 86.9% (95% CI 82.6-90.2%) for non-deleted cases (HR 4.43; 99% CI 1.15-17.03; p=0.002) (event distribution in Table 2). Multivariate analysis confirmed the independent prognostic importance of 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.
Table 1: Frequency of CD200/BTLA deletions according to BCP-ALL genetic subtypes and genetic risk groups Not deleted Deleted p-value No (%) No (%) All patients 1098 56 Genetic subtypes <0.0001 ERGdel 36 (3.3) 1 (1.8) ETV6-RUNX1 248 (22.6) 34 (60.7) High hyperdiploidy 382 (34.8) 4 (7.1) BCR-ABL1 24 (2.2) 3 (5.4) Low hypo/near-haploidy 9 (0.8) 1 (1.8) MLL translocation 17 (1.5) 0 (0.0) iAMP21 21 (1.9) 4 (7.1) TCF3-PBX1 47 (4.3) 0 (0.0) B-other 314 (28.6) 9 (16.1) IKZF1del 172 (15.7) 10 (17.9) 0.7 Genetic groups * 0.004 Good-risk 666 (60.7) 39 (69.6) Intermediate-risk 361 (32.9) 9 (16.1) Poor-risk 71 (6.5) 8 (14.3) * Genetic risk groups were defined as follows: good-risk group include all patients with high hyperdiploidy, ETV6-RUNX1 or ERGdel; intermediate-risk group includes patients with TCF3-PBX1 and B-other patients; poor-risk group includes all patients with MLL translocation, low hypodiploidy/near-haploidy or iAMP21.
Table 2: Event types in CD200/BTLA deleted versus non-deleted patients Not deleted Deleted No (%) No (%) Intermediate-risk genetic group 361 9 EFS status NoCR 7 (1.9) 2 (22.2) CCR 283 (78.4) 3 (33.3) Relapse 67 (18.6) 4 (44.4) TRM 4 (1.1) 0 (0.0) Abbreviations: CR, complete remission; CCR, continuous complete remission; TRM, treatment related mortality.

Disclosures
No relevant conflicts of interest to declare.