A risk score including microdeletions improves relapse prediction for standard and medium risk precursor B‐cell acute lymphoblastic leukaemia in children

Abstract

To prevent relapse, high risk paediatric acute lymphoblastic leukaemia (ALL) is treated very intensively. However, most patients who eventually relapse have standard or medium risk ALL with low minimal residual disease (MRD) levels. We analysed recurrent microdeletions and other clinical prognostic factors in a cohort of 475 uniformly treated non-high risk precursor B-cell ALL patients with the aim of better predicting relapse and refining risk stratification. Lower relapse-free survival at 7 years (RFS) was associated with IKZF1 intragenic deletions (P < 0·0001); P2RY8-CRLF2 gene fusion (P < 0·0004); Day 33 MRD>5 × 10 (P < 0·0001) and High National Cancer Institute (NCI) risk (P < 0·0001). We created a predictive model based on a risk score (RS) for deletions, MRD and NCI risk, extending from an RS of 0 (RS0) for patients with no unfavourable factors to RS2 + for patients with 2 or 3 high risk factors. RS0, RS1, and RS2 + groups had RFS of 93%, 78% and 49%, respectively, and overall survival (OS) of 99%, 91% and 71%. The RS provided greater discrimination than MRD-based risk stratification into standard (89% RFS, 96% OS) and medium risk groups (79% RFS, 91% OS). We conclude that this RS may enable better early therapeutic stratification and thus improve cure rates for childhood ALL.

Minimal Residual Disease in Acute Lymphoblastic Leukemia

“…41 Similarly, in pediatric ALL, presence of IKZF1 intragenic deletion and P2RY8-CRLF2 provides additional prognostic information over MRD alone. 42…”

CKLF and IL1B transcript levels at diagnosis are predictive of relapse in children with pre‐B‐cell acute lymphoblastic leukaemia

“…These MRD intervention trials [Berlin–Frankfurt–Munster (iBFM), Children's Oncology Group (COG) and others] also revealed incompleteness in the stratification criteria as some medium‐ and low‐risk patients also relapsed. While further stratification based on the presence of IKZF1 intragenic deletions and P2RY8–CRLF2 gene fusions would improve the identification of high relapse risk, 3 the inability to identify 100% of the patients who will relapse suggests that other aspects of ALL biology also play a role in relapse.…”

Minimal Residual Disease in Acute Lymphoblastic Leukemia: Technical and Clinical Advances

“…Likewise, in childhood ALL, the generation of a risk score based on the combination of MRD at day 33, the presence of IKZF1 intragenic deletion and P2RY8-CRLF2 , which proved more discriminative of outcome that MRD evaluation alone, has been recently reported (131).…”