Demographic, clinical, and outcome features of children with acute lymphoblastic leukemia and CRLF2 deregulation: results from the MRC ALL97 clinical trial

Deregulated expression of CRLF2 (CRLF2-d) arises via its juxtaposition to the IGH@ enhancer or P2RY8 promoter. Among 865 BCP-ALL children treated on MRC ALL97, 52 (6%) has CRLF2-d but it was more prevalent among Down syndrome patients (54%). P2RY8-CRLF2 (n=43) was more frequent than IGH@-CRLF2 (n=9). CRLF2-d was not associated with age, sex or white cell count, but IGH@- CRLF2 patients were older than P2RY8-CRLF2 patients (median 8 v 4 years, p=0.0017). Patients with CRLF2-d were more likely to present with enlarged livers and spleens (38% v 18%, p<0.001). CRLF2-d was not seen in conjunction with established chromosomal translocations but 6 (12%) cases had high hyperdiploidy and 5 (10%) iAMP21. Univariate analysis suggested that CRLF2-d was associated with an inferior outcome: [EFS HR=2.27 (95% CI 1.48-3.47), p<0.001, OS 3.69 (2.34-5.84), p<0.001]. However, multivariate analysis indicated that its effect was mediated by other risk factors such as cytogenetics and DS status [EFS 1.45 (0.88-2.39), p=0.140, OS 1.90 (1.08-3.36), p=0.027]. Although the outcome of IGH@-CRLF2 patients appeared inferior compared to P2RY8-CRLF2 patients the result was not significant [EFS 2.69 (1.15-6.31), p=0.023; OS 2.86 (1.15-6.79), p=0.021]. Therefore, we concluded that patients with CRLF2-d should be classified into the intermediate cytogenetic risk group.