Poor prognosis for P2RY8-CRLF2 fusion but not for CRLF2 over-expression in children with intermediate risk B-cell precursor acute lymphoblastic leukemia.

Pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has achieved an 80% cure rate as a result of a risk adapted therapy largely based on Minimal Residual Disease (MRD) monitoring. However, relapse is still the most frequent adverse event, occurring mainly in the patients with intermediate MRD levels (Intermediate risk, IR), emphasizing the need for new prognostic markers. We analyzed the prognostic impact of CRLF2 over-expression and P2RY8-CRLF2 fusion in 464 BCP-ALL patients (not affected by Down Syndrome and BCR-ABL negative) enrolled in the AIEOP-BFM ALL2000 study in Italy. In 22/464 (4.7%) samples RQ-PCR showed CRLF2 over-expression (20 times higher than the overall median). P2RY8-CRLF2 fusion was detected in 22/365 (6%) cases, with 10/22 cases also showing CRLF2 over-expression. P2RY8-CRLF2 fusion was the most relevant prognostic factor independent of CRLF2 over-expression with a 3-fold increase in risk of relapse. Significantly, the Cumulative Incidence of Relapse of the P2RY8-CRLF2+ patients in the IR group was high (61.1%±12.9 vs. 17.6%±2.6, P<0.0001), similar to High risk patients in AIEOP-BFM ALL2000 study. These results were confirmed in a cohort of patients treated in Germany. In conclusion, P2RY8-CRLF2 identifies a subset of BCP-ALL patients currently stratified as IR that could be considered for treatment intensification