Independent prognostic value of BCR-ABL1-like signature and IKZF1 deletion, but not high CRLF2 expression, in children with B-cell precursor ALL

Abstract

Most relapses in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) are not predicted using current prognostic features. Here, we determined the co-occurrence and independent prognostic relevance of 3 recently identified prognostic features: BCR-ABL1-like gene signature, deletions in IKZF1, and high CRLF2 messenger RNA expression (CRLF2-high). These features were determined in 4 trials representing 1128 children with ALL: DCOG ALL-8, ALL9, ALL10, and Cooperative ALL (COALL)-97/03. BCR-ABL1-like, IKZF1-deleted, and CRLF2-high cases constitute 33.7% of BCR-ABL1-negative, MLL wild-type BCP-ALL cases, of which BCR-ABL1-like and IKZF1 deletion (co)occurred most frequently. Higher cumulative incidence of relapse was found for BCR-ABL1-like and IKZF1-deleted, but not CRLF2-high, cases relative to remaining BCP-ALL cases, reflecting the observations in each of the cohorts analyzed separately. No relapses occurred among cases with CRLF2-high as single feature, whereas 62.9% of all relapses in BCR-ABL1-negative, MLL wild-type BCP-ALL occurred in cases with BCR-ABL1-like signature and/or IKZF1 deletion. Both the BCR-ABL1-like signature and IKZF1 deletions were prognostic features independent of conventional prognostic markers in a multivariate model, and both remained prognostic among cases with intermediate minimal residual disease. The BCR-ABL1-like signature and an IKZF1 deletion, but not CRLF2-high, are prognostic factors and are clinically of importance to identify high-risk patients who require more intensive and/or alternative therapies.

Figure 1

CIR for the BCR-ABL1-like expression signature, IKZF1-deleted, and high CRLF2 mRNA expression in newly diagnosed children with BCR-ABL1–negative, MLL wild-type BCP-ALL. CIR with death as a competing event was calculated using the method of Fine and Gray in a pooled analysis of all 4 study cohorts and plotted against the time from initial diagnosis. For each feature, CIR at the 5-year follow-up is given in parentheses. (A) CIR of 94 BCR-ABL1-like and 442 non–BCR-ABL1-like BCP-ALL cases. (B) CIR of 136 IKZF1-deleted (DEL) and 721 IKZF1 wild-type (WT) cases. (C) Comparison between 55 cases with high CRLF2 expression and 481 cases with low CRLF2 expression.

Figure 2

CIR for IKZF1 status among subtypes of ALL. CIR with death as a competing event was calculated for the DCOG ALL-10 study cases with (A) high hyperdiploid ALL (>50 chromosomes) including 21 IKZF1-deleted and 87 wild-type cases; (B) ETV6-RUNX1–positive ALL including 4 IKZF1-deleted and 100 wild-type cases; (C) non–BCR-ABL1-like B-other ALL including 5 IKZF1-deleted and 22 wild-type cases; and (D) BCR-ABL1-like ALL including 10 IKZF1-deleted and 19 wild-type cases. For each feature, the CIR at 5 years of follow-up is indicated in parentheses.

Figure 3

Frequency of BCR-ABL1-like, IKZF1-deleted, and CRLF2-high mRNA expression features among children with BCR-ABL1–negative, MLL wild-type BCP-ALL. (A) Distribution of cases with BCR-ABL1-like, IKZF1-deleted, and/or CRLF2-high mRNA expression in 507 children with BCR-ABL1–negative, MLL wild-type BCP-ALL. See also supplemental Table 5A. (B) Pie chart depicting the distribution of patients carrying 1 or more of the aforementioned features. Collectively, these 3 features constitute 33.7% of BCR-ABL1–negative, MLL wild-type BCP-ALL cases as shown in panel A. See also supplemental Table 5A. (C) Pie chart depicting the percentages of relapsed patients carrying 1, 2, or 3 features. In total, 62.9% of all relapsed cases were associated with BCR-ABL1-like and/or IKZF1-deleted features. See also supplemental Table 5B.

Figure 4

Interaction between BCR-ABL1-like and IKZF1 status for predicting relapse. CIR with death as a competing event for cases with or without a deletion in IKZF1 among BCR-ABL1-like and non–BCR-ABL1-like ALL cases. The box below the graphs indicates the 5-year CIR, and P values compared with the reference group of non–BCR-ABL1-like and IKZF1 wild-type cases (black line). BCR-ABL1–positive and MLL-rearranged cases were excluded from this analysis.