BCR-ABL1-Like Cases In Pediatric Acute Lymphoblastic Leukemia: A Comparison Between COG/St. Jude and Dutch DCOG Signatures

Pediatric precursor B-cell acute lymphoblastic leukemia (BCP-ALL) with the BCR-ABL1 translocation forms a small group with a poor prognosis. Approximately 15% of BCP-ALL cases are characterized by a gene expression signature similar to BCR-ABL1-positive disease. This so-called BCR-ABL1-like group shares the poor prognosis of the BCR-ABL1-positive subtype but without presence of a BCR-ABL1 translocation. Using different cohorts and methods, two different BCR-ABL1-like signatures have been identified (Den Boer et al., Lancet Oncol 2009; Mullighan et al., New Engl J Med 2009). Both signatures identify groups of patients with a poor prognosis and with deletions in B-cell development genes (Den Boer et al., Lancet Oncol 2009; Roberts et al., Cancer Cell 2012). The aim of this study was to compare these two signatures and the association to molecular aberrations and clinical outcome in diagnostic samples of the Dutch Childhood Oncology Group (DCOG) and the German Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia (COALL).

The BCP-ALL study cohort consisted of 452 patients, including 146 patients with B-precursor ALL without known recurrent aberrations (BCR-ABL1 translocation, ETV6-RUNX1 translocation, MLL rearrangements, TCF3 rearrangements, hyperdiploidy). BCR-ABL1-like cases were identified in these 146 B-precursor cases using Prediction Analysis of Microarrays (PAM) with 257 probe sets (Roberts et al., Cancer Cell 2012) and separately by Hierarchical Clustering (HC) with 110 probe sets (Den Boer et al., Lancet Oncol 2009), using Affymetrix U133Plus2 expression data. Frequencies of molecular aberrations detected by multiplex ligation-dependent probe amplification, array-comparative genomic hybridization and Sanger sequencing, including IKZF1 deletions, JAK2 mutations and CRLF2 aberrations, were compared between groups of patient samples classified by the two prediction algorithms using Fisher's Exact test. We analyzed the cumulative incidence of relapse (CIR) with death as a competing event.

In the DCOG/COALL cohort, which included patients from all ALL risk groups, we identified 33 BCR-ABL1-like cases with the PAM signature, of which 24 (73%) were high-risk according to the NCI-Rome criteria (WBC ≥ 50 cells/nl and/or age ≥ 10 years), and 79 cases with the HC signature, of which 57 (72%) were high-risk. Compared with 59 B-other cases not identified by either of the two BCR-ABL1-like signatures, the most enriched molecular aberrations in the PAM-identified group were IKZF1 deletions (52% vs 19%, p=0.002), high CRLF2 expression (39% vs 8%, p<0.001), intrachromosomal amplification of chromosome 21 (iAMP21; 32% vs 0%, p<0.0001), and RB1 deletions (23% vs 6%, p=0.04). Enriched aberrations in the HC-identified group included IKZF1 deletions (38% vs 19%, p=0.02), dic(9;20) (28% vs 4%, p<0.001), and iAMP21 (15% vs 0%, p=0.002), while BTG1 deletions occurred less frequently (6% vs 17%, p=0.04). Directly comparing PAM and HC-identified BCR-ABL-like cases indicated significantly higher proportions of CRLF2-high (p=0.004) and JAK2 mutations (p=0.02) in the PAM group, and higher dic(9;20) in the HC group (p=0.03). Next, we compared the overlap between cases identified by the two signatures. PAM identified 32% (25/79) of the BCR-ABL1-like cases identified by HC, and vice versa HC identified 76% (25/33) of the cases identified by PAM. The cumulative incidence of relapse at 5-years in the BCR-ABL1-like groups identified by PAM (20%, p=0.04), HC (27%, p<0.0001), or both methods (18%, p=0.15), was worse than in the non-BCR-ABL1-like/BCR-ABL1-negative/MLL wild-type BCP-ALL reference group (8.1%). Cases identified only by HC (31%, p<0.0001) or only by PAM (25%, p=0.05) also had higher 5-year cumulative relapse incidences than the reference group.

Both BCR-ABL1-like expression signatures defined by HC or PAM identified a group of patients with an unfavorable prognosis in the DCOG/COALL study. The two groups largely overlapped, but each signature also identified unique patients not identified by the other signature. Importantly, each of the signatures was associated with poor outcome, while patients identified by both signatures (PAM/HC-double positive) did not have a worse outcome than those identified only by PAM or HC. Since the two signatures are partially complementary, we suggest that both should be used.

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