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

Abstract

Key Points• BCR-ABL1-like signature and IKZF1 deletions are clinically important to identify high-risk acute lymphoblastic patients.Most relapses in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) are not predicted using current prognostic features. Here, we determined the cooccurrence 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. (Blood. 2013;122(15):2622-2629

Suppressors and activators of JAK-STAT signaling at diagnosis and relapse of acute lymphoblastic leukemia in Down syndrome

“…Indeed, about two-thirds of kinase-driven ALLs, commonly called "Philadelphia like" (Ph-like) ALLs, demonstrate activation of this pathway similarly to DS-ALL (11,12). The prognosis of these leukemias is worse (11)(12)(13)(14)(15)(16)(17)(18)(19) and a clinical trial incorporating ruxolitinib into the chemotherapy backbone for newly diagnosed patients has been recently opened (NCT02723994).…”

BCR-ABL1-like cases in pediatric acute lymphoblastic leukemia: a comparison between DCOG/Erasmus MC and COG/St. Jude signatures

“…This signature comparison study comprised children with newly diagnosed BCP-ALL negative for the known aberrations BCR-ABL1, ETV6-RUNX1, MLL rearrangement, TCF3 rearrangement, and high-hyperdiploidy in consecutive Dutch Childhood Oncology Group (DCOG) and German Cooperative ALL trials (146 cases), 2,6 and the P9906 study of the US Childhood Oncology Group (COG) (143 cases). 2,4-6 Molecular aberrations were determined as described in the Online Supplementary Methods.…”

“…4,5 The signature developed by Den Boer et al is based on hierarchical clustering (HC) of 110 gene probe sets identified to predict the major pediatric ALL subtypes (T-cell ALL, ETV6-RUNX1, high-hyperdiploidy, TCF3 or MLL-rearranged, BCR-ABL1). 2,6 This group of BCR-ABL1-like patients had frequent deletions in B-cell development genes (e.g. IKZF1), dic(9;20), and intrachromosomal amplification of chromosome 21 (iAMP21).…”

Redefining ALL classification: toward detecting high-risk ALL and implementing precision medicine

“…Ph-like ALL is associated with high-risk clinical features, a poor response to induction chemotherapy, elevated minimal residual disease (MRD) levels, and/or poor survival. 7,14,22,30,51,52 Several observations indicate that tyrosine kinase inhibitors (TKIs) may be effective in Ph-like ALL. Kinase fusions and sequence mutations confer cytokine-independent proliferation in mouse pre-B-cell lines that is abrogated by tyrosine kinase inhibitors (TKIs), ABL1 inhibitors such as imatinib and dasatinib for ABL-class fusions, and JAK2 inhibitors for JAK-STAT-activating alterations.…”