EBF1-PDGFRB fusion in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL): genetic profile and clinical implications

Approximately 15% of pediatric B cell precursor acute lymphoblastic leukemia (BCP-ALL) is characterized by gene expression similar to that of BCR-ABL1-positive disease and unfavorable prognosis. This BCR-ABL1-like subtype shows a high frequency of B-cell development gene aberrations and tyrosine kinase-activating lesions. To evaluate the clinical significance of tyrosine kinase gene fusions in children with BCP-ALL, we studied the frequency of recently identified tyrosine kinase fusions, associated genetic features, and prognosis in a representative Dutch/German cohort. We identified 14 tyrosine kinase fusions among 77 BCR-ABL1-like cases (18%) and none among 76 non-BCR-ABL1-like B-other cases. Novel exon fusions were identified for RCSD1-ABL2 and TERF2-JAK2. JAK2 mutation was mutually exclusive with tyrosine kinase fusions and only occurred in cases with high CRLF2 expression. The non/late response rate and levels of minimal residual disease in the fusion-positive BCR-ABL1-like group were higher than in the non-BCR-ABL1-like B-others (p<0.01), and also higher, albeit not statistically significant, compared with the fusion-negative BCR-ABL1-like group. The 8-year cumulative incidence of relapse in the fusion-positive BCR-ABL1-like group (35%) was comparable with that in the fusion-negative BCR-ABL1-like group (35%), and worse than in the non-BCR-ABL1-like B-other group (17%, p=0.07). IKZF1 deletions, predominantly other than the dominant-negative isoform and full deletion, co-occurred with tyrosine kinase fusions. This study shows that tyrosine kinase fusion-positive cases are a high-risk subtype of BCP-ALL, which warrants further studies with specific kinase inhibitors to improve outcome.

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“…An alternative approach screens patients selected by poor early clinical response for tyrosine kinase fusions [10]. …”

Section: Discussionmentioning

confidence: 99%

“…A large Japanese study screened all B-other cases by transcriptome analysis or multiplexed RT-PCR for 15 fusions and found both methods similarly sensitive [9]. Other studies describe systematic screens in B-other cases by FISH or RT-PCR to detect specific tyrosine kinase fusions [10–11]. …”

Section: Introductionmentioning

confidence: 99%

Tyrosine kinase fusion genes in pediatric BCR-ABL1-like acute lymphoblastic leukemia

et al. 2016

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“…6 Notably, high levels of end-of-induction MRD and induction failures appear to be particularly common in Ph-like cases harboring the EBF1-PDGFRB fusion. 13 In a multivariable analysis, the presence of a Ph-like GEP constitutes an independent negative prognostic factor. 14 This is further supported by the inferior outcomes of Ph-like ALL patients compared with non-Ph-like ALL across all age groups, with a dismal prognosis for young adults with Ph-like ALL (Figure 1).…”

Section: Ph-like All: the Clinical Picturementioning

confidence: 99%

Ph-like acute lymphoblastic leukemia

Tran

Loh

2016

Hematology

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Philadelphia chromosome–like acute lymphoblastic leukemia (Ph-like ALL) is a newly identified high-risk (HR) B-lineage ALL subtype, accounting for ∼15% of children with National Cancer Institute–defined HR B-ALL. It occurs more frequently in adolescents and adults, having been reported in as much as 27% of young adults with ALL between 21 and 39 years of age. It exhibits adverse clinical features, confers a poor prognosis, and harbors a diverse range of genetic alterations that activate cytokine receptor genes and kinase signaling pathways, making it amenable to treatment with tyrosine kinase inhibitor (TKI) therapy. Multiple groups are currently conducting clinical trials to prospectively screen patients with Ph-like ALL and incorporate the relevant TKI for those harboring ABL-class gene rearrangements or those with JAK-STAT pathway alterations. The success of combinatorial treatment of TKI with chemotherapy in the setting of Ph-positive ALL suggests that this approach may similarly improve outcomes for patients with Ph-like ALL. Hence, Ph-like ALL illustrates the modern treatment paradigm of precision medicine and presents unique opportunities for harnessing international collaborations to further improve outcomes for patients with ALL.

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“…4 PDGFRb-containing fusions have been reported in B-cell malignancies, 5,6 but not T-ALL. Fusions of the B-cell lymphoid transcription factor early B-cell factor 1 (EBF1) with PDGFRb occur in ~8% of children with Ph-like ALL.…”

mentioning

confidence: 99%

“…Pomicter, 1 Thai Hoa Tran, 5 Brian J. Druker, 3,4 Jeffrey W. Tyner,3 Rodney R. Miles, 1,6 James M. Graham, 1,7 Jae-Yeon Hwang, 1,7 Katherine E. Varley, 1,7 …”

mentioning

confidence: 99%

A novel AGGF1-PDGFRb fusion in pediatric T-cell acute lymphoblastic leukemia

et al. 2017

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EBF1-PDGFRB fusion in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL): genetic profile and clinical implications

Abstract: Key Points EBF1-PDGFRB fusion accounts for ∼0.5% of B-cell precursor acute lymphoblastic leukemia and 2.7% of the B-other subtype. EBF1-PDGFRB-positive patients are MRD positive and are slow early responders who respond to imatinib.

Cited by 117 publications

References 15 publications

Tyrosine kinase fusion genes in pediatric BCR-ABL1-like acute lymphoblastic leukemia

Tyrosine kinase fusion genes in pediatric BCR-ABL1-like acute lymphoblastic leukemia

Ph-like acute lymphoblastic leukemia

A novel AGGF1-PDGFRb fusion in pediatric T-cell acute lymphoblastic leukemia

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