Abstract 4729: Frequency of actionable gene fusions in patients with Philadelphia chromosome-like (Ph-like) B-acute lymphoblastic leukemia (ALL): A retrospective study from the Children's Oncology Group (COG)

• Published in: Cancer research (Chicago, Ill.) Ill.), 2015-08, Vol.75 (15_Supplement), p.4729-4729
• Main Authors: Reshmi, Shalini C., Harvey, Richard C., Smith, Amy, Chen, I-Ming, Valentine, Marc, Liu, Yu, Li, Yongjin, Zhang, Jinghui, Roberts, Kathryn G., Shao, Ying, Easton, John, Payne-Turner, Debbie, Devidas, Meenakshi, Heerema, Nyla, Carroll, Andrew J., Raetz, Elizabeth A., Borowitz, Michael J., Wood, Brent L., Angiolillo, Anne L., Burke, Michael M., Salzer, Wanda L., Zweidler-McKay, Patrick A., Rabin, Karen R., Carroll, William L., Loh, Mignon L., Hunger, Stephen P., Mullighan, Charles G., Willman, Cheryl L., Gastier-Foster, Julie M.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2015-4729

Introduction: While cure rates exceed 80%, many children with B-ALL still relapse. Many of these patients (pts) display a Ph-like gene expression profile (GEP), but lack canonical BCR-ABL1 fusion. We have identified alternate kinase fusions in Ph-like ALL that induce cell proliferation sensitive to tyrosine kinase inhibitors (TKI) (Roberts, NEJM 2014). We report retrospective analyses of 1390 B-ALL pts, 885 NCI high risk and 505 standard risk B-ALL pts with elevated minimal residual disease. Methods: Cases were screened using an 8-gene Taqman low-density array (LDA) PCR assay to identify the Ph-like GEP (Harvey, ASH 2013). Ph-like cases with elevated CRLF2 expression were tested for CRLF2 rearrangement (CRLF2-R; P2RY8-CRLF2 by Taqman PCR on the LDA card and IGH-CRLF2 by FISH). JAK mutations in CRLF2-R cases were tested by Sanger sequencing. Ph-like cases without CRLF2-R were tested for previously identified kinase fusions involving ABL1, ABL2, CSF1R, JAK2, NTRK3, and PDGFRB by RT-PCR. Ph-like cases without detected fusions underwent RNA-sequencing, either using standard Illumina library preparation or a customized kinome capture kit (Agilent). Results: 339 (24%) pts were Ph-like. BCR-ABL1 (N = 45) and ETV6-RUNX1 (N = 11) were excluded from further analyses, as the former already receives TKI therapy and ETV6-RUNX1 ALL lacks targetable kinase fusions (unpublished). Of the remaining 283 Ph-like cases, 153 were CRLF2high (defined by CRLF2 expression levels on the LDA card). 61 (40%) had P2RY8-CRLF2 fusion, and of the remaining 91 CRLF2high cases, 56 of 69 tested had CRLF2-R (55 to IGH, 1 to an unknown partner). Thus, 117/130 (90%) CRLF2high Ph-like cases had a documented CRLF2 genomic lesion and 52 (44%) of these had a JAK mutation. Of the 130 Ph-like CRLF2low cases, 61 (47%) had a previously reported targetable TK fusion identified by RT-PCR, kinome capture or RNA sequencing. These included: 38 ABL class fusions (17 ABL1, 5 ABL2, 3 CSF1R, 13 PDGFRB) sensitive to imatinib/dasatinib; 14 JAK2 and 8 EPOR fusions sensitive to ruxolitinib; and 1 NTRK3 fusion sensitive to crizotinib. Nine cases had known fusions with new alternate breakpoints, and an additional 9 cases had fusions of novel N-terminal partners with known actionable C-terminal kinase genes. RNA sequencing identified 8 cases with IGH-EPOR fusions not previously captured by the kinome assay, indicating the cryptic and complex nature of this rearrangement. Conclusion: Almost half of Ph-like pediatric B-