Keeping PACE with Ph Positive to Ph-Like Detection in B-Lineage Acute Lymphoblastic Leukemia: A Practical and Cost Effective (PACE) Approach in a Resource Constrained Setting
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Philadelphia (Ph)-like or BCR-ABL like acute lymphoblastic leukemia (ALL) is defined on the basis of a gene expression profile that is similar to Ph-positive ALL. It comprises a wide spectrum of genetic lesions affecting primarily the cytokine receptor and/or kinase signalling genes. It accounts for approximately 10–15% of pediatric ALL, and is more common in patients who are high-risk according to the National Cancer Institute criteria. Presence of Ph-like mutations is an independent predictor of poor outcome. However, there is vast potential to utilize targeted therapy to improve survival in this group. The sizeable range of genetic lesions varying from translocations, fusions, point mutations and deletions make the diagnosis challenging. Hence, a practical and cost effective approach is required to enable identification in resource constrained settings. Patients with recurrent cytogenetic abnormalities such as ETV6-RUNX1, high hyperdiploidy, TCF3-PBX1, BCR-ABL1 and KMT2A (MLL) rearrangement need not be tested, as these are mutually exclusive with BCR-ABL like mutations. Detection of CRLF2 overexpression, which is the commonest abnormality, is employed as the first step. In patients lacking overexpression, testing for tyrosine kinase fusions can be performed. However, the goal should be to employ a combination of molecular diagnostic techniques such as reverse transcriptase polymerase chain reaction (PCR), real time quantitative PCR, fluorescence in situ hybridization and Sanger sequencing to detect genetic lesions that are amenable to targeted therapy.
KeywordsCopy number anomalies High risk ALL IKAROS MLPA Precision medicine
Compliance with Ethical Standards
Conflict of interest
The authors declare that they have no conflict of interest. Author identifying information is on the title page that is submitted separate from the manuscript.
This article does not contain any studies with human participants or animals performed by any of the authors.
- 2.Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®), PDQ Cancer Information Summaries, NCBI Bookshelf [Internet] (2017). https://www.ncbi.nlm.nih.gov/books/NBK65763/. Accessed 26 November 2017
- 3.Mullighan CG (2014) The genomic landscape of acute lymphoblastic leukemia in children and young adults. Hematol Am Soc Hematol Educ Program 2014(1):174–180Google Scholar
- 5.Hunger SP (2011) Tyrosine kinase inhibitor use in pediatric Philadelphia chromosome-positive acute lymphoblastic anemia. Hematol Am Soc Hematol Educ Program 2011:361–365Google Scholar
- 7.Tran TH, Loh ML (2016) Ph-like acute lymphoblastic leukemia. Hematol Am Soc Hematol Educ Program 2016(1):561–566Google Scholar
- 11.van der Veer A, Waanders E, Pieters R, Willemse ME, Van Reijmersdal SV, Russell LJ et al (2013) Independent prognostic value of BCR-ABL1-like signature and IKZF1 deletion, but not high CRLF2 expression, in children with B-cell precursor ALL. Blood 122(15):2622–2629CrossRefPubMedPubMedCentralGoogle Scholar
- 18.Harvey RC, Mullighan CG, Chen IM, Wharton W, Mikhail FM, Carroll AJ et al (2010) Rearrangement of CRLF2 is associated with mutation of JAK kinases, alteration of IKZF1, Hispanic/Latino ethnicity, and a poor outcome in pediatric B-progenitor acute lymphoblastic leukemia. Blood 115:5312–5321CrossRefPubMedPubMedCentralGoogle Scholar
- 21.Harvey RC, Mullighan CG, Wang X, Dobbin KK, Davidson GS, Bedrick EJ et al (2010) Identification of novel cluster groups in pediatric high-risk B-precursor acute lymphoblastic leukemia with gene expression profiling: correlation with genome-wide DNA copy number alterations, clinical characteristics, and outcome. Blood 116(23):4874–4884CrossRefPubMedPubMedCentralGoogle Scholar
- 23.Harvey RC, Kang H, Roberts KG et al (2013) Development and validation of a highly sensitive and specific gene expression classifier to prospectively screen and identify B-precursor acute lymphoblastic leukemia (ALL) patients with a Philadelphia chromosome-like (Ph-like or BCR-ABL1-Like) signature for therapeutic targeting and clinical intervention [ASH abstract 826]. Blood 122:2622–2629CrossRefGoogle Scholar
- 26.Derrieux C, Freynet N, Frayfer J, Delabesse E, Clappier E, Defasque S et al (2018) A case of B-cell precursor acute lymphoblastic leukemia with IL3-IGH rearrangement revealed by thromboembolism and marked eosinophilia. Leuk Lymphoma. https://doi.org/10.1080/10428194.2018.1430796 CrossRefPubMedGoogle Scholar
- 28.Cario G, Zimmermann M, Romey R, Gesk S, Vater I, Harbott J et al (2010) Presence of the P2RY8-CRLF2 rearrangement is associated with a poor prognosis in non-high-risk precursor B-cell acute lymphoblastic leukemia in children treated according to the ALL-BFM 2000 protocol. Blood 115(26):5393–5397CrossRefPubMedGoogle Scholar