Advertisement

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

  • Sidharth Totadri
  • Minu Singh
  • Amita Trehan
  • Neelam Varma
  • Prateek Bhatia
Review Article
  • 70 Downloads

Abstract

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.

Keywords

Copy number anomalies High risk ALL IKAROS MLPA Precision medicine 

Notes

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.

Ethical Approval

This article does not contain any studies with human participants or animals performed by any of the authors.

References

  1. 1.
    Pui C-H, Yang JJ, Hunger SP, Pieters R, Schrappe M, Biondi A et al (2015) Childhood acute lymphoblastic leukemia: progress through collaboration. J Clin Oncol 33(27):2938–2948CrossRefPubMedPubMedCentralGoogle Scholar
  2. 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. 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
  4. 4.
    Locatelli F, Schrappe M, Bernardo ME, Rutella S (2012) How I treat relapsed childhood acute lymphoblastic leukemia. Blood 120(14):2807–2816CrossRefPubMedGoogle Scholar
  5. 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
  6. 6.
    Tasian SK, Loh ML, Hunger SP (2017) Philadelphia chromosome-like acute lymphoblastic leukemia. Blood 130(19):2064–2072CrossRefPubMedGoogle Scholar
  7. 7.
    Tran TH, Loh ML (2016) Ph-like acute lymphoblastic leukemia. Hematol Am Soc Hematol Educ Program 2016(1):561–566Google Scholar
  8. 8.
    Roberts KG, Li Y, Payne-Turner D, Harvey RC, Yang Y-L, Pei D et al (2014) Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. N Engl J Med 371(11):1005–1015CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Boer JM, Steeghs EMP, Marchante JRM, Boeree A, Beaudoin JJ, Beverloo HB et al (2017) Tyrosine kinase fusion genes in pediatric BCR-ABL1-like acute lymphoblastic leukemia. Oncotarget 8(3):4618–4628CrossRefPubMedGoogle Scholar
  10. 10.
    Roberts KG, Pei D, Campana D, Payne-Turner D, Li Y, Cheng C et al (2014) Outcomes of children with BCR-ABL1–like acute lymphoblastic leukemia treated with risk-directed therapy based on the levels of minimal residual disease. J Clin Oncol 32(27):3012–3020CrossRefPubMedPubMedCentralGoogle Scholar
  11. 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
  12. 12.
    Boer JM, Marchante JRM, Evans WE, Horstmann MA, Escherich G, Pieters R et al (2015) BCR-ABL1-like cases in pediatric acute lymphoblastic leukemia: a comparison between DCOG/Erasmus MC and COG/St. Jude signatures. Haematologica 100(9):e354–e357CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Izraeli S (2014) Beyond Philadelphia: ‘Ph-like’ B cell precursor acute lymphoblastic leukemias–diagnostic challenges and therapeutic promises. Curr Opin Hematol 21(4):289–296CrossRefPubMedGoogle Scholar
  14. 14.
    Wells J, Jain N, Konopleva M (2017) Philadelphia chromosome-like acute lymphoblastic leukemia: progress in a new cancer subtype. Clin Adv Hematol Oncol 15(7):554–561PubMedGoogle Scholar
  15. 15.
    Iacobucci I, Mullighan CG (2017) Genetic basis of acute lymphoblastic leukemia. J Clin Oncol 35(9):975–983CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Ge Z, Gu Y, Xiao L, Han Q, Li J, Chen B et al (2016) Co-existence of IL7R high and SH2B3 low expression distinguishes a novel high-risk acute lymphoblastic leukemia with Ikaros dysfunction. Oncotarget 7:46014–46027PubMedPubMedCentralGoogle Scholar
  17. 17.
    Roberts KG, Morin RD, Zhang J, Hirst M, Zhao Y, Su X et al (2012) Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia. Cancer Cell 22:153–166CrossRefPubMedPubMedCentralGoogle Scholar
  18. 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
  19. 19.
    Den Boer ML, van Slegtenhorst M, De Menezes RX, Cheok MH, Buijs-Gladdines JG, Peters ST et al (2009) A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study. Lancet Oncol 10:125–134CrossRefGoogle Scholar
  20. 20.
    Moorman AV, Enshaei A, Schwab C, Wade R, Chilton L, Elliott A et al (2014) A novel integrated cytogenetic and genomic classification refines risk stratification in pediatric acute lymphoblastic leukemia. Blood 124(9):1434–1444CrossRefPubMedGoogle Scholar
  21. 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
  22. 22.
    Chiaretti S, Gianfelici V, O’Brien SM, Mullighan CG (2016) Advances in the genetics and therapy of acute lymphoblastic leukemia. Am Soc Clin Oncol Educ Book 35:e314–e322CrossRefPubMedGoogle Scholar
  23. 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
  24. 24.
    Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM et al (2016) The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127:2391–2405CrossRefPubMedGoogle Scholar
  25. 25.
    Moorman AV (2016) New and emerging prognostic and predictive genetic biomarkers in B-cell precursor acute lymphoblastic leukemia. Haematologica 101:407–416CrossRefPubMedPubMedCentralGoogle Scholar
  26. 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
  27. 27.
    Reshmi SC, Harvey RC, Roberts KG, Stonerock E, Smith A, Jenkins H et al (2017) Targetable kinase gene fusions in high-risk B-ALL: a study from the Children’s Oncology Group. Blood 129(25):3352–3361PubMedPubMedCentralGoogle Scholar
  28. 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
  29. 29.
    Shochat C, Tal N, Bandapalli OR, Palmi C, Ganmore I, te Kronnie G et al (2011) Gain-of-function mutations in interleukin-7 receptor-α (IL7R) in childhood acute lymphoblastic leukemias. J Exp Med 208(5):901–908CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Imamura T, Kiyokawa N, Kato M, Imai C, Okamoto Y, Yano M et al (2016) Characterization of pediatric Philadelphia-negative B-cell precursor acute lymphoblastic leukemia with kinase fusions in Japan. Blood Cancer J 6:e419CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Welsh SJ, Churchman ML, Togni M, Mullighan CG, Hagman J (2018) Deregulation of kinase signaling and lymphoid development in EBF1-PDGFRB ALL leukemogenesis. Leukemia 32:38–48CrossRefPubMedGoogle Scholar
  32. 32.
    Weston BW, Hayden MA, Roberts KG, Bowyer S, Hsu J, Fedoriw G et al (2013) Tyrosine kinase inhibitor therapy induces remission in a patient with refractory EBF1-PDGFRB-positive acute lymphoblastic leukemia. J Clin Oncol 31:e413–e416CrossRefPubMedGoogle Scholar

Copyright information

© Indian Society of Hematology and Blood Transfusion 2018

Authors and Affiliations

  1. 1.Pediatric Hematology-Oncology Unit, Department of Pediatrics, Advanced Pediatrics CenterPostgraduate Institute of Medical Education and ResearchChandigarhIndia
  2. 2.Department of HematologyPostgraduate Institute of Medical Education and ResearchChandigarhIndia

Personalised recommendations