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Management of Philadelphia Chromosome-Like Acute Lymphoblastic Leukemia (Ph-Like ALL)

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Pathogenesis and Treatment of Leukemia

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Abstract

BCR-ABL1-like or Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) ALL is a subset of high-risk (HR) B-ALL associated with high relapse risk and inferior clinical outcomes. Ph-like ALL was first described with a kinase-activated gene expression profile similar to that of Philadelphia chromosome-positive ALL (Ph+ ALL) and frequent IKZF1 (Ikaros) alterations, yet lacking the canonical BCR-ABL1 oncogene fusion (Mullighan et al., Blood. 2009;360:470–80; Den Boer et al., Lancet Oncol. 2009;10:125–34; Harvey et al., Blood. 2010;116:4874–84). Advances in high-throughput sequencing technologies during the past decade have unraveled the genomic landscape of Ph-like ALL, revealing a diverse array of kinase-activating alterations that may be amenable to molecularly targeted therapies (Tasian et al., Blood. 2017;130:2064–72). Ph-like ALL is now included as a provisional disease entity in the World Health Organization 2016 classification of acute leukemias (Arber et al., Blood. 2016;127:2391–405). Thorough characterization of the epidemiology, clinical portrait, and biology of Ph-like ALL across the age spectrum has subsequently led to current precision medicine trials investigating the therapeutic potential of tyrosine kinase inhibitor-based therapies for children, adolescents, and adults with Ph-like ALL. These efforts have been somewhat challenging to translate given the genomic heterogeneity and diagnostic complexity of Ph-like ALL, and the most optimal treatment paradigm for this high-risk group of patients has yet to be established. This chapter aims to provide a state-of-the-art review of the epidemiology, clinical features, and biology of Ph-like ALL, highlight the challenges in implementing pragmatic and cost-effective diagnostic algorithms in the clinic, and describe the milieu of treatment strategies under active clinical or preclinical investigation that strives to decrease relapse risk and improve long-term survival for patients with this high-risk leukemia subtype.

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References

  1. Mullighan CG, Su X, Zhang J, Radtke I, Phillips LA, Miller CB, et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med. 2009;360(5):470–80.

    PubMed  PubMed Central  Google Scholar 

  2. Den Boer ML, van Slegtenhorst M, De Menezes RX, Cheok MH, Buijs-Gladdines JG, Peters ST, et al. A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study. Lancet Oncol. 2009;10(2):125–34.

    Google Scholar 

  3. Boer JM, Marchante JR, Evans WE, Horstmann MA, Escherich G, Pieters R, et al. BCR-ABL1-like cases in pediatric acute lymphoblastic leukemia: a comparison between DCOG/Erasmus MC and COG/St. Jude signatures. Haematologica. 2015;100(9):e354–7.

    PubMed  PubMed Central  Google Scholar 

  4. Pui CH, Roberts KG, Yang JJ, Mullighan CG. Philadelphia chromosome-like acute lymphoblastic leukemia. Clin Lymphoma Myeloma Leuk. 2017;17(8):464–70.

    PubMed  PubMed Central  Google Scholar 

  5. Tran TH, Loh ML. Ph-like acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program. 2016;2016(1):561–6.

    PubMed  PubMed Central  Google Scholar 

  6. Harvey RC, Tasian SK. Clinical diagnostics and treatment strategies for Philadelphia chromosome-like acute lymphoblastic leukemia. Blood Adv. 2020;4(1):218–28.

    PubMed  PubMed Central  Google Scholar 

  7. Roberts KG, Li Y, Payne-Turner D, Harvey RC, Yang YL, Pei D, et al. Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. N Engl J Med. 2014;371(11):1005–15.

    PubMed  PubMed Central  Google Scholar 

  8. Roberts KG, Morin RD, Zhang J, Hirst M, Zhao Y, Su X, et al. Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia. Cancer Cell. 2012;22(2):153–66.

    PubMed  PubMed Central  Google Scholar 

  9. Tasian SK, Loh ML, Hunger SP. Philadelphia chromosome-like acute lymphoblastic leukemia. Blood. 2017;130(19):2064–72.

    PubMed  PubMed Central  Google Scholar 

  10. van der Veer A, Waanders E, Pieters R, Willemse ME, Van Reijmersdal SV, Russell LJ, et al. Independent prognostic value of BCR-ABL1-like signature and IKZF1 deletion, but not high CRLF2 expression, in children with B-cell precursor ALL. Blood. 2013;122(15):2622–9.

    PubMed  PubMed Central  Google Scholar 

  11. Roberts KG, Reshmi SC, Harvey RC, Chen IM, Patel K, Stonerock E, et al. Genomic and outcome analyses of Ph-like ALL in NCI standard-risk patients: a report from the Children’s Oncology Group. Blood. 2018;132(8):815–24.

    PubMed  PubMed Central  Google Scholar 

  12. Russell LJ, Capasso M, Vater I, Akasaka T, Bernard OA, Calasanz MJ, et al. Deregulated expression of cytokine receptor gene, CRLF2, is involved in lymphoid transformation in B-cell precursor acute lymphoblastic leukemia. Blood. 2009;114(13):2688–98.

    PubMed  Google Scholar 

  13. Hertzberg L, Vendramini E, Ganmore I, Cazzaniga G, Schmitz M, Chalker J, et al. Down syndrome acute lymphoblastic leukemia, a highly heterogeneous disease in which aberrant expression of CRLF2 is associated with mutated JAK2: a report from the International BFM Study Group. Blood. 2010;115(5):1006–17.

    PubMed  Google Scholar 

  14. Mullighan CG, Miller CB, Radtke I, Phillips LA, Dalton J, Ma J, et al. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature. 2008;453(7191):110–4.

    PubMed  Google Scholar 

  15. Slayton WB, Schultz KR, Kairalla JA, Devidas M, Mi X, Pulsipher MA, et al. Dasatinib plus intensive chemotherapy in children, adolescents, and young adults with philadelphia chromosome-positive acute lymphoblastic leukemia: results of Children’s Oncology Group Trial AALL0622. J Clin Oncol. 2018;36(22):2306–14.

    PubMed  PubMed Central  Google Scholar 

  16. van der Veer A, Zaliova M, Mottadelli F, De Lorenzo P, Te Kronnie G, Harrison CJ, et al. IKZF1 status as a prognostic feature in BCR-ABL1-positive childhood ALL. Blood. 2014;123(11):1691–8.

    PubMed  Google Scholar 

  17. Martinelli G, Iacobucci I, Storlazzi CT, Vignetti M, Paoloni F, Cilloni D, et al. IKZF1 (Ikaros) deletions in BCR-ABL1-positive acute lymphoblastic leukemia are associated with short disease-free survival and high rate of cumulative incidence of relapse: a GIMEMA AL WP report. J Clin Oncol. 2009;27(31):5202–7.

    PubMed  Google Scholar 

  18. Churchman ML, Mullighan CG. Ikaros: Exploiting and targeting the hematopoietic stem cell niche in B-progenitor acute lymphoblastic leukemia. Exp Hematol. 2017;46:1–8.

    PubMed  Google Scholar 

  19. Churchman ML, Low J, Qu C, Paietta EM, Kasper LH, Chang Y, et al. Efficacy of retinoids in IKZF1-mutated BCR-ABL1 acute lymphoblastic leukemia. Cancer Cell. 2015;28(3):343–56.

    PubMed  PubMed Central  Google Scholar 

  20. Vairy S, Tran TH. IKZF1 alterations in acute lymphoblastic leukemia: the Good, the Bad and the Ugly. Blood Rev. 2020: Manuscript under revision.

    Google Scholar 

  21. Tran TH, Harris MH, Nguyen JV, Blonquist TM, Stevenson KE, Stonerock E, et al. Prognostic impact of kinase-activating fusions and IKZF1 deletions in pediatric high-risk B-lineage acute lymphoblastic leukemia. Blood Adv. 2018;2(5):529–33.

    PubMed  PubMed Central  Google Scholar 

  22. Stanulla M, Dagdan E, Zaliova M, Moricke A, Palmi C, Cazzaniga G, et al. IKZF1(plus) defines a new minimal residual disease-dependent very-poor prognostic profile in pediatric B-cell precursor acute lymphoblastic leukemia. J Clin Oncol. 2018;36(12):1240–9.

    PubMed  Google Scholar 

  23. Steeghs EMP, Boer JM, Hoogkamer AQ, Boeree A, de Haas V, de Groot-Kruseman HA, et al. Copy number alterations in B-cell development genes, drug resistance, and clinical outcome in pediatric B-cell precursor acute lymphoblastic leukemia. Sci Rep. 2019;9(1):4634.

    PubMed  PubMed Central  Google Scholar 

  24. Zaliova M, Stuchly J, Winkowska L, Musilova A, Fiser K, Slamova M, et al. Genomic landscape of pediatric B-other acute lymphoblastic leukemia in a consecutive European cohort. Haematologica. 2019;104(7):1396–406.

    PubMed  PubMed Central  Google Scholar 

  25. Fedullo AL, Messina M, Elia L, Piciocchi A, Gianfelici V, Lauretti A, et al. Prognostic implications of additional genomic lesions in adult Philadelphia chromosome-positive acute lymphoblastic leukemia. Haematologica. 2019;104(2):312–8.

    PubMed  PubMed Central  Google Scholar 

  26. Perez-Andreu V, Roberts KG, Harvey RC, Yang W, Cheng C, Pei D, et al. Inherited GATA3 variants are associated with Ph-like childhood acute lymphoblastic leukemia and risk of relapse. Nat Genet. 2013;45(12):1494–8.

    PubMed  PubMed Central  Google Scholar 

  27. Roberts KG, Gu Z, Payne-Turner D, McCastlain K, Harvey RC, Chen IM, et al. High frequency and poor outcome of philadelphia chromosome-like acute lymphoblastic leukemia in adults. J Clin Oncol. 2017;35(4):394–401.

    PubMed  Google Scholar 

  28. Tasian SK, Hurtz C, Wertheim GB, Bailey NG, Lim MS, Harvey RC, et al. High incidence of Philadelphia chromosome-like acute lymphoblastic leukemia in older adults with B-ALL. Leukemia. 2017;31(4):981–4.

    PubMed  Google Scholar 

  29. Tasian SK, Doral MY, Borowitz MJ, Wood BL, Chen IM, Harvey RC, et al. Aberrant STAT5 and PI3K/mTOR pathway signaling occurs in human CRLF2-rearranged B-precursor acute lymphoblastic leukemia. Blood. 2012;120(4):833–42.

    PubMed  PubMed Central  Google Scholar 

  30. Mullighan CG, Collins-Underwood JR, Phillips LA, Loudin MG, Liu W, Zhang J, et al. Rearrangement of CRLF2 in B-progenitor- and Down syndrome-associated acute lymphoblastic leukemia. Nat Genet. 2009;41(11):1243–6.

    PubMed  PubMed Central  Google Scholar 

  31. Scheeren FA, van Lent AU, Nagasawa M, Weijer K, Spits H, Legrand N, et al. Thymic stromal lymphopoietin induces early human B-cell proliferation and differentiation. Eur J Immunol. 2010;40(4):955–65.

    PubMed  Google Scholar 

  32. Isaksen DE, Baumann H, Zhou B, Nivollet S, Farr AG, Levin SD, et al. Uncoupling of proliferation and Stat5 activation in thymic stromal lymphopoietin-mediated signal transduction. J Immunol. 2002;168(7):3288–94.

    PubMed  Google Scholar 

  33. Isaksen DE, Baumann H, Trobridge PA, Farr AG, Levin SD, Ziegler SF. Requirement for stat5 in thymic stromal lymphopoietin-mediated signal transduction. J Immunol. 1999;163(11):5971–7.

    PubMed  Google Scholar 

  34. Herold T, Schneider S, Metzeler KH, Neumann M, Hartmann L, Roberts KG, et al. Adults with Philadelphia chromosome-like acute lymphoblastic leukemia frequently have IGH-CRLF2 and JAK2 mutations, persistence of minimal residual disease and poor prognosis. Haematologica. 2017;102(1):130–8.

    PubMed  PubMed Central  Google Scholar 

  35. Moorman AV, Schwab C, Ensor HM, Russell LJ, Morrison H, Jones L, et al. IGH@ translocations, CRLF2 deregulation, and microdeletions in adolescents and adults with acute lymphoblastic leukemia. J Clin Oncol. 2012;30(25):3100–8.

    PubMed  Google Scholar 

  36. Yoda A, Yoda Y, Chiaretti S, Bar-Natan M, Mani K, Rodig SJ, et al. Functional screening identifies CRLF2 in precursor B-cell acute lymphoblastic leukemia. Proc Natl Acad Sci U S A. 2010;107(1):252–7.

    PubMed  Google Scholar 

  37. Reshmi SC, Harvey RC, Roberts KG, Stonerock E, Smith A, Jenkins H, et al. Targetable kinase gene fusions in high risk B-ALL: a study from the Children’s Oncology Group. Blood. 2017;129(25):3352–61.

    PubMed  PubMed Central  Google Scholar 

  38. Tasian SK, Dai, Y, Devidas M, Roberts KG, Harvey RC, Chen IL, Carroll AJ, Heerema NA, Reshmi SC, Gastier-Foster J, Borowitz MJ, Wood B, Mullighan CM, Willman CL, Maloney KW, Larsen EC, Angiolillo AL, Schore RS, Burke MJ, Salzer WL, Winick NJ, Carroll WL, Hunger SP, Raetz EA, Rabin KR, Loh ML. Outcomes of patients with CRLF2-overexpressing acute lymphoblastic leukemia without down syndrome: a report from the Children’s Oncology Group. Blood. 2020;136(Supplement 1):1095. https://ashpublications.org/blood/article/136/Supplement%201/45/470879/Outcomes-of-Patients-with-CRLF2-Overexpressing?searchresult=1.

  39. Roberts KG, Mullighan CG. Genomics in acute lymphoblastic leukaemia: insights and treatment implications. Nat Rev Clin Oncol. 2015;12(6):344–57.

    PubMed  Google Scholar 

  40. Iacobucci I, Li Y, Roberts KG, Dobson SM, Kim JC, Payne-Turner D, et al. Truncating erythropoietin receptor rearrangements in acute lymphoblastic leukemia. Cancer Cell. 2016;29(2):186–200.

    PubMed  PubMed Central  Google Scholar 

  41. Jabbour E, Short NJ, Ravandi F, Huang X, Daver N, DiNardo CD, et al. Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia: long-term follow-up of a single-centre, phase 2 study. Lancet Haematol. 2018;5(12):e618–e27.

    PubMed  PubMed Central  Google Scholar 

  42. Wiemels JL, Kang M, Chang JS, Zheng L, Kouyoumji C, Zhang L, et al. Backtracking RAS mutations in high hyperdiploid childhood acute lymphoblastic leukemia. Blood Cells Mol Dis. 2010;45(3):186–91.

    PubMed  PubMed Central  Google Scholar 

  43. Holmfeldt L, Wei L, Diaz-Flores E, Walsh M, Zhang J, Ding L, et al. The genomic landscape of hypodiploid acute lymphoblastic leukemia. Nat Genet. 2013;45(3):242–52.

    PubMed  PubMed Central  Google Scholar 

  44. Irving J, Matheson E, Minto L, Blair H, Case M, Halsey C, et al. Ras pathway mutations are prevalent in relapsed childhood acute lymphoblastic leukemia and confer sensitivity to MEK inhibition. Blood. 2014;124(23):3420–30.

    PubMed  PubMed Central  Google Scholar 

  45. Roberts KG, Janke LJ, Zhao Y, Seth A, Ma J, Finkelstein D, et al. ETV6-NTRK3 induces aggressive acute lymphoblastic leukemia highly sensitive to selective TRK inhibition. Blood. 2018;132(8):861–5.

    PubMed  PubMed Central  Google Scholar 

  46. Nardi V, Ku N, Frigault MJ, Dubuc AM, Tsai HK, Amrein PC, et al. Clinical response to larotrectinib in adult Philadelphia chromosome-like ALL with cryptic ETV6-NTRK3 rearrangement. Blood Adv. 2020;4(1):106–11.

    PubMed  PubMed Central  Google Scholar 

  47. Schewe DM, Lenk L, Vogiatzi F, Winterberg D, Rademacher AV, Buchmann S, et al. Larotrectinib in TRK fusion-positive pediatric B-cell acute lymphoblastic leukemia. Blood Adv. 2019;3(22):3499–502.

    PubMed  PubMed Central  Google Scholar 

  48. Brown LM, Bartolo RC, Davidson NM, Schmidt B, Brooks I, Challis J, et al. Targeted therapy and disease monitoring in CNTRL-FGFR1-driven leukaemia. Pediatr Blood Cancer. 2019;66(10):e27897.

    PubMed  Google Scholar 

  49. Helsten T, Schwaederle M, Kurzrock R. Fibroblast growth factor receptor signaling in hereditary and neoplastic disease: biologic and clinical implications. Cancer Metastasis Rev. 2015;34(3):479–96.

    PubMed  PubMed Central  Google Scholar 

  50. Owattanapanich W, Rujirachun P, Ungprasert P, Buaboonnam J, Techavichit P. Prevalence and clinical outcome of philadelphia-like acute lymphoblastic leukemia: systematic review and meta-analysis. Clin Lymphoma Myeloma Leuk. 2020;20(1):e22–9.

    PubMed  Google Scholar 

  51. Jain N, Roberts KG, Jabbour E, Patel K, Eterovic AK, Chen K, et al. Ph-like acute lymphoblastic leukemia: a high-risk subtype in adults. Blood. 2017;129(5):572–81.

    PubMed  PubMed Central  Google Scholar 

  52. Harvey RC, Mullighan CG, Chen IM, Wharton W, Mikhail FM, Carroll AJ, et al. 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. 2010;115(26):5312–21.

    PubMed  PubMed Central  Google Scholar 

  53. Madzio J, Pastorczak A, Sedek L, Braun M, Taha J, Wypyszczak K, et al. GATA3 germline variant is associated with CRLF2 expression and predicts outcome in pediatric B-cell precursor acute lymphoblastic leukemia. Genes Chromosomes Cancer. 2019;58(9):619–26.

    PubMed  Google Scholar 

  54. Boer JM, Koenders JE, van der Holt B, Exalto C, Sanders MA, Cornelissen JJ, et al. Expression profiling of adult acute lymphoblastic leukemia identifies a BCR-ABL1-like subgroup characterized by high non-response and relapse rates. Haematologica. 2015;100(7):e261–4.

    PubMed  PubMed Central  Google Scholar 

  55. Loh ML, Zhang J, Harvey RC, Roberts K, Payne-Turner D, Kang H, et al. Tyrosine kinome sequencing of pediatric acute lymphoblastic leukemia: a report from the Children’s Oncology Group TARGET Project. Blood. 2013;121(3):485–8.

    PubMed  PubMed Central  Google Scholar 

  56. Weston BW, Hayden MA, Roberts KG, Bowyer S, Hsu J, Fedoriw G, et al. Tyrosine kinase inhibitor therapy induces remission in a patient with refractory EBF1-PDGFRB-positive acute lymphoblastic leukemia. J Clin Oncol. 2013;31(25):e413–6.

    PubMed  Google Scholar 

  57. Lengline E, Beldjord K, Dombret H, Soulier J, Boissel N, Clappier E. Successful tyrosine kinase inhibitor therapy in a refractory B-cell precursor acute lymphoblastic leukemia with EBF1-PDGFRB fusion. Haematologica. 2013;98(11):e146–8.

    PubMed  PubMed Central  Google Scholar 

  58. Schwab C, Ryan SL, Chilton L, Elliott A, Murray J, Richardson S, et al. EBF1-PDGFRB fusion in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL): genetic profile and clinical implications. Blood. 2016;127(18):2214–8.

    PubMed  Google Scholar 

  59. Ding YY, Stern JW, Jubelirer TF, Wertheim GB, Li F, Chang F, et al. Clinical efficacy of ruxolitinib and chemotherapy in a child with Philadelphia chromosome-like acute lymphoblastic leukemia with GOLGA5-JAK2 fusion and induction failure. Haematologica. 2018;103(9):e427–31.

    PubMed  PubMed Central  Google Scholar 

  60. Maloney KW, Devidas M, Wang C, Mattano LA, Friedmann AM, Buckley P, et al. Outcome in children with standard-risk B-cell acute lymphoblastic leukemia: results of Children’s Oncology Group Trial AALL0331. J Clin Oncol. 2020;38(6):602–12.

    PubMed  Google Scholar 

  61. den Boer ML, Cario G, Moorman AV, Boer JM, de Groot-Kruseman HA, Fiocco M, et al. Outcomes of paediatric patients with B-cell acute lymphocytic leukaemia with ABL-class fusion in the pre-tyrosine-kinase inhibitor era: a multicentre, retrospective, cohort study. Lancet Haematol. 2021;8(1):e55–66.

    PubMed  Google Scholar 

  62. Stock W, Luger SM, Advani AS, Yin J, Harvey RC, Mullighan CG, et al. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood. 2019;133(14):1548–59.

    PubMed  PubMed Central  Google Scholar 

  63. Chiaretti S, Messina M, Della Starza I, Piciocchi A, Cafforio L, Cavalli M, et al. Philadelphia-like acute lymphoblastic leukemia is associated with minimal residual disease persistence and poor outcome. First report of the minimal residual disease-oriented GIMEMA LAL1913. Haematologica. 2020;106(6):1559–68.

    PubMed Central  Google Scholar 

  64. Kang H, Chen IM, Wilson CS, Bedrick EJ, Harvey RC, Atlas SR, et al. Gene expression classifiers for relapse-free survival and minimal residual disease improve risk classification and outcome prediction in pediatric B-precursor acute lymphoblastic leukemia. Blood. 2010;115(7):1394–405.

    PubMed  PubMed Central  Google Scholar 

  65. Surrey LF, MacFarland SP, Chang F, Cao K, Rathi KS, Akgumus GT, et al. Clinical utility of custom-designed NGS panel testing in pediatric tumors. Genome Med. 2019;11(1):32.

    PubMed  PubMed Central  Google Scholar 

  66. Chang F, Lin F, Cao K, Surrey LF, Aplenc R, Bagatell R, et al. Development and clinical validation of a large fusion gene panel for pediatric cancers. J Mol Diagn. 2019;21(5):873–83.

    PubMed  PubMed Central  Google Scholar 

  67. He J, Abdel-Wahab O, Nahas MK, Wang K, Rampal RK, Intlekofer AM, et al. Integrated genomic DNA/RNA profiling of hematologic malignancies in the clinical setting. Blood. 2016;127(24):3004–14.

    PubMed  PubMed Central  Google Scholar 

  68. Schultz KR, Carroll A, Heerema NA, Bowman WP, Aledo A, Slayton WB, et al. Long-term follow-up of imatinib in pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia: Children’s Oncology Group study AALL0031. Leukemia. 2014;28(7):1467–71.

    PubMed  PubMed Central  Google Scholar 

  69. Wassmann B, Pfeifer H, Goekbuget N, Beelen DW, Beck J, Stelljes M, et al. Alternating versus concurrent schedules of imatinib and chemotherapy as front-line therapy for Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Blood. 2006;108(5):1469–77.

    PubMed  Google Scholar 

  70. Shen S, Chen X, Cai J, Yu J, Gao J, Hu S, et al. Effect of dasatinib vs imatinib in the treatment of pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia: a randomized clinical trial. JAMA Oncol. 2020;6(3):358–66.

    PubMed  PubMed Central  Google Scholar 

  71. Lilly MB, Ottmann OG, Shah NP, Larson RA, Reiffers JJ, Ehninger G, et al. Dasatinib 140 mg once daily versus 70 mg twice daily in patients with Ph-positive acute lymphoblastic leukemia who failed imatinib: results from a phase 3 study. Am J Hematol. 2010;85(3):164–70.

    PubMed  Google Scholar 

  72. Roberts KG, Yang YL, Payne-Turner D, Lin W, Files JK, Dickerson K, et al. Oncogenic role and therapeutic targeting of ABL-class and JAK/STAT activating kinase alterations in Ph-like ALL. Blood Adv. 2017;1(20):1657–71.

    PubMed  PubMed Central  Google Scholar 

  73. Kobayashi K, Miyagawa N, Mitsui K, Matsuoka M, Kojima Y, Takahashi H, et al. TKI dasatinib monotherapy for a patient with Ph-like ALL bearing ATF7IP/PDGFRB translocation. Pediatr Blood Cancer. 2015;62(6):1058–60.

    PubMed  Google Scholar 

  74. Fazio F, Barberi W, Cazzaniga G, Fazio G, Messina M, Della Starza I, et al. Efficacy of imatinib and chemotherapy in a pediatric patient with Philadelphia-like acute lymphoblastic leukemia with Ebf1-Pdgfrb fusion transcript. Leuk Lymphoma. 2020;61(2):469–72. https://pubmed.ncbi.nlm.nih.gov/31558067/.

  75. Cario G, Leoni V, Conter V, Attarbaschi A, Zaliova M, Sramkova L, et al. Relapses and treatment-related events contributed equally to poor prognosis in children with ABL-class fusion positive B-cell acute lymphoblastic leukemia treated according to AIEOP-BFM protocols. Haematologica. 2020;105(7):1887–94.

    PubMed  PubMed Central  Google Scholar 

  76. Tanasi I, Ba I, Sirvent N, Braun T, Cuccuini W, Ballerini P, et al. Efficacy of tyrosine kinase inhibitors in Ph-like acute lymphoblastic leukemia harboring ABL-class rearrangements. Blood. 2019;134(16):1351–5.

    PubMed  Google Scholar 

  77. Moorman AV, Schwab C, Winterman E, Hancock J, Castleton A, Cummins M, et al. Adjuvant tyrosine kinase inhibitor therapy improves outcome for children and adolescents with acute lymphoblastic leukaemia who have an ABL-class fusion. Br J Haematol. 2020;191(5):844–51.

    Google Scholar 

  78. Inaba H, Azzato EM, Mullighan CG. Integration of next-generation sequencing to treat acute lymphoblastic leukemia with targetable lesions: the St. Jude Children’s Research Hospital Approach. Front Pediatr. 2017;5:258.

    PubMed  PubMed Central  Google Scholar 

  79. Maude SL, Tasian SK, Vincent T, Hall JW, Sheen C, Roberts KG, et al. Targeting JAK1/2 and mTOR in murine xenograft models of Ph-like acute lymphoblastic leukemia. Blood. 2012;120(17):3510–8.

    PubMed  PubMed Central  Google Scholar 

  80. Tasian SK, Teachey DT, Li Y, Shen F, Harvey RC, Chen IM, et al. Potent efficacy of combined PI3K/mTOR and JAK or ABL inhibition in murine xenograft models of Ph-like acute lymphoblastic leukemia. Blood. 2017;129(2):177–87.

    PubMed  PubMed Central  Google Scholar 

  81. Zhang Q, Shi C, Han L, Jain N, Roberts KG, Ma H, et al. Inhibition of mTORC1/C2 signaling improves anti-leukemia efficacy of JAK/STAT blockade in CRLF2 rearranged and/or JAK driven Philadelphia chromosome-like acute B-cell lymphoblastic leukemia. Oncotarget. 2018;9(8):8027–41.

    PubMed  PubMed Central  Google Scholar 

  82. Khan M, Siddiqi R, Tran TH. Philadelphia chromosome-like acute lymphoblastic leukemia: a review of the genetic basis, clinical features, and therapeutic options. Semin Hematol. 2018;55(4):235–41.

    PubMed  Google Scholar 

  83. Wu SC, Li LS, Kopp N, Montero J, Chapuy B, Yoda A, et al. Activity of the type II JAK2 inhibitor CHZ868 in B cell acute lymphoblastic leukemia. Cancer Cell. 2015;28(1):29–41.

    PubMed  PubMed Central  Google Scholar 

  84. Hurtz C, Tasian SK, Wertheim G, Astles R, Zebrowski A, Perl AE, et al. Adaptive reactivation of signaling pathways as a novel mechanism of resistance to JAK inhibitors in Ph-like ALL. Blood. 2016;128(22):755.

    Google Scholar 

  85. Gotesman M, Vo T-TT, Mallya S, Zhang Q, Shi C, Müschen M, et al. mTOR kinase inhibitors enhance efficacy of TKIs in preclinical models of Ph-like B-ALL. Blood. 2016;128(22):2763.

    Google Scholar 

  86. Hurtz C, Wertheim GB, Loftus JP, Blumenthal D, Lehman A, Li Y, et al. Oncogene-independent BCR-like signaling adaptation confers drug resistance in Ph-like ALL. J Clin Invest. 2020;130(7):3637–53.

    PubMed  PubMed Central  Google Scholar 

  87. Tasian SK, Assad A, Hunter DS, Du Y, Loh ML. A Phase 2 study of ruxolitinib with chemotherapy in children with Philadelphia chromosome-like acute lymphoblastic leukemia (INCB18424-269/AALL1521): dose-finding results from the part 1 safety phase. Blood. 2018;132(Supplement 1):555.

    Google Scholar 

  88. Place AE, Karol SE, Forlenza CJ, Gambart M, Cooper TM, Fraser C, et al. Pediatric patients with relapsed/refractory acute lymphoblastic leukemia harboring heterogeneous genomic profiles respond to venetoclax in combination with chemotherapy. Blood. 2020;136 (Supplement 1):2793. https://ashpublications.org/blood/article/136/Supplement%201/30/470553/Venetoclax-Alone-or-in-Combinationwith?searchresult=1.

  89. Leonard JT, Rowley JS, Eide CA, Traer E, Hayes-Lattin B, Loriaux M, et al. Targeting BCL-2 and ABL/LYN in Philadelphia chromosome-positive acute lymphoblastic leukemia. Sci Transl Med. 2016;8(354):354ra114.

    PubMed  Google Scholar 

  90. Moujalled DM, Hanna DT, Hediyeh-Zadeh S, Pomilio G, Brown L, Litalien V, et al. Cotargeting BCL-2 and MCL-1 in high-risk B-ALL. Blood Adv. 2020;4(12):2762–7.

    PubMed  PubMed Central  Google Scholar 

  91. El Fakih R, Savani B, Mohty M, Aljurf M. Hematopoietic cell transplant consideration for Philadelphia chromosome-like acute lymphoblastic leukemia patients. Biol Blood Marrow Transplant. 2020;26(1):e16–20.

    Google Scholar 

  92. Schultz KR, Bowman WP, Aledo A, Slayton WB, Sather H, Devidas M, et al. Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children's oncology group study. J Clin Oncol. 2009;27(31):5175–81.

    PubMed  PubMed Central  Google Scholar 

  93. Biondi A, Schrappe M, De Lorenzo P, Castor A, Lucchini G, Gandemer V, et al. Imatinib after induction for treatment of children and adolescents with Philadelphia-chromosome-positive acute lymphoblastic leukaemia (EsPhALL): a randomised, open-label, intergroup study. Lancet Oncol. 2012;13(9):936–45.

    PubMed  PubMed Central  Google Scholar 

  94. Roberts KG, Pei D, Campana D, Payne-Turner D, Li Y, Cheng C, et al. 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. 2014;32(27):3012–20.

    PubMed  PubMed Central  Google Scholar 

  95. Siegel SE, Stock W, Johnson RH, Advani A, Muffly L, Douer D, et al. Pediatric-inspired treatment regimens for adolescents and young adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: a review. JAMA Oncol. 2018;4(5):725–34.

    PubMed  PubMed Central  Google Scholar 

  96. Kantarjian H, Ravandi F, Short NJ, Huang X, Jain N, Sasaki K, et al. Inotuzumab ozogamicin in combination with low-intensity chemotherapy for older patients with Philadelphia chromosome-negative acute lymphoblastic leukaemia: a single-arm, phase 2 study. Lancet Oncol. 2018;19(2):240–8.

    PubMed  Google Scholar 

  97. Kantarjian H, Stein A, Gokbuget N, Fielding AK, Schuh AC, Ribera JM, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376(9):836–47.

    PubMed  PubMed Central  Google Scholar 

  98. DeFilipp Z, Advani AS, Bachanova V, Cassaday RD, Deangelo DJ, Kebriaei P, et al. Hematopoietic cell transplantation in the treatment of adult acute lymphoblastic leukemia: updated 2019 evidence-based review from the American society for transplantation and cellular therapy. Biol Blood Marrow Transplant. 2019;25(11):2113–23.

    PubMed  Google Scholar 

  99. Gokbuget N, Dombret H, Bonifacio M, Reichle A, Graux C, Faul C, et al. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood. 2018;131(14):1522–31.

    PubMed  PubMed Central  Google Scholar 

  100. Kantarjian HM, DeAngelo DJ, Stelljes M, Martinelli G, Liedtke M, Stock W, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016;375(8):740–53.

    PubMed  PubMed Central  Google Scholar 

  101. Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439–48.

    PubMed  PubMed Central  Google Scholar 

  102. Martinelli G, Boissel N, Chevallier P, Ottmann O, Gokbuget N, Topp MS, et al. Complete hematologic and molecular response in adult patients with relapsed/refractory Philadelphia chromosome-positive B-precursor acute lymphoblastic leukemia following treatment with blinatumomab: results from a phase ii, single-arm, multicenter study. J Clin Oncol. 2017;35(16):1795–802.

    PubMed  Google Scholar 

  103. Rambaldi A, Ribera JM, Kantarjian HM, Dombret H, Ottmann OG, Stein AS, et al. Blinatumomab compared with standard of care for the treatment of adult patients with relapsed/refractory Philadelphia chromosome-positive B-precursor acute lymphoblastic leukemia. Cancer. 2020;126(2):304–10.

    PubMed  Google Scholar 

  104. von Stackelberg A, Locatelli F, Zugmaier G, Handgretinger R, Trippett TM, Rizzari C, et al. Phase I/Phase II study of blinatumomab in pediatric patients with relapsed/refractory acute lymphoblastic leukemia. J Clin Oncol. 2016;34(36):4381–9.

    Google Scholar 

  105. Gore L, Locatelli F, Zugmaier G, Handgretinger R, O'Brien MM, Bader P, et al. Survival after blinatumomab treatment in pediatric patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia. Blood Cancer J. 2018;8(9):80.

    PubMed  PubMed Central  Google Scholar 

  106. Zhao Y, Aldoss I, Qu C, Crawford JC, Gu Z, Allen EK, et al. Tumor intrinsic and extrinsic determinants of response to blinatumomab in adults with B-ALL. Blood. 2021;137(4):471–84.

    PubMed  PubMed Central  Google Scholar 

  107. Assi R, Kantarjian H, Short NJ, Daver N, Takahashi K, Garcia-Manero G, et al. Safety and efficacy of blinatumomab in combination with a tyrosine kinase inhibitor for the treatment of relapsed Philadelphia chromosome-positive leukemia. Clin Lymphoma Myeloma Leuk. 2017;17(12):897–901.

    PubMed  Google Scholar 

  108. King AC, Pappacena JJ, Tallman MS, Park JH, Geyer MB. Blinatumomab administered concurrently with oral tyrosine kinase inhibitor therapy is a well-tolerated consolidation strategy and eradicates measurable residual disease in adults with Philadelphia chromosome positive acute lymphoblastic leukemia. Leuk Res. 2019;79:27–33.

    PubMed  PubMed Central  Google Scholar 

  109. Petruzziello F, Giagnuolo G, Cazzaniga G, Beneduce G, Locatelli F, Stellato P, Fazio G, Mirabelli G, Menna G, Parasole R. Successful of chemo-free treatment with dasatinib and blinatumomab in a pediatric EBF1-PDGFRβ positive acute lymphoblastic leukemia. Blood. 2018;132(Suppl 1):5213.

    Google Scholar 

  110. Foa R, Bassan R, Vitale A, Elia L, Piciocchi A, Puzzolo MC, et al. Dasatinib-blinatumomab for Ph-positive acute lymphoblastic leukemia in adults. N Engl J Med. 2020;383(17):1613–23.

    PubMed  Google Scholar 

  111. Leonard J, Kosaka Y, Malla P, LaTocha D, Lamble A, Hayes-Lattin B, et al. Concomitant use of a dual ABL/Src kinase inhibitor eliminates the in vitroefficacy of blinatumomab against Ph+ ALL. Blood. 2021;137(7):939–44.

    PubMed  PubMed Central  Google Scholar 

  112. Weber EW, Lynn RC, Sotillo E, Lattin J, Xu P, Mackall CL. Pharmacologic control of CAR-T cell function using dasatinib. Blood Adv. 2019;3(5):711–7.

    PubMed  PubMed Central  Google Scholar 

  113. Jabbour E. Inotuzumab ozogamicin may overcome the impact of Philadelphia chromosome (Ph)-like phenotype in adult patients with relapsed/refractory ALL. Blood. 2019;134:1641.

    Google Scholar 

  114. O'Brien MM, Ji L, Shah NN, Rheingold SR, Bhojwani D, Yi JS, et al. A phase 2 trial of inotuzumab ozogamicin (InO) in children and young adults with relapsed or refractory (R/R) CD22+ B-acute lymphoblastic leukemia (B-ALL): results from Children’s Oncology Group Protocol AALL1621. Blood. 2019;134(Supplement 1):741.

    Google Scholar 

  115. Bhojwani D, Sposto R, Shah NN, Rodriguez V, Yuan C, Stetler-Stevenson M, et al. Inotuzumab ozogamicin in pediatric patients with relapsed/refractory acute lymphoblastic leukemia. Leukemia. 2019;33(4):884–92.

    PubMed  Google Scholar 

  116. Angelova E, Audette C, Kovtun Y, Daver N, Wang SA, Pierce S, et al. CD123 expression patterns and selective targeting with a CD123-targeted antibody-drug conjugate (IMGN632) in acute lymphoblastic leukemia. Haematologica. 2019;104(4):749–55.

    PubMed  PubMed Central  Google Scholar 

  117. Lyapichev KA, Sukswai N, Angelova E, Kersh MJ, Pierce S, Konopleva M, et al. CD123 expression in Philadelphia chromosome-like B acute lymphoblastic leukemia/lymphoma. Clin Lymphoma Myeloma Leuk. 2021;21(4):e317–20.

    PubMed  Google Scholar 

  118. Han L, Jorgensen JL, Brooks C, Shi C, Zhang Q, Nogueras Gonzalez GM, et al. Antileukemia efficacy and mechanisms of action of SL-101, a novel anti-CD123 antibody conjugate, in acute myeloid leukemia. Clin Cancer Res. 2017;23(13):3385–95.

    PubMed  PubMed Central  Google Scholar 

  119. Kovtun Y, Jones GE, Adams S, Harvey L, Audette CA, Wilhelm A, et al. A CD123-targeting antibody-drug conjugate, IMGN632, designed to eradicate AML while sparing normal bone marrow cells. Blood Adv. 2018;2(8):848–58.

    PubMed  PubMed Central  Google Scholar 

  120. Chichili GR, Huang L, Li H, Burke S, He L, Tang Q, et al. A CD3xCD123 bispecific DART for redirecting host T cells to myelogenous leukemia: preclinical activity and safety in nonhuman primates. Sci Transl Med. 2015;7(289):289ra82.

    PubMed  Google Scholar 

  121. Qin H, Cho M, Haso W, Zhang L, Tasian SK, Oo HZ, et al. Eradication of B-ALL using chimeric antigen receptor-expressing T cells targeting the TSLPR oncoprotein. Blood. 2015;126(5):629–39.

    PubMed  PubMed Central  Google Scholar 

  122. Pui CH, Yang JJ, Hunger SP, Pieters R, Schrappe M, Biondi A, et al. Childhood acute lymphoblastic leukemia: progress through collaboration. J Clin Oncol. 2015;33(27):2938–48.

    PubMed  PubMed Central  Google Scholar 

  123. Shah NP, Sawyers CL. Mechanisms of resistance to STI571 in Philadelphia chromosome-associated leukemias. Oncogene. 2003;22(47):7389–95.

    PubMed  Google Scholar 

  124. Soverini S, Branford S, Nicolini FE, Talpaz M, Deininger MW, Martinelli G, et al. Implications of BCR-ABL1 kinase domain-mediated resistance in chronic myeloid leukemia. Leuk Res. 2014;38(1):10–20.

    PubMed  Google Scholar 

  125. Soverini S, Hochhaus A, Nicolini FE, Gruber F, Lange T, Saglio G, et al. BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. Blood. 2011;118(5):1208–15.

    PubMed  Google Scholar 

  126. Soverini S, Colarossi S, Gnani A, Rosti G, Castagnetti F, Poerio A, et al. Contribution of ABL kinase domain mutations to imatinib resistance in different subsets of Philadelphia-positive patients: by the GIMEMA Working Party on Chronic Myeloid Leukemia. Clin Cancer Res. 2006;12(24):7374–9.

    PubMed  Google Scholar 

  127. Druker BJ. Circumventing resistance to kinase-inhibitor therapy. N Engl J Med. 2006;354(24):2594–6.

    PubMed  Google Scholar 

  128. Yeung DT, Moulton DJ, Heatley SL, Nievergall E, Dang P, Braley J, et al. Relapse of BCR-ABL1-like ALL mediated by the ABL1 kinase domain mutation T315I following initial response to dasatinib treatment. Leukemia. 2015;29(1):230–2.

    PubMed  Google Scholar 

  129. Zhang Y, Gao Y, Zhang H, Zhang J, He F, Hnizda A, et al. PDGFRB mutation and tyrosine kinase inhibitor resistance in Ph-like acute lymphoblastic leukemia. Blood. 2018;131(20):2256–61.

    PubMed  PubMed Central  Google Scholar 

  130. Harvey RC, Mullighan CG, Wang X, Dobbin KK, Davidson GS, Bedrick EJ, et al. 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. 2010;116(23):4874–84.

    PubMed  PubMed Central  Google Scholar 

  131. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391–405.

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Division of Pediatric Hematology-Oncology, Charles-Bruneau Cancer Center, CHU Sainte-Justine, Montreal, QC, Canada

    Thai Hoa Tran

  2. Department of Pediatrics, University of Montreal, QC, Canada

    Thai Hoa Tran

  3. Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Sarah K. Tasian

  4. Department of Pediatrics and Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

    Sarah K. Tasian

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  1. Thai Hoa Tran
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Correspondence to Sarah K. Tasian .

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  1. Department of Medicine, Queen Mary Hospital, Hongkong, Hong Kong

    Harinder Gill

  2. Department of Medicine, Queen Mary Hospital, Hongkong, Hong Kong

    Yok-Lam Kwong

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Dr. Tasian receives research support from Incyte Corporation for Ph-like ALL studies.

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Tran, T.H., Tasian, S.K. (2023). Management of Philadelphia Chromosome-Like Acute Lymphoblastic Leukemia (Ph-Like ALL). In: Gill, H., Kwong, YL. (eds) Pathogenesis and Treatment of Leukemia. Springer, Singapore. https://doi.org/10.1007/978-981-99-3810-0_23

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