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Novel Biomarkers and Molecular Targets in ALL

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Abstract

Purpose of Review

Acute lymphoblastic leukemia (ALL) is a widely heterogeneous disease in terms of genomic alterations, treatment options, and prognosis. While ALL is considered largely curable in children, adults tend to have higher risk disease subtypes and do not respond as favorably to conventional chemotherapy. Identifying genomic drivers of leukemogenesis and applying targeted therapies in an effort to improve disease outcomes is an exciting focus of current ALL research. Here, we review recent updates in ALL targeted therapy and present promising opportunities for future research.

Recent Findings

With the utilization of next-generation sequencing techniques, the genomic landscape of ALL has greatly expanded to encompass novel subtypes characterized by recurrent chromosomal rearrangements, gene fusions, sequence mutations, and distinct gene expression profiles. The evolution of small molecule inhibitors and immunotherapies, and the exploration of unique therapy combinations are some examples of recent advancements in the field.

Summary

Targeted therapies are becoming increasingly important in the treatment landscape of ALL to improve outcomes and minimize toxicity. Significant recent advancements have been made in the detection of susceptible genomic drivers and the use of novel therapies to target them.

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References

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  1. SEER Cancer Stat Facts: Acute Lymphocytic Leukemia. NCI. [Accessed 26th Feb 2023]. https://seer.cancer.gov/statfacts/html/alyl.html

  2. DeAngelo D, Jabbour E, Advani A. Recent advances in managing acute lymphoblastic leukemia. Am Soc Clin Oncol Educ Book. 2020;40:330–42. https://doi.org/10.1200/EDBK_280175.

    Article  PubMed  Google Scholar 

  3. Wieduwilt M. Ph+ ALL in 2022: is there an optimal approach? Hematology Am Soc Hematol Educ Program. 2022;2022(1):206–12. https://doi.org/10.1182/hematology.2022000338.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Malard F, Mohty M. Acute lymphoblastic leukaemia. The Lancet. 2020;395(10230):1146–62. https://doi.org/10.1016/S0140-6736(19)33018-1.

    Article  CAS  Google Scholar 

  5. Vignetti M, Fazi P, Cimino G, Martinelli G, Di Raimondo F, Ferrara F, et al. Imatinib plus steroids induces complete remissions and prolonged survival in elderly Philadelphia chromosome-positive patients with acute lymphoblastic leukemia without additional chemotherapy: results of the Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) LAL0201-B protocol. Blood Adv. 2007;109(9):3676–8. https://doi.org/10.1182/blood-2006-10-052746.

    Article  CAS  Google Scholar 

  6. Iacobucci I, Kimura S, Mullighan CG. Biologic and therapeutic implications of genomic alterations in acute lymphoblastic leukemia. J Clin Med. 2021;10(17):3792. https://doi.org/10.3390/jcm10173792.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Hirabayashi S, Ohki K, Nakabayashi K, Ichikawa H, Momozawa Y, Okamura K, et al. Tokyo Children’s Cancer Study Group (TCCSG) ZNF384-related fusion genes define a subgroup of childhood B-cell precursor acute lymphoblastic leukemia with a characteristic immunotype. Haematologica. 2017;102(1):118–29. https://doi.org/10.3324/haematol.2016.151035.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. • Arber D, Orazi A, Hasserjian R, Borowitz M, Calvo K, Kvasnicka H, et al. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data. Blood. 2022;140(11):1200–28. https://doi.org/10.1182/blood.2022015850. Updates to the classification of ALL, including provisional entities.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Haider M, Anwer F. Genetics, Philadelphia Chromosome. [Updated 2023 Jul 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK560689/.

  10. Druker B, Sawyers C, Kantarjian H, Resta D, Reese S, Ford J, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med. 2001;344:1038–42. https://doi.org/10.1056/NEJM200104053441402.

    Article  PubMed  CAS  Google Scholar 

  11. Rowe J, Buck G, Burnett A, Chopra R, Wiernik P, Richards S, et al. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005;106:3760–7. https://doi.org/10.1182/blood-2005-04-1623.

    Article  PubMed  CAS  Google Scholar 

  12. Redaelli S, Piazza R, Rostagno R, Magistroni V, Perini P, Marega M, et al. Activity of bosutinib dasatinib and nilotinib against 18 imatinib-resistant BCR/ABL mutants. J Clin Oncol. 2009;27(3):469–71. https://doi.org/10.1200/JCO.2008.19.8853.

    Article  PubMed  CAS  Google Scholar 

  13. O’Hare T, Shakespeare W, Zhu X, Eide C, Rivera V, Wang F, et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009;16(5):401–12. https://doi.org/10.1016/j.ccr.2009.09.028.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. • Jabbour E, Kantarjian H, Aldoss I, Montesinos P, Leonard J, Gomez-Almaguer E, et al. First report of PhALLCON: a phase 3 study comparing ponatinib (pon) vs imatinib (im) in newly diagnosed patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). ASCO Plenary Series. 2023;41. https://doi.org/10.1200/JCO.2023.41.36_suppl.398868. First trial to compare ponatinib versus imatinib in Ph+ ALL; ponatinib had significantly more MRD negative remissions.

  15. Eide C, Zabriskie M, Savage Stevens S, Antelope O, Vellore N, Than H, et al. Combining the allosteric inhibitor asciminib with ponatinib suppresses emergence of and restores efficacy against highly resistant BCR-ABL1 mutants. Cancer Cell. 2019;36(4):431–43. https://doi.org/10.1016/j.ccell.2019.08.004.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Wylie A, Schoepfer J, Jahnke W, Cowan-Jacob S, Loo A, Furet P, et al. The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1. Nature. 2017;543(7647):733–7. https://doi.org/10.1038/nature21702.

    Article  PubMed  CAS  Google Scholar 

  17. • Luskin M, Stevenson K, Mendez L, Wang E, Wadleigh M, Garcia J, et al. A phase I study of asciminib (ABL001) in combination with dasatinib and prednisone for BCR-ABL1-positive ALL in adults. Blood. 2021;138:2305. https://doi.org/10.1182/blood-2021-149225. Phase I trial indicating that dual ABL1 kinase inhibition is feasible.

    Article  Google Scholar 

  18. Zerbit J, Tamburini J, Goldwirt L, Decroocq J, Cayuela JM, Chapuis N, et al. Asciminib and ponatinib combination in Philadelphia chromosome-positive acute lymphoblastic leukemia. Leuk Lymphoma. 2021;62(14):3558–60. https://doi.org/10.1080/10428194.2021.1966787.

    Article  PubMed  CAS  Google Scholar 

  19. Leonard J, Rowley J, Hayes-Lattin B, Tyner J, Loriaux M, Druker B, et al. Dual targeting of Ph+ ALL with dasatinib and ABT-199 (venetoclax). In: Poster presented at: 57th ASH Annual Meeting; December 2015; Orlando, FL. [abstract taken from Blood. 2015;126(23):1329]. https://doi.org/10.1182/blood.V126.23.1329.1329.

  20. Scherr M, Kirchhoff H, Battmer K, Wohlan K, Lee C, Ricke-Hoch M, et al. Optimized induction of mitochondrial apoptosis for chemotherapy-free treatment of BCR-ABL+acute lymphoblastic leukemia. Leukemia. 2019;33(6):1313–23. https://doi.org/10.1038/s41375-018-0315-6.

    Article  PubMed  CAS  Google Scholar 

  21. Wang H, Yang C, Shi T, Zhang Y, Qian J, Wang Y, et al. Venetoclax-ponatinib for T315I/compound-mutated Ph+ acute lymphoblastic leukemia. Blood Cancer J. 2022;12(20). https://doi.org/10.1038/s41408-022-00621-9.

  22. Short N, Konopleva M, Kadia T, Kebriaei P, Daver N, Huang X, et al. An effective chemotherapy-free regimen of ponatinib plus venetoclax for relapsed/refractory Philadelphia chromosome-positive acute lymphoblastic leukemia. Am J Hematol. 2021;96:e229–32. https://doi.org/10.1002/ajh.26175.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Martinelli G, Papayannidis C, Piciocchi A, Robustelli V, Soverini S, Terragna C, et al. INCB84344-201: Ponatinib and steroids in frontline therapy for unfit patients with Ph+ acute lymphoblastic leukemia. Blood Adv. 2022;6(6):1742–53. https://doi.org/10.1182/bloodadvances.2021004821.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Rousselot P, Coude M, Gokbuget N, Passerini C, Hayette S, Cayuela J, et al. Dasatinib and low-intensity chemotherapy in elderly patients with Philadelphia chromosome–positive ALL. Blood. 2016;128(6):774–82. https://doi.org/10.1182/blood-2016-02-700153.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Ottmann O, Pfeifer H, Cayuela J, Spiekermann K, Jung W, Beck J, et al. Nilotinib (Tasigna®) and low intensity chemotherapy for first-line treatment of elderly patients with BCR-ABL1-positive acute lymphoblastic leukemia: final results of a prospective multicenter trial (EWALL-PH02). Blood. 2018;123:31. https://doi.org/10.1182/blood-2018-99-114552.

    Article  Google Scholar 

  26. Wieduwilt M, Yin J, Wetzler M, Uy G, Powell B, Kolitz J, et al. A phase II study of Dasatinib and dexamethasone as primary therapy followed by transplantation for adults with newly diagnosed Ph/BCR-ABL1-positive acute lymphoblastic leukemia (Ph+ ALL): final results of alliance/CALGB study 10701. Blood. 2018;132:309. https://doi.org/10.1182/blood-2018-99-120029.

    Article  Google Scholar 

  27. Foà R, Bassan R, Vitale A, Elia L, Piciocchi A, Puzzolo M, et al. Dasatinib-blinatumomab for Ph-positive acute lymphoblastic leukemia in adults. N Engl J Med. 2020;383(17):1613–23. https://doi.org/10.1056/NEJMoa2016272.

    Article  PubMed  Google Scholar 

  28. Jabbour E, Short N, Jain N, Huang X, Montalban-Bravo G, Banerjee P, et al. Ponatinib and blinatumomab for Philadelphia chromosome-positive acute lymphoblastic leukaemia: a US, single-centre, single-arm, phase 2 trial. The Lancet Haematol. 2023;10(1):e24–34. https://doi.org/10.1016/S2352-3026(22)00319-2.

    Article  PubMed  CAS  Google Scholar 

  29. Fedullo A, 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). https://doi.org/10.3324/haematol.2018.196055

  30. Sasaki Y, Kantarjian H, Short N, Wang F, Furudate K, Uryu H, et al. Genetic correlates in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia treated with Hyper-CVAD plus dasatinib or ponatinib. Leukemia. 2022;36:1253–60. https://doi.org/10.1038/s41375-021-01496-8.

    Article  PubMed  CAS  Google Scholar 

  31. Chiaretti S, Bassan R, Vitale A, Elia L, Piciocchi A, Puzzolo C, et al. Dasatinib-blinatumomab combination for the front-line treatment of adult Ph+ ALL patients. Updated Results of the Gimema LAL2116 D-Alba Trial. Blood. 2019;134:740. https://doi.org/10.1182/blood-2019-128759.

    Article  Google Scholar 

  32. Roberts K, Li Y, Payne-Turner D, Harvey R, Yang Y, Pei D, et al. Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. N Engl J Med. 2014;371(11):1005–15. https://doi.org/10.1056/NEJMoa1403088.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Jain N, Roberts K, Jabbour E, Patel K, Eterovic A, Chen K, et al. Ph-like acute lymphoblastic leukemia: a high-risk subtype in adults. Blood. 2017;129(5):572–81. https://doi.org/10.1182/blood-2016-07-726588.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Sasaki K, Yamauchi T, Semba Y, Nogami J, Imanaga H, Terasaki T, et al. Genome-wide CRISPR-Cas9 screen identifies rationally designed combination therapies for CRLF2-rearranged Ph-like ALL. Blood. 2022;139(5):748–60. https://doi.org/10.1182/blood.2021012976.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Aldoss I, Afkhami M, Yang D, Gu Z, Mokhtari S, Shahani S, et al. High response rates and transition to transplant after novel targeted and cellular therapies in adults with relapsed/refractory acute lymphoblastic leukemia with Philadelphia-like fusions. Am J Hematol. 2023;98(6):848–56. https://doi.org/10.1080/10428194.2023.2197538.

    Article  PubMed  CAS  Google Scholar 

  36. Britten O, Ragusa D, Tosi S, Kamel Y. MLL-Rearranged acute leukemia with t(4;11)(q21;q23)-current treatment options. is there a role for CAR-T cell therapy? Cells. 2019;8(11):1341. https://doi.org/10.3390/cells8111341.

  37. • Krivtsov A, Evans K, Gadrey J, Eschle B, Hatton C, Uckelmann H, et al. A Menin-MLL inhibitor induces specific chromatin changes and eradicates disease in models of MLL-rearranged leukemia. Cancer Cell. 2019;36(6):660–73. https://doi.org/10.1016/j.ccell.2019.11.001. Preclinical efficacy of an orally bioavailable Menin inhibitor in MLL-rearranged leukemia.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Daigle S, Olhava E, Therkelsen C, Basavapathruni A, Jin L, Boriack-Sjodin P, et al. Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. Blood. 2013;122(6):1017–25. https://doi.org/10.1182/blood-2013-04-497644.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Stein E, Garcia-Manero G, Rizzieri D, Tibes R, Berdeja J, Savona M, et al. The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia. Blood. 2018;131(24):2661–9. https://doi.org/10.1182/blood-2017-12-818948.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Perner F, Gadrey J, Xiong Y, Hatton C, Eschle BK, Weiss A, et al. Novel inhibitors of the histone methyltransferase DOT1L show potent antileukemic activity in patient-derived xenografts. Blood. 2020;136(17):1983–8. https://doi.org/10.1182/blood.2020006113.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Romana S, Poirel H, Leconiat M, Flexor M, Mauchauffe M, Jonveaux P, et al. High frequency of t(12;21) in childhood B-lineage acute lymphoblastic leukemia. Blood. 1995;86(11):4263–9. https://doi.org/10.1182/blood.V86.11.4263.bloodjournal86114263.

    Article  PubMed  CAS  Google Scholar 

  42. Lilljebjörn H, Henningsson R, Hyrenius-Wittsten A, Olsson L, Orsmark-Pietras C, von Palffy S, et al. Identification of ETV6-RUNX1-like and DUX4-rearranged subtypes in paediatric B-cell precursor acute lymphoblastic leukaemia. Nat Commun. 2016;7(11790). https://doi.org/10.1038/ncomms11790.

  43. Lilljebjorn H, Fioretos T. New oncogenic subtypes in pediatric B-cell precursor acute lymphoblastic leukemia. Blood. 2017;130(12):1395–401. https://doi.org/10.1182/blood-201.

    Article  PubMed  Google Scholar 

  44. Lejman M, Chalupnik A, Chilimoniuk Z, Dobosz M. Genetic biomarkers and their clinical implications in B-cell acute lymphoblastic leukemia in children. Int J Mol Sci 2022 2022;23(5):2755. https://doi.org/10.3390/ijms23052755.

  45. Polak R, Bierings M, van der Leije C, Sanders M, Roovers O, Marchante J, et al. Autophagy inhibition as a potential future targeted therapy for ETV6-RUNX1-driven B-cell precursor acute lymphoblastic leukemia. Haematologica. 2019;104(4). https://doi.org/10.3324/haematol.2018.193631.

  46. Serafin V, Porcu E, Cortese G, Mariotto E, Veltri G, Bresolin S, et al. SYK targeting represents a potential therapeutic option for relapsed resistant pediatric ETV6-RUNX1 B-acute lymphoblastic leukemia patients. Int J Mol Sci. 2019;20(24):6175. https://doi.org/10.3390/ijms20246175.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Ågerstam H, Lilljebjorn H, Rissler M, Sandén C, Fioretos T. IL1RAP is expressed in several subtypes of pediatric acute lymphoblastic leukemia and can be used as a target to eliminate ETV6::RUNX1-positive leukemia cells in preclinical models. Haematologica. 2023;108(2):599–604. https://doi.org/10.3324/haematol.2022.281059.

    Article  PubMed  CAS  Google Scholar 

  48. Robbrecht D, Jungels C, Sorensen M, Spanggaard I, Eskens F, Fretland S, et al. First-in-human phase 1 dose-escalation study of CAN04, a first-in-class interleukin-1 receptor accessory protein (IL1RAP) antibody in patients with solid tumours. Br J Cancer. 2022;126:1010–7. https://doi.org/10.1038/s41416-021-01657-7.

    Article  PubMed  CAS  Google Scholar 

  49. Salvaris R, Fedele P. Targeted therapy in acute lymphoblastic leukaemia. J Pers Med. 2021;11(8):715. https://doi.org/10.3390/jpm11080715.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Zhao X, Wang P, Diedrich J, Smart B, Reyes N, Yoshimura S, et al. Epigenetic activation of the FLT3 gene by ZNF384 fusion confers a therapeutic susceptibility in acute lymphoblastic leukemia. Nat Commun. 2022;13(5401). https://doi.org/10.1038/s41467-022-33143-w.

  51. Gu Z, Churchman M, Roberts K, Li Y, Lui Y, Harvey R, et al. Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia. Nat Commun. 2016;7. https://doi.org/10.1038/ncomms13331

  52. Ryan S, Matheson E, Grossmann V, Sinclair P, Bashton M, Schwab C, et al. The role of the RAS pathway in iAMP21-ALL. Leukemia. 2016;30:1824–31. https://doi.org/10.1038/leu.2016.80.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Aumann S, Shaulov A, Haran A, Gross Even-Zohar N, Vainstein V, Nachmias B. The emerging role of venetoclax-based treatments in acute lymphoblastic leukemia. Int J Mol Sci. 2022;23(18):10957. https://doi.org/10.3390/ijms231810957.

  54. Peirs S, Matthijssens F, Goossens S, Van de Walle I, Ruggero K, de Bock C, et al. ABT-199 mediated inhibition of BCL-2 as a novel therapeutic strategy in T-cell acute lymphoblastic leukemia. Blood. 2014;124:3738–47. https://doi.org/10.1182/blood-2014-05-574566.

    Article  PubMed  CAS  Google Scholar 

  55. Kehr S, Vogler M. It’s time to die: BH3 mimetics in solid tumors. Biochim Biophys Acta Mol Cell Res. 2021;1868(5):118987. https://doi.org/10.1016/j.bbamcr.2021.118987.

    Article  PubMed  CAS  Google Scholar 

  56. Jain N, Stevenson K, Winer E, Garcia J, Stone R, Jabbour E, et al. A multicenter phase i study combining venetoclax with mini-hyper-CVD in older adults with untreated and relapsed/refractory acute lymphoblastic leukemia. Blood. 2019;134:3867. https://doi.org/10.1182/blood-2019-129988.

    Article  Google Scholar 

  57. • Venugopal S, Kantarjian H, Short N, Thompson P, Pemmaraju N, Jain N, et al. A phase II study of mini-hyper-CVD plus venetoclax in patients with Philadelphia chromosome-negative acute lymphoblastic leukemia. Blood. 2021;138:1239. https://doi.org/10.1182/blood-2021-153826. Venetoclax plus chemotherapy was safe and effective in Ph-negative ALL.

    Article  Google Scholar 

  58. Pullarkat V, Lacayo N, Jabbour E, Rubnitz J, Bajel A, Laetsch T, et al. Venetoclax and navitoclax in combination with chemotherapy in patients with relapsed or refractory acute lymphoblastic leukemia and lymphoblastic lymphoma. Cancer Discov. 2021;11(6):1440–53. https://doi.org/10.1158/2159-8290.CD-20-1465.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Rubnitz J, Alexander T, Laetsch T, Khaw S, Pullarkat V, Opferman J, et al. Venetoclax and navitoclax in pediatric patients with acute lymphoblastic leukemia and lymphoblastic lymphoma. Blood. 2020;136:12–3. https://doi.org/10.1182/blood-2020-134582.

    Article  Google Scholar 

  60. Arora S, Vachhani P, Bachiashvili K, Jamy O. Venetoclax with chemotherapy in relapse/refractory early T-cell precursor acute lymphoblastic leukemia. Leuk Lymphoma. 2021;62(9):2292–4. https://doi.org/10.1080/10428194.2021.1897807.

    Article  PubMed  CAS  Google Scholar 

  61. Chonghaile T, Roderick J, Glenfield C, Ryan J, Sallan S, Silverman L, et al. Maturation stage of T-cell acute lymphoblastic leukemia determines BCL-2 versus BCL-XL dependence and sensitivity to ABT-199. Cancer Discov. 2014;4(9):1074–87. https://doi.org/10.1158/2159-8290.CD-14-0353.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Zhang X, Li J, Jin J, Yu W, et al. Relapsed/refractory early T-cell precursor acute lymphoblastic leukemia was salvaged by venetoclax plus HAG regimen. Ann Hematol. 2020;99:395–7. https://doi.org/10.1007/s00277-019-03902-9.

    Article  PubMed  Google Scholar 

  63. Kong J, Chen N, Li M, Zhang J, Wu X, Zong L, et al. Venetoclax and decitabine in refractory TP53-mutated early T-cell precursor acute lymphoblastic leukemia. Ann Hematol. 2021;101:697–9. https://doi.org/10.1007/s00277-021-04530-y.

    Article  PubMed  CAS  Google Scholar 

  64. Choudhary G, Al-harbi S, Mazumder S, Hill B, Smith M, Bodo J, et al. MCL-1 and BCL-xL-dependent resistance to the BCL-2 inhibitor ABT-199 can be overcome by preventing PI3K/AKT/mTOR activation in lymphoid malignancies. Cell Death Dis. 2015;6:e1593. https://doi.org/10.1038/cddis.2014.525.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Moujalled D, Hanna D, 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;23(4):2762–7. https://doi.org/10.1182/bloodadvances.2019001416.

    Article  CAS  Google Scholar 

  66. Gocho Y, Liu J, Hu J, Yang W, Dharia NV, Zhang J, et al. Network-based systems pharmacology reveals heterogeneity in LCK and BCL2 signaling and therapeutic sensitivity of T-cell acute lymphoblastic leukemia. Nature. 2021;2(3):284–99. https://doi.org/10.1038/s43018-020-00167-4.

    Article  CAS  Google Scholar 

  67. Shi Y, Beckett M, Blair H, Tirtakusuma R, Nakjang S, Enshaei A, et al. Phase II-like murine trial identifies synergy between dexamethasone and dasatinib in T-cell acute lymphoblastic leukemia. Haematologica. 2021;106(4):1056–66. https://doi.org/10.3324/haematol.2019.241026.

    Article  PubMed  CAS  Google Scholar 

  68. Yoshimura S, Panetta J, Hu J, Li L, Gocho Y, Du G, et al. Preclinical pharmacokinetic and pharmacodynamic evaluation of dasatinib and ponatinib for the treatment of T-cell acute lymphoblastic leukemia. Leukemia. 2023;37(6):1194–203. https://doi.org/10.1038/s41375-023-01900-5.

    Article  PubMed  CAS  Google Scholar 

  69. He Y, Zhang J, Zhang Y, Hu Z, Wang P, Gan W, et al. Dasatinib-therapy induced sustained remission in a child with refractory TCF7-SPI1 T-cell acute lymphoblastic leukemia. Pediatr Blood Cancer. 2022;69(8):e29724. https://doi.org/10.1002/pbc.29724.

    Article  PubMed  CAS  Google Scholar 

  70. Deenik W, Beverloo H, van der Poel-van de LS, Wattel M, van Esser J, Valk P, et al. Rapid complete cytogenetic remission after upfront dasatinib monotherapy in a patient with a NUP214-ABL1-positive T-cell acute lymphoblastic leukemia. Leukemia. 2009;23(3):627–9. https://doi.org/10.1038/leu.2008.318.

    Article  PubMed  CAS  Google Scholar 

  71. Franquiz M, Short N. Blinatumomab for the treatment of adult B-cell acute lymphoblastic leukemia: toward a new era of targeted immunotherapy. Biologics. 2020;14:23–34. https://doi.org/10.2147/BTT.S202746.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Hoffmann P, Hofmeister R, Brischwein K, Brandl C, Crommer S, Bargou R, et al. Serial killing of tumor cells by cytotoxic T cells redirected with a CD19-/CD3-bispecific single-chain antibody construct. Int J Cancer. 2005;115(1):98–104. https://doi.org/10.1002/ijc.20908.

    Article  PubMed  CAS  Google Scholar 

  73. Kantarjian H, Stein A, Gokbuget N, Fielding A, Schuh A, Ribera J, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376:836–47. https://doi.org/10.1056/NEJMoa1609783.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Gökbuget 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. https://doi.org/10.1182/blood-2017-08-798322.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. FDA. FDA granted accelerated approval to blinatumomab (Blincyto, Amgen Inc.) for the treatment of adult and pediatric patients with B-cell precursor acute lymphoblastic leukemia. 2018. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-granted-accelerated-approval-blinatumomab-blincyto-amgen-inc-treatment-adult-and-pediatric#:~:text=acute%20lymphoblastic%20leukemia-,FDA%20granted%20accelerated%20approval%20to%20blinatumomab%20.

  76. The ASCO Post Staff. FDA Grants Full Approval to Blinatumomab for MRD-Positive B-Cell Precursor ALL. The ASCO Post. 2023. https://ascopost.com/news/june-2023/fda-grants-full-approval-to-blinatumomab-for-mrd-positive-b-cell-precursor-all/.

  77. Litzow M, Sun Z, Paietta E, Mattison R, Lazarus H, Rowe J, et al. Consolidation therapy with blinatumomab improves overall survival in newly diagnosed adult patients with B-lineage acute lymphoblastic leukemia in measurable residual disease negative remission: results from the ECOG-ACRIN E1910 Randomized Phase III National Cooperative Clinical Trials Network Trial. Presented at: 64th ASH Annual Meeting; December 2022; New Orleans, LA. [abstract taken from Blood. 2022;140 (Supplement 2): LBA-1]. https://doi.org/10.1182/blood-2022-171751.

  78. June C, Sadelain M. Chimeric antigen receptor therapy. N Engl J Med. 2018;379:64–73. https://doi.org/10.1056/NEJMra1706169.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Cappell K, Kochenderfer J. Long-term outcomes following CAR T cell therapy: what we know so far. Nat Rev Clin Oncol. 2023;20:359–71. https://doi.org/10.1038/s41571-023-00754-1.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. •• Shah B, Ghobadi A, Oluwole O, Logan A, Boissel N, Cassaday R, et al. KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study. The Lancet. 2021;398(10299):491–502. https://doi.org/10.1016/S0140-6736(21)01222-8. Brexucabtagene autoleucel induced deep and durable remissions in R/R B-ALL.

    Article  CAS  Google Scholar 

  81. Roloff G, Faramand R, Aldoss I, Kopmar N, Schwartz M, Dekker S, et al. Outcomes following brexucabtagene autoleucel administered as an FDA-approved therapy for adults with relapsed/refractory B-ALL. ASCO. 2023;41:7001. https://doi.org/10.1200/JCO.2023.41.16_suppl.7001.

    Article  Google Scholar 

  82. •• Roddie C, Karamjeet S, Tholouli E, Shaughnessy P, Barba P, Guerreiro M, et al. Safety and efficacy of obecabtagene autoleucel (obe-cel, AUTO1), a fast-off rate CD19 CAR, in relapsed/ refractory adult B-cell acute lymphoblastic leukemia (r/r B-ALL): Top line results of the pivotal FELIX study. In: Presented at: 2023 ASCO Annual Meeting; June 2023; Chicago, IL. [abstract taken from Journal of Clinical Oncology. 2023;4 (Supplement 16):7000]. https://doi.org/10.1200/JCO.2023.41.16_suppl.7000. Obe-cel demonstrated efficacy and low rates of grade 3 or greater CRS or ICANS.

  83. Smulski C, Eibel H. BAFF and BAFF-receptor in B Cell selection and survival. Front Immunol. 2018;9:2285. https://doi.org/10.3389/fimmu.2018.02285.

  84. • Qin H, Dong Z, Wang X, Cheng W, Wen F, Xue W, et al. CAR T cells targeting BAFF-R can overcome CD19 antigen loss in B cell malignancies. Science Translational Medicine. 2019;11(511). https://doi.org/10.1126/scitranslmed.aaw9414. Preclinical data demonstrating efficacy of BAFF-R CAR-T after CD19 antigen loss.

  85. Turazzi N, Fazio G, Rossi V, Rolink A, Cazzaniga G, Biondi A, et al. Engineered T cells towards TNFRSF13C (BAFFR): a novel strategy to efficiently target B-cell acute lymphoblastic leukaemia. Br J Haematol. 2018;182:939–43. https://doi.org/10.1111/bjh.14899.

    Article  PubMed  CAS  Google Scholar 

  86. •• Spiegel J, Patel S, Muffly L, Hossain N, Oak J, Baird J, et al. CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial. Nat Med. 2021;27:1419–31. https://doi.org/10.1038/s41591-021-01436-0. Phase I trial of CD19/CD22 dual-specific CAR-T.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Gardner R, Finney O, Brakke H, Rhea S, Hicks R, Doolittle D, et al. Starting T cell and cell product phenotype are associated with durable remission of leukemia following CD19 CAR-T cell immunotherapy. Blood. 2018;132:4022. https://doi.org/10.1182/blood-2018-99-117493.

    Article  Google Scholar 

  88. •• Pan J, Tan Y, Wang G, Deng B, Ling Z, Song W, et al. Donor-derived CD7 chimeric antigen receptor T cells for T-cell acute lymphoblastic leukemia: first-in-human, phase I trial. J Clin Oncol. 2021;39(30):3340–51. https://doi.org/10.1200/JCO.21.00389. Tolerability and efficacy of CD7 CAR-T in phase I trial for R/R T-ALL.

    Article  PubMed  CAS  Google Scholar 

  89. Zhang Y, Li C, Du M, Jiang H, Luo W, Tang L, et al. Allogenic and autologous anti-CD7 CAR-T cell therapies in relapsed or refractory T-cell malignancies. Blood Cancer J. 2023;13(61). https://doi.org/10.1038/s41408-023-00822-w.

  90. Bride K, Vincent T, Im S, Aplenc R, Barrett D, Carroll W, et al. Preclinical efficacy of daratumumab in T-cell acute lymphoblastic leukemia. Blood. 2018;131(9):995–9. https://doi.org/10.1182/blood-2017-07-794214.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. • Hogan L, Batla T, Teachey D, Sirvent F, Moppett J, Puyo P, et al. Efficacy and safety of daratumumab (DARA) in pediatric and young adult patients (pts) with relapsed/refractory T-cell acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL): Results from the phase 2 DELPHINUS study. In: Presented at: 2022 ASCO Annual Meeting; June 2022; Chicago, IL. [abstract taken from Journal of Clinical Oncology. 2022;40]. https://doi.org/10.1200/JCO.2022.40.16_suppl.10001. Phase 2 study of daratumumab and chemotherapy was effective and safe in pediatric and young adult R/R T-ALL.

  92. Boissel N, Chevallier P, Doronin V, Griskevicius L, Maschan A, McCloskey J, et al. Isatuximab monotherapy in patients with refractory T-acute lymphoblastic leukemia or T-lymphoblastic lymphoma: Phase 2 study. Cancer Med. 2022;11(5):1292–8. https://doi.org/10.1002/cam4.4478.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Baruchel A, Abrahamsson J, Bertran Y, Gonzalez O, Nysom K, Quinones W, et al. Isatuximab in combination with chemotherapy in pediatric patients with relapsed/refractory acute lymphoblastic leukemia or acute myeloid leukemia (ISAKIDS): interim analysis. Blood. 2021;138:516. https://doi.org/10.1182/blood-2021-150272.

    Article  Google Scholar 

  94. Caracciolo D, Mancuso A, Polera N, Froio C, D’Aquino G, Riillo C, et al. The emerging scenario of immunotherapy for T-cell acute lymphoblastic leukemia: advances, challenges and future perspectives. Experimental Hematology & Oncology. 2023;12(5). https://doi.org/10.1186/s40164-022-00368-w.

  95. Riillo C, Caracciolo D, Grillone K, Polerà N, Tuccillo FM, Bonelli P, et al. A novel bispecific T-cell engager (CD1a x CD3ε) BTCE is effective against cortical-derived T cell acute lymphoblastic leukemia (T-ALL) cells. Cancers (Basel). 2022;14(12):2886. https://doi.org/10.3390/cancers14122886.

    Article  PubMed  CAS  Google Scholar 

  96. Ohki K, Butler E, Kiyokawa N, Hirabayashi S, Bergmann A, Moricke A, et al. Clinical characteristics and outcomes of B-cell precursor ALL with MEF2D rearrangements: a retrospective study by the Ponte di Legno Childhood ALL Working Group. Leukemia. 2022;37:212–6. https://doi.org/10.1038/s41375-022-01737-4.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Suzuki K, Okuno Y, Kawashima N, Muramatsu H, Okuno T, Wang X, et al. MEF2D-BCL9 fusion gene is associated with high-risk acute B-cell precursor lymphoblastic leukemia in adolescents. J Clin Oncol. 2016;34:3451–9. https://doi.org/10.1200/JCO.2016.66.5547.

    Article  PubMed  CAS  Google Scholar 

  98. Zhang M, Zhang H, Li Z, Bai L, Wang Q, Li J, et al. Functional, structural, and molecular characterizations of the leukemogenic driver MEF2D-HNRNPUL1 fusion. Blood. 2022;140(12):1390–407. https://doi.org/10.1182/blood.2022016241.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Mara S, Runfola V, Pannese, M, Caronni C, Giambruno R, Campolungo D, et al. P334: Characterization of a DUX4-R inhibitor as a possible treatment for acute lymphoblastic leukemia. Hemasphere. 2022;6:234–5. https://doi.org/10.1097/01.HS9.0000844224.03782.c8.

  100. Boer J, Valsecchi M, Hormann F, Antic Z, Zaliova M, Schwab C, et al. NUTM1-rearranged infant and pediatric B cell precursor acute lymphoblastic leukemia: a good prognostic subtype identified in a collaborative international study. Blood. 2020;136:25–6. https://doi.org/10.1182/blood-2020-139376.

    Article  Google Scholar 

  101. Boer J, Valsecchi M, Hormann F, Antic Z, Zaliova M, Schwab C, et al. Favorable outcome of NUTM1-rearranged infant and pediatric B cell precursor acute lymphoblastic leukemia in a collaborative international study. Leukemia. 2021;35:2978–82. https://doi.org/10.1038/s41375-021-01333-y.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Lasko L, Jakob C, Edalji R, Qiu W, Montgomery D, Digiammarino E, et al. Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours. Nature. 2017;550(7674):128–32. https://doi.org/10.1038/nature24028.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Esteves G, Ferreira J, Afonso R, Martins C, Zagalo C, Felix A. HDAC overexpression in a NUT midline carcinoma of the parotid gland with exceptional survival: a case report. Head Neck Pathol. 2020;14:1117–22. https://doi.org/10.1007/s12105-020-01130-6.

    Article  PubMed  PubMed Central  Google Scholar 

  104. Zaliova M, Winkowska L, Stuchly J, Fiser K, Triska P, Zwyrtkova M, et al. A novel class of ZNF384 aberrations in acute leukemia. Blood Adv. 2021;5(21):4393–7. https://doi.org/10.1182/bloodadvances.2021005318.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Lin N, Yan X, Cai D, Wang L. Leukemia with TCF3-ZNF384 rearrangement as a distinct subtype of disease with distinct treatments: perspectives from a case report and literature review. Front Oncol. 2021. https://doi.org/10.3389/fonc.2021.709036.

    Article  PubMed  PubMed Central  Google Scholar 

  106. Hirabayashi S, Butler E, Ohki K, Kiyokawa N, Bergmann A, Moricke A, et al. Clinical characteristics and outcomes of B-ALL with ZNF384 rearrangements: a retrospective analysis by the Ponte di Legno Childhood ALL Working Group. Leukemia. 2021;35:3272–7. https://doi.org/10.1038/s41375-021-01199-0.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Giacomo D, La Starza R, Gorello P, Pellanera F, Atak Z, Keersmaecker K, et al. 14q32 rearrangements deregulating BCL11B mark a distinct subgroup of T-lymphoid and myeloid immature acute leukemia. Blood. 2021;138(9):773–84. https://doi.org/10.1182/blood.2020010510.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Damelin M, Bankovich A, Bernstein J, Lucas J, Chen L, Williams S, et al. A PTK7-targeted antibody-drug conjugate reduces tumor-initiating cells and induces sustained tumor regressions. Sci Transl Med. 2017;9(372):eaag2611. https://doi.org/10.1126/scitranslmed.aag2611.

    Article  PubMed  CAS  Google Scholar 

  109. Jie Y, Liu G, Feng L, Li Y, E M, Wu L, et al. PTK7-targeting CAR T-cells for the treatment of lung cancer and other malignancies. Front Immunol. 2021;12:665970. https://doi.org/10.3389/fimmu.2021.665970.

  110. Schwab C, Harrison C. Advances in B-cell precursor acute lymphoblastic leukemia genomics. Hemasphere. 2018;2(4):e53. https://doi.org/10.1097/HS9.0000000000000053.

    Article  PubMed  PubMed Central  Google Scholar 

  111. Koleilat A, Smadbeck J, Zepeda-Mendoza C, Williamson C, Pitel B, Golden C, et al. Characterization of unusual iAMP21 B-lymphoblastic leukemia (iAMP21-ALL) from the Mayo Clinic and Children’s Oncology Group. Genes Chromosomes Cancer. 2022;61(12):710–9. https://doi.org/10.1002/gcc.23084.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Moorman AV, Robinson H, Schwab C, Richards SM, Hancock J, Mitchell CD, et al. Risk-directed treatment intensification significantly reduces the risk of relapse among children and adolescents with acute lymphoblastic leukemia and intrachromosomal amplification of chromosome 21: a comparison of the MRC ALL97/99 and UKALL2003 trials. J Clin Oncol. 2013;31(27):3389–96. https://doi.org/10.1200/JCO.2013.48.9377.

    Article  PubMed  Google Scholar 

  113. Fischer U, Forster M, Rinaldi A, Risch T, Sungalee S, Warnatz HJ, et al. Genomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options. Nat Genet. 2015;47(9):1020–9. https://doi.org/10.1038/ng.3362.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Huang Y, Bourquin J. Targeting the oncogenic activity of TCF3-HLF in leukemia. Mol Cell Oncol. 2020;7(3):1709391. https://doi.org/10.1080/23723556.2019.1709391.

  115. Glover J, Loriaux M, Tyner J, Druker B, Chang B. In vitro sensitivity to dasatinib in lymphoblasts from a patient with t(17;19)(q22;p13) gene rearrangement pre-B acute lymphoblastic leukemia. Pediatr Blood Cancer. 2011;59(3):576–9. https://doi.org/10.1002/pbc.23383.

    Article  PubMed  Google Scholar 

  116. Wu S, Lu J, Su D, Yang F, Zhang Y, Hu S. The advantage of chimeric antigen receptor T cell therapy in pediatric acute lymphoblastic leukemia with E2A-HLF fusion gene positivity: a case series. Transl Pediatr. 2021;10(3):686–91. https://doi.org/10.21037/tp-20-323.

    Article  PubMed  PubMed Central  Google Scholar 

  117. Wang P, He Y, Wang J, Ye Q, Zhang H, Zhang W. BCL2 Antagonist venetoclax combined with non aggressive chemotherapy in treating fatal TCF3-HLF positive acute lymphoblastic leukemia. Clinics in Oncology. Clin Oncol. 2021;6:1830.

  118. Leonard J, Wolf J, Degnin M, Eide C, LaTocha D, Lenz K, et al. Aurora A kinase as a target for therapy in TCF3-HLF rearranged acute lymphoblastic leukemia. Haematologica. 2021;106(11):2990–4. https://doi.org/10.3324/haematol.2021.278692.

  119. Mouttet B, Vinti L, Ancliff P, Bodmer N, Brethon B, Cario G, et al. Durable remissions in TCF3-HLF positive acute lymphoblastic leukemia with blinatumomab and stem cell transplantation. Haematologica. 2019;104(6):e244–7. https://doi.org/10.3324/haematol.2018.210104.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Li Y, Gupta G, Molofsky A, Xie Y, Shihabi N, McCormick J, Jaffe ES. B lymphoblastic leukemia/lymphoma with Burkitt-like morphology and IGH/MYC rearrangement: report of 3 cases in adult patients. Am J Surg Pathol. 2018;42(2):269–76. https://doi.org/10.1097/PAS.0000000000000982.

    Article  PubMed  PubMed Central  Google Scholar 

  121. Bomken S, Enshaei A, Schwalbe E, Mikkulasova A, Dai Y, Zaka M, et al. Molecular characterization and clinical outcome of B-cell precursor acute lymphoblastic leukemia with IG-MYC rearrangement. Haematologica. 2023;108(3). https://doi.org/10.3324/haematol.2021.280557.

  122. • Garralda E, Moreno V, Alonso G, Corral E, Hernandez-Guerrero T, Ramon J, et al. Dose escalation study of OMO-103, a first in class Pan-MYC-Inhibitor in patients (pts) with advanced solid tumors. Eur J Cancer. 2022;174:S5–6. https://doi.org/10.1016/S0959-8049(22)00820-6. The first phase I trial of a direct MYC inhibitor; tested in solid tumors.

  123. Jia Z, Gu Z. PAX5 alterations in B-cell acute lymphoblastic leukemia. Front Oncol. 2022;12:1023606. https://doi.org/10.3389/fonc.2022.1023606.

  124. Jung M, Schieck M, Hofmann W, Tauscher M, Lentes J, Bergmann A, et al. Frequency and prognostic impact of PAX5 p.P80R in pediatric acute lymphoblastic leukemia patients treated on an AIEOP-BFM acute lymphoblastic leukemia protocol. Genes Chromosomes Cancer. 2020;59(11):667–71. https://doi.org/10.1002/gcc.22882.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Passet M, Boissel N, Sigaux F, Saillard C, Bargetzi M, Ba I, et al. PAX5 P80R mutation identifies a novel subtype of B-cell precursor acute lymphoblastic leukemia with favorable outcome. Blood. 2019;133(3):280–4. https://doi.org/10.1182/blood-2018-10-882142.

    Article  PubMed  CAS  Google Scholar 

  126. Tran T, Loh M. Ph-like acute lymphoblastic leukemia. Hematol Am Soc Hematol Educ Program. 2016;1:561–6. https://doi.org/10.1182/asheducation-2016.1.561.

    Article  Google Scholar 

  127. Harvey R, Tasian S. Clinical diagnostics and treatment strategies for Philadelphia chromosome–like acute lymphoblastic leukemia. Blood Adv. 2020;4(1):218–28. https://doi.org/10.1182/bloodadvances.2019000163.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. Aldoss I, Advani A. Have any strategies in Ph-like ALL been shown to be effective? Best Pract Res Clin Haematol. 2021;34(1):101242. https://doi.org/10.1016/j.beha.2021.101242

  129. Tasian S, Teachey D, Li Y, Shen F, Harvey R, Chen I, 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. https://doi.org/10.1182/blood-2016-05-707653.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Akahane K, Li Z, Etchin J, Berezovskaya A, Gjini E, Masse C, et al. Anti-leukaemic activity of the TYK2 selective inhibitor NDI-031301 in T-cell acute lymphoblastic leukaemia. Br J Haematol. 2017;177(2):271–82. https://doi.org/10.1111/bjh.14563.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Shirazi P, Eadie L, Heatley S, Page E, François M, Hughes T, et al. Exploring the oncogenic and therapeutic target potential of the MYB-TYK2 fusion gene in B-cell acute lymphoblastic leukemia. Cancer Gene Ther. 2022;29(8–9):1140–52. https://doi.org/10.1038/s41417-021-00421-6.

    Article  PubMed  CAS  Google Scholar 

  132. Roberts K, Janke L, 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;132:861–5. https://doi.org/10.1182/blood-2018-05-849554.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Nardi V, Ku N, Frigault M, Dubuc A, Tsai H, Amrein P, et al. Clinical response to larotrectinib in adult Philadelphia chromosome–like ALL with cryptic ETV6-NTRK3 rearrangement. Blood. 2020;4(1):106–11. https://doi.org/10.1182/bloodadvances.2019000769.

    Article  Google Scholar 

  134. Meyer LD-MC, Maude S, Shannon K, Teachey D, Hermiston M. CRLF2 rearrangement in Ph-like acute lymphoblastic leukemia predicts relative glucocorticoid resistance that is overcome with MEK or Akt inhibition. PLoS One. 2019;14(7):e0220026.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Qin H, Cho M, Haso W, Zhang L, Tasian S, Oo H, et al. Eradication of B-ALL using chimeric antigen receptor–expressing T cells targeting the TSLPR oncoprotein. Blood. 2015;126(5):629–39. https://doi.org/10.1182/blood-2014-11-612903.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  136. Li Z, Lee S, Chin W, Lu Y, Jiang N, Lim E, et al. Distinct clinical characteristics of DUX4- and PAX5-altered childhood B-lymphoblastic leukemia. Blood Adv. 2021;5(23):5226–38. https://doi.org/10.1182/bloodadvances.2021004895.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. Fazio G, Bresolin S, Silvestri D, Quadri M, Saitta C, Vendramini E, et al. PAX5 fusion genes are frequent in poor risk childhood acute lymphoblastic leukaemia and can be targeted with BIBF1120. EBioMedicine. 2022;83:104224. https://doi.org/10.1016/j.ebiom.2022.104224.

  138. Stanulla M, Dagdan E, Zaliova M, Möricke A, Palmi C, Cazzaniga G, TRANSCALL Consortium; International BFM Study Group, et al. IKZF1plus 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. https://doi.org/10.1200/JCO.2017.74.3617.

    Article  PubMed  CAS  Google Scholar 

  139. Braun M, Pastorczak A, Sedek L, Taha J, Madzio J, Jatczak-Pawlik I, et al. Prognostic significance of IKZF1 deletions and IKZF1plus profile in children with B-cell precursor acute lymphoblastic leukemia treated according to the ALL-IC BFM 2009 protocol. Hematol Oncol. 2022;40(3):430–41. https://doi.org/10.1002/hon.2973.

    Article  PubMed  CAS  Google Scholar 

  140. Rogers J, Gupta R, Reyes JM, Gundry MC, Medrano G, Guzman A, et al. Modeling IKZF1 lesions in B-ALL reveals distinct chemosensitivity patterns and potential therapeutic vulnerabilities. Blood Adv. 2021;5(19):3876–90. https://doi.org/10.1182/bloodadvances.2020002408v.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Gupta R, Rogers J, Long X, Medrano G, Reyes J, Redell M, et al. Targeting activated signaling pathways for the treatment of IKZF1-deleted B lymphoblastic leukemia. Blood. 2019;134:3789. https://doi.org/10.1182/blood-2019-127209.

    Article  Google Scholar 

  142. Butler M, Vervoot B, van Ingen SD, Jongeneel L, van der Zwet J, Marke R, et al. Reversal of IKZF1-induced gluco corticoid resistance by dual targeting of AKT and ERK signaling pathways. Front Oncol. 2022;12:905665. https://doi.org/10.3389/fonc.2022.905665.

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De Sa, H., Leonard, J. Novel Biomarkers and Molecular Targets in ALL. Curr Hematol Malig Rep 19, 18–34 (2024). https://doi.org/10.1007/s11899-023-00718-3

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