The New Therapeutic Strategies in Pediatric T-Cell Acute Lymphoblastic Leukemia

Marta Weronika Lato, Anna Przysucha, Sylwia Grosman, Joanna Zawitkowska, Monika Lejman, Marta Weronika Lato, Anna Przysucha, Sylwia Grosman, Joanna Zawitkowska, Monika Lejman

Abstract

Childhood acute lymphoblastic leukemia is a genetically heterogeneous cancer that accounts for 10-15% of T-cell acute lymphoblastic leukemia (T-ALL) cases. The T-ALL event-free survival rate (EFS) is 85%. The evaluation of structural and numerical chromosomal changes is important for a comprehensive biological characterization of T-ALL, but there are currently no genetic prognostic markers. Despite chemotherapy regimens, steroids, and allogeneic transplantation, relapse is the main problem in children with T-ALL. Due to the development of high-throughput molecular methods, the ability to define subgroups of T-ALL has significantly improved in the last few years. The profiling of the gene expression of T-ALL has led to the identification of T-ALL subgroups, and it is important in determining prognostic factors and choosing an appropriate treatment. Novel therapies targeting molecular aberrations offer promise in achieving better first remission with the hope of preventing relapse. The employment of precisely targeted therapeutic approaches is expected to improve the cure of the disease and quality of life of patients. These include therapies that inhibit Notch1 activation (bortezomib), JAK inhibitors in ETP-ALL (ruxolitinib), BCL inhibitors (venetoclax), and anti-CD38 therapy (daratumumab). Chimeric antigen receptor T-cell therapy (CAR-T) is under investigation, but it requires further development and trials. Nelarabine-based regimens remain the standard for treating the relapse of T-ALL.

Keywords: T-ALL; novel therapies; pediatrics.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The molecular therapeutic targets used in preclinical and clinical studies of T-ALL treatment.

References

    1. Chiaretti S., Zini G., Bassan R. Diagnosis and Subclassification of Acute Lymphoblastic leukemia. Mediterr. J. Hematol. Infect. Dis. 2014;6:e2014073. doi: 10.4084/mjhid.2014.073.
    1. Bongiovanni D., Saccomani V., Piovan E. Aberrant Signaling Pathways in T-Cell Acute Lymphoblastic Leukemia. Int. J. Mol. Sci. 2017;18:1904. doi: 10.3390/ijms18091904.
    1. Bhojwani D., Yang J.J., Pui C.-H. Biology of Childhood Acute Lymphoblastic Leukemia. Pediatr. Clin. N. Am. 2015;62:47–60. doi: 10.1016/j.pcl.2014.09.004.
    1. Cooper T.M. Role of nelarabine in the treatment of T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma. Ther. Clin. Risk Manag. 2007;3:1135–1141.
    1. Karrman K., Johansson B. Pediatric T-cell acute lymphoblastic leukemia. Genes Chromosom. Cancer. 2017;56:89–116. doi: 10.1002/gcc.22416.
    1. Cooper S.L., Brown P.A. Treatment of Pediatric Acute Lymphoblastic Leukemia. Pediatr. Clin. N. Am. 2015;62:61–73. doi: 10.1016/j.pcl.2014.09.006.
    1. Fattizzo B., Rosa J., Giannotta J.A., Baldini L., Fracchiolla N.S. The Physiopathology of T-Cell Acute Lymphoblastic Leukemia: Focus on Molecular Aspects. Front. Oncol. 2020;10:273. doi: 10.3389/fonc.2020.00273.
    1. Kunz J.B., Rausch T., Bandapalli O.R., Eilers J., Pechanska P., Schuessele S., Assenov Y., Stütz A.M., Kirschner-Schwabe R., Hof J., et al. Pediatric T-cell lymphoblastic leukemia evolves into relapse by clonal selection, acquisition of mutations and promoter hypomethylation. Haematologica. 2015;100:1442–1450. doi: 10.3324/haematol.2015.129692.
    1. Mroczek A., Zawitkowska J., Kowalczyk J., Lejman M. Comprehensive Overview of Gene Rearrangements in Childhood T-Cell Acute Lymphoblastic Leukaemia. Int. J. Mol. Sci. 2021;22:808. doi: 10.3390/ijms22020808.
    1. Raetz E.A., Teachey D.T. T-cell acute lymphoblastic leukemia. Hematology. 2016;2016:580–588. doi: 10.1182/asheducation-2016.1.580.
    1. Genescà E., Morgades M., Montesinos P., Barba P., Gil C., Guàrdia R., Moreno M.-J., Martínez-Carballeira D., García-Cadenas I., Vives S., et al. Unique clinico-biological, genetic and prognostic features of adult early T-cell precursor acute lymphoblastic leukemia. Haematologica. 2020;105:e294–e297. doi: 10.3324/haematol.2019.225078.
    1. Vadillo E., Dorantes-Acosta E., Pelayo R., Schnoor M. T cell acute lymphoblastic leukemia (T-ALL): New insights into the cellular origins and infiltration mechanisms common and unique among hematologic malignancies. Blood Rev. 2018;32:36–51. doi: 10.1016/j.blre.2017.08.006.
    1. Coustan-Smith E., Mullighan C.G., Onciu M., Behm F.G., Raimondi S.C., Pei D., Cheng C., Su X., Rubnitz J.E., Basso G., et al. Early T-cell precursor leukaemia: A subtype of very high-risk acute lymphoblastic leukaemia. Lancet Oncol. 2009;10:147–156. doi: 10.1016/S1470-2045(08)70314-0.
    1. Ferrando A. Can one target T-cell ALL? Best Pr. Res. Clin. Haematol. 2018;31:361–366. doi: 10.1016/j.beha.2018.10.001.
    1. Haydu J.E., Ferrando A.A. Early T-cell precursor acute lymphoblastic leukaemia. Curr. Opin. Hematol. 2013;20:369–373. doi: 10.1097/MOH.0b013e3283623c61.
    1. Alonso-Alonso R., Mondéjar R., Martínez N., García-Diaz N., Pérez C., Merino D., Rodríguez M., Esteve-Codina A., Fuste B., Gut M., et al. Identification of tipifarnib sensitivity biomarkers in T-cell acute lymphoblastic leukemia and T-cell lymphoma. Sci. Rep. 2020;10:6721. doi: 10.1038/s41598-020-63434-5.
    1. Liu Y., Easton J., Shao Y., Maciaszek J., Wang Z., Wilkinson M.R., McCastlain K., Edmonson M., Pounds S.B., Meenakshi D., et al. The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia. Nat. Genet. 2017;49:1211–1218. doi: 10.1038/ng.3909.
    1. Berg S.L., Blaney S.M., Devidas M., Lampkin T.A., Murgo A.J., Bernstein M., Billett A.L., Kurtzberg J., Reaman G., Gaynon P.S., et al. Phase II Study of Nelarabine (compound 506U78) in Children and Young Adults with Refractory T-Cell Malignancies: A Report From the Children’s Oncology Group. J. Clin. Oncol. 2005;23:3376–3382. doi: 10.1200/JCO.2005.03.426.
    1. Teachey D.T., O’Connor D. How I treat newly diagnosed T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma in children. Blood J. Am. Soc. Hematol. 2020;135:159–166. doi: 10.1182/blood.2019001557.
    1. Teachey D.T., Pui C.-H. Comparative features and outcomes between paediatric T-cell and B-cell acute lymphoblastic leukaemia. Lancet Oncol. 2019;20:e142–e154. doi: 10.1016/S1470-2045(19)30031-2.
    1. Dunsmore K.P., Winter S.S., Devidas M., Wood B.L., Esiashvili N., Chen Z., Eisenberg N., Briegel N., Hayashi R.J., Gastier-Foster J.M., et al. Children’s Oncology Group AALL0434: A Phase III Randomized Clinical Trial Testing Nelarabine in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia. J. Clin. Oncol. 2020;38:3282–3293. doi: 10.1200/JCO.20.00256.
    1. McMahon C.M., Luger S.M. Relapsed T Cell ALL: Current Approaches and New Directions. Curr. Hematol. Malign. Rep. 2019;14:83–93. doi: 10.1007/s11899-019-00501-3.
    1. Dunsmore K.P., Winter S., Devidas M., Wood B.L., Esiashvili N., Eisenberg N., Briegel N., Hayashi R.J., Gastier-Foster J.M., Carroll A.J., et al. COG AALL0434: A randomized trial testing nelarabine in newly diagnosed t-cell malignancy. J. Clin. Oncol. 2018;36:10500. doi: 10.1200/JCO.2018.36.15_suppl.10500.
    1. Fuster J.L. Current approach to relapsed acute lymphoblastic leukemia in children. World J. Hematol. 2014;3:49. doi: 10.5315/wjh.v3.i3.49.
    1. Ritchey A.K., Pollock B.H., Lauer S.J., Andejeski Y., Buchanan G.R. Improved Survival of Children With Isolated CNS Relapse of Acute Lymphoblastic Leukemia: A Pediatric Oncology Group Study. J. Clin. Oncol. 1999;17:3745–3752. doi: 10.1200/JCO.1999.17.12.3745.
    1. Masurekar A.N., Parker C.A., Shanyinde M., Moorman A.V., Hancock J.P., Sutton R., Ancliff P.J., Morgan M., Goulden N.J., Fraser C., et al. Outcome of Central Nervous System Relapses In Childhood Acute Lymphoblastic Leukaemia—Prospective Open Cohort Analyses of the ALLR3 Trial. PLoS ONE. 2014;9:e108107. doi: 10.1371/journal.pone.0108107.
    1. Raetz E.A., Borowitz M.J., Devidas M., Linda S.B., Hunger S.P., Winick N.J., Camitta B.M., Gaynon P.S., Carroll W.L. Reinduction Platform for Children with First Marrow Relapse of Acute Lymphoblastic Leukemia: A Children’s Oncology Group Study. J. Clin. Oncol. 2008;26:3971–3978. doi: 10.1200/JCO.2008.16.1414.
    1. Nguyen K., Devidas M., Cheng S.-C., La M., Raetz E.A., Carroll W.L., Winick N.J., Hunger S.P., Gaynon P.S., Loh M.L. Factors influencing survival after relapse from acute lymphoblastic leukemia: A Children’s Oncology Group study. Leukemia. 2008;22:2142–2150. doi: 10.1038/leu.2008.251.
    1. Mujtaba T., Dou Q.P. Advances in the understanding of mechanisms and therapeutic use of bortezomib. Discov. Med. 2011;12:471–480.
    1. Terwilliger T., Abdul-Hay M. Acute lymphoblastic leukemia: A comprehensive review and 2017 update. Blood Cancer J. 2017;7:e577. doi: 10.1038/bcj.2017.53.
    1. August K.J., Guest E.M., Lewing K., Hays J.A., Gamis A.S. Treatment of children with relapsed and refractory acute lymphoblastic leukemia with mitoxantrone, vincristine, pegaspargase, dexamethasone, and bortezomib. Pediatr. Blood Cancer. 2020;67:e28062. doi: 10.1002/pbc.28062.
    1. Reismüller B., Peters C., Dworzak M.N., Pötschger U., Urban C., Meister B., Schmitt K., Dieckmann K., Gadner H., Attarbaschi A., et al. Outcome of Children and Adolescents with a Second or Third Relapse of Acute Lymphoblastic Leukemia (ALL)): A population-based analysis of the Austrian ALL-BFM (Berlin-Frankfurt-Münster) study group. J. Pediatr. Hematol. Oncol. 2013;35:e200–e204. doi: 10.1097/MPH.0b013e318290c3d6.
    1. Hunger S.P., Mullighan C.G. Acute Lymphoblastic Leukemia in Children. N. Engl. J. Med. 2015;373:1541–1552. doi: 10.1056/NEJMra1400972.
    1. Chang Y.-H., Yu C.-H., Jou S.-T., Lin C.-Y., Lin K.-H., Lu M.-Y., Wu K.-H., Chang H.-H., Lin D.-T., Lin S.-W., et al. Targeted sequencing to identify genetic alterations and prognostic markers in pediatric T-cell acute lymphoblastic leukemia. Sci. Rep. 2021;11:769. doi: 10.1038/s41598-020-80613-6.
    1. Paganin M., Ferrando A. Molecular pathogenesis and targeted therapies for NOTCH1-induced T-cell acute lymphoblastic leukemia. Blood Rev. 2011;25:83–90. doi: 10.1016/j.blre.2010.09.004.
    1. Wei P., Walls M., Qiu M., Ding R., Denlinger R.H., Wong A., Tsaparikos K., Jani J.P., Hosea N.A., Sands M., et al. Evaluation of Selective γ-Secretase Inhibitor PF-03084014 for Its Antitumor Efficacy and Gastrointestinal Safety to Guide Optimal Clinical Trial Design. Mol. Cancer Ther. 2010;9:1618–1628. doi: 10.1158/1535-7163.MCT-10-0034.
    1. DeAngelo D.J., Stone R.M., Silverman L.B., Stock W., Attar E.C., Fearen I., Dallob A., Matthews C., Stone J., Freedman S.J., et al. A phase I clinical trial of the notch inhibitor MK-0752 in patients with T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) and other leukemias. J. Clin. Oncol. 2006;24:6585. doi: 10.1200/jco.2006.24.18_suppl.6585.
    1. Samon J.B., Castillo-Martin M., Hadler M., Ambesi-Impiobato A., Paietta E., Racevskis J., Wiernik P.H., Rowe J.M., Jakubczak J., Randolph S., et al. Preclinical Analysis of the γ-Secretase Inhibitor PF-03084014 in Combination with Glucocorticoids in T-cell Acute Lymphoblastic Leukemia. Mol. Cancer Ther. 2012;11:1565–1575. doi: 10.1158/1535-7163.MCT-11-0938.
    1. Sanchez-Martin M., Ambesi-Impiombato A., Qin Y., Herranz D., Bansal M., Girardi T., Paietta E., Tallman M.S., Rowe J.M., De Keersmaecker K., et al. Synergistic antileukemic therapies inNOTCH1-induced T-ALL. Proc. Natl. Acad. Sci. USA. 2017;114:2006–2011. doi: 10.1073/pnas.1611831114.
    1. Hounjet J., Habets R., Schaaf M.B., Hendrickx T.C., Barbeau L.M.O., Yahyanejad S., Rouschop K.M., Groot A.J., Vooijs M. The anti-malarial drug chloroquine sensitizes oncogenic NOTCH1 driven human T-ALL to γ-secretase inhibition. Oncogene. 2019;38:5457–5468. doi: 10.1038/s41388-019-0802-x.
    1. Zheng R., Li M., Wang S., Liu Y. Advances of target therapy on NOTCH1 signaling pathway in T-cell acute lymphoblastic leukemia. Exp. Hematol. Oncol. 2020;9:31. doi: 10.1186/s40164-020-00187-x.
    1. Girardi T., Vicente C., Cools J., De Keersmaecker K. The genetics and molecular biology of T-ALL. Blood. 2017;129:1113–1123. doi: 10.1182/blood-2016-10-706465.
    1. Pikman Y., Alexe G., Roti G., Conway A.S., Furman A., Lee E.S., Place A.E., Kim S., Saran C., Modiste R., et al. Synergistic Drug Combinations with a CDK4/6 Inhibitor in T-cell Acute Lymphoblastic Leukemia. Clin. Cancer Res. 2017;23:1012–1024. doi: 10.1158/1078-0432.CCR-15-2869.
    1. Canté-Barrett K., Spijkers-Hagelstein J.A.P., Buijs-Gladdines J.G.C.A.M., Uitdehaag J.C.M., Smits W., Van Der Zwet J., Buijsman R., Zaman G., Pieters R., Meijerink J.P.P. MEK and PI3K-AKT inhibitors synergistically block activated IL7 receptor signaling in T-cell acute lymphoblastic leukemia. Leukemia. 2016;30:1832–1843. doi: 10.1038/leu.2016.83.
    1. Belver L., Ferrando L.B.A. The genetics and mechanisms of T cell acute lymphoblastic leukaemia. Nat. Rev. Cancer. 2016;16:494–507. doi: 10.1038/nrc.2016.63.
    1. Maude S.L., Dolai S., Delgado-Martin C., Vincent T., Robbins A., Selvanathan A., Ryan T., Hall J., Wood A.C., Tasian S.K., et al. Efficacy of JAK/STAT pathway inhibition in murine xenograft models of early T-cell precursor (ETP) acute lymphoblastic leukemia. Blood. 2015;125:1759–1767. doi: 10.1182/blood-2014-06-580480.
    1. Daver N., Boumber Y., Kantarjian H., Ravandi F., Cortes J., Rytting M.E., Kawedia J.D., Basnett J., Culotta K.S., Zeng Z., et al. A Phase I/II Study of the mTOR Inhibitor Everolimus in Combination with HyperCVAD Chemotherapy in Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia. Clin. Cancer Res. 2015;21:2704–2714. doi: 10.1158/1078-0432.CCR-14-2888.
    1. Place A.E., Pikman Y., Stevenson K.E., Harris M.H., Pauly M., Sulis M.-L., Hijiya N., Gore L., Cooper T.M., Loh M.L., et al. Phase I trial of the mTOR inhibitor everolimus in combination with multi-agent chemotherapy in relapsed childhood acute lymphoblastic leukemia. Pediatr. Blood Cancer. 2018;65:e27062. doi: 10.1002/pbc.27062.
    1. Follini E., Marchesini M., Roti G. Strategies to Overcome Resistance Mechanisms in T-Cell Acute Lymphoblastic Leukemia. Int. J. Mol. Sci. 2019;20:3021. doi: 10.3390/ijms20123021.
    1. Ni Chonghaile T., Roderick J.E., Glenfield C., Ryan J., Sallan S.E., Silverman L.B., Loh M.L., Hunger S.P., Wood B., DeAngelo D.J., 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;4:1074–1087. doi: 10.1158/-14-0353.
    1. Peirs S., Matthijssens F., Goossens S., Van De Walle I., Ruggero K., De Bock C.E., Degryse S., Canté-Barrett K., Briot D., Clappier E., et al. ABT-199 mediated inhibition of BCL-2 as a novel therapeutic strategy in T-cell acute lymphoblastic leukemia. Blood. 2014;124:3738–3747. doi: 10.1182/blood-2014-05-574566.
    1. Numan Y., Alfayez M., Maiti A., Alvarado Y., Jabbour E.J., Ferrajoli A., Konoplev S.N., Kantarjian H.M., Bose P. First Report of Clinical Response to Venetoclax in Early T-Cell Precursor Acute Lymphoblastic Leukemia. JCO Precis. Oncol. 2018;2 doi: 10.1200/PO.18.00127.
    1. Zappone E., Cencini E., Defina M., Sicuranza A., Gozzetti A., Ciofini S., Raspadori D., Mecacci B., Bocchia M. Venetoclax in association with decitabine as effective bridge to transplant in a case of relapsed early T-cell lymphoblastic leukemia. Clin. Case Rep. 2020;8:2000–2002. doi: 10.1002/ccr3.3041.
    1. Bose P., Gandhi V.V., Konopleva M.Y. Pathways and mechanisms of venetoclax resistance. Leuk. Lymphoma. 2017;58:2026–2039. doi: 10.1080/10428194.2017.1283032.
    1. La Starza R., Cambò B., Pierini A., Bornhauser B., Montanaro A., Bourquin J.-P., Mecucci C., Roti G. Venetoclax and Bortezomib in Relapsed/Refractory Early T-Cell Precursor Acute Lymphoblastic Leukemia. JCO Precis. Oncol. 2019;3 doi: 10.1200/PO.19.00172.
    1. Richard-Carpentier G., Jabbour E., Short N.J., Rausch C.R., Savoy J.M., Bose P., Yilmaz M., Jain N., Borthakur G., Ohanian M., et al. Clinical Experience with Venetoclax Combined with Chemotherapy for Relapsed or Refractory T-Cell Acute Lymphoblastic Leukemia. Clin. Lymphoma Myeloma Leuk. 2020;20:212–218. doi: 10.1016/j.clml.2019.09.608.
    1. McEwan A., Pitiyarachchi O., Viiala N. Relapsed/Refractory ETP-ALL Successfully Treated with Venetoclax and Nelarabine as a Bridge to Allogeneic Stem Cell Transplant. HemaSphere. 2020;4:e379. doi: 10.1097/HS9.0000000000000379.
    1. Palomero T., Ferrando A. Targeted cellular immunotherapy for T cell malignancies. Nat. Med. 2017;23:1402–1403. doi: 10.1038/nm.4458.
    1. Alcantara M., Tesio M., June C.H., Houot R. CAR T-cells for T-cell malignancies: Challenges in distinguishing between therapeutic, normal, and neoplastic T-cells. Leukemia. 2018;32:2307–2315. doi: 10.1038/s41375-018-0285-8.
    1. Cooper M.L., Choi J., Staser K., Ritchey J.K., Devenport J.M., Eckardt K., Rettig M.P., Wang B., Eissenberg L.G., Ghobadi A., et al. An “off-the-shelf” fratricide-resistant CAR-T for the treatment of T cell hematologic malignancies. Leukemia. 2018;32:1970–1983. doi: 10.1038/s41375-018-0065-5.
    1. Sánchez-Martínez D., Baroni M.L., Gutierrez-Agüera F., Roca-Ho H., Blanch-Lombarte O., González-García S., Torrebadell M., Junca J., Ramírez-Orellana M., Velasco-Hernández T., et al. Fratricide-resistant CD1a-specific CAR T cells for the treatment of cortical T-cell acute lymphoblastic leukemia. Blood. 2019;133:2291–2304. doi: 10.1182/blood-2018-10-882944.
    1. Mamonkin M., Rouce R.H., Tashiro H., Brenner M.K. A T-cell–directed chimeric antigen receptor for the selective treatment of T-cell malignancies. Blood. 2015;126:983–992. doi: 10.1182/blood-2015-02-629527.
    1. Gomes-Silva D., Srinivasan M., Sharma S., Lee C.M., Wagner D.L., Davis T.H., Rouce R.H., Bao G., Brenner M.K., Mamonkin M. CD7-edited T cells expressing a CD7-specific CAR for the therapy of T-cell malignancies. Blood. 2017;130:285–296. doi: 10.1182/blood-2017-01-761320.
    1. Bride K.L., Vincent T.L., Im S.-Y., Aplenc R., Barrett D.M., Carroll W.L., Carson R., Dai Y., Devidas M., Dunsmore K.P., et al. Preclinical efficacy of daratumumab in T-cell acute lymphoblastic leukemia. Blood. 2018;131:995–999. doi: 10.1182/blood-2017-07-794214.
    1. Hodby K.A., Marks D.I. Recent Advances in the Management of Acute Lymphoblastic Leukaemia. Curr. Treat. Options Oncol. 2020;21:23. doi: 10.1007/s11864-020-0712-8.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren