Significance of immunophenotypic, cytogenetic, and molecular markers in adult patients with T-cell lymphoblastic leukemia

Background. Current chemotherapy protocols for T-cell acute lymphoblastic leukemia (T-ALL) allow achieving a 5-year overall survival of 60–90 %, but relapsed and refractory forms remain incurable situations.

Aim. To determine the significance of immunophenotypic, cytogenetic and molecular markers in adult T-ALL patients receiving therapy according to the ALL-2016 protocol.

Materials and methods. From December 2016 to June 2022, 113 patients with primary T-ALL were included in the study. Cytogenetic study was performed in 104 (92 %) patients; anomalies in the IKZF1 and NOTCH1 genes were investigated in 43 (38 %) patients.

Results. The worst prognosis was in patients with ETP and near-ETP variants of T-ALL (3-year disease-free survival was 54 % in ETP group, 33 % in near-ETP group vs TI/II – 79 %, TIII – 89 %, TIV – 75 %). In early T-ALL variants, abnormal karyotype was most common (ETP – 80.7 %, near-ETP – 60 %). Aberrations in NOTCH1 gene were found in 53 % of cases (in 23 out of 43 patients), and no mutations were found in IKZF1 gene in our study. In the group with no NOTCH1 abnormalities, the overall survival was significantly worse than in the group with abnormalities (NOTCH1– – 52 % vs NOTCH1+ –81 %; p = 0.05).

1. Coustan-Smith E., Mullighan C.G., Onciu M. et al. Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia. Lancet Oncol 2009;10(2):147–56. DOI: 10.1016/S1470-2045(08)70314-0

2. Wood B.L., Winter S.S., Dunsmore K.P. et al. T-lymphoblastic leukemia (T-ALL) shows excellent outcome, lack of significance of the early thymic precursor (ETP) immunophenotype, and validation of the prognostic value of end-induction minimal residual disease (MRD) in Children’s Oncology Group (COG) Study AALL0434. Blood 2016;127(15):1863–9. DOI: 10.1182/blood-2015-08-661702

3. Valiev T.T., Shervashidze M.A., Osipova I.V. et al. ALL-IC BFM 2002 protocol: treatment results of acute lymphoblastic leukemia in children in a multicenter clinical trial. Klinicheskaya onkogematologiya. Fundamentalnye issledovaniya i klinicheskaya praktika = Clinical Oncohematology. Basic Research and Clinical Practice 2022;15(2):119–29. (In Russ.).

4. Morita K., Jain N., Kantarjian H. et al. Outcome of T-cell acute lymphoblastic leukemia/lymphoma: Focus on near-ETP phenotype and differential impact of nelarabine. Am J Hematol 2021;96(5):589–98. DOI: 10.1002/ajh.26144

5. Genescà E., Morgades M., González-Gil C. et al. Adverse prognostic impact of complex karyotype (≥3 cytogenetic alterations) in adult T-cell acute lymphoblastic leukemia (T-ALL). Leuk Res 2021;109:106612. DOI: 10.1016/j.leukres.2021.106612

6. Korkina Yu.S., Valiev T.T., Kirgizov K.I. et al. early T-cell precursor leukemia: questions of diagnosis, treatment and description of own clinical case. Rossiyskiy zhurnal detskoy gematologii i onkologii = Russian Journal of Pediatric Hematology and Oncology 2022;9(4):107–13. (In Russ.).

7. Abaza Y., M Kantarjian H., Faderl S. et al. Hyper-CVAD plus nelarabine in newly diagnosed adult T-cell acute lymphoblastic leukemia and T-lymphoblastic lymphoma. Am J Hematol 2018;93(1):91–9. DOI: 10.1002/ajh.24947

8. Marks D.I., Rowntree C. Management of adults with T-cell lymphoblastic leukemia. Blood 2017;129(9):1134–42. DOI: 10.1182/blood-2016-07-692608

9. 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(1):31. DOI: 10.1186/s40164-020-00187-x

10. Weng A.P., Ferrando A.A., Lee W. et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 2004;306(5694):269–71. DOI: 10.1126/science.1102160

11. Clappier E., Collette S., Grardel N. et al. NOTCH1 and FBXW7 mutations have a favorable impact on early response to treatment, but not on outcome, in children with T-cell acute lymphoblastic leukemia (T-ALL) treated on EORTC trials 58881 and 58951. Leukemia 2010;24(12):2023–31. DOI: 10.1038/leu.2010.205

12. Kox C., Zimmermann M., Stanulla M. et al. The favorable effect of activating NOTCH1 receptor mutations on long-term outcome in T-ALL patients treated on the ALL-BFM 2000 protocol can be separated from FBXW7 loss of function. Leukemia 2010;24(12):2005–13. DOI: 10.1038/leu.2010.203

13. Larson Gedman A., Chen Q., Kugel Desmoulin S. et al. The impact of NOTCH1, FBW7 and PTEN mutations on prognosis and downstream signaling in pediatric T-cell acute lymphoblastic leukemia: a report from the Children’s Oncology Group. Leukemia 2009;23(8):1417–25. DOI: 10.1038/leu.2009.64

14. Zuurbier L., Homminga I., Calvert V. et al. NOTCH1 and/or FBXW7 mutations predict for initial good prednisone response but not for improved outcome in pediatric T-cell acute lymphoblastic leukemia patients treated on DCOG or COALL protocols. Leukemia 2010;24(12):2014–22. DOI: 10.1038/leu.2010.204

15. Asnafi V., Buzyn A., Le Noir S. et al. NOTCH1/FBXW7 mutation identifies a large subgroup with favorable outcome in adult T-cell acute lymphoblastic leukemia (T-ALL): a Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) study. Blood 2009;113(17):3918–24. DOI: 10.1182/blood-2008-10-184069

16. Baldus C.D., Thibaut J., Goekbuget N. et al. Prognostic implications of NOTCH1 and FBXW7 mutations in adult acute T-lymphoblastic leukemia. Haematologica 2009;94(10):1383–90. DOI: 10.3324/haematol.2008.005272

17. Jenkinson S., Koo K., Mansour M.R. et al. Impact of NOTCH1/ FBXW7 mutations on outcome in pediatric T-cell acute lymphoblastic leukemia patients treated on the MRC UKALL 2003 trial. Leukemia 2013;27(1):41–7. DOI: 10.1038/leu.2012.176

18. Mansour M.R., Sulis M.L., Duke V. et al. Prognostic implications of NOTCH1 and FBXW7 mutations in adults with T-cell acute lymphoblastic leukemia treated on the MRC UKALLXII/ECOG E2993 protocol. J Clin Oncol 2009;27(26):4352–6. DOI: 10.1200/JCO.2009.22.0996

19. Wu C.Y., Li Y.L., Dong X.Y. et al. Characteristics and prognostic effects of NOTCH1/FBXW7 gene mutations in T-cell acute lymphoblastic leukemia patients. Zhonghua Yi Xue Za Zhi 2022; 102(25):1910–7. DOI: 10.3760/cma.j.cn112137-20211025-02358

20. Georgopoulos K., Bigby M., Wang J.H. et al. The Ikaros gene is required for the development of all lymphoid lineages. Cell 1994;79(1):143–56. DOI: 10.1016/0092-8674(94)90407-3

21. Olsson L., Johansson B. Ikaros and leukaemia. Br J Haematol 2015;169(4):479–91. DOI: 10.1111/bjh.13342

22. Kuiper R.P., Waanders E., van der Velden V.H. et al. IKZF1 deletions predict relapse in uniformly treated pediatric precursor B-ALL. Leukemia 2010;24(7):1258–64. DOI: 10.1038/leu.2010.87

23. Rebollo A., Schmitt C. Ikaros, Aiolos and Helios: transcription regulators and lymphoid malignancies. Immunol Cell Biol 2003;81(3):171–5. DOI: 10.1046/j.1440-1711.2003.01159.x

24. Mullighan C.G., Su X., Zhang J. et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med 2009;360(5):470–80. DOI: 10.1056/NEJMoa0808253

25. Mullighan C.G., Goorha S., Radtke I. et al. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature 2007;446(7137):758–64. DOI: 10.1038/nature05690

26. Kobitzsch B., Gökbuget N., Schwartz S. et al. Loss-of-function but not dominant-negative intragenic IKZF1 deletions are associated with an adverse prognosis in adult BCR-ABL-negative acute lymphoblastic leukemia. Haematologica 2017;102(10):1739–47. DOI: 10.3324/haematol.2016.161273

27. Marçais A., Jeannet R., Hernandez L. et al. Genetic inactivation of Ikaros is a rare event in human T-ALL. Leuk Res 2010;34(4):426–9. DOI: 10.1016/j.leukres.2009.09.012

28. Witkowski M.T., Cimmino L., Hu Y. et al. Activated Notch counteracts Ikaros tumor suppression in mouse and human T-cell acute lymphoblastic leukemia. Leukemia 2015;29(6):1301–11. DOI: 10.1038/leu.2015.27

29. Yali D., Bing H., Jonathon P. et al. Regulation of heterochromatin landscape in T-cell acute lymphoblastic leukemia. Blood 2021:138(1):2217. DOI: 10.1182/blood-2021-154388

30. Xia R., Cheng Y., Han X. et al. Ikaros proteins in tumor: current perspectives and new developments. Front Mol Biosci 2021;8:788440. DOI: 10.3389/fmolb.2021.788440

31. Mortuza F.Y., Papaioannou M., Moreira I.M. et al. Minimal residual disease tests provide an independent predictor of clinical outcome in adult acute lymphoblastic leukemia. J Clin Oncol 2002;20(4):1094–104. DOI: 10.1200/JCO.2002.20.4.1094

32. Pemmaraju N., Kantarjian H., Jorgensen J.L. et al. Significance of recurrence of minimal residual disease detected by multiparameter flow cytometry in patients with acute lymphoblastic leukemia in morphological remission. Am J Hematol 2017;92(3):279–85. DOI: 10.1002/ajh.24629

33. Xu M., Liu H., Liu Y. et al. Gene mutations and pretransplant minimal residual disease predict risk of relapse in adult patients after allogeneic hematopoietic stem-cell transplantation for T cell acute lymphoblastic leukemia. Leuk Lymphoma 2019;60(11):2744–53. DOI: 10.1080/10428194.2019.1597270

34. Wang H., Zhou Y., Huang X. et al. Minimal residual disease level determined by flow cytometry provides reliable risk stratification in adults with T-cell acute lymphoblastic leukaemia. Br J Haematol 2021;193(6):1096–104. DOI: 10.1111/bjh.17424

35. Galtseva I.V. Minimal residual disease monitoring in patients with acute leukemia using multiparametric flow cytometry. Dis. … doctor of medical sciences. Moscow, 2022. 45 p. (In Russ.).

36. Konova Z.V., Parovichnikova E.N., Galtseva I.V. et al. Prognostic value of minimal residual disease before allogeneic hematopoietic stem cell transplantation in patients with acute leukemia. Gematologiya i transfuziologiya = Russian Journal of Hematology and Transfusiology 2021;66(4):539–55. (In Russ.). DOI: 10.35754/0234-5730-2021-66-4-539-555

37. Bene M.C., Castoldi G., Knapp W. et al. Proposals for the immunological classification of acute leukemias. European Group for the Immunological Characterization of Leukemias (EGIL). Leukemia 1995;9(10):1783–6.

38. Miller S.A., Dykes D.D., Polesky H.F. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988;16(3):1215. DOI: 10.1093/nar/16.3.1215

39. Caye A., Beldjord K., Mass-Malo K. et al. Breakpoint-specific multiplex polymerase chain reaction allows the detection of IKZF1 intragenic deletions and minimal residual disease monitoring in B-cell precursor acute lymphoblastic leukemia. Haematologica 2013;98(4):597–601. DOI: 10.3324/haematol.2012.073965

40. Campregher P.V., Petroni R.C., Muto N.H. et al. A novel assay for the identification of NOTCH1 PEST domain mutations in chronic lymphocytic leukemia. Biomed Res Int 2016;2016:4247908. DOI: 10.1155/2016/4247908

41. Breit S., Stanulla M., Flohr T. et al. Activating NOTCH1 mutations predict favorable early treatment response and long-term outcome in childhood precursor T-cell lymphoblastic leukemia. Blood 2006;108(4):1151–7. DOI: 10.1182/blood-2005-12-4956

42. Trinquand A., Tanguy-Schmidt A., Ben Abdelali R. et al. Toward a NOTCH1/FBXW7/RAS/PTEN-based oncogenetic risk classification of adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study. J Clin Oncol 2013;31(34):4333–42. DOI: 10.1200/JCO.2012.48.5292

43. Schrappe M., Valsecchi M.G., Bartram C.R. et al. Late MRD response determines relapse risk overall and in subsets of childhood T-cell ALL: results of the AIEOP-BFM-ALL 2000 study. Blood 2011;118(8):2077–84. DOI: 10.1182/blood-2011-03-338707

44. Burns M.A., Place A.E., Stevenson K.E. et al. Identification of prognostic factors in childhood T-cell acute lymphoblastic leukemia: results from DFCI ALL Consortium Protocols 05-001 and 11-001. Pediatr Blood Cancer 2021;68(1):e28719. DOI: 10.1002/pbc.28719

45. Chonghaile T.N., Roderick J.E., Glenfield C. 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. DOI: 10.1158/2159-8290.CD-14-0353

46. Gavrilina O.A., Parovichnikova E.N., Troitskaya V.V. et al. The use of venetoclax with decitabine in the treatment of resistant forms, relapses and MRD persistence in adult acute T-lymphoblastic leukemia. Gematologiya i transfuziologiya = Hematology and Transfusiology 2020;65(1):64–5. (In Russ.).

47. Parovichnikova E.N., Gavrilina O.A., Troitskaya V.V. et al. Venetoclax plus decitabine in the treatment of MRD-persistent and relapsed/refractory T-cell acute lymphoblastic leukemia. EHA 2020;294346:EP427.