Blood Res.  2022 Sep;57(3):175-196. 10.5045/br.2022.2022104.

Relevance of flow cytometric categorization and end-of-induction measurable residual disease assessment in pediatric and adult T-lymphoblastic leukemia patients

• Bommannan K
• Arumugam JR
• Radhakrishnan V
• Kalaiyarasi JP
• Karunakaran P
• Mehra N
• Sagar TG
• Sundersingh S

• KMID: 2533246
• DOI: http://doi.org/10.5045/br.2022.2022104

Abstract

Background
T-lymphoblastic leukemia (T-ALL) patients expressing myeloid/stem cell antigens are classified as early T-cell precursor lymphoblastic leukemia (ETP-ALL) or near-ETP-ALL.
Methods
Clinico-laboratory profiles, flow cytometric end-of-induction measurable residual disease (EOI-MRD), and survival of treatment naïve T-ALL patients were analyzed according to their immunophenotypic subtypes.
Results
Among 81 consecutive T-ALL patients diagnosed, 21% (N=17) were ETP-ALL and 19% (N=15) were near-ETP-ALL. EOI-MRD was detectable in 39% of the 59 samples tested (31.6% of pediatric samples and 52.4% of adult samples). The frequency of EOI-MRD positivity was significantly higher among ETP-ALL (75%, P =0.001) and near-ETP-ALL (71%, P =0.009) patients compared to that in conventional-T-ALL (con-T-ALL) patients (22.5%). CD8 (P =0.046) and CD38 (P =0.046) expressions were significantly upregulated in the EOI blasts of con-T-ALL and ETP-ALL samples, respectively. The 2-year rates of overall (OS), relapse-free (RFS), and event-free survival (EFS) among the T-ALL patients (pediatric vs. adult) was 79.5% vs. 39.8% (P ＜0.001), 84.3% vs. 60.4% (P =0.026), and 80.3% vs. 38% (P ＜0.001), respectively. Univariate analysis revealed that 2-year EFS and RFS of pediatric T-ALL patients was independent of T-ALL subtype and was influenced only by EOI-MRD status. However, 2-year OS, RFS, and EFS among adult T-ALL patients were EOI-MRD independent and influenced only by the near-ETP-ALL phenotype.
Conclusion
Two-year survival among pediatric and adult T-ALL patients is attributed to EOI-MRD status and near-ETP-ALL phenotype, respectively.

Keyword

Measurable residual disease; Flow cytometry; T-lineage acute lymphoblastic leuke mia; ETP-ALL; Near-ETP-ALL

Figure

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  Fig. 1 Percentage of patients expressing lineage-specific and non-specific antigens across the immunophenotypic subtypes of T-ALL.

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  Fig. 2 Two-year overall survival (OS), relapse-free survival (RFS), and event-free survival (EFS) across all immunophenotypic subcategories of T-ALL analyzed together among all age groups (first row), pediatric patients (second row), and adult patients (third row).

Reference

1. Swerdlow SH, Campo E, Harris NL, et al. 2017; WHO classification of tumours of haematopoietic and lymphoid tissues. Revised 4th ed. Lyon, France:. IARC Press,. 421.

2. Coustan-Smith E, Mullighan CG, Onciu M, et al. 2009; Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia. Lancet Oncol. 10:147–56. DOI: 10.1016/S1470-2045(08)70314-0. PMID: 19147408. PMCID: PMC2840241.

3. Wu D, Sherwood A, Fromm JR, et al. 2012; High-throughput sequencing detects minimal residual disease in acute T lymphoblastic leukemia. Sci Transl Med. 4:134ra63. DOI: 10.1126/scitranslmed.3003656. PMID: 22593176.

4. Wood BL, Winter SS, Dunsmore KP, et al. 2014; 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 (ASH Annual Meeting Abstracts). 124:1. DOI: 10.1182/blood.V124.21.1.1.

5. Lin N, Liu ZH, Wang PP, Fu W, Yan XJ, Li Y. 2020; Immunophenotypic analysis of patients with adult acute T-lymphoblastic leukemia. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 28:442–5. DOI: 10.19746/j.cnki.issn.1009-2137.2020.02.014. PMID: 32319376.

6. Tembhare PR, Chatterjee G, Khanka T, et al. 2021; Eleven-marker 10-color flow cytometric assessment of measurable residual disease for T-cell acute lymphoblastic leukemia using an approach of exclusion. Cytometry B Clin Cytom. 100:421–33. DOI: 10.1002/cyto.b.21939. PMID: 32812702.

7. Tembhare PR, Narula G, Khanka T, et al. 2020; Post-induction measurable residual disease using multicolor flow cytometry is strongly predictive of inferior clinical outcome in the real-life management of childhood T-cell acute lymphoblastic leukemia: a study of 256 patients. Front Oncol. 10:577. DOI: 10.3389/fonc.2020.00577. PMID: 32391267. PMCID: PMC7193086. PMID: 0c471dc5b20a4712ab1ed07e20b61c8a.

8. Modvig S, Madsen HO, Siitonen SM, et al. 2019; Minimal residual disease quantification by flow cytometry provides reliable risk stratification in T-cell acute lymphoblastic leukemia. Leukemia. 33:1324–36. DOI: 10.1038/s41375-018-0307-6. PMID: 30552401.

9. Thörn I, Forestier E, Botling J, et al. 2011; Minimal residual disease assessment in childhood acute lymphoblastic leukaemia: a Swedish multi‐centre study comparing real‐time polymerase chain reaction and multicolour flow cytometry. Br J Haematol. 152:743–53. DOI: 10.1111/j.1365-2141.2010.08456.x. PMID: 21250970.

10. Gudapati P, Khanka T, Chatterjee G, et al. 2020; CD304/neuropilin‐1 is a very useful and dependable marker for the measurable residual disease assessment of B‐cell precursor acute lymphoblastic leukemia. Cytometry B Clin Cytom. 98:328–35. DOI: 10.1002/cyto.b.21866. PMID: 31944572.

11. Manabe A, Ohara A, Hasegawa D, et al. 2008; Significance of the complete clearance of peripheral blasts after 7 days of prednisolone treatment in children with acute lymphoblastic leukemia: the Tokyo Children's Cancer Study Group Study L99-15. Haematologica. 93:1155–60. DOI: 10.3324/haematol.12365. PMID: 18519521.

12. Cherian T, John R, Joseph LL, et al. 2021; Complete peripheral blast clearance is superior to the conventional cut-off of 1000/µL in predicting relapse in pediatric pre-B acute lymphoblastic leukemia. Indian J Hematol Blood Transfus. 37:366–71. DOI: 10.1007/s12288-020-01354-0. PMID: 34267453. PMCID: PMC8239084.

13. Bommannan BKK, Arumugam JR, Sundersingh S, Rajan PT, Radhakrishnan V, Sagar TG. 2019; CD19 negative and dim precursor B-lineage acute lymphoblastic leukemias: real-world challenges in a targeted-immunotherapy era. Leuk Lymphoma. 60:3154–60. DOI: 10.1080/10428194.2019.1625043. PMID: 31184238.

14. Dworzak MN, Buldini B, Gaipa G, et al. 2018; AIEOP‐BFM consensus guidelines 2016 for flow cytometric immunophenotyping of pediatric acute lymphoblastic leukemia. Cytometry B Clin Cytom. 94:82–93. DOI: 10.1002/cyto.b.21518. PMID: 28187514.

15. Chopra A, Bakhshi S, Pramanik SK, et al. 2014; Immunophenotypic analysis of T‐acute lymphoblastic leukemia. A CD 5‐based ETP‐ALL perspective of non‐ETP T‐ALL. Eur J Haematol. 92:211–8. DOI: 10.1111/ejh.12238. PMID: 24329989.

16. Sędek Ł, Theunissen P, Sobral da Costa E, et al. 2019; Differential expression of CD73, CD86 and CD304 in normal vs. leukemic B-cell precursors and their utility as stable minimal residual disease markers in childhood B-cell precursor acute lymphoblastic leukemia. J Immunol Methods. 475:112429. DOI: 10.1016/j.jim.2018.03.005. PMID: 29530508.

17. Haydu JE, Ferrando AA. 2013; Early T-cell precursor acute lymphoblastic leukaemia. Curr Opin Hematol. 20:369–73. DOI: 10.1097/MOH.0b013e3283623c61. PMID: 23695450. PMCID: PMC3886681.

18. Neumann M, Heesch S, Gökbuget N, et al. 2012; Clinical and molecular characterization of early T-cell precursor leukemia: a high-risk subgroup in adult T-ALL with a high frequency of FLT3 mutations. Blood Cancer J. 2:e55. DOI: 10.1038/bcj.2011.49. PMID: 22829239. PMCID: PMC3270253.

19. Van Vlierberghe P, Ambesi-Impiombato A, Perez-Garcia A, et al. 2011; ETV6 mutations in early immature human T cell leukemias. J Exp Med. 208:2571–9. DOI: 10.1084/jem.20112239. PMID: 22162831. PMCID: PMC3244026.

20. Jain N, Lamb AV, O'Brien S, et al. 2016; Early T-cell precursor acute lymphoblastic leukemia/lymphoma (ETP-ALL/LBL) in adolescents and adults: a high-risk subtype. Blood. 127:1863–9. DOI: 10.1182/blood-2015-08-661702. PMID: 26747249. PMCID: PMC4915808.

21. Zhang Y, Qian JJ, Zhou YL, et al. 2020; Comparison of early T-cell precursor and non-ETP subtypes among 122 Chinese adults with acute lymphoblastic leukemia. Front Oncol. 10:1423. DOI: 10.3389/fonc.2020.01423. PMID: 32974153. PMCID: PMC7473208. PMID: 04fa1d45900b4e4a84fe67e26e49d3d1.

22. Liao HY, Sun ZY, Wang YX, Jin YM, Zhu HL, Jiang NG. 2019; Outcome of 126 adolescent and adult T-cell acute leukemia/lymphoma patients and the prognostic significance of early T-cell precursor leukemia subtype. Zhonghua Xue Ye Xue Za Zhi. 40:561–7. DOI: 10.3760/cma.j.issn.0253-2727.2019.07.005. PMID: 32397018. PMCID: PMC7364909.

23. Ma M, Wang X, Tang J, et al. 2012; Early T-cell precursor leukemia: a subtype of high risk childhood acute lymphoblastic leukemia. Front Med. 6:416–20. DOI: 10.1007/s11684-012-0224-4. PMID: 23065427.

24. Montero I, Rios E, Parody R, Perez-Hurtado JM, Martin-Noya A, Rodriguez JM. 2003; CD56 in T-cell acute lymphoblastic leukaemia: a malignant transformation of an early myeloid-lymphoid progenitor? Haematologica. 88:ELT26. PMID: 12857578.

25. Fischer L, Gökbuget N, Schwartz S, et al. 2009; CD56 expression in T-cell acute lymphoblastic leukemia is associated with non-thymic phenotype and resistance to induction therapy but no inferior survival after risk-adapted therapy. Haematologica. 94:224–9. DOI: 10.3324/haematol.13543. PMID: 19109214. PMCID: PMC2635409.

26. Fuhrmann S, Schabath R, Möricke A, et al. 2018; Expression of CD56 defines a distinct subgroup in childhood T‐ALL with inferior outcome. Results of the ALL‐BFM 2000 trial. Br J Haematol. 183:96–103. DOI: 10.1111/bjh.15503. PMID: 30028023.

27. Dalmazzo LF, Jácomo RH, Marinato AF, et al. 2009; The presence of CD56/CD16 in T‐cell acute lymphoblastic leukaemia correlates with the expression of cytotoxic molecules and is associated with worse response to treatment. Br J Haematol. 144:223–9. DOI: 10.1111/j.1365-2141.2008.07457.x. PMID: 19016721.

28. Garg S, Gupta SK, Bakhshi S, Mallick S, Kumar L. 2019; ETP-ALL with aberrant B marker expression: case series and a brief review of literature. Int J Lab Hematol. 41:e32–7. DOI: 10.1111/ijlh.12942. PMID: 30407727.

29. Roshal M, Fromm JR, Winter S, Dunsmore K, Wood BL. 2010; Immaturity associated antigens are lost during induction for T cell lymphoblastic leukemia: implications for minimal residual disease detection. Cytometry B Clin Cytom. 78:139–46. DOI: 10.1002/cyto.b.20511. PMID: 20155852. PMCID: PMC3025860.

30. Singh N, Agrawal N, Sood R, et al. 2019; T-ALL minimal residual disease using a simplified gating strategy and its clinico-hematologic correlation: a single center experience from North India. Indian J Hematol Blood Transfus. 35:707–10. DOI: 10.1007/s12288-019-01106-9. PMID: 31741623. PMCID: PMC6825102.

31. Tembhare PR, Sriram H, Khanka T, et al. 2020; Flow cytometric evaluation of CD38 expression levels in the newly diagnosed T-cell acute lymphoblastic leukemia and the effect of chemotherapy on its expression in measurable residual disease, refractory disease and relapsed disease: an implication for anti-CD38 immunotherapy. J Immunother Cancer. 8:e000630. DOI: 10.1136/jitc-2020-000630. PMID: 32439800. PMCID: PMC7247386. PMID: 8e0cf6b29323454fb32aa2e1c341589b.

32. Chen S, Wainwright DA, Wu JD, et al. 2019; CD73: an emerging checkpoint for cancer immunotherapy. Immunotherapy. 11:983–97. DOI: 10.2217/imt-2018-0200. PMID: 31223045. PMCID: PMC6609898.

33. Conter V, Valsecchi MG, Buldini B, et al. 2016; Early T-cell precursor acute lymphoblastic leukaemia in children treated in AIEOP centres with AIEOP-BFM protocols: a retrospective analysis. Lancet Haematol. 3:e80–6. DOI: 10.1016/S2352-3026(15)00254-9. PMID: 26853647.

34. Inukai T, Kiyokawa N, Campana D, et al. 2012; Clinical significance of early T‐cell precursor acute lymphoblastic leukaemia: results of the Tokyo Children's Cancer Study Group Study L99‐15. Br J Haematol. 156:358–65. DOI: 10.1111/j.1365-2141.2011.08955.x. PMID: 22128890.