Early T-Cell Precursor Lymphoblastic Leukemia

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Primary Author(s)*

Fei Yang, MD, FACMG, Kaiser Permanente Northwest

Cancer Category/Type

T-Lymphoblastic Leukemia (T-ALL)

Cancer Sub-Classification / Subtype

Early T-Cell Precursor Lymphoblastic Leukemia (ETP-ALL)

Definition / Description of Disease

Early T-Cell Precursor Lymphoblastic Leukemia (ETP-ALL) is a subtype of T-Lymphoblastic Leukemia (T-ALL) and is suggested to derive from thymic cells at the early T-cell precursor (ETP) differentiation stage[1]. The normal counterpart is the ETP cells that are the earliest thymic progenitors immigrated from the bone marrow to the thymus, with retention of a certain level of multilineage pluripotency rather than common lymphoid progenitors [2]. The ETP-ALL subtype has characteristic immunophenotypic and genomic profile compared with other subtypes of T-ALL. Under the 2016 version World Health Organization (WHO) classification[3], ETP-ALL is defined based on the immunophenotype of the leukemic cells:

  1. positive for intracytoplasmic CD3 and CD7, and positive (≥25% of blasts population) for at least one stem cell/myeloid marker (CD117, CD34, HLA-DR, CD13, CD33, CD11b, or CD65)
  2. negative to dim positive for CD5 (<75% positive)
  3. negative for CD1a, CD8, and MPO

However, the aforementioned immunophenotypic criteria have been reported not be able to identify all ETP-ALL cases as detected by gene expression profiling, and "negativity for CD4" has been proposed to be added to the criteria [4].

Synonyms / Terminology

Early thymic precursor (ETP) acute lymphoblastic leukemia (ALL)[5]

Epidemiology / Prevalence

Early T-Cell Precursor Lymphoblastic Leukemia (ETP-ALL) is uncommon, reported in about 5-17% of pediatric acute lymphoblastic leukemia (ALL) and 5-10% of adult ALL cases, respectively[2][6][7].

Clinical Features

The clinical features of ETP-ALL are similar to that of other subtypes of T-ALL, including a high leukocyte count, anterior mediastinal mass or other tissue mass, lymphadenopathy, hepatosplenomegaly[8][7]. Some patients who develop an anterior mediastinal mass can lead to superior vena cava syndrome.

Sites of Involvement

Similar to non-ETP T-ALL, the sites of involvement include bone marrow, lymph node, extra nodal and anterior mediastinal mass (thymus)[8][7].

Morphologic Features

Currently there is no specific morphologic feature reported for ETP-ALL.

Immunophenotype

Finding Marker
Positive (universal) intracytoplasmic CD3, CD7, and at least one stem cell or myeloid antigen (CD34, HLA-DR, CD13, CD33, CD117, CD11b, CD65)[3][9][6]
Positive (subset) dim expression of CD5 (<75% positive)[3][6], CD2[3]
Negative (universal) CD1a, CD8[3][6]
Negative (subset) CD5[3][6]

Chromosomal Rearrangements (Gene Fusions)

MEF2C (5q14) rearrangement or rearrangement involving MEF2C-related cofactors have been reported in about 50% of ETP-ALL cases[10], which have been validated in an independent ETP-ALL patient cohort[11]. Ectopic MEF2C expression due to rearrangement has been demonstrated as an oncogenic driver of ETP-ALL by upregulating LMO2 and LYL1, which lead to differentiation block of early thymocytes.

STIL-TAL1 fusion was only found in 3/23 ETP-ALL cases but not in 7 T-lymphoid/myeloid mixed phenotype acute leukemia (T/M-MPAL) cases in a study by Noronha et al [12], which could potentially help in distinguish these two disease entities. Further studies are warranted to confirm this finding.

Other chromosomal rearrangements involving KMT2A have been observed in ETP-ALL [12].

Individual Region Genomic Gain/Loss/LOH

Currently there is no specific copy number alterations/LOH that is associated with ETP-ALL.

Characteristic Chromosomal Patterns

Currently there is no specific chromosomal alteration that is characteristic for ETP-ALL.

Gene Mutations (SNV/INDEL)

Genes encoding transcription factors for development and differentiation (ETV6, GATA3, HOXA, LMO2, RUNX1, WT1), kinase signaling (FLT3, JAK1, JAK3, IL7R, KRAS, NRAS), and epigenetic modifiers (DNMT3A, EED, EZH2, PHF6, SUZ12) are commonly mutated in ETP-ALL [6]. More typical T-ALL mutations, such as NOTCH1 mutations and CDKN1/2 mutations are less frequent in ETP-ALL [2].

Gene; Genetic Alteration Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other) Prevalence (COSMIC / TCGA / Other) Concomitant Mutations Mutually Exclusive Mutations Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
IL7R; Variable activating mutations Oncogene 33 - 42% in adult ETP-ALL [13][14] core componenets of the PRC2: EZH2, SUZ12, and EED associated with slow response to chemotherapy [13] Ruxolitinib is evaluated in pre-clinical and clinical studies [15][16][6]
Components of PRC2: EZH2, SUZ12, EED; variable LOF mutations TSG 48% of pediatric ETP-ALL [14] BET inhibitors are evaluated in the pre-clinical studies [17]
FLT3; Activating mutations including ITD and TKD Oncogene 35% of adult ETP-ALL [18] FLT3 inhibitors are evaluated in the pre-clinical studies [18]

Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

Epigenomic Alterations

GATA3 encodes a transcription factor that is required for the development of T lymphocytes at multiple late differentiation steps [19]. Silencing of GATA3 via hypermethylation has been observed in 33% of adult ETP-ALL in a study of 70 adult ETP-ALL patients [20].

Genes and Main Pathways Involved

Gene; Genetic Alteration Pathway Pathophysiologic Outcome
EZH2, SUZ12, and EED; Inactivating mutations Epigenetic regulation/Histone modification cell maturation arrest
IL7R; Activating mutations JAK/STAT signaling pathway cell differentiation block

Diagnostic Testing Methods

Clinical, morphological, and immunophenotypic findings are generally sufficient for diagnosis. ETP-ALL has distinct gene expression profile, however, this approach is not feasible in the current setting of routine diagnostic laboratories.

Familial Forms

Unknown

Additional Information

The prognosis of this disease entity was initially considered poor compared to other subtypes of T-ALL based on few small studies [1][8][21]. However, more recent studies with larger patient cohorts suggested that the overall outcome with appropriate therapy appeared to not differ significantly from other subtypes [22][23].

Links

N/A

References

  1. 1.0 1.1 Coustan-Smith, Elaine; et al. (2009-02). "Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia". The Lancet. Oncology. 10 (2): 147–156. doi:10.1016/S1470-2045(08)70314-0. ISSN 1474-5488. PMC 2840241. PMID 19147408. Check date values in: |date= (help)
  2. 2.0 2.1 2.2 Jain, Nitin; et al. (2016-04-14). "Early T-cell precursor acute lymphoblastic leukemia/lymphoma (ETP-ALL/LBL) in adolescents and adults: a high-risk subtype". Blood. 127 (15): 1863–1869. doi:10.1182/blood-2015-08-661702. ISSN 1528-0020. PMC 4915808. PMID 26747249.
  3. 3.0 3.1 3.2 3.3 3.4 3.5 Arber, Daniel A.; et al. (2016-05-19). "The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia". Blood. 127 (20): 2391–2405. doi:10.1182/blood-2016-03-643544. ISSN 1528-0020. PMID 27069254.
  4. Zuurbier, Linda; et al. (2014-01). "Immature MEF2C-dysregulated T-cell leukemia patients have an early T-cell precursor acute lymphoblastic leukemia gene signature and typically have non-rearranged T-cell receptors". Haematologica. 99 (1): 94–102. doi:10.3324/haematol.2013.090233. ISSN 1592-8721. PMC 4007923. PMID 23975177. Check date values in: |date= (help)
  5. Bond, Jonathan; et al. (2017-08-10). "Early Response-Based Therapy Stratification Improves Survival in Adult Early Thymic Precursor Acute Lymphoblastic Leukemia: A Group for Research on Adult Acute Lymphoblastic Leukemia Study". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 35 (23): 2683–2691. doi:10.1200/JCO.2016.71.8585. ISSN 1527-7755. PMID 28605290.
  6. 6.0 6.1 6.2 6.3 6.4 6.5 6.6 Sin, Chun-Fung; et al. (2021). "Early T-Cell Precursor Acute Lymphoblastic Leukemia: Diagnosis, Updates in Molecular Pathogenesis, Management, and Novel Therapies". Frontiers in Oncology. 11: 750789. doi:10.3389/fonc.2021.750789. ISSN 2234-943X. PMC 8666570 Check |pmc= value (help). PMID 34912707 Check |pmid= value (help).
  7. 7.0 7.1 7.2 Borowitz MJ, et al., (2016).T-lymphoblastic leukemia/lymphoma, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4thedition.Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, Editors. IARC Press: Lyon, France, p176-178.
  8. 8.0 8.1 8.2 Inukai, Takeshi; et al. (2012-02). "Clinical significance of early T-cell precursor acute lymphoblastic leukaemia: results of the Tokyo Children's Cancer Study Group Study L99-15". British Journal of Haematology. 156 (3): 358–365. doi:10.1111/j.1365-2141.2011.08955.x. ISSN 1365-2141. PMID 22128890. Check date values in: |date= (help)
  9. Raetz, Elizabeth A.; et al. (2016-12-02). "T-cell acute lymphoblastic leukemia". Hematology. 2016 (1): 580–588. doi:10.1182/asheducation-2016.1.580. ISSN 1520-4391. PMC 6142501. PMID 27913532.CS1 maint: PMC format (link)
  10. Homminga I, Pieters R, Langerak A, de Rooi J, Stubbs A, Verstegen M, et al. MEF2C as Novel Oncogene for Early T-Cell Precursor (ETP) Leukemia. Blood (2010) 116:9–9. doi: 10.1182/blood.V116.21.9.9
  11. Meijer M, Cordo V, Hagelaar R, Smits W, Meijerink J. Manipulating MEF2C: Discovering Novel Drugs to Target ETP-ALL. Blood (2021) 138 (Supplement 1): 3325. doi.org/10.1182/blood-2021-150176.
  12. 12.0 12.1 Noronha, Elda Pereira; et al. (2019). "T-lymphoid/myeloid mixed phenotype acute leukemia and early T-cell precursor lymphoblastic leukemia similarities with NOTCH1 mutation as a good prognostic factor". Cancer Management and Research. 11: 3933–3943. doi:10.2147/CMAR.S196574. ISSN 1179-1322. PMC 6504706. PMID 31118806.
  13. 13.0 13.1 Kim, Rathana; et al. (2020-07). "Adult T-cell acute lymphoblastic leukemias with IL7R pathway mutations are slow-responders who do not benefit from allogeneic stem-cell transplantation". Leukemia. 34 (7): 1730–1740. doi:10.1038/s41375-019-0685-4. ISSN 1476-5551. PMID 31992840. Check date values in: |date= (help)
  14. 14.0 14.1 Zhang, Jinghui; et al. (2012-01-11). "The genetic basis of early T-cell precursor acute lymphoblastic leukaemia". Nature. 481 (7380): 157–163. doi:10.1038/nature10725. ISSN 1476-4687. PMC 3267575. PMID 22237106.
  15. Delgado-Martin, C.; et al. (2017-12). "JAK/STAT pathway inhibition overcomes IL7-induced glucocorticoid resistance in a subset of human T-cell acute lymphoblastic leukemias". Leukemia. 31 (12): 2568–2576. doi:10.1038/leu.2017.136. ISSN 1476-5551. PMC 5729333. PMID 28484265. Check date values in: |date= (help)
  16. Maude, Shannon L.; et al. (2015-03-12). "Efficacy of JAK/STAT pathway inhibition in murine xenograft models of early T-cell precursor (ETP) acute lymphoblastic leukemia". Blood. 125 (11): 1759–1767. doi:10.1182/blood-2014-06-580480. ISSN 1528-0020. PMC 4357583. PMID 25645356.
  17. Andrieu, Guillaume P.; et al. (2021-11-11). "PRC2 loss of function confers a targetable vulnerability to BET proteins in T-ALL". Blood. 138 (19): 1855–1869. doi:10.1182/blood.2020010081. ISSN 1528-0020. PMID 34125178 Check |pmid= value (help).
  18. 18.0 18.1 Neumann, Martin; et al. (2013). "FLT3 mutations in early T-cell precursor ALL characterize a stem cell like leukemia and imply the clinical use of tyrosine kinase inhibitors". PloS One. 8 (1): e53190. doi:10.1371/journal.pone.0053190. ISSN 1932-6203. PMC 3554732. PMID 23359050.
  19. Hosoya, Tomonori; et al. (2009-12-21). "GATA-3 is required for early T lineage progenitor development". The Journal of Experimental Medicine. 206 (13): 2987–3000. doi:10.1084/jem.20090934. ISSN 1540-9538. PMC 2806453. PMID 19934022.
  20. Fransecky, L.; et al. (2016-09-22). "Silencing of GATA3 defines a novel stem cell-like subgroup of ETP-ALL". Journal of Hematology & Oncology. 9 (1): 95. doi:10.1186/s13045-016-0324-8. ISSN 1756-8722. PMC 5034449. PMID 27658391.
  21. Ma, Meilin; et al. (2012-12). "Early T-cell precursor leukemia: a subtype of high risk childhood acute lymphoblastic leukemia". Frontiers of Medicine. 6 (4): 416–420. doi:10.1007/s11684-012-0224-4. ISSN 2095-0225. PMID 23065427. Check date values in: |date= (help)
  22. Patrick, Katharine; et al. (2014-08). "Outcome for children and young people with Early T-cell precursor acute lymphoblastic leukaemia treated on a contemporary protocol, UKALL 2003". British Journal of Haematology. 166 (3): 421–424. doi:10.1111/bjh.12882. ISSN 1365-2141. PMID 24708207. Check date values in: |date= (help)
  23. Wood, Brent L.; et al. (2014-12-06). "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. 124 (21): 1–1. doi:10.1182/blood.V124.21.1.1. ISSN 0006-4971.

Notes

*Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome.