View source for HAEM4Backup:Early T-Cell Precursor Lymphoblastic Leukemia

{{Under Construction}}

==Primary Author(s)*==

Fei Yang, MD, FACMG, Kaiser Permanente Northwest

__TOC__

==Cancer Category/Type==

[https://ccga.io/index.php/T-Lymphoblastic_Leukemia/Lymphoma 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<ref name=":10">{{Cite journal|last=Coustan-Smith|first=Elaine|last2=Mullighan|first2=Charles G.|last3=Onciu|first3=Mihaela|last4=Behm|first4=Frederick G.|last5=Raimondi|first5=Susana C.|last6=Pei|first6=Deqing|last7=Cheng|first7=Cheng|last8=Su|first8=Xiaoping|last9=Rubnitz|first9=Jeffrey E.|date=2009-02|title=Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia|url=https://pubmed.ncbi.nlm.nih.gov/19147408|journal=The Lancet. Oncology|volume=10|issue=2|pages=147–156|doi=10.1016/S1470-2045(08)70314-0|issn=1474-5488|pmc=2840241|pmid=19147408}}</ref>. 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 <ref name=":2">{{Cite journal|last=Jain|first=Nitin|last2=Lamb|first2=Audrey V.|last3=O'Brien|first3=Susan|last4=Ravandi|first4=Farhad|last5=Konopleva|first5=Marina|last6=Jabbour|first6=Elias|last7=Zuo|first7=Zhuang|last8=Jorgensen|first8=Jeffrey|last9=Lin|first9=Pei|date=2016-04-14|title=Early T-cell precursor acute lymphoblastic leukemia/lymphoma (ETP-ALL/LBL) in adolescents and adults: a high-risk subtype|url=https://pubmed.ncbi.nlm.nih.gov/26747249|journal=Blood|volume=127|issue=15|pages=1863–1869|doi=10.1182/blood-2015-08-661702|issn=1528-0020|pmc=4915808|pmid=26747249}}</ref>. 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<ref name=":0" />, ETP-ALL is defined based on the immunophenotype of the leukemic cells:

#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)
#negative to dim positive for CD5 (<75% positive)
#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 <ref>{{Cite journal|last=Zuurbier|first=Linda|last2=Gutierrez|first2=Alejandro|last3=Mullighan|first3=Charles G.|last4=Canté-Barrett|first4=Kirsten|last5=Gevaert|first5=A. Olivier|last6=de Rooi|first6=Johan|last7=Li|first7=Yunlei|last8=Smits|first8=Willem K.|last9=Buijs-Gladdines|first9=Jessica G. C. A. M.|date=2014-01|title=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|url=https://pubmed.ncbi.nlm.nih.gov/23975177|journal=Haematologica|volume=99|issue=1|pages=94–102|doi=10.3324/haematol.2013.090233|issn=1592-8721|pmc=4007923|pmid=23975177}}</ref>.

==Synonyms / Terminology==

Early thymic precursor (ETP) acute lymphoblastic leukemia (ALL)<ref>{{Cite journal|last=Bond|first=Jonathan|last2=Graux|first2=Carlos|last3=Lhermitte|first3=Ludovic|last4=Lara|first4=Diane|last5=Cluzeau|first5=Thomas|last6=Leguay|first6=Thibaut|last7=Cieslak|first7=Agata|last8=Trinquand|first8=Amélie|last9=Pastoret|first9=Cedric|date=2017-08-10|title=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|url=https://pubmed.ncbi.nlm.nih.gov/28605290|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=35|issue=23|pages=2683–2691|doi=10.1200/JCO.2016.71.8585|issn=1527-7755|pmid=28605290}}</ref> 

==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<ref name=":2" /><ref name=":5">{{Cite journal|last=Sin|first=Chun-Fung|last2=Man|first2=Pui-Hei Marcus|date=2021|title=Early T-Cell Precursor Acute Lymphoblastic Leukemia: Diagnosis, Updates in Molecular Pathogenesis, Management, and Novel Therapies|url=https://pubmed.ncbi.nlm.nih.gov/34912707|journal=Frontiers in Oncology|volume=11|pages=750789|doi=10.3389/fonc.2021.750789|issn=2234-943X|pmc=8666570|pmid=34912707}}</ref><ref name=":4" />.

==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<ref name=":3">{{Cite journal|last=Inukai|first=Takeshi|last2=Kiyokawa|first2=Nobutaka|last3=Campana|first3=Dario|last4=Coustan-Smith|first4=Elaine|last5=Kikuchi|first5=Akira|last6=Kobayashi|first6=Miyuki|last7=Takahashi|first7=Hiroyuki|last8=Koh|first8=Katsuyoshi|last9=Manabe|first9=Atsushi|date=2012-02|title=Clinical significance of early T-cell precursor acute lymphoblastic leukaemia: results of the Tokyo Children's Cancer Study Group Study L99-15|url=https://pubmed.ncbi.nlm.nih.gov/22128890|journal=British Journal of Haematology|volume=156|issue=3|pages=358–365|doi=10.1111/j.1365-2141.2011.08955.x|issn=1365-2141|pmid=22128890}}</ref><ref name=":4">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.</ref>. 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)<ref name=":3" /><ref name=":4" />.

==Morphologic Features==

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

==Immunophenotype==

{| class="wikitable sortable"
|-
!Finding!!Marker
|-
|Positive (universal)||intracytoplasmic CD3, CD7, and at least one stem cell or myeloid antigen (CD34, HLA-DR, CD13, CD33, CD117, CD11b, CD65)<ref name=":0">{{Cite journal|last=Arber|first=Daniel A.|last2=Orazi|first2=Attilio|last3=Hasserjian|first3=Robert|last4=Thiele|first4=Jürgen|last5=Borowitz|first5=Michael J.|last6=Le Beau|first6=Michelle M.|last7=Bloomfield|first7=Clara D.|last8=Cazzola|first8=Mario|last9=Vardiman|first9=James W.|date=2016-05-19|title=The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia|url=https://pubmed.ncbi.nlm.nih.gov/27069254|journal=Blood|volume=127|issue=20|pages=2391–2405|doi=10.1182/blood-2016-03-643544|issn=1528-0020|pmid=27069254}}</ref><ref>{{Cite journal|last=Raetz|first=Elizabeth A.|last2=Teachey|first2=David T.|date=2016-12-02|title=T-cell acute lymphoblastic leukemia|url=https://ashpublications.org/hematology/article/2016/1/580/21136/Tcell-acute-lymphoblastic-leukemia|journal=Hematology|language=en|volume=2016|issue=1|pages=580–588|doi=10.1182/asheducation-2016.1.580|issn=1520-4391|pmc=PMC6142501|pmid=27913532}}</ref><ref name=":5" />
|-
|Positive (subset)||dim expression of CD5 (<75% positive)<ref name=":0" /><ref name=":5" />, CD2<ref name=":0" />
|-
|Negative (universal)||CD1a, CD8<ref name=":0" /><ref name=":5" />
|-
|Negative (subset)||CD5<ref name=":0" /><ref name=":5" />
|}

==Chromosomal Rearrangements (Gene Fusions)==

''MEF2C'' (5q14) rearrangement or rearrangement involving ''MEF2C''-related cofactors have been reported in about 50% of ETP-ALL cases<ref>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</ref>, which have been validated in an independent ETP-ALL patient cohort<ref>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.</ref>. 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 <ref name=":6">{{Cite journal|last=Noronha|first=Elda Pereira|last2=Marques|first2=Luísa Vieira Codeço|last3=Andrade|first3=Francianne Gomes|last4=Sardou-Cezar|first4=Ingrid|last5=Dos Santos-Bueno|first5=Filipe Vicente|last6=Zampier|first6=Carolina Da Paz|last7=Terra-Granado|first7=Eugênia|last8=Pombo-de-Oliveira|first8=Maria S.|date=2019|title=T-lymphoid/myeloid mixed phenotype acute leukemia and early T-cell precursor lymphoblastic leukemia similarities with NOTCH1 mutation as a good prognostic factor|url=https://pubmed.ncbi.nlm.nih.gov/31118806|journal=Cancer Management and Research|volume=11|pages=3933–3943|doi=10.2147/CMAR.S196574|issn=1179-1322|pmc=6504706|pmid=31118806}}</ref>, 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 <ref name=":6" />. 
==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 <ref name=":5" />. More typical T-ALL mutations, such as ''NOTCH1'' mutations and CDKN1/2 mutations are less frequent in ETP-ALL <ref name=":2" />.

{| class="wikitable sortable"
|-
!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 <ref name=":7">{{Cite journal|last=Kim|first=Rathana|last2=Boissel|first2=Nicolas|last3=Touzart|first3=Aurore|last4=Leguay|first4=Thibaut|last5=Thonier|first5=Florian|last6=Thomas|first6=Xavier|last7=Raffoux|first7=Emmanuel|last8=Huguet|first8=Françoise|last9=Villarese|first9=Patrick|date=2020-07|title=Adult T-cell acute lymphoblastic leukemias with IL7R pathway mutations are slow-responders who do not benefit from allogeneic stem-cell transplantation|url=https://pubmed.ncbi.nlm.nih.gov/31992840|journal=Leukemia|volume=34|issue=7|pages=1730–1740|doi=10.1038/s41375-019-0685-4|issn=1476-5551|pmid=31992840}}</ref><ref name=":8">{{Cite journal|last=Zhang|first=Jinghui|last2=Ding|first2=Li|last3=Holmfeldt|first3=Linda|last4=Wu|first4=Gang|last5=Heatley|first5=Sue L.|last6=Payne-Turner|first6=Debbie|last7=Easton|first7=John|last8=Chen|first8=Xiang|last9=Wang|first9=Jianmin|date=2012-01-11|title=The genetic basis of early T-cell precursor acute lymphoblastic leukaemia|url=https://pubmed.ncbi.nlm.nih.gov/22237106|journal=Nature|volume=481|issue=7380|pages=157–163|doi=10.1038/nature10725|issn=1476-4687|pmc=3267575|pmid=22237106}}</ref>
|core componenets of the PRC2: EZH2, SUZ12, and EED
|
|
|
|associated with slow response to chemotherapy <ref name=":7" />
|Ruxolitinib is evaluated in pre-clinical and clinical studies <ref>{{Cite journal|last=Delgado-Martin|first=C.|last2=Meyer|first2=L. K.|last3=Huang|first3=B. J.|last4=Shimano|first4=K. A.|last5=Zinter|first5=M. S.|last6=Nguyen|first6=J. V.|last7=Smith|first7=G. A.|last8=Taunton|first8=J.|last9=Winter|first9=S. S.|date=2017-12|title=JAK/STAT pathway inhibition overcomes IL7-induced glucocorticoid resistance in a subset of human T-cell acute lymphoblastic leukemias|url=https://pubmed.ncbi.nlm.nih.gov/28484265|journal=Leukemia|volume=31|issue=12|pages=2568–2576|doi=10.1038/leu.2017.136|issn=1476-5551|pmc=5729333|pmid=28484265}}</ref><ref>{{Cite journal|last=Maude|first=Shannon L.|last2=Dolai|first2=Sibasish|last3=Delgado-Martin|first3=Cristina|last4=Vincent|first4=Tiffaney|last5=Robbins|first5=Alissa|last6=Selvanathan|first6=Arthavan|last7=Ryan|first7=Theresa|last8=Hall|first8=Junior|last9=Wood|first9=Andrew C.|date=2015-03-12|title=Efficacy of JAK/STAT pathway inhibition in murine xenograft models of early T-cell precursor (ETP) acute lymphoblastic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/25645356|journal=Blood|volume=125|issue=11|pages=1759–1767|doi=10.1182/blood-2014-06-580480|issn=1528-0020|pmc=4357583|pmid=25645356}}</ref><ref name=":5" />
|-
|Components of PRC2: EZH2, SUZ12, EED; variable LOF mutations
|TSG
|48% of pediatric ETP-ALL <ref name=":8" />
|
|
|
|
|
|BET inhibitors are evaluated in the pre-clinical studies <ref>{{Cite journal|last=Andrieu|first=Guillaume P.|last2=Kohn|first2=Milena|last3=Simonin|first3=Mathieu|last4=Smith|first4=Charlotte L.|last5=Cieslak|first5=Agata|last6=Dourthe|first6=Marie-Émilie|last7=Charbonnier|first7=Guillaume|last8=Graux|first8=Carlos|last9=Huguet|first9=Françoise|date=2021-11-11|title=PRC2 loss of function confers a targetable vulnerability to BET proteins in T-ALL|url=https://pubmed.ncbi.nlm.nih.gov/34125178|journal=Blood|volume=138|issue=19|pages=1855–1869|doi=10.1182/blood.2020010081|issn=1528-0020|pmid=34125178}}</ref>
|-
|FLT3; Activating mutations including ITD and TKD
|Oncogene
|35% of adult ETP-ALL <ref name=":9">{{Cite journal|last=Neumann|first=Martin|last2=Coskun|first2=Ebru|last3=Fransecky|first3=Lars|last4=Mochmann|first4=Liliana H.|last5=Bartram|first5=Isabelle|last6=Sartangi|first6=Nasrin Farhadi|last7=Heesch|first7=Sandra|last8=Gökbuget|first8=Nicola|last9=Schwartz|first9=Stefan|date=2013|title=FLT3 mutations in early T-cell precursor ALL characterize a stem cell like leukemia and imply the clinical use of tyrosine kinase inhibitors|url=https://pubmed.ncbi.nlm.nih.gov/23359050|journal=PloS One|volume=8|issue=1|pages=e53190|doi=10.1371/journal.pone.0053190|issn=1932-6203|pmc=3554732|pmid=23359050}}</ref>
|
|
|
|
|
|FLT3 inhibitors are evaluated in the pre-clinical studies <ref name=":9" />
|}
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 <ref>{{Cite journal|last=Hosoya|first=Tomonori|last2=Kuroha|first2=Takashi|last3=Moriguchi|first3=Takashi|last4=Cummings|first4=Dustin|last5=Maillard|first5=Ivan|last6=Lim|first6=Kim-Chew|last7=Engel|first7=James Douglas|date=2009-12-21|title=GATA-3 is required for early T lineage progenitor development|url=https://pubmed.ncbi.nlm.nih.gov/19934022|journal=The Journal of Experimental Medicine|volume=206|issue=13|pages=2987–3000|doi=10.1084/jem.20090934|issn=1540-9538|pmc=2806453|pmid=19934022}}</ref>. Silencing of ''GATA3'' via hypermethylation has been observed in 33% of adult ETP-ALL in a study of 70 adult ETP-ALL patients <ref>{{Cite journal|last=Fransecky|first=L.|last2=Neumann|first2=M.|last3=Heesch|first3=S.|last4=Schlee|first4=C.|last5=Ortiz-Tanchez|first5=J.|last6=Heller|first6=S.|last7=Mossner|first7=M.|last8=Schwartz|first8=S.|last9=Mochmann|first9=L. H.|date=2016-09-22|title=Silencing of GATA3 defines a novel stem cell-like subgroup of ETP-ALL|url=https://pubmed.ncbi.nlm.nih.gov/27658391|journal=Journal of Hematology & Oncology|volume=9|issue=1|pages=95|doi=10.1186/s13045-016-0324-8|issn=1756-8722|pmc=5034449|pmid=27658391}}</ref>. 

==Genes and Main Pathways Involved==
{| class="wikitable sortable"
|-
!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
|}
==Genetic 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 <ref name=":10" /><ref name=":3" /><ref>{{Cite journal|last=Ma|first=Meilin|last2=Wang|first2=Xiang|last3=Tang|first3=Jingyan|last4=Xue|first4=Huiliang|last5=Chen|first5=Jing|last6=Pan|first6=Ci|last7=Jiang|first7=Hua|last8=Shen|first8=Shuhong|date=2012-12|title=Early T-cell precursor leukemia: a subtype of high risk childhood acute lymphoblastic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/23065427|journal=Frontiers of Medicine|volume=6|issue=4|pages=416–420|doi=10.1007/s11684-012-0224-4|issn=2095-0225|pmid=23065427}}</ref>. However, more recent studies with larger patient cohorts suggested that the overall outcome with appropriate therapy appeared to not differ significantly from other subtypes <ref>{{Cite journal|last=Patrick|first=Katharine|last2=Wade|first2=Rachel|last3=Goulden|first3=Nick|last4=Mitchell|first4=Chris|last5=Moorman|first5=Anthony V.|last6=Rowntree|first6=Clare|last7=Jenkinson|first7=Sarah|last8=Hough|first8=Rachael|last9=Vora|first9=Ajay|date=2014-08|title=Outcome for children and young people with Early T-cell precursor acute lymphoblastic leukaemia treated on a contemporary protocol, UKALL 2003|url=https://pubmed.ncbi.nlm.nih.gov/24708207|journal=British Journal of Haematology|volume=166|issue=3|pages=421–424|doi=10.1111/bjh.12882|issn=1365-2141|pmid=24708207}}</ref><ref>{{Cite journal|last=Wood|first=Brent L.|last2=Winter|first2=Stuart S.|last3=Dunsmore|first3=Kimberly P.|last4=Devidas|first4=Meenakshi|last5=Chen|first5=Si|last6=Asselin|first6=Barbara|last7=Esiashvili|first7=Natia|last8=Loh|first8=Mignon L.|last9=Winick|first9=Naomi J.|date=2014-12-06|title=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|url=https://doi.org/10.1182/blood.V124.21.1.1|journal=Blood|volume=124|issue=21|pages=1–1|doi=10.1182/blood.V124.21.1.1|issn=0006-4971}}</ref>. 

==Links==

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==References==
<references />

==Notes==
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