Difference between revisions of "HAEM5:T-prolymphocytic leukaemia"

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{{DISPLAYTITLE:T-prolymphocytic leukaemia}}
 
{{DISPLAYTITLE:T-prolymphocytic leukaemia}}
 +
 
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (5th ed.)]]
 
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (5th ed.)]]
  
 
{{Under Construction}}
 
{{Under Construction}}
  
−
<span style="color:#0070C0">(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ HGVS-based nomenclature for variants], as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples). Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see </span><u>[[Author_Instructions]]</u><span style="color:#0070C0"> and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>])</span>
+
<span style="color:#0070C0">(''General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ HGVS-based nomenclature for variants], as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column to a table, click nearby within the table and select the > symbol that appears to be given options. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see'' </span><u>''[[Author_Instructions]]''</u><span style="color:#0070C0"> ''and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>])''</span>
−
 
 
 
==Primary Author(s)*==
 
==Primary Author(s)*==
−
 
+
Parastou Tizro, MD, Celeste Eno, PHD, Sumire Kitahara, MD
−
Put your text here<span style="color:#0070C0"> (''Name and affiliation; example:'' Jane Smith, PhD, Institute of Genomics) </span>
+
==WHO Classification of Disease==
−
 
+
<span style="color:#0070C0">(Will be autogenerated; Book will include name of specific book and have a link to the online WHO site)</span>
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__TOC__
+
{| class="wikitable"
−
 
+
!Structure
−
==Cancer Category / Type==
+
!Disease
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+
|-
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Put your text here
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|Book
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+
|
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==Cancer Sub-Classification / Subtype==
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|-
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|Category
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Put your text here
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|
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|-
 +
|Family
 +
|
 +
|-
 +
|Type
 +
|
 +
|-
 +
|Subtype(s)
 +
|
 +
|}
 
==Definition / Description of Disease==
 
==Definition / Description of Disease==
−
 
+
T-prolymphocytic leukemia (T-PLL) is an aggressive form of T-cell leukemia marked by the proliferation of small to medium-sized prolymphocytes exhibiting a mature post-thymic T-cell phenotype. This condition is characterized by the juxtaposition of TCL1A or MTCP1 genes to a TR locus, typically the TRA/TRD locus.
−
Put your text here <span style="color:#0070C0">(''Instructions: Brief description of approximately one paragraph - include disease context relative to other WHO classification categories referring to the specific WHO book pages, diagnostic criteria if applicable, and differential diagnosis if applicable'') </span>
 
−
 
 
 
==Synonyms / Terminology==
 
==Synonyms / Terminology==
−
 
+
T-cell chronic lymphocytic leukemia
−
Put your text here <span style="color:#0070C0">(''Instructions: Include currently used terms and major historical ones, adding “(historical)” after the latter.'') </span>
 
−
 
 
 
==Epidemiology / Prevalence==
 
==Epidemiology / Prevalence==
−
 
+
T-PLL is a rare disorder, comprising about 2% of all mature lymphoid leukemia cases in adults. It primarily occurs in the elderly, with a median age of 65 years (ranging from 30 to 94 years) and shows a slight male predominance with a male to female ratio of 1.33:1.
−
Put your text here
 
−
 
 
 
==Clinical Features==
 
==Clinical Features==
−
 
+
The most prevalent symptom of the disease is a leukemic presentation, characterized by a rapid, exponential increase in lymphocyte counts, which exceed 100 × 10^9/L in 75% of patients. Approximately 30% of patients may initially experience an asymptomatic, slow-progressing phase, but this typically develops into an active disease state.
−
Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table'') </span>
 
 
{| class="wikitable"
 
{| class="wikitable"
 
|'''Signs and Symptoms'''
 
|'''Signs and Symptoms'''
−
|EXAMPLE Asymptomatic (incidental finding on complete blood counts)
+
|B symptoms (Fever, night sweats, weight loss)
 +
Hepatosplenomegaly (Frequently observed)
 +
 
 +
Generalized lymphadenopathy with slightly enlarged lymph nodes (Frequently observed)
  
−
EXAMPLE B-symptoms (weight loss, fever, night sweats)
+
Cutaneous involvement (20%)
  
−
EXAMPLE Fatigue
+
Malignant effusions (15%)
  
−
EXAMPLE Lymphadenopathy (uncommon)
+
Asymptomatic and indolent phase (30% of cases)
 
|-
 
|-
 
|'''Laboratory Findings'''
 
|'''Laboratory Findings'''
−
|EXAMPLE Cytopenias
+
|Anemia and thrombocytopenia
  
−
EXAMPLE Lymphocytosis (low level)
+
Marked lymphocytosis > 100 × 10^9/L (75% of cases)
−
|}
+
 
 +
Atypical lymphocytosis > 5 × 10^9/L
  
−
==Sites of Involvement==
+
Serum lactate dehydrogenase (LDH) (increased-may reflect disease burden) 
  
−
Put your text here <span style="color:#0070C0">(''Instruction: Indicate physical sites; Example: nodal, extranodal, bone marrow'') </span>
+
β 2 microglobulin (B2M) (increased-may reflect disease burden) 
  
 +
|}
 +
==Sites of Involvement==
 +
Peripheral blood, bone marrow, spleen (mostly red pulp), liver, lymph node (mostly paracortical), and sometimes skin and serosa (primarily pleura). Extra lymphatic and extramedullary atypical manifestations including skin, muscles and intestines are particularly common in relapse.
 
==Morphologic Features==
 
==Morphologic Features==
−
 
+
Blood smears in T-PLL typically reveal anemia, thrombocytopenia, and leukocytosis, with atypical lymphocytes in three morphological forms. The most common form (75% of cases) features medium-sized cells with a high nuclear-to-cytoplasmic ratio, moderately condensed chromatin, a single visible nucleolus, and slightly basophilic cytoplasm. In 20% of cases, the cells appear as a small cell variant with densely condensed chromatin and an inconspicuous nucleolus. About 5% of cases exhibit a cerebriform variant with irregular nuclei resembling those in mycosis fungoides. Regardless of the nuclear features, a common morphological characteristic is the presence of cytoplasmic protrusions or blebs.<ref>{{Cite journal|last=Eichhorn|first=G. L.|date=1979-02|title=Aging, genetics, and the environment: potential of errors introduced into genetic information transfer by metal ions|url=https://pubmed.ncbi.nlm.nih.gov/374897|journal=Mechanisms of Ageing and Development|volume=9|issue=3-4|pages=291–301|doi=10.1016/0047-6374(79)90106-4|issn=0047-6374|pmid=374897}}</ref> Bone marrow aspirates show clusters of these neoplastic cells, with a mixed pattern of involvement including diffuse and interstitial, in trephine core biopsy.
−
Put your text here
 
−
 
 
 
==Immunophenotype==
 
==Immunophenotype==
−
 
+
T-cell prolymphocytes show strong staining with alpha-naphthyl acetate esterase and acid phosphatase, presenting a distinctive dot-like pattern, but cytochemistry is not commonly used for diagnosis.
−
Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table'') </span>
 
−
 
 
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
 
|-
 
|-
 
!Finding!!Marker
 
!Finding!!Marker
 
|-
 
|-
−
|Positive (universal)||EXAMPLE CD1
+
|Positive (universal)||cyTCL1 (highest specificity), CD2, CD3 (may be weak), CD5, CD7 (strong), TCR-α/β, S100 (30% of cases)
 
|-
 
|-
−
|Positive (subset)||EXAMPLE CD2
+
|Positive (subset)||CD4 (in some cases CD4+/CD8+ or CD4-/CD8+), CD52 (therapeutic target), activation markers are variable (CD25, CD38, CD43, CD26, CD27)
 
|-
 
|-
−
|Negative (universal)||EXAMPLE CD3
+
|Negative (universal)||TdT, CD1a, CD57, CD16, HTLV1
 
|-
 
|-
−
|Negative (subset)||EXAMPLE CD4
+
|Negative (subset)||CD8 (in some cases CD4+/CD8+ or CD4-/CD8+)
 
|}
 
|}
−
 
 
==Chromosomal Rearrangements (Gene Fusions)==
 
==Chromosomal Rearrangements (Gene Fusions)==
−
 
+
Rearrangements involving the TCL1 (T-cell leukemia/lymphoma1) family genes—TCL1A, MTCP1 (mature T-cell proliferation), or TCL1B (also known as TCL1/MTCP1-like 1 [TML1])—are relatively specific to T-PLL. These are present in more than 90% of cases, either as inv(14)(q11q32) or t(14;14)(q11;q32) (involving TCL1A or TCL1B), or t(X;14)(q28;q11) (involving MTCP1). T-PLL-ISG).
−
Put your text here and fill in the table
 
−
 
 
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
 
|-
 
|-
Line 88: Line 90:
 
!Notes
 
!Notes
 
|-
 
|-
−
|EXAMPLE t(9;22)(q34;q11.2)||EXAMPLE 3'ABL1 / 5'BCR||EXAMPLE der(22)||EXAMPLE 20% (COSMIC)
+
|inv(14)(q11.2q32.1)
−
EXAMPLE 30% (add reference)
+
t(14;14)(q11.2;q32.1)
 +
|TCL1A/B ,TRD|| ||inv(14) ~60%
 +
t(14;14) ~25%
 
|Yes
 
|Yes
−
|No
 
 
|Yes
 
|Yes
−
|EXAMPLE
+
|Yes
−
 
+
|These genetic abnormalities serve as diagnostic markers and generally indicate an aggressive disease. This is due to their role in overexpressing oncogenes like TCL1A.
−
The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).
+
|-
−
|}
+
|t(X;14)(q28;q11.2)
−
+
|MTCP1, TRD
 +
|
 +
|Low (5%)
 +
|
 +
|
 +
|Yes
 +
|
 +
|}
 
==Individual Region Genomic Gain / Loss / LOH==
 
==Individual Region Genomic Gain / Loss / LOH==
−
 
+
Approximately 70-80% of T-PLL karyotypes are complex, which is considered minor diagnostic criteria, and usually include 3-5 or more structural aberrations. Common cytogenetic abnormalities include those of chromosome 8, such as idic(8)(p11.2), t(8;8)(p11.2;q12), and trisomy 8q. Other frequent changes are deletions in 12p13 and 22q, gains in 8q24 (MYC), and abnormalities in chromosomes 5p, 6, and 17.
−
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Includes aberrations not involving gene fusions. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable.'') </span>
 
−
 
 
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
 
|-
 
|-
Line 110: Line 118:
 
!Notes
 
!Notes
 
|-
 
|-
−
|EXAMPLE
+
|8
 +
|Gain
 +
|idic(8)(p11)
 +
 
 +
t(8;8)(p11;q12)
  
−
7
+
trisomy 8q<br />8q24 (''MYC'')
−
|EXAMPLE Loss
+
|idic(8)(p11.2)
−
|EXAMPLE
 
  
−
chr7:1- 159,335,973 [hg38]
+
t(8;8)(p11.2;q12)
−
|EXAMPLE
 
  
−
chr7
+
trisomy 8q<br />8q24 (''MYC'')
 +
|Yes
 +
|No
 +
|No
 +
|Recurrent secondary finding (70-80% of cases). Minor diagnostic criteria. <ref>{{Cite journal|last=Staber|first=Philipp B.|last2=Herling|first2=Marco|last3=Bellido|first3=Mar|last4=Jacobsen|first4=Eric D.|last5=Davids|first5=Matthew S.|last6=Kadia|first6=Tapan Mahendra|last7=Shustov|first7=Andrei|last8=Tournilhac|first8=Olivier|last9=Bachy|first9=Emmanuel|date=2019-10-03|title=Consensus criteria for diagnosis, staging, and treatment response assessment of T-cell prolymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/31292114|journal=Blood|volume=134|issue=14|pages=1132–1143|doi=10.1182/blood.2019000402|issn=1528-0020|pmc=7042666|pmid=31292114}}</ref>
 +
|-
 +
|5
 +
|Abnormality
 +
|5p, 5q<ref>{{Cite journal|last=Tirado|first=Carlos A.|last2=Starshak|first2=Phillip|last3=Delgado|first3=Paul|last4=Rao|first4=Nagesh|date=2012-08-20|title="T-cell prolymphocytic leukemia (T-PLL), a heterogeneous disease exemplified by two cases and the important role of cytogenetics: a multidisciplinary approach"|url=https://pubmed.ncbi.nlm.nih.gov/23211026|journal=Experimental Hematology & Oncology|volume=1|issue=1|pages=21|doi=10.1186/2162-3619-1-21|issn=2162-3619|pmc=3514161|pmid=23211026}}</ref>
 +
|
 
|Yes
 
|Yes
 
|Yes
 
|Yes
 
|No
 
|No
−
|EXAMPLE
+
|Minor diagnostic criteria
−
 
+
|-
−
Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference).
+
|6
 +
|Abnormality
 +
|6p
 +
|
 +
|No
 +
|
 +
|
 +
|
 +
|-
 +
|11
 +
|Loss
 +
|11q
 +
|ch11q21-q23.3
 +
|Yes
 +
|Yes
 +
|Yes
 +
|Frequent, Minor diagnostic criteria.
 +
|-
 +
|12
 +
|Loss
 +
|12p
 +
|12p13
 +
|Yes
 +
|
 +
|
 +
|Minor diagnostic criteria
 +
|-
 +
|13
 +
|Loss
 +
|13q
 +
|13q14.3
 +
|Yes
 +
|
 +
|
 +
|Minor diagnostic criteria
 +
|-
 +
|17
 +
|Abnormality
 +
|17p, 17q
 +
|17p13
 +
|
 +
|Yes
 +
|Yes (resistance to therapy)
 +
|
 
|-
 
|-
−
|EXAMPLE
+
|22
 +
|Loss
 +
|Monosomy 22
 +
del(22q)
 +
|
  
−
8
 
−
|EXAMPLE Gain
 
−
|EXAMPLE
 
  
−
chr8:1-145,138,636 [hg38]
+
22q11-12 <ref>{{Cite journal|last=Stengel|first=Anna|last2=Kern|first2=Wolfgang|last3=Zenger|first3=Melanie|last4=Perglerová|first4=Karolina|last5=Schnittger|first5=Susanne|last6=Haferlach|first6=Torsten|last7=Haferlach|first7=Claudia|date=2014-12-06|title=A Comprehensive Cytogenetic and Molecular Genetic Characterization of Patients with T-PLL Revealed Two Distinct Genetic Subgroups and JAK3 Mutations As an Important Prognostic Marker|url=https://doi.org/10.1182/blood.V124.21.1639.1639|journal=Blood|volume=124|issue=21|pages=1639–1639|doi=10.1182/blood.v124.21.1639.1639|issn=0006-4971}}</ref><ref name=":0">{{Cite journal|last=Fang|first=Hong|last2=Beird|first2=Hannah C.|last3=Wang|first3=Sa A.|last4=Ibrahim|first4=Andrew F.|last5=Tang|first5=Zhenya|last6=Tang|first6=Guilin|last7=You|first7=M. James|last8=Hu|first8=Shimin|last9=Xu|first9=Jie|date=2023-09|title=T-prolymphocytic leukemia: TCL1 or MTCP1 rearrangement is not mandatory to establish diagnosis|url=https://pubmed.ncbi.nlm.nih.gov/37443196|journal=Leukemia|volume=37|issue=9|pages=1919–1921|doi=10.1038/s41375-023-01956-3|issn=1476-5551|pmid=37443196}}</ref>
−
|EXAMPLE
 
  
−
chr8
+
(most common)
−
|No
+
|
−
|No
+
|
−
|No
+
|
−
|EXAMPLE
+
|Leading to the dysregulation of genes such as BCL11B, which is crucial in T-cell development and function.<ref name=":0" />
−
 
+
Minor diagnostic criteria
−
Common recurrent secondary finding for t(8;21) (add reference).
 
 
|}
 
|}
 
==Characteristic Chromosomal Patterns==
 
==Characteristic Chromosomal Patterns==
−
 
+
<br />
−
Put your text here <span style="color:#0070C0">(''EXAMPLE PATTERNS: hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis'')</span>
 
−
 
 
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
 
|-
 
|-
Line 156: Line 215:
 
!Notes
 
!Notes
 
|-
 
|-
−
|EXAMPLE
+
|inv(14)(q11q32)
−
 
+
t(14;14)(q11.2;q32.1)
−
Co-deletion of 1p and 18q
+
|Yes
 +
|Yes
 
|Yes
 
|Yes
−
|No
+
|<span class="blue-text">EXAMPLE:</span>
−
|No
 
−
|EXAMPLE:
 
−
 
 
 
See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
 
See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
 
|}
 
|}
 
==Gene Mutations (SNV / INDEL)==
 
==Gene Mutations (SNV / INDEL)==
−
 
+
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent and common as well either disease defining and/or clinically significant. Can include references in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Do not delete table.'') </span>
−
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent and common as well either disease defining and/or clinically significant. Can include references in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity.'') </span>
 
−
 
 
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
 
|-
 
|-
Line 178: Line 233:
 
!Notes
 
!Notes
 
|-
 
|-
−
|EXAMPLE: TP53; Variable LOF mutations
+
|ATM
 +
|TSG
 +
|53% (COSMIC)
 +
|''ATM'' mutation/deletion
 +
|None specified
 +
|Yes
 +
|Yes
 +
|Yes (PARP inhibitors, NCT03263637)
 +
|Deletions of or missense mutations at the ''ATM'' locus are found in up to 80% to 90% of T-PLL cases. (T-PLL-ISG).
 +
|-
 +
|''FBXW10''
 +
|TSG
 +
|72% (COSMIC)
 +
|''JAK/STAT'' pathway
 +
|None specified
 +
|Unknown
 +
|Unknown
 +
|Unknown
 +
|
 +
|-
 +
|''IL2RG,'' ''JAK1, JAK3, STAT5B''
 +
|Oncogene
 +
|8% ''JAK1''
  
−
EXAMPLE:
+
34% ''JAK3''
  
−
EGFR; Exon 20 mutations
+
16% ''STAT5B''
  
−
EXAMPLE: BRAF; Activating mutations
+
2% ''IL2RG''
−
|EXAMPLE: TSG
 
−
|EXAMPLE: 20% (COSMIC)
 
  
−
EXAMPLE: 30% (add Reference)
+
(COSMIC)
−
|EXAMPLE: IDH1 R123H
+
|''ATM, TP53'', Epigenetic modifiers <ref name=":1">{{Cite journal|last=Andersson|first=E. I.|last2=Pützer|first2=S.|last3=Yadav|first3=B.|last4=Dufva|first4=O.|last5=Khan|first5=S.|last6=He|first6=L.|last7=Sellner|first7=L.|last8=Schrader|first8=A.|last9=Crispatzu|first9=G.|date=2018-03|title=Discovery of novel drug sensitivities in T-PLL by high-throughput ex vivo drug testing and mutation profiling|url=https://pubmed.ncbi.nlm.nih.gov/28804127|journal=Leukemia|volume=32|issue=3|pages=774–787|doi=10.1038/leu.2017.252|issn=1476-5551|pmid=28804127}}</ref><ref name=":2">{{Cite journal|last=Pinter-Brown|first=Lauren C.|date=2021-12-30|title=JAK/STAT: a pathway through the maze of PTCL?|url=https://doi.org/10.1182/blood.2021014238|journal=Blood|volume=138|issue=26|pages=2747–2748|doi=10.1182/blood.2021014238|issn=0006-4971}}</ref>
−
|EXAMPLE: EGFR amplification
+
|Typically, mutations within this pathway occur in a mutually exclusive manner.<ref name=":3">{{Cite journal|last=Kiel|first=Mark J.|last2=Velusamy|first2=Thirunavukkarasu|last3=Rolland|first3=Delphine|last4=Sahasrabuddhe|first4=Anagh A.|last5=Chung|first5=Fuzon|last6=Bailey|first6=Nathanael G.|last7=Schrader|first7=Alexandra|last8=Li|first8=Bo|last9=Li|first9=Jun Z.|date=2014-08-28|title=Integrated genomic sequencing reveals mutational landscape of T-cell prolymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/24825865|journal=Blood|volume=124|issue=9|pages=1460–1472|doi=10.1182/blood-2014-03-559542|issn=1528-0020|pmc=4148768|pmid=24825865}}</ref>
 +
|Yes
 +
|Yes
 
|
 
|
 +
|The cumulative prevalence of these mutations in T-PLL is approximately 60%.  (Dr jaffe book)
 +
|-
 +
|''EZH2''
 +
|Oncogene, TSG
 +
|16% (COSMIC)
 +
|JAK/STAT pathway<ref name=":1" /><ref name=":2" />
 +
|None specified
 +
|No
 +
|Yes
 +
|See note
 +
|EZH2 inhibitors like tazemetostat have shown efficacy in other hematologic malignancies, providing a rationale for their potential use in T-PLL
 +
|-
 +
|''BCOR''
 +
|TSG
 +
|8% (COSMIC)
 +
|''JAK/STAT'' pathway<ref name=":1" /><ref name=":2" />
 +
|None specified
 +
|No
 +
|Yes
 +
|Yes??
 
|
 
|
 +
|-
 +
|''SAMHD1''
 +
|TSG
 +
|~7-20%<ref name=":4">{{Cite journal|last=Johansson|first=Patricia|last2=Klein-Hitpass|first2=Ludger|last3=Choidas|first3=Axel|last4=Habenberger|first4=Peter|last5=Mahboubi|first5=Bijan|last6=Kim|first6=Baek|last7=Bergmann|first7=Anke|last8=Scholtysik|first8=René|last9=Brauser|first9=Martina|date=2018-01-19|title=SAMHD1 is recurrently mutated in T-cell prolymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/29352181|journal=Blood Cancer Journal|volume=8|issue=1|pages=11|doi=10.1038/s41408-017-0036-5|issn=2044-5385|pmc=5802577|pmid=29352181}}</ref><ref>{{Cite journal|last=Schrader|first=A.|last2=Crispatzu|first2=G.|last3=Oberbeck|first3=S.|last4=Mayer|first4=P.|last5=Pützer|first5=S.|last6=von Jan|first6=J.|last7=Vasyutina|first7=E.|last8=Warner|first8=K.|last9=Weit|first9=N.|date=2018-02-15|title=Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL|url=https://pubmed.ncbi.nlm.nih.gov/29449575|journal=Nature Communications|volume=9|issue=1|pages=697|doi=10.1038/s41467-017-02688-6|issn=2041-1723|pmc=5814445|pmid=29449575}}</ref>
 
|
 
|
−
|EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).
+
|None specified
−
<br />
+
|Yes
−
|}
+
|
−
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.
+
|
−
 
+
|''SAMHD1'' mutations may indicate a defective DNA damage response and aggressive disease <ref name=":4" />
 +
|-
 +
|''CHEK2''
 +
|TSG
 +
|5% (COSMIC)
 +
|''ATM, TP53, JAK/STA''T pathway, Epigenetic modifiers
 +
|None specified
 +
|No
 +
|Yes
 +
|No
 +
|''CHEK2'' mutations may indicate a defective DNA damage response and aggressive disease <ref name=":3" /><ref>{{Cite journal|last=Braun|first=Till|last2=Dechow|first2=Annika|last3=Friedrich|first3=Gregor|last4=Seifert|first4=Michael|last5=Stachelscheid|first5=Johanna|last6=Herling|first6=Marco|date=2021|title=Advanced Pathogenetic Concepts in T-Cell Prolymphocytic Leukemia and Their Translational Impact|url=https://pubmed.ncbi.nlm.nih.gov/34869023|journal=Frontiers in Oncology|volume=11|pages=775363|doi=10.3389/fonc.2021.775363|issn=2234-943X|pmc=8639578|pmid=34869023}}</ref>
 +
|-
 +
|''TP53''
 +
|TSG
 +
|2% (COSMIC)
 +
|''ATM, JAK/STA''T pathway, Epigenetic modifiers
 +
|None specified
 +
|No
 +
|Yes
 +
|Associated with resistance to therapy
 +
|Mutations in TP53 are less frequent than deletions<ref>{{Cite journal|last=Stengel|first=Anna|last2=Kern|first2=Wolfgang|last3=Zenger|first3=Melanie|last4=Perglerová|first4=Karolína|last5=Schnittger|first5=Susanne|last6=Haferlach|first6=Torsten|last7=Haferlach|first7=Claudia|date=2016-01|title=Genetic characterization of T-PLL reveals two major biologic subgroups and JAK3 mutations as prognostic marker|url=https://pubmed.ncbi.nlm.nih.gov/26493028|journal=Genes, Chromosomes & Cancer|volume=55|issue=1|pages=82–94|doi=10.1002/gcc.22313|issn=1098-2264|pmid=26493028}}</ref>
 +
|}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==
 
==Epigenomic Alterations==
−
 
+
Research indicates that epigenetic modifications in the regulatory regions of key oncogenes and genes involved in DNA damage response and T-cell receptor regulation are clearly present. These changes are closely associated with the transcriptional dysregulation that forms the core lesions of T-PLL.<ref>{{Cite journal|last=Tian|first=Shulan|last2=Zhang|first2=Henan|last3=Zhang|first3=Pan|last4=Kalmbach|first4=Michael|last5=Lee|first5=Jeong-Heon|last6=Ordog|first6=Tamas|last7=Hampel|first7=Paul J.|last8=Call|first8=Timothy G.|last9=Witzig|first9=Thomas E.|date=2021-04-15|title=Epigenetic alteration contributes to the transcriptional reprogramming in T-cell prolymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/33859327|journal=Scientific Reports|volume=11|issue=1|pages=8318|doi=10.1038/s41598-021-87890-9|issn=2045-2322|pmc=8050249|pmid=33859327}}</ref>
−
Put your text here
 
−
 
 
 
==Genes and Main Pathways Involved==
 
==Genes and Main Pathways Involved==
−
 
+
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Can include references in the table. Do not delete table.'')</span>
−
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Can include references in the table.'')</span>
 
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
 
|-
 
|-
 
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
 
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
 
|-
 
|-
−
|EXAMPLE: BRAF and MAP2K1; Activating mutations
+
|''TCL1A/B rearrangement''
−
|EXAMPLE: MAPK signaling
+
|''AKT'' signaling and TCR signal amplification pathways
−
|EXAMPLE: Increased cell growth and proliferation
+
|Increased cell survival and proliferation
 
|-
 
|-
−
|EXAMPLE: CDKN2A; Inactivating mutations
+
|''MTCP1''
−
|EXAMPLE: Cell cycle regulation
+
|''AKT'' signaling and TCR signal amplification pathways
−
|EXAMPLE: Unregulated cell division
+
|Increased cell survival and proliferation
 
|-
 
|-
−
|EXAMPLE:  KMT2C and ARID1A; Inactivating mutations
+
|''ATM, CHEK2''
−
|EXAMPLE:  Histone modification, chromatin remodeling
+
|DNA damage repair pathway
−
|EXAMPLE:  Abnormal gene expression program
+
|Genomic instability
 +
|-
 +
|''JAK1, JAK3, STAT5B''
 +
|''JAK-STAT'' pathway
 +
|Unchecked cell growth and survival
 +
|-
 +
|''IL2RG''
 +
|''JAK-STAT'' pathway, Cytokine signaling
 +
|Promoting lymphocyte proliferation
 +
|-
 +
|''EZH2''
 +
|Transcription regulator
 +
|Altering the epigenetic landscape
 
|}
 
|}
 
==Genetic Diagnostic Testing Methods==
 
==Genetic Diagnostic Testing Methods==
−
 
+
Cytogenetics (FISH, CpG-stimulated Karyotype, SNP microarray), PCR for TRB/TRG and Next-Generation Sequencing (NGS). The genetic diagnostic process involves detecting clonal rearrangements of the TR gene and rearrangements of the TCL1 gene at the TRB or TRG loci.
−
Put your text here
 
−
 
 
 
==Familial Forms==
 
==Familial Forms==
−
 
+
There is no noticeable familial clustering. However, a subset of cases may develop in the context of ataxia-telangiectasia (AT), which is characterized by germline mutations in the ATM gene.  Here there is a combined heterozygosity in the form of biallelic inactivating mutations of the ''ATM'' tumor suppressor gene.<ref>{{Cite journal|last=Suarez|first=Felipe|last2=Mahlaoui|first2=Nizar|last3=Canioni|first3=Danielle|last4=Andriamanga|first4=Chantal|last5=Dubois d'Enghien|first5=Catherine|last6=Brousse|first6=Nicole|last7=Jais|first7=Jean-Philippe|last8=Fischer|first8=Alain|last9=Hermine|first9=Olivier|date=2015-01-10|title=Incidence, presentation, and prognosis of malignancies in ataxia-telangiectasia: a report from the French national registry of primary immune deficiencies|url=https://pubmed.ncbi.nlm.nih.gov/25488969|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=33|issue=2|pages=202–208|doi=10.1200/JCO.2014.56.5101|issn=1527-7755|pmid=25488969}}</ref> Penetrance of the tumor phenotype is about 10% to 15% by early adulthood.<ref>{{Cite journal|last=Taylor|first=A. M.|last2=Metcalfe|first2=J. A.|last3=Thick|first3=J.|last4=Mak|first4=Y. F.|date=1996-01-15|title=Leukemia and lymphoma in ataxia telangiectasia|url=https://pubmed.ncbi.nlm.nih.gov/8555463|journal=Blood|volume=87|issue=2|pages=423–438|issn=0006-4971|pmid=8555463}}</ref> It represents nearly 3% of all malignancies in patients with ataxia-telangiectasia.<ref>{{Cite journal|last=Li|first=Geling|last2=Waite|first2=Emily|last3=Wolfson|first3=Julie|date=2017-12-26|title=T-cell prolymphocytic leukemia in an adolescent with ataxia-telangiectasia: novel approach with a JAK3 inhibitor (tofacitinib)|url=https://pubmed.ncbi.nlm.nih.gov/29296924|journal=Blood Advances|volume=1|issue=27|pages=2724–2728|doi=10.1182/bloodadvances.2017010470|issn=2473-9529|pmc=5745136|pmid=29296924}}</ref>
−
Put your text here <span style="color:#0070C0">(''Instructions: Include associated hereditary conditions/syndromes that cause this entity or are caused by this entity.'') </span>
 
−
 
 
 
==Additional Information==
 
==Additional Information==
−
 
+
In T-PLL, the rapid growth of the disease necessitates immediate initiation of treatment. The most effective first-line treatment is alemtuzumab, an anti-CD52 antibody with remission rates over 80%. However, these remissions usually last only 1-2 years. To potentially extend remission, eligible patients are advised to undergo allogeneic blood stem cell transplantation (allo-SCT) during their first complete remission, which can lead to longer remission durations of over 4-5 years for 15-30% of patients. Consequently, the prognosis for T-PLL remains poor, with median overall survival times under two years and five-year survival rates below 5%[https://clinicaltrials.gov/study/NCT03989466 . Ongoing research is exploring molecularly targeted drugs and signaling pathway inhibitors, for routine clinical use in treating T-PLL.]
−
Put your text here
 
−
 
 
 
==Links==
 
==Links==
−
 
+
(use the "Link" icon that looks like two overlapping circles at the top of the page) <span style="color:#0070C0">(''Instructions: Highlight text to which you want to add a link in this section or elsewhere, select the "Link" icon at the top of the page, and search the name of the internal page to which you want to link this text, or enter an external internet address by including the "<nowiki>http://www</nowiki>." portion.'')</span>
−
Put your text placeholder here (or anywhere appropriate on the page) and use the "Link" icon at the top of the page <span style="color:#0070C0">(''Instructions: Once you have a text placeholder entered to which you want to add a link, highlight that text, select the "Link" icon at the top of the page, and search the name of the internal page to which you want to link this text, or enter an external internet address including the "<nowiki>http://www</nowiki>." portion.'')</span>
 
−
 
 
 
==References==
 
==References==
−
(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking on where you want to insert the reference, selecting the “Cite” icon at the top of the page, and using the “Automatic” tab option to search such as by PMID to select the reference to insert. The reference list in this section will be automatically generated and sorted.''</span> <span style="color:#0070C0">''If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">) </span> <references />
+
<references />
−
 
+
==Notes==
−
'''EXAMPLE Book'''
+
<nowiki>*</nowiki>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.
−
 
 
−
#Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p129-171.
 
  
−
==Notes==
+
[[Category:HAEM5]]
−
<nowiki>*</nowiki>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.
+
[[Category:DISEASE]]
−
<nowiki>*</nowiki>''Citation of this Page'': “T-prolymphocytic leukaemia”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:T-prolymphocytic_leukaemia</nowiki>.
+
[[Category:Diseases T]]
−
[[Category:HAEM5]][[Category:DISEASE]][[Category:Diseases T]]
+
<references />

Latest revision as of 20:11, 30 May 2024


Haematolymphoid Tumours (5th ed.)

(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column to a table, click nearby within the table and select the > symbol that appears to be given options. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support)

Primary Author(s)*

Parastou Tizro, MD, Celeste Eno, PHD, Sumire Kitahara, MD

WHO Classification of Disease

(Will be autogenerated; Book will include name of specific book and have a link to the online WHO site)

Structure Disease
Book
Category
Family
Type
Subtype(s)

Definition / Description of Disease

T-prolymphocytic leukemia (T-PLL) is an aggressive form of T-cell leukemia marked by the proliferation of small to medium-sized prolymphocytes exhibiting a mature post-thymic T-cell phenotype. This condition is characterized by the juxtaposition of TCL1A or MTCP1 genes to a TR locus, typically the TRA/TRD locus.

Synonyms / Terminology

T-cell chronic lymphocytic leukemia

Epidemiology / Prevalence

T-PLL is a rare disorder, comprising about 2% of all mature lymphoid leukemia cases in adults. It primarily occurs in the elderly, with a median age of 65 years (ranging from 30 to 94 years) and shows a slight male predominance with a male to female ratio of 1.33:1.

Clinical Features

The most prevalent symptom of the disease is a leukemic presentation, characterized by a rapid, exponential increase in lymphocyte counts, which exceed 100 × 10^9/L in 75% of patients. Approximately 30% of patients may initially experience an asymptomatic, slow-progressing phase, but this typically develops into an active disease state.

Signs and Symptoms B symptoms (Fever, night sweats, weight loss)

Hepatosplenomegaly (Frequently observed)

Generalized lymphadenopathy with slightly enlarged lymph nodes (Frequently observed)

Cutaneous involvement (20%)

Malignant effusions (15%)

Asymptomatic and indolent phase (30% of cases)

Laboratory Findings Anemia and thrombocytopenia

Marked lymphocytosis > 100 × 10^9/L (75% of cases)

Atypical lymphocytosis > 5 × 10^9/L

Serum lactate dehydrogenase (LDH) (increased-may reflect disease burden)

β 2 microglobulin (B2M) (increased-may reflect disease burden)

Sites of Involvement

Peripheral blood, bone marrow, spleen (mostly red pulp), liver, lymph node (mostly paracortical), and sometimes skin and serosa (primarily pleura). Extra lymphatic and extramedullary atypical manifestations including skin, muscles and intestines are particularly common in relapse.

Morphologic Features

Blood smears in T-PLL typically reveal anemia, thrombocytopenia, and leukocytosis, with atypical lymphocytes in three morphological forms. The most common form (75% of cases) features medium-sized cells with a high nuclear-to-cytoplasmic ratio, moderately condensed chromatin, a single visible nucleolus, and slightly basophilic cytoplasm. In 20% of cases, the cells appear as a small cell variant with densely condensed chromatin and an inconspicuous nucleolus. About 5% of cases exhibit a cerebriform variant with irregular nuclei resembling those in mycosis fungoides. Regardless of the nuclear features, a common morphological characteristic is the presence of cytoplasmic protrusions or blebs.[1] Bone marrow aspirates show clusters of these neoplastic cells, with a mixed pattern of involvement including diffuse and interstitial, in trephine core biopsy.

Immunophenotype

T-cell prolymphocytes show strong staining with alpha-naphthyl acetate esterase and acid phosphatase, presenting a distinctive dot-like pattern, but cytochemistry is not commonly used for diagnosis.

Finding Marker
Positive (universal) cyTCL1 (highest specificity), CD2, CD3 (may be weak), CD5, CD7 (strong), TCR-α/β, S100 (30% of cases)
Positive (subset) CD4 (in some cases CD4+/CD8+ or CD4-/CD8+), CD52 (therapeutic target), activation markers are variable (CD25, CD38, CD43, CD26, CD27)
Negative (universal) TdT, CD1a, CD57, CD16, HTLV1
Negative (subset) CD8 (in some cases CD4+/CD8+ or CD4-/CD8+)

Chromosomal Rearrangements (Gene Fusions)

Rearrangements involving the TCL1 (T-cell leukemia/lymphoma1) family genes—TCL1A, MTCP1 (mature T-cell proliferation), or TCL1B (also known as TCL1/MTCP1-like 1 [TML1])—are relatively specific to T-PLL. These are present in more than 90% of cases, either as inv(14)(q11q32) or t(14;14)(q11;q32) (involving TCL1A or TCL1B), or t(X;14)(q28;q11) (involving MTCP1). T-PLL-ISG).

Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
inv(14)(q11.2q32.1)

t(14;14)(q11.2;q32.1)

TCL1A/B ,TRD inv(14) ~60%

t(14;14) ~25%

Yes Yes Yes These genetic abnormalities serve as diagnostic markers and generally indicate an aggressive disease. This is due to their role in overexpressing oncogenes like TCL1A.
t(X;14)(q28;q11.2) MTCP1, TRD Low (5%) Yes

Individual Region Genomic Gain / Loss / LOH

Approximately 70-80% of T-PLL karyotypes are complex, which is considered minor diagnostic criteria, and usually include 3-5 or more structural aberrations. Common cytogenetic abnormalities include those of chromosome 8, such as idic(8)(p11.2), t(8;8)(p11.2;q12), and trisomy 8q. Other frequent changes are deletions in 12p13 and 22q, gains in 8q24 (MYC), and abnormalities in chromosomes 5p, 6, and 17.

Chr # Gain / Loss / Amp / LOH Minimal Region Genomic Coordinates [Genome Build] Minimal Region Cytoband Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
8 Gain idic(8)(p11)

t(8;8)(p11;q12)

trisomy 8q
8q24 (MYC)

idic(8)(p11.2)

t(8;8)(p11.2;q12)

trisomy 8q
8q24 (MYC)

Yes No No Recurrent secondary finding (70-80% of cases). Minor diagnostic criteria. [2]
5 Abnormality 5p, 5q[3] Yes Yes No Minor diagnostic criteria
6 Abnormality 6p No
11 Loss 11q ch11q21-q23.3 Yes Yes Yes Frequent, Minor diagnostic criteria.
12 Loss 12p 12p13 Yes Minor diagnostic criteria
13 Loss 13q 13q14.3 Yes Minor diagnostic criteria
17 Abnormality 17p, 17q 17p13 Yes Yes (resistance to therapy)
22 Loss Monosomy 22

del(22q)


22q11-12 [4][5]

(most common)

Leading to the dysregulation of genes such as BCL11B, which is crucial in T-cell development and function.[5]

Minor diagnostic criteria

Characteristic Chromosomal Patterns


Chromosomal Pattern Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
inv(14)(q11q32)

t(14;14)(q11.2;q32.1)

Yes Yes Yes EXAMPLE:

See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).

Gene Mutations (SNV / INDEL)

Put your text here and fill in the table (Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent and common as well either disease defining and/or clinically significant. Can include references in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Do not delete table.)

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
ATM TSG 53% (COSMIC) ATM mutation/deletion None specified Yes Yes Yes (PARP inhibitors, NCT03263637) Deletions of or missense mutations at the ATM locus are found in up to 80% to 90% of T-PLL cases. (T-PLL-ISG).
FBXW10 TSG 72% (COSMIC) JAK/STAT pathway None specified Unknown Unknown Unknown
IL2RG, JAK1, JAK3, STAT5B Oncogene 8% JAK1

34% JAK3

16% STAT5B

2% IL2RG

(COSMIC)

ATM, TP53, Epigenetic modifiers [6][7] Typically, mutations within this pathway occur in a mutually exclusive manner.[8] Yes Yes The cumulative prevalence of these mutations in T-PLL is approximately 60%. (Dr jaffe book)
EZH2 Oncogene, TSG 16% (COSMIC) JAK/STAT pathway[6][7] None specified No Yes See note EZH2 inhibitors like tazemetostat have shown efficacy in other hematologic malignancies, providing a rationale for their potential use in T-PLL
BCOR TSG 8% (COSMIC) JAK/STAT pathway[6][7] None specified No Yes Yes??
SAMHD1 TSG ~7-20%[9][10] None specified Yes SAMHD1 mutations may indicate a defective DNA damage response and aggressive disease [9]
CHEK2 TSG 5% (COSMIC) ATM, TP53, JAK/STAT pathway, Epigenetic modifiers None specified No Yes No CHEK2 mutations may indicate a defective DNA damage response and aggressive disease [8][11]
TP53 TSG 2% (COSMIC) ATM, JAK/STAT pathway, Epigenetic modifiers None specified No Yes Associated with resistance to therapy Mutations in TP53 are less frequent than deletions[12]

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

Research indicates that epigenetic modifications in the regulatory regions of key oncogenes and genes involved in DNA damage response and T-cell receptor regulation are clearly present. These changes are closely associated with the transcriptional dysregulation that forms the core lesions of T-PLL.[13]

Genes and Main Pathways Involved

Put your text here and fill in the table (Instructions: Can include references in the table. Do not delete table.)

Gene; Genetic Alteration Pathway Pathophysiologic Outcome
TCL1A/B rearrangement AKT signaling and TCR signal amplification pathways Increased cell survival and proliferation
MTCP1 AKT signaling and TCR signal amplification pathways Increased cell survival and proliferation
ATM, CHEK2 DNA damage repair pathway Genomic instability
JAK1, JAK3, STAT5B JAK-STAT pathway Unchecked cell growth and survival
IL2RG JAK-STAT pathway, Cytokine signaling Promoting lymphocyte proliferation
EZH2 Transcription regulator Altering the epigenetic landscape

Genetic Diagnostic Testing Methods

Cytogenetics (FISH, CpG-stimulated Karyotype, SNP microarray), PCR for TRB/TRG and Next-Generation Sequencing (NGS). The genetic diagnostic process involves detecting clonal rearrangements of the TR gene and rearrangements of the TCL1 gene at the TRB or TRG loci.

Familial Forms

There is no noticeable familial clustering. However, a subset of cases may develop in the context of ataxia-telangiectasia (AT), which is characterized by germline mutations in the ATM gene. Here there is a combined heterozygosity in the form of biallelic inactivating mutations of the ATM tumor suppressor gene.[14] Penetrance of the tumor phenotype is about 10% to 15% by early adulthood.[15] It represents nearly 3% of all malignancies in patients with ataxia-telangiectasia.[16]

Additional Information

In T-PLL, the rapid growth of the disease necessitates immediate initiation of treatment. The most effective first-line treatment is alemtuzumab, an anti-CD52 antibody with remission rates over 80%. However, these remissions usually last only 1-2 years. To potentially extend remission, eligible patients are advised to undergo allogeneic blood stem cell transplantation (allo-SCT) during their first complete remission, which can lead to longer remission durations of over 4-5 years for 15-30% of patients. Consequently, the prognosis for T-PLL remains poor, with median overall survival times under two years and five-year survival rates below 5%. Ongoing research is exploring molecularly targeted drugs and signaling pathway inhibitors, for routine clinical use in treating T-PLL.

Links

(use the "Link" icon that looks like two overlapping circles at the top of the page) (Instructions: Highlight text to which you want to add a link in this section or elsewhere, select the "Link" icon at the top of the page, and search the name of the internal page to which you want to link this text, or enter an external internet address by including the "http://www." portion.)

References

  1. ↑ Eichhorn, G. L. (1979-02). "Aging, genetics, and the environment: potential of errors introduced into genetic information transfer by metal ions". Mechanisms of Ageing and Development. 9 (3–4): 291–301. doi:10.1016/0047-6374(79)90106-4. ISSN 0047-6374. PMID 374897. Check date values in: |date= (help)
  2. ↑ Staber, Philipp B.; et al. (2019-10-03). "Consensus criteria for diagnosis, staging, and treatment response assessment of T-cell prolymphocytic leukemia". Blood. 134 (14): 1132–1143. doi:10.1182/blood.2019000402. ISSN 1528-0020. PMC 7042666 Check |pmc= value (help). PMID 31292114.
  3. ↑ Tirado, Carlos A.; et al. (2012-08-20). ""T-cell prolymphocytic leukemia (T-PLL), a heterogeneous disease exemplified by two cases and the important role of cytogenetics: a multidisciplinary approach"". Experimental Hematology & Oncology. 1 (1): 21. doi:10.1186/2162-3619-1-21. ISSN 2162-3619. PMC 3514161. PMID 23211026.
  4. ↑ Stengel, Anna; et al. (2014-12-06). "A Comprehensive Cytogenetic and Molecular Genetic Characterization of Patients with T-PLL Revealed Two Distinct Genetic Subgroups and JAK3 Mutations As an Important Prognostic Marker". Blood. 124 (21): 1639–1639. doi:10.1182/blood.v124.21.1639.1639. ISSN 0006-4971.
  5. ↑ 5.0 5.1 Fang, Hong; et al. (2023-09). "T-prolymphocytic leukemia: TCL1 or MTCP1 rearrangement is not mandatory to establish diagnosis". Leukemia. 37 (9): 1919–1921. doi:10.1038/s41375-023-01956-3. ISSN 1476-5551. PMID 37443196 Check |pmid= value (help). Check date values in: |date= (help)
  6. ↑ 6.0 6.1 6.2 Andersson, E. I.; et al. (2018-03). "Discovery of novel drug sensitivities in T-PLL by high-throughput ex vivo drug testing and mutation profiling". Leukemia. 32 (3): 774–787. doi:10.1038/leu.2017.252. ISSN 1476-5551. PMID 28804127. Check date values in: |date= (help)
  7. ↑ 7.0 7.1 7.2 Pinter-Brown, Lauren C. (2021-12-30). "JAK/STAT: a pathway through the maze of PTCL?". Blood. 138 (26): 2747–2748. doi:10.1182/blood.2021014238. ISSN 0006-4971.
  8. ↑ 8.0 8.1 Kiel, Mark J.; et al. (2014-08-28). "Integrated genomic sequencing reveals mutational landscape of T-cell prolymphocytic leukemia". Blood. 124 (9): 1460–1472. doi:10.1182/blood-2014-03-559542. ISSN 1528-0020. PMC 4148768. PMID 24825865.
  9. ↑ 9.0 9.1 Johansson, Patricia; et al. (2018-01-19). "SAMHD1 is recurrently mutated in T-cell prolymphocytic leukemia". Blood Cancer Journal. 8 (1): 11. doi:10.1038/s41408-017-0036-5. ISSN 2044-5385. PMC 5802577. PMID 29352181.
  10. ↑ Schrader, A.; et al. (2018-02-15). "Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL". Nature Communications. 9 (1): 697. doi:10.1038/s41467-017-02688-6. ISSN 2041-1723. PMC 5814445. PMID 29449575.
  11. ↑ Braun, Till; et al. (2021). "Advanced Pathogenetic Concepts in T-Cell Prolymphocytic Leukemia and Their Translational Impact". Frontiers in Oncology. 11: 775363. doi:10.3389/fonc.2021.775363. ISSN 2234-943X. PMC 8639578 Check |pmc= value (help). PMID 34869023 Check |pmid= value (help).
  12. ↑ Stengel, Anna; et al. (2016-01). "Genetic characterization of T-PLL reveals two major biologic subgroups and JAK3 mutations as prognostic marker". Genes, Chromosomes & Cancer. 55 (1): 82–94. doi:10.1002/gcc.22313. ISSN 1098-2264. PMID 26493028. Check date values in: |date= (help)
  13. ↑ Tian, Shulan; et al. (2021-04-15). "Epigenetic alteration contributes to the transcriptional reprogramming in T-cell prolymphocytic leukemia". Scientific Reports. 11 (1): 8318. doi:10.1038/s41598-021-87890-9. ISSN 2045-2322. PMC 8050249 Check |pmc= value (help). PMID 33859327 Check |pmid= value (help).
  14. ↑ Suarez, Felipe; et al. (2015-01-10). "Incidence, presentation, and prognosis of malignancies in ataxia-telangiectasia: a report from the French national registry of primary immune deficiencies". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 33 (2): 202–208. doi:10.1200/JCO.2014.56.5101. ISSN 1527-7755. PMID 25488969.
  15. ↑ Taylor, A. M.; et al. (1996-01-15). "Leukemia and lymphoma in ataxia telangiectasia". Blood. 87 (2): 423–438. ISSN 0006-4971. PMID 8555463.
  16. ↑ Li, Geling; et al. (2017-12-26). "T-cell prolymphocytic leukemia in an adolescent with ataxia-telangiectasia: novel approach with a JAK3 inhibitor (tofacitinib)". Blood Advances. 1 (27): 2724–2728. doi:10.1182/bloodadvances.2017010470. ISSN 2473-9529. PMC 5745136. PMID 29296924.

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