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<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>
<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<span style="color:#0070C0"> </span>
Parastou Tizro, MD, Celeste Eno, PHD, Sumire Kitahara, MD
==WHO Classification of Disease==
==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>
<span style="color:#0070C0">(Will be autogenerated; Book will include name of specific book and have a link to the online WHO site)</span>
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.
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==
==Synonyms / Terminology==
T-cell chronic lymphocytic leukemia
==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.
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==
==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
{| class="wikitable"
{| class="wikitable"
|'''Signs and Symptoms'''
|'''Signs and Symptoms'''
|Hepatosplenomegaly (Frequently observed)
|B symptoms (Fever, night sweats, weight loss)
Hepatosplenomegaly (Frequently observed)
Generalized lymphadenopathy with slightly enlarged lymph nodes (Frequently observed
Generalized lymphadenopathy with slightly enlarged lymph nodes (Frequently observed
|-
|-
|'''Laboratory Findings'''
|'''Laboratory Findings'''
|Anaemia and thrombocytopenia
|Anemia and thrombocytopenia
Marked lymphocytosis > 100 × 10^9/L (75% of cases)
Marked lymphocytosis > 100 × 10^9/L (75% of cases)
Atypical lymphocytosis > 5 × 10^9/L
|}
|}
==Sites of Involvement==
==Sites of Involvement==
Peripheral blood, bone marrow, spleen, liver, lymph node, and sometimes skin and serosa
Peripheral blood, bone marrow, spleen, liver, lymph node, and sometimes skin and serosa. Extra lymphatic and extramedullary atypical manifestations including skin, muscles and intestines are particularly common in relapse.
==Morphologic Features==
==Morphologic Features==
Blood smears display anemia, thrombocytopenia, and leukocytosis, predominantly of atypical lymphocytes. Bone marrow aspirates show aggregates of neoplastic lymphoid cells.
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 with characteristic cytoplasmic blebs. 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.<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.
==Immunophenotype==
==Immunophenotype==
Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table. Do not delete table.'') </span>
Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table. Do not delete table.'') </span>
!Finding!!Marker
!Finding!!Marker
|-
|-
|Positive (universal)||CD2, CD3 (may be weak), CD5, CD7
|Positive (universal)||cyTCL1(highest specificity), CD2, CD3 (may be weak), CD5, CD7 (strong), TCR-α/β
|-
|-
|Positive (subset)||CD4 (in some cases CD4+/CD8+ or CD4-/CD8+), CD52
|Positive (subset)||CD4 (in some cases CD4+/CD8+ or CD4-/CD8+), CD52, activation markers are variable (CD25, CD38, CD43, CD26, CD27)
|-
|-
|Negative (universal)||TdT, CD1a
|Negative (universal)||TdT, CD1a, CD57, CD16
|-
|-
|Negative (subset)||CD8 (in some cases CD4+/CD8+ or CD4-/CD8+)
|Negative (subset)||CD8 (in some cases CD4+/CD8+ or CD4-/CD8+)
!Notes
!Notes
|-
|-
|t(14;14)(q11;q32)
|inv(14)(q11q32)
|TCL1A/TRD||<span class="blue-text">EXAMPLE:</span> der(22)||<span class="blue-text">EXAMPLE:</span> 20% (COSMIC)
t(14;14)(q11;q32)
|TCL1A/TRD|| ||inv(14) ~60%
t(14;14) ~25%
|Yes
|Yes
|Yes
|Yes
|Yes
|<span class="blue-text">EXAMPLE:</span>
|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)
|t(X;14)(q28;q11.2)
|}
|}
==Individual Region Genomic Gain / Loss / LOH==
==Individual Region Genomic Gain / Loss / LOH==
Approximately, 70-80% of T-PLL karyotypes are complex, typically containing 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.
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
t(8;8)(p11.2;q12)
t(8;8)(p11.2;q12)
trisomy 8q<br />
trisomy 8q<br />8q24 (''MYC'')
|chr8
|chr8
|Yes
|No
|No
|No
|No
|No
|Recurrent secondary finding <ref>{{Cite journal|last=Matutes|first=E.|last2=Brito-Babapulle|first2=V.|last3=Swansbury|first3=J.|last4=Ellis|first4=J.|last5=Morilla|first5=R.|last6=Dearden|first6=C.|last7=Sempere|first7=A.|last8=Catovsky|first8=D.|date=1991-12-15|title=Clinical and laboratory features of 78 cases of T-prolymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/1742486|journal=Blood|volume=78|issue=12|pages=3269–3274|issn=0006-4971|pmid=1742486}}</ref>
|-
|11
|Loss
|11q23.3
|ch11
|Yes
|Yes
|Yes
|Frequent
|-
|-
|5
|
|
|
|
|
|
|
|
|
|
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|-
|14
|Loss
|14q
|chr14
|
|
|
|In approximately (37%)
|-
|12
|Loss
|12p13
|chr12
|
|
|
|
|-
|-
|inv(14)(q11q32)
|inv(14)(q11q32)
|<span class="blue-text">EXAMPLE:</span> Yes
|Yes
|<span class="blue-text">EXAMPLE:</span> No
|<span class="blue-text">EXAMPLE:</span> No
|<span class="blue-text">EXAMPLE:</span> No
|<span class="blue-text">EXAMPLE:</span> No
|
|
|-
|-
|TCL1A
|ATM
|Oncogene
|TSG
|
|
|ATM mutations
|ATM mutations
|
|
|-
|-
|''EZH2''
|
|
|
|
|
|
|
|
|
|-
|''FBXW10''
|
|
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|
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|
|
|
|-
|''CHEK2''
|
|
|
|
|
|
|-
|-
|''JAK1, JAK3, STAT5B''
|Oncogene
|
|
|
|
|
|
|
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|-
|''IL2RG''
|
|
|
|
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''BRAF'' and ''MAP2K1''; Activating mutations
|''TCL1A rearrangement''
|''AKT'' signaling and TCR signal amplification pathways
|<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation
|Increased cell survival and proliferation
|-
|-
|TCL1A
|''MTCP1''
|T-cell signaling
|''AKT'' signaling and TCR signal amplification pathways
|Increased cell survival and proliferation
|Increased cell survival and proliferation
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''KMT2C'' and ''ARID1A''; Inactivating mutations
|''ATM, CHEK2''
|<span class="blue-text">EXAMPLE:</span> Histone modification, chromatin remodeling
|DNA damage repair pathway
|<span class="blue-text">EXAMPLE:</span> Abnormal gene expression program
|Genomic instability
|-
|''JAK1, JAK3, STAT5B''
|''JAK-STAT'' pathway
|Unchecked cell growth and survival
|-
|''IL2RG''
|Cytokine signaling
|Promoting lymphocyte proliferation
|-
|''EZH2''
|Transcription regulator
|Altering the epigenetic landscape
|}
|}
==Genetic Diagnostic Testing Methods==
==Genetic Diagnostic Testing Methods==
The genetic diagnostic process involves detecting clonal rearrangements of the TR gene and rearrangements of the TCL1 gene at the TRB or TRG loci.
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==
==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>
==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.]
==Links==
==Links==
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