Changes

t(14;14) ~25%

t(14;14) ~25%

|Yes

|Yes

|Yes

|No

|Yes (although not established as a therapeutic marker, it associated with poor response to conventional chemotherapy)

|No

|These genetic abnormalities serve as diagnostic markers and generally indicate an aggressive disease. This is due to their role in overexpressing oncogenes like ''TCL1A''. '''Major diagnostic criteria'''.<ref name=":6" />

|These genetic abnormalities serve as diagnostic markers and generally indicate an aggressive disease. This is due to their role in overexpressing oncogenes like ''TCL1A''. '''Major diagnostic criteria'''.<ref name=":6" />

|-

|-

|Yes

|Yes

|No

|No

|Yes (although not established as a therapeutic marker, it associated with poor response to conventional chemotherapy)

|No

|'''Major diagnostic criteria'''.<ref name=":6" />

|'''Major diagnostic criteria'''.<ref name=":6" />

|}

|}

|Yes

|Yes

|Yes

|Yes

|Yes

|Yes (poor

|Frequent, '''Minor diagnostic criteria'''.<ref name=":6" />

|Frequent, '''Minor diagnostic criteria'''.<ref name=":6" />

|-

|-

|Yes

|Yes

|No

|No

|Haploinsufficiency of the CDKN1B gene at the 12p13 locus contributes to the development of T-PLL.<ref>{{Cite journal|last=Le Toriellec|first=Emilie|last2=Despouy|first2=Gilles|last3=Pierron|first3=Gaëlle|last4=Gaye|first4=Nogaye|last5=Joiner|first5=Marjorie|last6=Bellanger|first6=Dorine|last7=Vincent-Salomon|first7=Anne|last8=Stern|first8=Marc-Henri|date=2008-02-15|title=Haploinsufficiency of CDKN1B contributes to leukemogenesis in T-cell prolymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/18073348|journal=Blood|volume=111|issue=4|pages=2321–2328|doi=10.1182/blood-2007-06-095570|issn=0006-4971|pmid=18073348}}</ref>

|Haploinsufficiency of the ''CDKN1B'' gene at the 12p13 locus contributes to the development of T-PLL.<ref>{{Cite journal|last=Le Toriellec|first=Emilie|last2=Despouy|first2=Gilles|last3=Pierron|first3=Gaëlle|last4=Gaye|first4=Nogaye|last5=Joiner|first5=Marjorie|last6=Bellanger|first6=Dorine|last7=Vincent-Salomon|first7=Anne|last8=Stern|first8=Marc-Henri|date=2008-02-15|title=Haploinsufficiency of CDKN1B contributes to leukemogenesis in T-cell prolymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/18073348|journal=Blood|volume=111|issue=4|pages=2321–2328|doi=10.1182/blood-2007-06-095570|issn=0006-4971|pmid=18073348}}</ref>

'''Minor diagnostic criteria'''.<ref name=":6" />

'''Minor diagnostic criteria'''.<ref name=":6" />

|-

|-

|Yes

|Yes

|Yes (resistance to therapy)

|Yes (resistance to therapy)

|May include TP53 gene at 17p13.1. <ref name=":7" />

|May include ''TP53'' gene at 17p13.1 <ref name=":7" />

|-

|-

|22

|22

|No

|No

|No

|No

|Leading to the dysregulation of genes such as BCL11B, which is crucial in T-cell development and function.<ref name=":0" />

|Leading to the dysregulation of genes such as ''BCL11B'', which is crucial in T-cell development and function.<ref name=":0" />

'''Minor diagnostic criteria'''.<ref name=":6" />

'''Minor diagnostic criteria'''.<ref name=":6" />

|}

|}

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

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

|Yes

|Yes

|Yes

|No

|Yes

|No

|The most common chromosomal abnormality in T-PLL involves an inversion of chromosome 14, with breakpoints at q11.2 and q32.1, observed in about 60-80% of patients and described as inv(14). Additionally, in 10-20% of cases, there is a translocation t(14;14)(q11.2;q32.1)

|The most common chromosomal abnormality in T-PLL involves an inversion of chromosome 14, with breakpoints at q11.2 and q32.1, observed in about 60-80% of patients and described as inv(14). Additionally, in 10-20% of cases, there is a translocation t(14;14)(q11.2;q32.1)

|}

|}

==Gene Mutations (SNV / INDEL)==

==Gene Mutations (SNV / INDEL)==

Although gene mutations beyond TCL1 family alterations are not yet recognized as diagnostic criteria and remain under investigation for T-PLL, the mutational landscape of T-PLL provides valuable insights. These discoveries open up potential avenues for novel targeted therapies in treating this aggressive form of leukemia.  

Although gene mutations beyond ''TCL1'' family alterations are not yet recognized as diagnostic criteria and remain under investigation for T-PLL, the mutational landscape of T-PLL provides valuable insights. These discoveries open up potential avenues for novel targeted therapies in treating this aggressive form of leukemia.  

Deletions and mutations of the ATM gene (present in up to 90% of T-PLL cases but typically absent in other mature T-cell malignancies) are considered highly indicative for a diagnosis of suspected TCL1 family-negative T-PLL.<ref name=":8">{{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><ref name=":3" />

Deletions and mutations of the ATM gene (present in up to 90% of T-PLL cases but typically absent in other mature T-cell malignancies) are considered highly indicative for a diagnosis of suspected TCL1 family-negative T-PLL.<ref name=":8">{{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><ref name=":3" />

|-

|-

|''EZH2''

|''EZH2''

|Oncogene, TSG

|Both oncogene and TSG

|16% (COSMIC)

|16% (COSMIC)

|''JAK/STAT'' pathway<ref name=":1" /><ref name=":2" />

|''JAK/STAT'' pathway<ref name=":1" /><ref name=":2" />

|None specified

|None specified

|No

|No

|Yes

|No (see note)

|See note

|See note

|''EZH2'' inhibitors like tazemetostat have shown efficacy in other hematologic malignancies, providing a rationale for their potential use in T-PLL

|''EZH2'' inhibitors like tazemetostat have shown efficacy in other hematologic malignancies, providing a rationale for their potential use in T-PLL

|}

|}

==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.

Diagnosing T-PLL involves a combination of clinical evaluation, laboratory tests, imaging studies, and genetic testing to identify diagnostic criteria. T-cell clonality can be confirmed through PCR, NGS, or flow cytometry.<ref>{{Cite journal|last=Kotrova|first=Michaela|last2=Novakova|first2=Michaela|last3=Oberbeck|first3=Sebastian|last4=Mayer|first4=Petra|last5=Schrader|first5=Alexandra|last6=Knecht|first6=Henrik|last7=Hrusak|first7=Ondrej|last8=Herling|first8=Marco|last9=Brüggemann|first9=Monika|date=2018-11|title=Next-generation amplicon TRB locus sequencing can overcome limitations of flow-cytometric Vβ expression analysis and confirms clonality in all T-cell prolymphocytic leukemia cases|url=https://pubmed.ncbi.nlm.nih.gov/30414304|journal=Cytometry. Part A: The Journal of the International Society for Analytical Cytology|volume=93|issue=11|pages=1118–1124|doi=10.1002/cyto.a.23604|issn=1552-4930|pmid=30414304}}</ref> Patients with T-PLL often exhibit complex karyotypes with recurrent genetic features that aid in diagnosis. Therefore, cytogenetic studies are useful for distinguishing T-PLL from other T-lymphoproliferative disorders.<ref name=":6" />

 

 

# Karyotyping: To identify characteristic chromosomal abnormalities, such as inv(14)(q11q32), t(14;14)(q11;q32), or other translocations involving chromosome 14. '''Major diagnostic criteria'''

# Fluorescence In Situ Hybridization (FISH): To detect specific genetic abnormalities, such as TCL1 gene rearrangements as a '''Major diagnostic criterion''' or MYC as a '''Minor diagnostic criterion''' (alternatively, molecular studies could be used). see note.

 

<small><u>'''Note:''' ''TCL1A'' break-apart probes specific to the 14q32 region can identify translocations involving TCL1A. When a ''TCL1A'' rearrangement is not identified and the patient has T-cell prolymphocytic leukemia/lymphoma (T-PLL), reflex testing using the ''TRAD'' break-apart probe set may be performed.</u></small>

 

*Cytogenetics (FISH, CpG-stimulated Karyotype, SNP microarray)

# Polymerase Chain Reaction (PCR) and Reverse Transcription PCR (RT-PCR): To show the rearrangements of the TR gene (TCRB, TCRG loci) as a '''Major diagnostic criterion,''' and alternative to FISH rearrangements of the ''TCL1'' or ''MTCP'' genes at the ''TRD'' locus can be detected by PCR. '''Major diagnostic criteria'''

*PCR for TRB/TRG

# Next generation sequencing (NGS)-See note

*Next-Generation Sequencing (NGS)

==Familial Forms==

==Familial Forms==

While there is no noticeable familial clustering of T-cell prolymphocytic leukemia (T-PLL), a subset of cases can develop in the context of ataxia-telangiectasia (AT). AT is characterized by germline mutations in the ATM gene, and patients with AT are at an increased risk for various malignancies, including T-PLL. In these cases, biallelic inactivation of the ATM tumor suppressor gene occurs, with about 10% to 15% penetrance of the tumor phenotype by early adulthood. T-PLL represents nearly 3% of all malignancies in patients with ataxia-telangiectasia​. <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> <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> <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>

While there is no noticeable familial clustering of T-cell prolymphocytic leukemia (T-PLL), a subset of cases can develop in the context of ataxia-telangiectasia (AT). AT is characterized by germline mutations in the ''ATM'' gene, and patients with AT are at an increased risk for various malignancies, including T-PLL. In these cases, biallelic inactivation of the ''ATM'' tumor suppressor gene occurs, with about 10% to 15% penetrance of the tumor phenotype by early adulthood. T-PLL represents nearly 3% of all malignancies in patients with ataxia-telangiectasia​. <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> <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> <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 studies are exploring molecularly targeted drugs and signaling pathway inhibitors, for routine clinical use in treating T-PLL.]

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 studies are exploring molecularly targeted drugs and signaling pathway inhibitors, for routine clinical use in treating T-PLL.]