HAEM5:T-prolymphocytic leukaemia

Haematolymphoid Tumours (WHO Classification, 5th ed.)

Primary Author(s)*

Parastou Tizro, MD¹, Celeste C. Eno², PhD, Sumire Kitahara, MD²

¹City of Hope, Duarte, CA

²Cedars-Sinai, Los Angeles, CA

WHO Classification of Disease

Structure	Disease
Book	Haematolymphoid Tumours (5th ed.)
Category	T-cell and NK-cell lymphoid proliferations and lymphomas
Family	Mature T-cell and NK-cell neoplasms
Type	Mature T-cell and NK-cell leukaemias
Subtype(s)	T-prolymphocytic leukaemia

Related Terminology

Acceptable	N/A
Not Recommended	N/A

Gene Rearrangements

Rearrangements involving the TCL1 (T-cell leukemia/lymphoma 1) family genes—TCL1A, MTCP1 (mature T-cell proliferation), or TCL1B (also known as TCL1/MTCP1-like 1 [TML1])—are highly specific to T-PLL and occur in more than 90% of cases. These translocations juxtapose the TRA locus with the oncogenes TCL1A or TCL1B, or in the case of t(X;14), with the MTCP1 gene.

Driver Gene	Fusion(s) and Common Partner Genes	Molecular Pathogenesis	Typical Chromosomal Alteration(s)	Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
inv(14)	TCRα/δ and TCL1A	Pericentric inversion within chromosome 14, leading to juxtaposition of the TCRα/δ enhancer to the TCL1A locus and aberrant overexpression of TCL1A	inv(14)(q11.2q32.1)*	Common ~60%	D	No	These genetic abnormalities serve as diagnostic markers and generally indicate an aggressive disease. Major diagnostic criteria.
t(14;14)	TCRα/δ and TCL1A	Reciprocal translocation between the two homologous chromosome 14s, leading to juxtaposition of the TCRα/δ enhancer to the TCL1A locus and aberrant overexpression of TCL1A	t(14;14)(q11.2;q32.1)*	Recurrent ~20-25%	D	No	*In most diagnostic/genetic reports (e.g., FISH or karyotype), the inversion and translocation may grouped together. Their distinction is mainly cytogenetic, not biological.
t(X;14)	TCRα/δ and MTCP1	Transcriptional activation of MTCP1 via juxtaposition to TCRα/δ enhancer elements, leading to AKT pathway activation	t(X;14)(q28;q11.2)	Rare ~5%	D	No	Major diagnostic criteria. Rarely, t(X;7)(q28;q34) is observed, where the TCRβ enhancer (7q34) substitutes for TCRα/δ, leading to the same functional outcome

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.

Table: A list of clinically significant and/or recurrent CNAs and CN-LOH with potential or strong diagnostic, prognostic and treatment implications in T-PLL are listed below.

Chr #	Gain, Loss, Amp, LOH	Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]	Relevant Gene(s)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
8	Gain	idic(8)(p11.2) t(8;8)(p11.2;q12) trisomy 8q 8q24	AGO2 , MYC	D	No	Recurrent secondary finding (70-80% of cases). Minor diagnostic criteria.
5	Abnormality	5p, 5q	Unknown	D, P	No	Minor diagnostic criteria.
6	Abnormality	Gain of 6p, loss of 6q	Unknown	Unknown	No
11	Loss	11q21-q23.3	ATM	D, P, T	No	Frequent, Minor diagnostic criteria.PARP inhibitors may be considered as an off-label therapy (NCT03263637)
12	Loss	12p13	CDKN1B	D, P	No	Haploinsufficiency of the CDKN1B gene contributes to the development of T-PLL.Minor diagnostic criteria.
13	Loss	13q14.3		D	No	Minor diagnostic criteria.
17	Loss	17p13	TP53	P,T	No	May portend resistance to therapy
22	Loss	Monosomy 22 del(22q); 22q11-12 (most common)	BCL11B	D	No	Minor diagnostic criteria.

Diagnostic criteria

Diagnosis requires either all three major criteria or the first two major criteria along with one minor criterion:

• Major criteria:
  • 5 x 10⁹/L cells of T PLL phenotype in peripheral blood or bone marrow
  • T cell clonality by molecular or flow cytometry methods
  • Abnormalities of 14q32 or Xq28 or expression of TCL1A/B or MTC**
• Minor criteria:
  • Abnormalities involving chromosome 11
  • Abnormalities in chromosome 8
  • Abnormalities in chromosome 5, 12, 13, 22 or complex karyotype
  • Involvement of specific sites (spleen, effusions)

**Cases lacking these abnormalities may be referred to as "TCL1 family-negative T-PLL." by some investigators. It is, however, recommended in WHO-HAEM5 that such cases should preferably be classified as peripheral T-cell lymphoma NOS with leukemic involvement (after exclusion of other specific leukemic T-cell entities) as there are insufficient clinicopathological and molecular data to determine the relationship of TCL1 family–negative T-PLL to T-PLL.

Characteristic Chromosomal or Other Global Mutational Patterns

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).

Inv(14)(q11.2q32)

Chromosomal Pattern	Molecular Pathogenesis	Prevalence - Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
inv(14)(q11q32) t(14;14)(q11.2;q32.1)	TCL1A or MTCP1 activation with constitutive activation of the AKT signaling pathway, promoting proliferation and survival	Common	D	No	Major diagnostic criteria
ATM loss/mutation; del(11)(q22–q23)	Impaired DNA damage response → genomic instability, accumulation of secondary lesions	Common	D,P	No	Minor diagnostic criteria, the most frequent cooperating lesion

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.

Gene	Genetic Alteration	Tumor Suppressor Gene, Oncogene, Other	Prevalence - Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
ATM	Mutation/deletion, loss of heterozygosity, or biallelic mutation	Tumor Suppressor Gene	Common	D, P, T	No	Since alterations at the ATM locus are found in up to 80% to 90% of T-PLL cases, it can serve as a minor diagnostic criterion. 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.
FBXW10	Loss-of-function	Tumor Supressor Gene	Common	Unknown	No
IL2RG, JAK1, JAK3, STAT5B	Variable activating mutations	Oncogene	Variable based on gene; Recurrent to Common	D, P, T	No	Targeting this pathway with specific JAK/STAT pathway inhibitors, has shown promise in preclinical studies and early clinical trials. Combining JAK/STAT inhibitors with other treatments, like BCL-2 inhibitors, may enhance therapeutic efficacy and improve outcomes for T-PLL patients
EZH2	Loss-of-function	Both oncogene and Tumor Suppressor Gene	Recurrent	Unknown	No	EZH2 inhibitors like tazemetostat have shown efficacy in other hematologic malignancies, providing a rationale for off-label use in T-PLL
BCOR	Loss-of-function	Tumor Supressor Gene	Rare	Unknown	No	A negative impact on overall survival (OS) was not observed for T-PLL patients in the study. However, this might be attributable to the relatively low number of cases compared to studies on AML and MDS.
SAMHD1	Loss-of-function	Tumor Supressor Gene	Recurrent	D, P	No	SAMHD1 mutations may indicate a defective DNA damage response and aggressive disease
CHEK2	Loss-of-function	Tumor Supressor Gene	Rare	Unknown	No	CHEK2 mutations may indicate a defective DNA damage response and aggressive disease
TP53	Variable inactivating/loss of function mutations	Tumor Supressor Gene	Rare	P (may portend resistance to therapy)	No	Mutations in TP53 are less frequent than deletions.May show overexpression of p53 in some cases.

Note: A more extensive list of mutations can be found in cBioportal, COSMIC, 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.

Genes and Main Pathways Involved

The key pathways involved in the pathogenesis of T-cell prolymphocytic leukemia (T-PLL) include DNA damage repair, T-cell receptor (TCR) signaling, and epigenetic modulation. Additionally, there is frequent mutational activation of the IL2RG-JAK1-JAK3-STAT5B pathway, which plays a significant role in the disease's development and progression.

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

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. 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.

• Cytogenetic Analysis

1. 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
2. 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.

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.

• Molecular Genetic Testing

1. 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
2. Next generation sequencing (NGS)-See note

Note: Although alterations of TCL1A, TCL1B (TML1), or MTCP are present in more than 90% of cases, they are not found in 100% of cases. Taken together, assessment of clonal TCR rearrangement, cytogenetics, and FISH are relevant genetic tests to establish the diagnosis of T-PLL. Genetic sequencing is currently not a diagnostic requirement; however, it may provide information regarding the underlying pathogenesis of T-PLL or might help to identify relevant prognostic subgroups.

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​.

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

This disease is defined/characterized as detailed below:

• 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.

The epidemiology/prevalence of this disease is detailed below:

• T-PLL is an uncommon disease, accounting for approximately 2% of all mature lymphoid leukemias in adults. It mainly affects older individuals, with a median onset age of 65 years, ranging from 30 to 94 years. The disorder exhibits a slight male predominance, with a male to female ratio of 1.33:1.

The clinical features of this disease are detailed below:

• 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%)

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); β2 microglobulin (B2M) (increased-may reflect disease burden)

The sites of involvement of this disease are detailed below:

• 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.

The morphologic features of this disease are detailed below:

• 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.Bone marrow aspirates show clusters of these neoplastic cells, with a mixed pattern of involvement including diffuse and interstitial, in trephine core biopsy.

The immunophenotype of this disease is detailed below:

• Cytochemistry: 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.
• Immunophenotype: T-cell prolymphocytes exhibit a post-thymic T-cell phenotype. In 60% of cases, the cells are CD4+ and CD8-. In 25% of cases, they co-express both CD4 and CD8, while the remaining 15% are CD4- and CD8+.

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 (usually expressed at high density, 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+)

Links

See references.

Notes

*Citation of this Page: Tizro P, Eno C, Kitahara S.“T-prolymphocytici leukemia”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 01/6/2026, https://ccga.io/index.php/HAEM5:T-prolymphocytic_leukaemia.

*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 Associate Editor or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.

Prior Author(s): N/A