HAEM5:T-prolymphocytic leukaemia

Haematolymphoid Tumours (5th ed.)

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Primary Author(s)*

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

WHO Classification of Disease

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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

Sites of Involvement

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

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

Immunophenotype

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Finding	Marker
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, activation markers are variable (CD25, CD38, CD43, CD26, CD27)
Negative (universal)	TdT, CD1a, CD57, CD16
Negative (subset)	CD8 (in some cases CD4+/CD8+ or CD4-/CD8+)

Chromosomal Rearrangements (Gene Fusions)

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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)(q11q32) t(14;14)(q11;q32)	TCL1A/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, 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.

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)(p11.2) t(8;8)(p11.2;q12) trisomy 8q 8q24 (MYC)	chr8	Yes	No	No	Recurrent secondary finding
11	Loss	11q23.3	ch11	Yes	Yes	Yes	Frequent
5
14	Loss	14q	chr14				In approximately (37%)
12	Loss	12p13	chr12

Characteristic Chromosomal Patterns

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Chromosomal Pattern	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
inv(14)(q11q32)	Yes	EXAMPLE: No	EXAMPLE: No	EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).

Gene Mutations (SNV / INDEL)

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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
EXAMPLE: TP53; Variable LOF mutations EXAMPLE: EGFR; Exon 20 mutations EXAMPLE: BRAF; Activating mutations	EXAMPLE: TSG	EXAMPLE: 20% (COSMIC) EXAMPLE: 30% (add Reference)	EXAMPLE: IDH1 R123H	EXAMPLE: EGFR amplification	EXAMPLE: Yes	EXAMPLE: No	EXAMPLE: No	EXAMPLE: Excludes hairy cell leukemia (HCL) (add reference).
TCL1A	Oncogene		ATM mutations	None specified	Yes	Yes
EZH2
FBXW10
CHEK2
JAK1, JAK3, STAT5b, IL2RG
JAK1		20% (COSMIC) EXAMPLE: 30% (add Reference)
JAK3
STAT5B

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

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Genes and Main Pathways Involved

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Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
TCL1A	AKT signaling and TCR signal amplification pathways	Increased cell survival and proliferation
JAK1, JAK3, STAT5b, IL2RG	JAk-STAT pathway	EXAMPLE: Abnormal gene expression program

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. Penetrance of the tumor phenotype is about 10% to 15% by early adulthood. It 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 research is exploring molecularly targeted drugs and signaling pathway inhibitors, for routine clinical use in treating T-PLL.

Links

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References

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Notes

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