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

(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

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. 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)	TCL1 (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
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)(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) 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.
5	Abnormality	5p		Yes			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
14	Loss	14q					In approximately (37%)
17	Abnormality	17p, 17q
22	Loss	Monosomy 22 22q					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)	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
ATM	TSG	53% (COSMIC)	ATM mutation/deletion	None specified	Yes	Yes		Biallelic inactivation (missense mutations) of the ATM gene was demonstrated in virtually all sporadic cases of T-PLL (Dr. Jaffe book)
FBXW10	TSG	72% (COSMIC)
IL2RG, JAK1, JAK3, STAT5B	Oncogene	8% JAK1 34% JAK3 16% STAT5B 2% IL2RG (COSMIC)						The cumulative prevalence of these mutations in T-PLL is approximately 60%. Typically, mutations within this pathway occur in a mutually exclusive manner. (Dr jaffe book)
EZH2	Oncogene, TSG	16% (COSMIC)
BCOR	TSG	8% (COSMIC)
CHEK2	TSG	5% (COSMIC)
TP53	TSG	2% (COSMIC)						Rare

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/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. 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.

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References

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Notes

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