T-PLL (T Prolymphocytic leukemia) is mature and aggressive T-cell leukemias characterized by the proliferation of small to medium-sized prolymphocytes that show mature or post-thymic T cell phenotype. T-PLL involve peripheral blood (PB), bone marrow (BM), lymph nodes, liver, spleen, and skin. The name "prolymphocyte" is not accurate, as the tumor cells in this disease are of post-thymic T cell in origin.
T-PLL increases in ataxia-telangiectasia (ATM) patients. Whole-genome sequencing and whole-exome sequencing have demonstrated mutations in the following genes: IL2RG, JAK1, JAK3, STAT5B, EZH2, FBXW10, and CHEK2.
T-PLL is a rare T cell leukemia. The disease accounts for approximately 2% of cases of mature lymphocytic leukemia in adults. The pathology is common in elderly patients (older than 65 yrs) and relatively unreported in young adults. There is a slight male predominance with a male: female ratio of 1.33.
In healthy T cells, TCL1 is expressed in CD4-/CD8- cells, but not in cells at later stages of differentiation.
The overexpression of the TCL1 gene in humans has been involved in the development of T-PLL by affecting cell survival. TCL1 serve as a co-activator of the cell survival kinase AKT.
Chromosomal rearrangements that bring the TCL1 gene close to the T-cell antigen receptor (TCR)-alpha regulatory elements are frequent.
TCL1 and MTCP1 alterations play a crucial role in the pathogenesis of T-PLL by enhancing cell proliferation and survival. TCL1 and MTCP1 alterations lead to activation of protein kinase B (Akt), impairment of protein kinase C (PKC) theta and extracellular signal-regulated kinase (ERK) pathways. Their alterations are necessary initiating events but are not sufficient to drive leukemogenesis in T-PLL.
History and Physical
Diagnosis of T-PLL is usually established based on a combination of clinical presentation, imaging, morphology, genetics, and immunophenotype. Common symptoms of T-PLL include hepatomegaly, splenomegaly, and generalized lymphadenopathy. Skin lesions occur in 25% of patients. Effusions occur in about 20% of patients.
Leucocytosis (high count greater than 100 k), atypical lymphocytosis, anemia, and thrombocytopenia are common findings on Complete blood count and peripheral blood smear.
Variations in morphology and immunophenotype have been observed in T-PLL cases and can make the diagnosis challenging. Serum immunoglobulins are usually within normal limits. Serology for HTLV- 1 is negative, and is vital in excluding adult t-cell lymphoma.
Overall, the clinical presentation of T-PLL is variable. The majority of the cases show an aggressive course. However, an indolent clinical course is also possible.
Laboratory studies that are useful in assessing T-PLL patients include a CBC with smear evaluation, routine chemistries with liver and renal function and electrolytes, alkaline phosphatase and lactate dehydrogenase (LDH). Imaging studies to assess the extent of the disease include chest XR, Computed tomography (CT) of the chest, abdomen, and pelvis.
Peripheral blood smear assessment is useful in assessing T-PLL morphology. There are three reported morphologic variants observed in T-PLL. The typical variant is common and accounts to up to 75% of cases. In this variant, cells are usually small to medium in size. It is also lymphoid cells with non-granular basophilic cytoplasm; round, oval, or markedly irregular nuclei. It usually has visible, punched out nucleoli. The “small cell variant” (25%) shows cells that are relatively small in size; cells show condensed chromatin and small nucleolus. The “cerebriform (Sezary cell-like) variant” (5%) show cells with an irregular nuclear outline.
Irrespective of the nuclear features, a common morphological feature is cytoplasmic protrusions or blebs. Bone marrow aspirate/bone marrow biopsy in T-PLL cases usually show diffuse interstitial infiltrate. Immunohistochemistry (IHC) is generally necessary to confirm the diagnosis. IHC for TCL1 shows an overexpression in the majority of the cases. Western blot can assess TCL1 overexpression.
Tissue biopsy is sometimes necessary for assessing patients with unusual presentation. Spleen biopsy shows red pulp infiltration. Skin biopsy shows perivascular, peri-adnexal or more diffuse dermal infiltrate, without epidermotropism.
Flowcytometry is a useful tool that is usually necessary to confirm T-PLL diagnosis. Cells are negative for TdT, CD1a, and CD20. The cells are positive for CD3 (weak), CD2, CD5, CD7, CD52. The majority of cases are CD4+/CD8-. Some cases co-express CD4 and CD8, a feature unique to T-PLL. Few cases are CD4- and CD8+. CD52 is commonly positive. Some institutions also assess TCL1 Overexpression by flow cytometry; this approach will also be useful in the follow-up of residual disease after therapy.
Genetic studies are usually necessary to confirm the T-PLL diagnosis. TCR gene rearrangement is positive for clonal rearrangement. Chromosomal abnormalities are common. Rearrangements involving TCL1 is specific for T-PLL, these include: inv(14) (80%), t(14;14)(q11;q32) (10%) and t(X;14)(q28;q11). Other genetic abnormalities include: Abnormalities in chromosome 8, Del(12p13), abnormalities in chromosome 6 (33%) and chromosome 17 (26%) and deletion of TP53 gene (17p13).
Treatment / Management
Management of T-PLL depends on the patient's presentation.
1) Asymptomatic patients: These patients usually undergo observation. They should be followed monthly by physical examination and laboratory tests including complete blood count. The appearance of positive symptoms such as lymphadenopathy should warrant treatment.
2) Symptomatic patients should get alemtuzumab (anti-CD52 antibody). It has improved overall survival over the traditional alkylating agents or purine analog-based chemotherapy. For patients who fail to attain a complete remission with single-agent alemtuzumab, the addition of pentostatin, a purine analog should be considered. Once the patient reaches sustained remission, allogeneic or autologous hematopoietic cell transplantation (HCT) should be pursued to attain complete cure. Despite high initial response rate, the patients who do not receive bone marrow transplant has an overall median survival of 17 to 33 months.
Because the disease entity is rare, there is limited data regarding the treatment options. Patients who suffer recurrent or refractory disease should receive a referral for enrollment in clinical trials.
The differential diagnosis of T-PLL includes other lymphoid neoplasms with a leukemic presentation; some relevant entities include:
- B cell prolymphocytic leukemia (B-ALL)
- Chronic lymphocytic leukemia/Small lymphocytic lymphoma (CLL/SLL)
- Mycosis fungoides (MF)
- Adult T cell lymphoma/leukemia (ATCL)
- T cell large granular lymphocyte leukemia (LGL)
- Hairy cell leukemia (HCL)
T-PLL is an aggressive malignancy with a median survival of one to two years. The median overall survival is 21 month. Some patients may present with the indolent variant, this variant show better prognosis. Poor prognostic factors include age above 65, presence of effusion, hepatic of nervous system involvement, very bulky lymph nodes, high absolute lymphocytic count, high expression of TCL1 and AKT1, and JAK3 mutation.
T-PLL complications include bone marrow suppression, organ dysfunction and adverse effects related to high dose chemotherapy.
Deterrence and Patient Education
Patients should receive education about the prognosis and the possible adverse side effects from the chemotherapeutic regimes and hematopoietic stem cell transplantation before beginning treatment.
Pearls and Other Issues
T-PLL is a rare T cell leukemia that typically presents with both nodal and extranodal involvement. The cells express high levels of CD52 and also express pan-T cell markers (CD2, CD3, and CD7) and TCL1. Prognosis is poor despite therapy.
Enhancing Healthcare Team Outcomes
T-PLL is a rare leukemia. The prognosis is overall poor. T-PLL needs an interprofessional management approach with a medical oncologist, infectious disease physician, pharmacist, and oncology nurse, all working together as an interprofessional health team to bring about optimal clinical outcomes for the patient. [Level V] The oncology nurse and pharmacist should educate the patient on the adverse effects of the chemotherapy drugs used to manage this leukemia.