T-Cell Prolymphocytic Leukemia

Etiology

T-PLL has no known transformations, nor does it have any known environmental risk factors. Whole-genome and whole-exome sequencing have demonstrated mutations in the following genes: IL2RG, JAK1, JAK3, STAT5B, EZH2, FBXW10, and CHEK2.[2]  Patients with ataxia-telangiectasia mutation (ATM) have an increased incidence of T-PLL. ATM is an autosomal recessive disorder characterized by progressive neurological dysfunction (eg, ataxia), immunodeficiency, impaired organ development, and oculocutaneous telangiectasia. Mutations of the ATM gene on 11q23 occur in 80 to 90% of the T-PLL population. There is a rare association of T-PLL with breast malignancy and renal transplant.[3][4]

Epidemiology

T-PLL is a rare T-cell leukemia. It accounts for approximately 2% of mature lymphocytic leukemia cases in adults. The pathology is common in elderly patients (older than 65 years) aged 30 to 94. There is a slight male predominance, with a male-to-female ratio of 1.33.

Pathophysiology

In healthy T cells, TCL1 is expressed in CD4-/CD8- cells but not in cells at later stages of differentiation. The TCL1 gene rearrangements on chromosome 14 are the most common genomic alterations; they increase the gene's expression. The overexpression of the TCL1 gene and its protein in humans has been involved in developing T-PLL by being a co-activator of the cell survival kinase AKT.

The most frequent chromosome 14 alterations involve inv (14) (q11; q32) in 80% of patients and the TCL1a and 1 b, t (14; 14) (q11; q32) in 10% of cases; they also involve TCL1a/1 b and t (X; 14) (q28; q11), which involves MTCP1 (Mature T-Cell Proliferation 1). Fluorescence in situ hybridization (FISH) is often used to diagnose rearrangements of the T-cell receptor locus (TCL1). 

TCL1 and MTCP1 (rare) 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 for initiating events but are insufficient to drive leukemogenesis in T-PLL.[1] The accumulation of various mutations, with the resultant complex karyotype, is thought to be the driving force in T-PLL development. Complex karyotypes are very common in T-PLL, involving 70 to 80% of patients with abnormalities of chromosomes 6, 8, 2p, and 17p.[5] Abnormalities of chromosome 8 include trisomy 8 and isochromosome 8, leading to the overexpression of MYC. TP53 rarely occurs in T-PLL. JAK-STAT pathway genes IL2RG, JAK1, JAK3, and STAT5B also occur. There is an additional deletion of chromosome 11q22.3, the anomaly correlated with Ataxia-Telangiectasia. Patients frequently have mutations in genes coding for histone modifications, as exemplified by KMT2C, KMT2D, KMT 5A, and EZH2. 

History and Physical

Diagnosis of T-PLL is usually based on clinical presentation, imaging, morphology, genetics, and immunophenotype.[6][7][8][9] T-PLL symptoms include night sweats, weight loss, fatigue, and weakness. Leucocytosis (high count greater than 100 k), atypical lymphocytosis, anemia, and thrombocytopenia are common findings on the Complete blood count and peripheral blood smear. The bone marrow is positive in 100% of patients with cytopenias. A bone marrow biopsy is not necessary for the diagnosis. Significant clinical findings include hepatosplenomegaly, generalized lymphadenopathy, skin/mucosal lesions, and effusions (primarily pleural; secondarily peritoneal).

Evaluation

Laboratory studies 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), and chest X-ray and computed tomography (CT) of the chest, abdomen, and pelvis.[6] PET scans are not generally advocated. 

Peripheral blood smear assessment helps assess T-PLL morphology. There are 3 reported morphologic variants observed in T-PLL. The typical variant is common and accounts for 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 shows clumped chromatin. It usually has visible, punched-out nucleoli. The “small cell variant” (20%) shows cells that are relatively small in size; cells show condensed chromatin and small nucleolus (oft invisible to light microscopy). The “cerebriform (Sezary cell-like) variant” (5%) shows cells with an irregular nuclear outline. There are no clinical differences between these variants. T-PLL cannot be diagnosed definitively based on cell morphology alone.[10] 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 shows diffuse interstitial infiltrates. 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.[6][1]

Flow cytometry is a useful tool often necessary to confirm a T-PLL diagnosis. Cells are negative for TdT, CD1a, CD16, CD30, and CD20. They are positive for CD3 (weak), CD2, CD5, CD7, and CD52. There is some variation amongst CD4 and CD8 positivity; the majority (60%) of cases are CD4+ and CD8-. Twenty-five percent are positive for CD4 and CD8, and 15% are positive for CD8 but CD4-. 

Clonal T-cell receptor gene testing is obligatory for the initial evaluation. TCL1 protein testing using flow cytometry or immunohistochemistry is considered more sensitive than cytogenetics and a diagnostic objective. In extremely rare cases where patients have no TCL1A, TCL1B, or MTCP1 rearrangement/overexpression, the diagnosis of TCL1- T-PLL is made. Genetic studies are usually necessary to confirm the T-PLL diagnosis. TCR gene rearrangement is positive for clonal rearrangement. Complex chromosomal abnormalities are very 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 co-abnormalities can include defects in chromosome 8, del(12p13), chromosome 6 (33%), chromosome 17 (26%), and (rarely) deletion of the TP53 gene (17p13).[6][7]

Diagnostic Criteria For T-PLL as composed by the TPLL International Study Group.[10] Diagnose T-PLL with all 3 major criteria OR the first 2 (#1,#2) and 1 minor criterion.

Major Criteria

1. > 5 x 10(9) /L cells with TPLL phenotype in the peripheral blood or bone marrow
2. T-cell clonality [determined by TRB/TRG (T-cell receptor beta/gamma) or flow cytometry]
3. Abnormalities of 14q32 or Xq28 or expression of TCL 1a/b OR MTCP1

Minor Criteria

1. Chromosome 11 abnormalities (11q22.3), as in ATM
2. Chromosome 8 abnormalities [idic (8)(p11), t(8;8), trisomy 8]
3. Chromosome 5,12,13, and 22 abnormalities or a complex karyotype
4. Involvement of a TPLL specific site (eg, splenomegaly, effusions)

Treatment / Management

Asymptomatic patients should undergo observation and a "watch-and-wait" attitude. They should be followed monthly by physical examinations and laboratory tests, including complete blood counts. The appearance of symptoms warrants treatment. Recall that the asymptomatic period is a transitory respite. Anticipation and preparation are in order; patients progress. T-PLL treatment has become relatively restricted, and patients, where applicable, should be considered for clinical studies. The older armamentarium of splenectomy, splenic radiation, leukapheresis, and CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) are ineffective in treating T-PLL. Nucleoside agents such as fludarabine, cladribine, and Pentostatin have only a modicum effect. 

Alemtuzumab (AKA CAMPATH-1-H) remains the mainstay of therapy for treatment-naive patients as well as those with refractory or relapsed disease.[11][12][13] It carries a response rate (RR) of 90% with a complete response rate (CR) of about 80% in the treatment-naive. The intravenous format for 10 to 12 weeks is favored over the subcutaneous as the drug activity is reportedly lessened in the latter. There are no data to date to support the use of maintenance alemtuzumab. Alemtuzumab is a humanized unconjugated IgG1 monoclonal antibody against CD52, an antigen replete on T-cells. Alemtuzumab binds to CD52 and induces cell death by either complement-dependent cytotoxicity, antibody-dependent cytotoxicity, or apoptotic induction. Unfortunately, even with the best response, relapse follows therapy often well within 2 years of treatment. For this reason, hematopoietic stem cell transplant (HSCT) is used as a consolidative therapy. (B2)

Allogeneic HSCT (alloHSCT) is favored as consolidation therapy, particularly when started early (within a year of diagnosis) when used in patients who are fit for transplant protocols and for those patients in CR (NOT in partial response [PR] or less). Purportedly autologous and allogeneic HSCT have no significant differences, though data on the former are limited. Clinical opinion appears mixed, but alloHSCT, under ideal conditions for consolidation, has produced up to 7 years of disease control. 

As stated before, eligible patients should be screened for entry into clinical trials of newer agents when possible. Recent clinical trials have shown some potential for a BCL-2 (B-cell Lymphoma 2) inhibitor, Venetoclax, in T-PLL.[14] BCL-2 is an anti-apoptotic gene that conveys chemoresistance. Its overexpression prolongs cancer cell survival. The addition of Ruxolitinib is thought to potentiate Venetoclax's action. It is a JAK1 and JAK2 inhibitor - blocking the ATP sites of these kinases. Additional studies should be forthcoming. 

Differential Diagnosis

The differential diagnosis of T-PLL includes other lymphoid neoplasms with a leukemic presentation; some relevant entities include [15]:

• B cell prolymphocytic leukemia (B-PLL); B-PLL, compared to T-PLL, has minimal lymphadenopathy and rarely skin involvement. It shows a strong B-cell marker study (CD19, CD20, CD22) with additional positive markers of CD79a and CD5. CD23 is negative. The cytogenetics shows no t(11;14), but there is positivity for 13q del, 11q del, 17p del, or 6q del. The median survival in B-PLL is 3 years, measured in months for T-PLL. Cytologically, they bear a single prominent nucleolus. 
• Chronic lymphocytic leukemia/Small lymphocytic lymphoma (CLL/SLL): The cells are variably positive for CD5 and CD23 and weakly positive for CD22 and CD79b. They are CD10 negative. The cytogenetic analysis shows 13q del, 11q del, 17p del, or trisomy 12.
• Mycosis fungoides (MF) / Sezary syndrome (SS): Cells in Sezary syndrome are positive for CD2 and CD3. They are predominantly positive for CD4. They are positive for CD25 and negative for TCL1. They are usually negative for CD7 and CD26. Skin lesions may be found in as many as 20% of patients. A skin biopsy may be needed to exclude Sezary syndrome. The rash in SS is felt to be the harbinger of its lymphocytosis. 
• Adult T cell lymphoma/leukemia (ATLL): Chronic HTLV-1 infection is thought to be the etiology of this neoplasm. HTLV-1 PCR/serology is positive; T-PLL cells are negative for this indication. ATLL cells are TCL1 negative. They are positive for CD3, CD4, and CD25. They are CD7 negative; T-PLL cells are CD7 positive. By far, in ATLL, CD4 is more prevalent than CD8. Hypercalcemia is common in ATLL but NOT found in T-PLL. ATLL cells have a unique cytomorphology with "flower cells." These are cells having convoluted nuclei with condensed, homogenous chromatin. 
• T cell large granular lymphocyte leukemia (LGL): These cells are TCL1 negative but positive for CD2, CD3, CD8, CD16, and CD57. They variably express CD7 and rarely CD4. The patients may have mild-to-moderate splenomegaly but rarely lymphadenopathy. Cytopenias are a frequent finding. The cytology reveals large lymphocytes containing azurophilic granules. The median survival is over 10 years. 
• Hairy cell leukemia (HCL);  HCL is rare and is noted to be a low-grade mature B-cell cancer. 'Classic' HCL bears B-cell markers of CD19, CD20, and CD22. Markers more specific for this entity include CD11c, CD25, CD103, CD125, and CD200. An HCL variant exists that is missing both CD25 and CD123. CD22 and CD79b are variably expressed. However, the variant contains a characteristic BRAF-V600E mutation, a marker not evident in other B-cell maladies. The physical exam is noteworthy for massive splenomegaly, essentially its most prominent feature. Cellular morphology shows "hair"-like cytoplasmic projections. The variant form may manifest nucleoli.

Prognosis

T-PLL is an aggressive malignancy with a median survival of 1 to 2 years. The median overall survival is 21 months. Some patients may present with the indolent variant, which shows a better prognosis. Poor prognostic factors include age above 65, effusion, hepatic or nervous system involvement, bulky lymph nodes, high absolute lymphocytic count, high expression of TCL1 and AKT1, and JAK3 mutation.[1] Having at least 5 cytogenetic abnormalities was a negative prognostic factor for survival. An elevated LDH or beta-2-microglobulin reportedly portends a poor response to therapy. 

Complications

The administration of treatment requires preparatory measures to prevent problems. For alemtuzumab, preparation includes prophylaxis against tumor lysis syndrome, antimicrobial prophylaxis (Pneumocystis jiroveci and Herpesviridae [HSV, CMV]), and monitoring for CMV reactivation. CNS prophylaxis is currently not advocated, as bone marrow transplantation may be a serious consolidative therapy for T-PLL patients; the lengthy process of typing siblings with human leukocyte antigen (HLA) should be initiated as soon as possible.