T-cell prolymphocytic leukemia C91.60, C91.61

T-cell prolymphocytic leukemia is characterized by proliferation of small- to medium-sized prolymphocytes of post-thymic phenotype (Swerdlow SH et al. 2016; Herling M et al. 2004). It is classified as an aggressive T-cell leukemia. Because of its histogenesis, unique molecular biology, specific diagnostic criteria, its mostly highly dynamic clinical course, specific aspects of therapy, and generally poor prognosis, it should not be considered the "T-cell counterpart" of CLL.

Incidence: 0;1-0;2 new cases per 100,000 population / year. T-PLL affects approximately 2% of adult mature cell lymphocytic leukemias in Western industrialized countries. However, it is the most common primary leukemic form of peripheral T-cell neoplasms in Europe and North America. M:w= 1.0:1.33.

The cell of origin of T-cell prolymphocytic leukemia is considered to be an intermediate mature stage of a developing T-cell in the cortical thymus. This "prolymphocyte" probably arises from defective genomic rearrangement following physiological breakage events of T cell receptor (TZR) genes. The rearranged genes become adjacent to genes of the T-cell leukemia 1 (TCL1) oncogene family. The lymphoid tumor cell has a T-helper cell characteristic. This is thought to account for the lack of auto-aggressive or immunosuppressive properties. It also explains the rather non-specific clinical symptoms of T-PLL.

Constitutive activation of TCL1 oncogenes is considered to be the initiating step. Due to chromosomal aberrations inv(14)(q11q32 ) or t(14;14)(q11;q32 ) as well as t(X;14)(q28;q11 ), the gene locus of TCLA1 ( 14q32 ) or of its homologue MTCP1, which is also chromosome Xq28 lookalized, comes under the permanent activating influence of TRA(TZRα) enhancers located on chromosome 14q11. (Virgilio L et al 1994). This prevents the physiological silencing of TCLA1 or MTCP. Remark: TCLA1- and MTCP1-transgenic mice are considered as models of human T-PLL!

Other relevant gemetic lesions include deletions and mutations of the ATM gene (Schrader A et al. 2018), the key apical enzyme of the cellular response to DNA double-strand breaks.

Aberrations on chromosome 8 with amplifications of genes such as MYC, gain-of-function mutations(JAK3 or STAT5B), and versch. epigenetic alterations also contribute to leukemogenesis (Wahnschaffe et al. 2019).

A viral pathogenesis seems unlikely based on serological or genomic data. There is no striking familial clustering. However, T-PLL is frequently found in patients with ataxia telangiectasia (Louis-Bar syndrome). Here, inactivating mutations of the ATM tumor suppressor gene are present.

The median age of onset is 65 years (Herling M et al. 2008). Individuals with ataxia telangiectasia (Louis-Bar syndrome) have a higher incidence of T-PLL (former median age between 25-30 years (Suarez F et al. 2015).

Cytomorphology: Typical is the predominance of a prolymphocytic cell population in 3 variants, but otherwise clinically and immunophenotypically not significantly different:

75% typically medium-sized, prolymphocytic with a slightly loosened nucleus of smooth-bordered contour with a distinct nucleolus; the basophilic cytoplasm occasionally bears protrusions.

20% small-celled with highly condensed chromatin and barely visible nucleolus.

5% cerebriform with irregular, furrowed nuclear circumference as in Sézary cells.

Skin findings: Dermatological involvement is common. Facial edema and nonpruritic, erythematous papular exanthema that may confluence to form planar plaques are preferred (see Fig.). Erythema gyratum repens-like skin lesions have also been described (Cohen L et al. 2019).

The sequential procedure depends on the primary constellation of findings, usually in the case of the leading finding of lymphocytosis. If T-PLL is suspected, the following examinations are recommended:

Anmanesis: symptoms incl. poor performance, tendency to infection, B-symptoms, etc. previous blood counts, family history incl. potential stem cell donors.

Clinical examination: lymph node status, organomegaly, signs of bleeding and anemia, evidence of skin infiltration or effusions.

Laboratory: microscopically differentiated leukocytes; platelets, hemoglobin, prominent CD2+, CD3+, CD5+, CD7+, TZRα/β+ population, serum lactate dehydrogenase (LDH); assessment of growth kineticsGFR, hepatobiliary system, electrolytes, virology if therapy is planned.

Immunophenotyping: no expression of TdT and CD1a, absent TIA, CD57, CD16. aberrant CD4/CD8 ratio in 75% of cases, intracellular expression of TCL1A (highest specificity), very frequent CD26+ and CD27+, strong CD52 expression.

Cytogenetics: inv(14)(q11q32) or t(14;14)(q11;q32) in 85% of cases (high specificity), t(X;14)(q28;q11) in 5-10% of cases (high specificity), complex aberrant karyotype in >70% of cases, gain of 8q24 in 60% and loss of 11q22.3 in 40%.

Molecular genetics: monoclonal TRB and/or TRG gene arrangement (obligatory)

Imaging (sonography) spleen, liver, lymph node stations; possibly transthoracic echocardiogram before planned therapy

Other: in the case of suspicious neurological symptoms, possibly MRI and cerebrospinal fluid puncture (the latter under consideration of the risk of contamination).

Bone marrow shows diffuse interstitial infiltration with the above cell morphology. Lymph node infiltrations are diffuse often with prominent high-endothelial venules. They typically involve the paracortical zone and may omit the follicles. The spleen shows dense infiltrates of red pulp invading the capsule and atrophic white pulp.

Skin: Dense, perivascularly oriented nodular infiltrate of medium-sized, nuclear polymorphic cells. Notable for a lack of epidermotropism. Immunohistochemical detection of TCL1A distinguishes T-PLL from other T-cell infiltrates.

Immunophenotyping: The post-thymic, TdT- and CD1a-negative T cells usually express pan-T surface antigens LIKE CD2, CD3, CD5, CD7. In a proportion of cases, CD3 and/or TZRα/β can only be detected cytoplasmically. Approximately 60% of T-PLL show a CD4+/CD8- constellation, followed by CD4+/CD8+ co-expression in 25% and CD4-/CD8+ in 15% of cases, which is largely specific for T-PLL. Expression of CD7 and CD52 is stronger than in other T-cell malignancies. Variable detection of activation markers CD25, CD38 and CD43; CD26 and CD27 are regularly detectable. Markers for cytotoxic T cells such as TIA are very rare.

Intracellular detection of TCL1A protein largely confirms the diagnosis of T-PLL. Normal peripheral T cells are TCL1A negative and other T cell neoplasms that exceptionally express TCL1A, such as anecdotal T cell acute lymphoblastic leukemias (T-ALL), are easily delineated.

Molecular genetics: Detection of monoclonality via clonal TRB and/or TRG gene rearrangements is considered standard. Sequencing analyses, such as for the detection of mutations in ATM or JAK/STAT genes, are not part of the recommended routine investigations.

Cytogenetics: The karyotypes of T-PLL are complex in about 70% with more than 3-5 mostly structural aberrations (Kiel MJ et al. (2014). The most common group of recurrent lesions affects chromosome 14 in 90% of T-PLL and involves the TZRα/δ (TRA/D) locus on 14q11. This includes the inv(14)(q11q32) in 60%, followed by the t(14;14)(q11;q32) (25%), both of which translocate the TCL1 (TCL1A and -B) gene locus to the neighborhood of TZRα/δ (TRA/D). In approximately 5-10% of T-PLL, a t(X;14)(q28;q11) is present, activating the TCL1A homolog MTCP1.

Importantly for diagnostic criteria, cytogenetic detection of TCL1 gene rearrangements is less sensitive than flow cytometric or immunohistochemical detection of the corresponding proteins. In approximately 60% of T-PLL, an abnormality of chromosome 8 is also found, usually gains of 8q. Furthermore, frequent findings are: -11q in about 40%, -6q in about 35% or -13q in about 30% or deletions on Chr.22 in 25%.

The diagnosis of T-PLL requires a systematic evaluation of the special findings of the individual disciplines. The rarity of the disease poses a challenge. The diagnosis is primarily made from peripheral blood. Biopsies from lymph nodes, skin or bone marrow must be included.

The following features must be fulfilled according to WHO criteria (Staber PB et al. 2019):

Main criteria

• Monoclonal lymphocytosis of the blood (>5x103 /μl) with a mature T-cell immunophenotype

and

• Evidence of a chromosomal aberration involving loci 14q32.1 (TCL1A) or Xq28 (MTCP1).

or

• Evidence of T-cell specific expression of TCL1A or MTCP1p13 protein in flow cytometry or immunohistochemistry.

Ancillary criteria (≥ 2)

• Rapidly (exponentially) increasing blood lymphocyte counts with doubling times less than 6 months
• Additional evidence of chromosomal aberrations with gains on 8q or a del11q22 or a complex aberrant karyotype
• Presence of (hepato)splenomegaly or effusions
• Prolymphocytic morphology in the blood smear

• Reactive T-cell lymphocytosis (usually temporary, with lower lymphocyte counts, usually not monoclonal), e.g. in viral infections or in the context of autoimmune diseases.
• Leukemic lymphomas of the B-cell series, especially with splenomegaly such as CLL with prolymphocyte proliferation or B-PLL, but which can be easily differentiated by their expression of CD19 and the absence of the T-cell markers CD2, CD3, CD7 in immunophenotyping.

Other differential diagnoses:

• The T-precursor neoplasms T-ALL / T-cell lymphoblastic lymphoma (T-LBL) differ from T-PLL mainly by their immature (immune) phenotype together with the absence of the T-PLL-typical chromosome 14 aberrations, as well as the resulting lack of TCL1A expression.

Among the mature T-cell malignancies with leukemic presentation, the following primary leukemic forms should be distinguished from T-PLL:

• T-cell leukemia of large granular lymphocytes (T-LGL),
• Sézary syndrome (SS, de novo or from mycosis fungoides (MF),
• ATLL,
• Peripheral T-cell lymphoma (PTCL) with leukemic involvement including hepatosplenic T-cell lymphoma (HSTL).

General therapy structure: There is no evaluated curative therapy standard for T-PLL. According to current knowledge, T-PLL is not curable by conventional chemotherapy as well as by antibody-based therapy. The only potentially curative option is allo-SCT.

Asymptomatic disease: In patients with stable or slowly progressive disease ("inactive T-PLL"), about 30% areasymptomatic at first diagnosis. Close, e.g. monthly, observation intervals, especially with physical examination and blood count checks are necessary with special attention to the dynamics of lymphocytosis. LDTs of ≤ 8.5 months have been described as reflecting evident disease progression and as associated with a worse prognosis (Herling M et al. 2008).

Treatment indications of T-PLL: Initiation of anti-leukemic therapy is indicated for the following disease-associated problems:

• constitutional symptoms, e.g. fatigue (ECOG ≥2) or classic B symptoms.
• symptomatic anemia (<10g/dL) and / or thrombocytopenia (<100,000/μl) and / or frequent / prolonged infections
• Symptomatic or rapidly increasing (>50% in 2 months or doubling in diameter in <6 months) lymphadenopathy or clinically significant hepatosplenomegaly
• proven extranodal manifestations e.g. skin, effusions, CNS, muscle, intestine
• rapidly increasing lymphocytosis (e.g. if >30,000/µl as >50% in 2 months or doubling within 6 months); lymphocytes >50,000//µl to be justified as sole indication criterion in curative intended approach

First-line therapy: As a rule, the majority of patients are in sufficient general condition at initial diagnosis, e.g. ECOG-PS ≤3, to tolerate system therapy. Even in borderline status, e.g. ECOG-PS >3 , if it is directly caused mainly by T-PLL, system therapy is recommended. The calendar age is not a primary decision criterion for the implementation of a system therapy; T-PLL patients >80 years of age are indeed successfully treated with alemtuzumab (Serological tests for HSV (IgM, IgG), CMV (IgM, IgG), EBV (IgM, IgG), HBV (HBSAg, anti-HBc) and HCV (anti-HCV) should be performed before a planned therapy with the strongly immunosuppressive anti-CD52 antibody alemtuzumab. An interferon-γ release assay(QuantiFERONTM) is performed if latent infection with Mycobacterium tuberculosis is clinically or radiologically suspected; patients of reproductive age should receive counseling on fertility and methods of their preservation. Alemtuzumab and purine analogues, however, most likely do not result in infertility).

Initial remission induction: Initial therapy for T-PLL consists of systemic antibody or chemotherapy with the goal of complete remission (CR). The therapy of choice in this regard is alemtuzumab, preferably as a single agent and always intravenously 3x / week for 12-16 weeks ( Dearden C 2011;Dearden C 2012).

An alternative reg imen is initial polychemotherapy with 4 cycles of fludarabine/mitoxantrone/cyclophosphamide (FMC) followed by 6-12 weeks of alemtuzumab consolidation(Hopfinger G et al 2013). Overall response rates (ORR) after both regimens mentioned above are approximately 90-95%. A CR is achieved by intravenous alemtuzumab in monotherapy in about 80% therapy-naïve cases, while the CR rate after FMC alemtuzumab was about 50%; however, the latter were complete remissions confirmed by bone marrow biopsy.

Conventional therapies, such as chlorambucil, CHOP(cyclophosphamide, doxorubicin, vincristine, prednisone) or monotherapies with purine analogues such as fludarabine or pentostatin show unsatisfactory efficacy in the primary therapy of T-PLL. Their response rates are 30-45% and are usually of short duration; e.g. <3 months for CHOP or about 6 months for pentostatin (Mercieca J et al 1994). Therefore, they should not be used primarily.

Alemtuzumab remains the most effective single agent in T-PLL to date. The implementation of this antibody in the therapy of T-PLL has been the most significant step in improving overall survival (OS) to date. While this was approximately 7.5 months in the alkylant/pentostatin era ((Mercieca J et al. 1994), a historical comparison shows that 18 months OS was achieved after alemtuzumab (Dearden C 2012).

Allogeneic and autologous stem cell transplantation.

Despite the high overall response rates (90-95%) and CR rates (50-80%) after alemtuzumab-based initial treatment, almost all patients relapse without further therapy thereafter; e.g., relapse rate 96% with 5-year OS 0% (Dearden CE et al. 2001).

Conceptually, therefore, allo-SCT should already be included in first-line therapy in a consolidating manner after remission has been achieved.

In retrospective studies, the 3-year rates for progression-free survival (PFS)/overall survival (OS) are approximately 20-35%. In the prospective, more recent EBMT observational study, a relapse incidence of 38%, and PFS and OS of 30% and 42%, respectively, with an NRM of 32% were calculated at 4 years (Wiktor-Jedrzejczak W et al. 2019). There is little structured data available on autologous SZT.

Second-line therapy of T-PLL

Primary treatment failure: Inadequate treatment response to alemtuzumab is already observed in primary 5-10% of patients. Initially, alemtuzumab therapy should be intensified by daily doses, possibly also with a glucocorticoid. The addition of pentostatin is a strategy based on the data of monotherapy with ORR of 45% (Mercieca J et al 1994) and the combination of this purine analogue with alemtuzumab with resulting ORR of 69% (Ravandi Fet al 2009).

Whether other established substances such as bendamustine or cladribinin are more suitable combination partners with alemtuzumab in this situation is unclear.

In a smaller proportion of patients, the disease initially runs indolent and asymptomatic for a long time (often diagnosed by chance). Almost always, however, the transition to the exponential growth phase with the need for therapy follows within 1-2 years.

In the predominantly retrospective analyses, TCLA1 expression level and TZR/AKT signaling competence, lymphocyte doubling time (LDT), as well as parameters for tumor burden (LDH, anemia) or a complex aberrant karyotype were described as prognostically relevant (Hopfinger G et al. 2013). The overall rather poor prognosis and the rarity of T-PLL complicate the prospective validation of such prognostic factors.

The term "prolymphocyte" was chosen to better distinguish it from the lymphoid cell of chronic lymphocytic leukemia (CLL). In terms of terminology, this is deliberately not intended to refer to a "progenitor cell character". Due to its poor prognosis, T-cell prolymphocytic leukemia is not to be regarded as the T-cell counterpart of CLL.

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