T-cell prolymphocytic leukemia (T-PLL)
T-cell prolymphocytic leukemia is a very rare, usually aggressive malignant disease of the lymphatic system. To gain further insights into this very rare entity, every newly diagnosed T-PLL should be included in the German CLL Study Group Registry (DCLLSG) for the purpose of systematic data collection.
The pathological cell population develops from mature T cells that have already undergone imprinting in the thymus. Often the pathological cells are CD4+/CD8-, but there are also cases with CD4-/CD8+ or CD4+/CD8+. Characteristic and also relatively specific for the disease are rearrangements involving the "T-cell leukemia/lymphoma 1" (TCL1) gene family, which lead to pathological overexpression of the oncogenes TCL1A, TCL1B or MTCP1 (Staber et al. 2019). In recent years, patient survival has been significantly improved by treatment with anti-CD52 monoclonal antibodies (alemtuzumab) and stem cell transplantation.
Classification of T-PLL
T-cell prolymphocytic leukemia accounts for about 2% of all mature lymphocytic leukemias and is described by the WHO as a separate entity.
T-PLL WHO Classification 2017
(Swerdlow et al. 2017)
Mature T-cell neoplasm
T-cell prolymphocytic leukemia
There are three morphological variants:
small cell variant
Diagnostics according to consensus criteria of the international T-PLL study group
The diagnosis according to the criteria of the T-PLL International Study Group (T-PLL-ISG) can usually be made on the basis of cytomorphology and immunophenotype. Genetic tests can significantly support the diagnosis. Table 1 gives an overview of the consensus criteria established for the diagnosis of T-cell prolymphocytic leukemia (Staber et al. 2019). T-PLL cells can be found in peripheral blood, bone marrow, lymph nodes, spleen, liver or skin. In clinical routine, peripheral blood is usually sufficient to confirm the diagnosis (Staber et al. 2019). Differentiation from other mature cell lymphomas must be made by differential diagnosis (Swerdlow et al. 2016).
Table 1: Consensus criteria of the T-PLL-ISG
(according to Staber et al. 2019). The diagnosis of a T-PLL can be made if either all three main criteria are met, or the first two main criteria and one secondary criterion are met.
>5 x 109/l cells of T-PLL phenotype in peripheral blood or bone marrow
Abnormalities involving chromosome 11 (11q22.3; ATM)
|T-cell clonality (by PCR for TRB/TRG, or by flow cytometry)||Abnormalities in chromosome 8: idic(8)(p11), t(8;8), trisomy 8q|
|Abnormalities of 14q32 or Xq28 OR expression of TCL1A/B, or MTCP1*|
Abnormalities in chromosome 5, 12, 13, 22, or complex karyotype
Involvement of T-PLL specific site (eg, splenomegaly, effusions)
Diagnostics of T-PLL
The overall rather uniformly poor prognosis for patients and the rarity of T-PLL hinder the prospective validation of clinical or biological prognostic factors. In clinical practice, there are currently no validated prognostic factors that can be used as a basis for specific stratification and therapeutic decisions.
T-PLL patients can be enrolled in the registry study of the German CLL Study Group (DCLLSG) "Long-Term Follow-Up of Patients with CLL, B-PLL, T-PLL, SLL, T/ NK-LGL, HCL and Richter Transformation" (NCT02863692) at the University of Cologne (detailed information).
Therapy of T-PLL
With regard to the course of the T-PLL disease, two phases can be distinguished: the asymptomatic "inactive phase" and the "active phase", in which characteristic symptoms such as lymphadenopathy, leukocytosis, hepato- and/or splenomegaly occur. Only a small percentage is diagnosed in the inactive phase. Under these circumstances, a prudent watch-and-wait approach is usually indicated, which requires close monthly monitoring. After 1-2 years, even in diseases diagnosed in the inactive phase, a transition to the active phase requiring treatment occurs (Staber et al. 2019, Onkopedia Guideline T-PLL 2020).
The current gold standard in the treatment of T-PLL is treatment with the anti-CD52 monoclonal antibody alemtuzumab. Although the initial response is very good, with overall response rates of over 90% in some cases, recurrences almost always occur (Staber et al. 2019), with a median progression-free survival of approximately 12 months (Dearden et al. 2011, Hopfinger et al. 2013, Braun et al. 2020). Only stem cell transplantation represents a curative approach, but only about 30-50% of patients are eligible for this procedure (Onkopedia Guideline T-PLL 2020). Long-term remissions after allogeneic stem cell transplantation were observed in about 1/3 of the patients (Staber et al. 2019).
New therapeutic approaches result from the improved understanding of the pathobiology of the disease (see also Diagnostics, FISH and Molecular Genetics) and various drug screenings (Andersson et al. 2018, Dietrich et al. 2018, Schrader et al. 2018, Braun et al. 2020), which could lead to an improvement of the response time in first-line therapy as well as to new therapeutic strategies for the treatment of recurrent T-PLL and for maintenance therapy after stem cell transplantation.
In the class of small molecule inhibitors, the following agents in particular show ex vivo activity against T-PLL (Andersson et al. 2018, Braun et al. 2020) and are currently being investigated in clinical studies:
HDAC inhibitors (epigenetic regulation and reactivation of p53)
MDM2 inhibitors (reactivation of p53, thereby induction of apoptosis)
BCL2 inhibitors (induction of apoptosis)
Inhibitors of the JAK-STAT signaling pathway
T-PLL sensitivity to JAK inhibitors was also described in another ex vivo screening study (Dietrich et al. 2018). A Phase I study is currently investigating whether the response and especially the response time can be improved by combining alemtuzumab with the JAK1 inhibitor itacitinib (NCT03989466).
Sensitivity to BCL2 inhibitors was also observed in a further ex vivo screening approach (Boidol et al. 2017). Under venetoclax monotherapy, a transient partial response was achieved in two individual treatment trials in refractory T-PLL (Boidol et al. 2017). Another screen identified the tyrosine kinase inhibitor ibrutinib as a potential synergistic agent (Kornauth et al. 2019). After observing a substantial clinical response to combination therapy in two patients with relapsed T-PLL, a Phase II study was initiated to evaluate venetoclax/ibrutinib therapy (NCT03873493). A Phase I study is evaluating another potential synergism that may result in the induction of apoptosis by treatment with an MDM2 inhibitor and a BCL2 inhibitor (NCT04496349).