T-Cell Prolymphocytic Leukemia: Diagnosis, Pathogenesis, and Treatment

Abstract

T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive neoplasm of mature T-cells. Most patients with T-PLL present with lymphocytosis, anemia, thrombocytopenia, and hepatosplenomegaly. Correct identification of T-PLL is essential because treatment for this disease is distinct from that of other T-cell neoplasms. In 2019, the T-PLL International Study Group (TPLL-ISG) established criteria for the diagnosis, staging, and assessment of response to treatment of T-PLL with the goal of harmonizing research efforts and supporting clinical decision-making. T-PLL pathogenesis is commonly driven by T-cell leukemia 1 (TCL1) overexpression and ATM loss, genetic alterations that are incorporated into the TPLL-ISG diagnostic criteria. The cooperativity between TCL1 family members and ATM is seemingly unique to T-PLL across the spectrum of T-cell neoplasms. The role of the T-cell receptor, its downstream kinases, and JAK/STAT signaling are also emerging themes in disease pathogenesis and have obvious therapeutic implications. Despite improved understanding of disease pathogenesis, alemtuzumab remains the frontline therapy in the treatment of naïve patients with indications for treatment given its high response rate. Unfortunately, the responses achieved are rarely durable, and the majority of patients are not candidates for consolidation with hematopoietic stem cell transplantation. Improved understanding of T-PLL pathogenesis has unveiled novel therapeutic vulnerabilities that may change the natural history of this lymphoproliferative neoplasm and will be the focus of this concise review.

Keywords: ATM; BH3 mimetic; JAK; STAT; T-cell receptor; T-prolymphocytic leukemia (T-PLL); TCL1A; alemtuzumab.

Figure 1

Peripheral blood involvement by T-PLL. Representative images demonstrate that T-PLL tumor cells (Wright stain) can be variable in size and range from medium (right panel) to large (left panel), with irregular nuclear contours, condensed chromatin, and prominent nucleoli. The morphological and cytological features of T-PLL have been previously documented and described [2,6,7].

Figure 2

(A,B) Involvement of bone marrow with T-PLL. (A) Highlights of interstitial involvement by tumor cells (blue arrows). (B) The most common morphological pattern is composed of medium lymphocytes with round nuclear contours and central prominent nucleoli (blue arrows). (C) Focal aggregates of tumor cells are usually observed (dotted circles). (D) Small-cell morphology variant is characterized by small to medium forms with condensed chromatin (blue arrows). Occasional large “cerebriform” lymphocytes are also observed (red arrows). The morphological features characteristic of T-PLL bone marrow involvement have been previously described [2,6,7].

Figure 3

Skin involvement by T-PLL (black arrows). The tumor cells are predominantly distributed in a perivascular fashion, with no epidermotropism. Characteristic histological features of dermal involvement by T-PLL have been previously described [2,6,7].

Figure 4

Therapeutic pathways in T-PLL. While alemtuzumab is the current frontline therapy, an improved understanding of T-PLL pathogenesis is leading to potentially targetable vulnerabilities. These include attempts to reinstate p53 function through MDM2 inhibitors as well as exploitation of faulty double strand break repair via PARP inhibitors, inhibition of TCR activation through ITK inhibitors as well as AKT/PI3K inhibitors, JAK inhibitors which inhibit cell growth and differentiation through the JAK-STAT pathway, BH3 mimetics to promote BAX and BAK mediated cell death, epigenetic approaches including hypomethylating agents and HDAC inhibitors, and novel antibody targeting e.g., CCR7. The illustration was created using Biorender.com and is adapted from previous review articles [47,72,73].