What is T-cell (T) Large Granular Lymphocyte (LGL) leukemia?

T-Cell Large Granular Lymphocytic (T-LGL) Leukemia

T-LGL leukemia is a rare chronic lymphoproliferative disorder characterized by clonal expansion of cytotoxic T cells, typically presenting with cytopenias (particularly neutropenia and anemia) and often requiring immunosuppressive therapy when symptomatic. 1, 2

Disease Characteristics

Pathophysiology

• T-LGL leukemia results from clonal proliferation of large granular lymphocytes (cytotoxic T cells) driven by prolonged antigenic stimulation 2
• The disease involves apoptotic dysregulation primarily through constitutive activation of survival pathways, notably the JAK/STAT pathway 2
• This represents an intersection between physiological immune response, autoimmune disorder, and malignant clonal proliferation 1

Clinical Presentation

• The disease follows an indolent and often asymptomatic course 1
• Approximately 50% of cases require treatment due to severe transfusion-dependent anemia, severe neutropenia, or moderate neutropenia with recurrent infections 1
• Splenomegaly may be present, as documented in case reports showing spleen enlargement up to 16 cm 3
• Elevated lactate dehydrogenase levels can occur 3

Diagnostic Criteria

Morphologic and Immunophenotypic Features

• Diagnosis requires identification of morphologically characteristic large granular lymphocytes with irregularly shaped nuclei in peripheral blood 3
• Flow cytometry demonstrates an abnormal immunophenotype that is essential for diagnosis 3
• Typical immunophenotype shows positivity for CD2, CD3, CD5, CD8, granzyme, and TIA-1 3
• Cells are typically negative for CD4, CD56, hairy cell markers, CD10, MUM1, and bcl-1 3

Bone Marrow Findings

• Bone marrow biopsy reveals nodular and interstitial proliferation of small, partially atypical T lymphocytic cells 3
• T cell receptor rearrangement studies detect clonal T cell populations, confirming clonality 4

Distinction from Other Entities

• T-LGL must be distinguished from T-cell prolymphocytic leukemia and other mature T-cell neoplasms 5
• The disease differs from chronic lymphocytic leukemia (CLL), which requires ≥5,000 monoclonal B lymphocytes/μL for ≥3 months with mature-appearing lymphocytes and expression of CD5 and CD23 6

Treatment Approach

Observation vs. Active Treatment

• Observation alone is appropriate for asymptomatic patients without significant cytopenias 1, 3
• Treatment initiation is warranted for severe transfusion-dependent anemia, severe neutropenia, or moderate neutropenia with recurrent infections 1

First-Line Immunosuppressive Therapy

• Standard first-line treatment consists of immunosuppressive agents: methotrexate, cyclosporine, and cyclophosphamide 1, 7
• These agents achieve a cumulative response rate of approximately 60% based on longitudinal expertise and retrospective studies 1
• Cyclosporine combined with gradually reduced corticosteroid doses can lead to regression of splenomegaly and normalization of lactate dehydrogenase 3

Refractory Disease Management

• For relapsed/refractory disease, ruxolitinib (a JAK inhibitor) demonstrates an overall response rate of 86%, including complete and partial responses 7
• In a series of 21 patients, 47.6% were refractory to the three main immunosuppressive drugs at ruxolitinib initiation 7
• Ruxolitinib yielded 3 complete responses and 15 partial responses with median response duration of 4 months 7
• One-year event-free survival was 57% and one-year overall survival was 83% with ruxolitinib 7
• Neutropenia and anemia improved significantly with ruxolitinib, and complete molecular responses were documented 7

Alternative Therapies for Refractory Cases

• Rituximab (anti-CD20 antibody) has shown response in isolated refractory cases, though this is uncommon given the T-cell nature of the disease 4
• Anti-CD52 antibody alemtuzumab and purine analogues represent additional options for refractory disease 4

Important Clinical Considerations

Common pitfall: The disease is probably underdiagnosed due to its indolent nature and requirement for specific flow cytometry evaluation 3. Clinicians should maintain high suspicion in patients presenting with unexplained chronic neutropenia or anemia with lymphocytosis.

Key distinction: Unlike aggressive leukemias, T-LGL leukemia's relatively indolent clinical behavior means that not all patients require immediate treatment, and observation remains appropriate for asymptomatic cases 1, 3.