Large granular lymphocyte leukemia, rheumatoid arthritis, and Felty's syndrome

Large granular lymphocyte leukemia, rheumatoid arthritis, and Felty's syndrome

What every physician needs to know:

Large granular lymphocyte leukemia (LGL) is a lymphoproliferative disorder, marked by clonal expansion of large granular lymphocytes, usually T cell in origin (85%), with a minority that arise in the natural killer (NK) lineage (15%).

Median age of onset is 60 years, with no difference in male versus female incidence. The majority of patients in the western hemisphere with T-cell LGL present with symptoms related to chronic neutropenia, which predisposes them to recurrent bacterial infections. Infections usually involve the skin, oropharyngeal, and perirectal areas, but pneumonia and sepsis may also occur.

A prominent feature of T-cell LGL is its association with autoimmune disorders, the most common of which is rheumatoid arthritis, occurring in up to 25% of patients. Clinical manifestations of T-cell LGL may include splenomegaly, neutropenia, and rheumatoid arthritis, thus resembling patients with Felty’s syndrome. The articular manifestations of typical Felty’s syndrome and rheumatoid arthritis associated T-cell LGL are difficult to distinguish, and the occurrence of LGL in Felty’s syndrome is probably greater than what is reported.

Patients with LGL and rheumatoid arthritis also have the same high frequency of the HLA-DR4 haplotype as patients with Felty’s syndrome, thus linking them immunologically. This association suggests that these diseases may represent a continuum of a clinicopathological process, in which overlapping mechanisms may result in immune mediated neutrophil destruction, and thus similar symptoms.

Are you sure your patient has large granular lymphocyte leukemia? What should you expect to find?

The diagnosis of LGL is established by documentation of increased numbers of clonal LGL cells. Clinical findings of LGL are generally associated with neutropenia (neutrophil count less than 0.5 X 10^9¹ and include, but are not limited to, recurrent bacterial infections including, skin, subcutaneous tissue, urinary tract, bacteremia, and perirectal abscesses. B symptoms (fevers, chills, night sweats) are present in 20 to 30% of cases.

Mild to moderate splenomegaly is present in 20 to 50%. In general, rheumatological features in LGL with rheumatoid arthritis are milder than those seen in Felty’s syndrome, with joint destruction typically presenting more severely in the latter group. Moderate to severe anemia (hemoglobin less than 8g/dl) can be present in up to 20% of cases and may manifest as pure red cell aplasia or hemolytic anemia.

Beware of other conditions that can mimic large granular lymphocyte leukemia:

A significant number of healthy elderly individuals display benign monoclonal CD3+/CD8+ T cell expansions, which do not differ phenotypically from those observed in T-cell LGL patients. This so called T cell clonopathy of undetermined significance may overlap with indolent T-cell LGL.

Increased numbers of LGL can be transiently observed after a variety of viral infections; in some occurrences such LGL reactivity can be clonal in origin.

Which individuals are most at risk for developing large granular lymphocyte leukemia:

The etiology of LGL is not known. No formal epidemiological studies have been performed, so risk factors remain unknown. Patients with indolent T-cell LGL have a median age of approximately 60 years, equal numbers of males and females. Rheumatoid arthritis is present in approximately 11 to 36% of patients with LGL, compared to only 0.5 to 1% in the general population.

Felty’s syndrome is a rare sub category occurring in only about 1% of rheumatoid arthritis patients. However, as described, there is a genetic association among patients with LGL, rheumatoid arthritis, and Felty’s syndrome, as they share the same HLA-DR4 haplotype.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

LGL should be considered in patients with unexplained cytopenias or rheumatoid arthritis.

An important test is a careful review of the peripheral blood smear for detection of increased numbers of circulating LGL. LGL are intermediate to large lymphocytes, with an increased amount of pale cytoplasm containing a variable number of red granules as seen in Figure 1 (This figure was originally published in Blood: Lamy T, Loughran TP Jr. How I Treat LGL Leukemia. Blood. 2011;117:2764-2774. © the American Society of Hematology.).

The two other most important laboratory studies to establish the diagnosis are flow cytometry and T cell receptor gene rearrangement. The most typical phenotype of leukemic LGLs as determined by flow cytometry is CD3+TCRαβ+CD8+CD57+ and CD16+. Clonality is established by T-cell gene rearrangement studies. The methods to determine TCR gene rearrangement are through polymerase chain reaction (PCR) and Southern blotting.

Flow cytometry can also be utilized to suggest clonality since there are monoclonal antibodies available for approximately 70% of the variable region for families of the β chain (Vβ). A complete blood count will reveal important information with regard to the number of lymphocytes, platelets, neutrophils, and erythrocytes.

What imaging studies (if any) will be helpful in making or excluding the diagnosis of large granular lymphocyte leukemia?

Computed tomography scanning or ultrasound can be used for detection of splenomegaly in both Felty’s syndrome and LGL patients.

If you decide the patient has large granular lymphocyte leukemia, what therapies should you initiate immediately?

Most T-cell LGL patients follow an indolent course. However, therapy is indicated for severe neutropenia or anemia. The mainstay of treatment is weekly low dose immunosuppression with 10mg/m² of methotrexate (also known under the brand names Rheumatrex and Trexall). ^{Originally, this drug was used at high doses as an anti-cancer therapy, but later recognized as an anti-inflammatory and immunosuppressive agent effective at low doses, with the ability to alleviate rheumatoid arthritis, prevent graft-versus-host disease for allogeneic transplants, and to treat other chronic inflammatory and autoimmune diseases.}

Methotrexate is an established treatment for rheumatoid arthritis and has been successful in Felty’s syndrome patients with severe neutropenia. Given that activated T cells in rheumatoid arthritis (CD4+,CD28-,CD57+,HLA-DR+) have a similar immunophenotype to T-cell LGL cells (CD3+,CD28-CD57+HLA-DR+), this provides the rationale for use of methotrexate. Methotrexate has been associated with rare side effects consisting of gastrointestinal, cardiovascular, dermatologic, and ocular complaints. Much of the toxicity related to methotrexate administration appears to be related to its effects on folate metabolism and particularly affects systems with high cell turnover such as the gastrointestinal tract.

Patients that do not respond well to treatment with methotrexate may be provided with alternate treatments of cyclophosphamide at 50 to 100mg daily or cyclosporine A at 5 to 10mg/kg daily. It may take up to 4 months for response to occur, so treatment with these agents should not be abandoned prematurely. Similar to methotrexate, cyclophosphamide and cyclosporine A have potential associated toxicities, most prominent with long term therapy with cyclosporine A. In rare cases, cyclophosphamide has been implicated in therapy related acute myeloid leukemia.

More definitive therapies?

New targeted therapies are under development for T-cell LGL. One example is Tipifarnib, a farnesyltransferase inhibitor that has action on the MAP/ERK/RAS pathway. Although no hematologic responses were observed in a phase II study, promising biologic activity was demonstrated as evidenced by findings of decreased LGL in blood and bone marrow and improved marrow hematopoiesis (unpublished observations).

In addition, there was remarkable improvement in signs of pulmonary hypertension in one patient. A humanized monoclonal antibody directed toward the interleukin-2 receptor (IL-2R)/interleukin-15 receptor (IL-15R) and alemtuzumab, a monoclonal antibody against CD52 are also being studied.

What other therapies are helpful for reducing complications?

A short course of corticosteroids in addition to methotrexate treatment may help to alleviate B symptoms and improve blood cell counts more quickly.

Prednisone alone has been shown to improve neutrophil counts, but the LGL clone continues to persist. However, methotrexate may act as a steroid-sparing agent, allowing the prednisone dose to be tapered, while maintaining the neutrophil count in a normal range. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony stimulating factor (G-CSF) use in the management of patients with Felty’s syndrome has shown a sustained increase of ANC (absolute neutrophil count) to 1,000/ul or greater.

Splenectomy has proven beneficial in Felty’s syndrome patients that have neutrophil survival defects mediated by excessive immunoglobulin production by plasma cells in the spleen, but not in those patients with a cytotoxic lymphocyte proliferation defect; therefore it is rarely used as current therapy.

What should you tell the patient and the family about prognosis?

LGL is usually a chronic disease, with some patients remaining asymptomatic for several years.

Patients with uncomplicated cytopenias are usually not treated until there is symptomatic progression. Approximately 70% of patients require therapy, mostly because of recurrent bacterial infections secondary to neutropenia.

What if scenarios.

The most common pitfall is not considering the diagnosis of LGL in patients with rheumatoid arthritis or unexplained cytopenias. Once the diagnosis is established, the next concernis making a treatment decision.

The physician needs to be aware of the indications for treatment, as not all patients need immediate therapy. Also, it is very important to understand that patients needing therapy should not be treated with chemotherapy, but instead should receive an immunosuppressive regimen. Finally, clinicians need to understand that response to therapy is not immediate and that 4 months of treatment are required before an accurate evaluation of response is obtained.

In rheumatoid arthritis, a step wise approach, using clinical and laboratory investigation can help guide therapy, especially in patients with uncomplicated cytopenias versus those with symptoms related to complicated cytopenias.

Pathophysiology

Rheumatoid arthritis (RA) is the most common autoimmune condition seen in approximately 25% of individuals with T-cell LGL. These T-cell LGL patients share similarity with Felty’s syndrome, such as neutropenia, rheumatoid arthritis (RA), and splenomegaly.

Interestingly, patients with LGL (approximately 90%) and RA (approximately 86%) have the same HLA-DR4 haplotype in high frequency as patients with Felty’s Syndrome. As a result, rheumatoid arthritis patients in either T-cell LGL and Felty’s syndrome groups, share a common immunogenetic background. Dysregulated apoptosis appears to be the fundamental mechanism in pathogenesis. LGL cells in both LGL and rheumatoid arthritis are characterized by constitutive activation of survival signaling.

It is hypothesized that chronic T-cell LGL could be the result of viral infection or an endogenous autoantigen, which leads to the trigger of LGL expansion; a main difference in LGL compared to rheumatoid arthritis is the size of the clone. A dominant clone is easily detected in LGL; in contrast, the clonal size of T LGL cells in rheumatoid arthritis patients is relatively small.

What other clinical manifestations may help me to diagnose large granular lymphocyte leukemia?

LGL can be associated with a variety of hematologic presentations including chronic neutropenia, cyclic neutropenia, pure red cell aplasia, hemolytic anemia, and idiopathic thrombocytopenia purpura (ITP). There also appears to be an increased risk for development of B cell lymphoproliferative disorders with benign monoclonal gammopathy most commonly observed.

Although rheumatoid arthritis is the primary autoimmune disease associated with LGL, other diseases such as scleroderma, Sjorgren’s syndrome, and lupus are occasionally seen. Pulmonary hypertension has also been associated with LGL.

What other additional laboratory studies may be ordered?

Tests for B cell dysregulation are important, as LGL patients with autoimmune disease may also frequently have serological abnormalities suggesting an autoimmune process. Up to about 60% of patients can be positive for rheumatoid factor and up to about 40% are positive for antinuclear antibodies.

Circulating immune complexes and elevated levels of ß2 microglobulin are often observed. Quantitative immunoglobulin/serum protein electrophoresis often reveals polyclonal, and less often monoclonal hypergammaglobulinemia. Also, tests for human leukocyte antigen (HLA) genotyping can demonstrate the association between Felty’s syndrome, RA and LGL.

It is not usual practice to perform bone marrow aspiration/biopsy unless the diagnosis is uncertain, but may be particularly helpful in patients with normal levels of circulating LGL cells. In such cases, marrow findings may reveal diagnostic interstitial cluster of leukemic LGL in linear arrays.

Although clonal cytogenetic findings were originally used to define LGL, such tests are usually non-informative and have been replaced by TCR gene rearrangement studies. Most karyotypes for T-cell LGL patients will be normal, with fewer than about 10% showing some karyotypic abnormalities, which may include trisomies of chromosomes 3, 8, 14, deletions of chromosome 6 and 5q, and inversions of 12p and 14q.

What’s the evidence?

Lamy, T, Loughran, TP. ” How I Treat LGL Leukemia”. Blood. vol. 117. 2011. pp. 2764-2774. [An important test is a careful review of the peripheral blood smear for detection of increased numbers of circulating LGL. LGL are intermediate to large lymphocytes, with an increased amount of pale cytoplasm containing a variable number of red granules.]

Sokol, L, Loughran, TP. ” Large granular lymphocyte leukemia”. Oncologist.. vol. 11. 2006. pp. 263-273. [Comprehensive background describing the pathogenesis of LGL and details its subtypes.]

Starkebaum, G, Loughran, TP, Gaur, LK, Davis, P, Nepom, BS. ” Immunogenetic similarities between patients with Felty's syndrome and those with clonal expansions of large granular lymphocytes in rheumatoid arthritis”. Arthritis Rheum. vol. 40. 1997. pp. 624-626. [Also examines the association shared between LGL and Felty's syndrome in patients with rheumatoid arthritis.]

Rossi, D, Franceschetti, S, Capello, D. ” Transient monoclonal expansion of CD8+/CD 57+ T cell large granular lymphocytes after primary cytomegalovirus infection”. Am J Hematol. vol. 82. 2007. pp. 1103-1105. [Demonstrates that CD8+ T-cell expansions may sometimes result from viral infection and not malignancy alone.]

Battiwalla, M, Melenhorst, J, Saunthararajah, Y. ” HLA-DR4 predicts haematological response to cyclosporine in T-large granular lymphocyte lymphoproliferative disorders”. Br J Haematol. vol. 123. 2003. pp. 449-453. [A small clinical study demonstrating that patients with an HLA-DR4 phenotype responded favorably to cyclosporine treatment.]

Dhodapkar, MV, Li, CY, Lust, JA, Tefferi, A, Phyliky, RL. ” Clinical spectrum of clonal proliferations of T-large granular lymphocytes: a T-cell clonopathy of undetermined significance?”. Blood. vol. 84. 1994. pp. 1620-1627. [Highlights the variable diseases associated with T-LGL as well as the heterogeneity in co-morbid conditions between patients.]

Burks, EJ, Loughran, TP. ” Pathogenesis of neutropenia in large granular lymphocyte leukemia and Felty syndrome”. Blood Reviews. vol. 20. 2006. pp. 245-266. [Demonstrates the immunophenotype shared between rheumatoid arthritis and LGL.]

Freimark, B, Lanier, L, Phillips, J, Quertermous, T, Fox, R. ” Comparison of T cell receptor gene rearrangements in patients with large granular T cell leukemia and Felty's syndrome”. J Immunl. vol. 138. 1987. pp. 1724-1729. [Comparing the genetic similarities between T-cell LGL and Felty's syndrome.]

Zhang, R, Shah, MV, Loughran, TP. ” The root of many evils: indolent large granular lymphocyte leukaemia and associated disorders”. Hematol Oncol.. vol. 28. 2010. pp. 105-117. [Provides an overview of LGL biology and focuses on disorders related to indolent LGL.]

Wong, KF, Chan, JC, Liu, HS, Man, C, Kwong, YL. ” Chromosomal abnormalities in T-cell large granular lymphocyte leukaemia: report of two cases and review of the literature”. Br J Haematol.. vol. 116. 2002. pp. 598-600. [More case studies that examine the rare chromosomal abnormalities that are associated with T-cell LGL.]

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