• Disease Overview
  • Synonyms
  • Subdivisions
  • Signs & Symptoms
  • Causes
  • Affected Populations
  • Diagnosis
  • Standard Therapies
  • Clinical Trials and Studies
  • References
  • Programs & Resources
  • Complete Report
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Large Granular Lymphocyte Leukemia


Last updated: April 11, 2022
Years published: 2022


NORD gratefully acknowledges Bryna Shemo, MA, CCRC, Clinical Research Coordinator, LGL Leukemia Registry, and Thomas P. Loughran Jr., MD, Director, University of Virginia Cancer Center, for the preparation of this report.

Disease Overview


Large granular lymphocyte leukemia (LGLL) is a chronic blood disorder in which there is an increased number of large granular lymphocytes in the peripheral blood that accumulate over time. All cells in the body, including skin cells, liver cells and even immune cells, are meant to die off and be replaced by new cells throughout a person’s lifetime, but in patients with LGLL, large granular lymphocytes do not die off when they are supposed to. In general, LGLL is a disease that progresses very slowly, but these slow changes can lead to frequent infection, anemia and easy bleeding.


Usually, when someone has a viral infection like the flu, foreign antigens, such as viral proteins, are recognized by a specific type of white blood cell (usually a T-cell) and cause it to be activated to make many copies of itself (other T-cells) to battle the virus. These cells release toxic molecules to kill cells infected with the virus along with inflammatory signals called cytokines which tell the body that the virus has invaded. The body responds by prioritizing functions that fight the flu such as having the body make lymphocytes rather than other cell types like red blood cells, neutrophils or platelets. When these T-cells successfully fight off the virus, they die off to make room for other blood cells. Their death stops the release of the inflammatory signals, and the body goes back to its healthy, resting state. In people with LGL leukemia, these T-cells do not to die off, so the inflammatory signals keep being released, even when there is no longer a viral infection. The leukemic blood cells accumulate and there is less room for healthy cells. The leukemic cells also release inflammatory signals that tell the body to produce fewer red blood cells, platelets and neutrophils.

LGL leukemia was first reported by Dr. Thomas Loughran in 1985 and described in the publication “Leukemia of Large Granular Lymphocytes: Association with Clonal Chromosomal Abnormalities and Autoimmune Neutropenia, Thrombocytopenia and Hemolytic Anemia” (Loughran et al, 1985). He described a disease characterized by neutropenia (low neutrophils), anemia (low red blood cells) and thrombocytopenia (low platelets). Neutrophils are cells that try to kill any foreign substances in the body before they can cause infection. Red blood cells transport oxygen to organs and tissues. Platelets cause blood to clot and stop bleeding when injury occurs. Patients with low neutrophils may experience recurrent infections. Patients with low red blood cells may experience shortness of breath and fatigue. Patients with low platelets may have trouble getting bleeding to stop when they are injured.

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  • LGLL
  • large granular lymphocytic leukemia
  • LGL leukemia
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  • T-cell (T) LGL leukemia
  • chronic natural killer cell (NK)-LGL leukemia
  • aggressive NK-LGL leukemia
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Signs & Symptoms

The symptoms that patients with LGL leukemia most commonly experience are related to the changes in neutrophils, red blood cells and platelets. Changes in neutrophils are the most common, followed by changes in red blood cells, with changes in platelets being the least common. Patients can also have a combination of these changes. Many patients with LGL leukemia report fatigue and flu-like symptoms or other symptoms that are commonly associated with having an active infection, even when they do not have an infection (Lamy & Loughran, 2003). As discussed above, the LGL cells that do not die off continue to make the same inflammatory signals that they would during an active infection, so these additional symptoms are likely due to the body continuing to respond to those signals.

Patients with LGL leukemia have a higher-than-normal chance of having autoimmune diseases such as rheumatoid arthritis. Other autoimmune issues such as Sjogren syndrome, systemic lupus erythematosus and Hashimoto’s disease are also associated with LGL leukemia (Sokol & Loughran, 2006; Zhang et al. 2010). Swelling of the spleen and, rarely, the liver occurs in a small number of patients. Pure red cell aplasia has also been noted in a subset of patients.

Studies have shown a life expectancy of 10 years after diagnosis (Shah et al, 2016). Although this data was accurate in the population at the time, it is not fully representative of current survival expectations. This information was collected on patients whose disease progression was quite advanced and who were generally older than the current average LGLL patient. It is now possible to diagnosis LGL leukemia earlier in the disease process, and a recent small scale study (Rivero et al. 2021) along with more extensive unpublished data from a patient Registry indicates that patients have an average and mean lifespan that is within a few years of the national average.

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The exact cause of LGL leukemia is not known. Ongoing research in the Loughran Lab at the University of Virginia has led researchers to theorize that patients develop LGLL following exposure to foreign antigens, potentially due to a viral infection. It is proposed that cells that are fighting off that virus are transformed by gene changes (mutations) and cannot die off as they typically would after they have fought off the virus (Kanchan & Loughran, 2003). These mutations develop in a group of mature cells after birth, so they are not passed down to a patient’s children. Recent research studies have catalogued the most frequently mutated genes in LGL leukemia (Olson et al., 2021; Cheon et al., 2022).

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Affected populations

The incidence of LGL leukemia increases with age. It is usually diagnosed in older people and rarely occurs in individuals under 30 years old. LGLL almost never affects children and is very rare in patients under the age of twenty. In the United States, the incidence of LGLL is thought to be 0.2 to 0.72 cases out of every 1,000,000 people, but this may be an underestimate. Patients in an early stage of the disease or people without symptoms may go undiagnosed.

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LGL leukemia cells can develop from two different types of large granular lymphocytes, cytotoxic T-cells and natural killer (NK) cells. The type associated with NK cells is very rare, and accounts for only 10-15% of cases. LGL leukemia of either type typically exhibits a slow-moving, chronic disease course. However there is an aggressive form of NK type of LGL leukemia that is primarily seen in Asian populations and is distinctly different than the chronic type of NK-LGL leukemia. Therefore, it is important to have an accurate and thorough workup focused on the known markers for LGL leukemia to correctly categorize the type of LGL leukemia.

LGLL is usually discovered when an abnormally high white blood cell count and/or lower numbers of red blood cells, platelets or neutrophils are noticed in routine blood work. LGLs have a very distinctive cellular morphology and can be detected by visual examination of a blood smear on a microscope slide. A definitive diagnosis is established when there is an increased number of LGL in the blood which are clonally expanded. The combination of the following tests are required:

1. Complete blood cell count: This test will measure the number of various types of blood cells including white blood cells, red blood cells and platelets. A high number of lymphocytes and/or a low number of red blood cells, platelets or neutrophils can be indicators of LGL leukemia.

2. Flow cytometry: In this test blood cells are examined with antibodies to determine if there are more large granular lymphocytes in the blood than in a healthy individual. This test helps establish the diagnosis of LGL leukemia, differentiates between T and NK LGL leukemia and rules out other disorders.

3. T-cell gene rearrangement: This genetic test is used to show clonality, meaning that there is a group of cells with the same T-cell receptor, which indicates that they all came from the same parent cell.

Additional Testing

Bone marrow biopsy: This test is conducted by removing a sample of bone marrow and evaluating it to determine whether abnormal cells are present. This is usually not required to make a diagnosis of LGLL, since the testing above can be done on the blood. However, it is often done early in the diagnostic process to ensure that a more acute or potentially fatal illness, such as myelodysplastic syndrome (MDS) is not missed while evaluating the patient for LGLL.

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Standard Therapies


Many patients who are newly diagnosed with LGL leukemia will not need treatment for some time after diagnosis. These patients enter what is referred to as the “watch and wait” phase of their disease management. Physical exams and regular blood tests to look for falling numbers of red blood cells, platelets and neutrophils along with the onset of new symptoms related to LGLL may be all that is needed. A decline in blood counts below a certain level or onset of symptoms that continuously affect physical functioning are metrics that determine the need for treatment.

About 5-10% of LGLL patients never need treatment in their lifetime. The need for treatment is still based primarily on worsening blood counts or symptoms especially related to reduced neutrophil or red blood cell counts, not on the number of leukemic cells.

Treatment is generally recommended when absolute neutrophil count (ANC) drops below 0.5 cellsx10E9/L (500 cellsx10E6/L at some labs) or recurrent infections start to occur, when hemoglobin drops below 8.0 g/dL or a patient needs frequent blood transfusions, or when platelet count drops below 20 cellsx10E9/L. Patients with LGL leukemia-associated autoimmune disease, like rheumatoid arthritis, may be treated with medications to manage both the autoimmune disease symptoms and kill the LGLL cells. Patients with severe symptoms who do not fall into the lower blood count ranges may begin treatment before numbers fall into the at-risk range as well. The decision to start treatment is complex and should be made under the close supervision of a patient’s treating physician. The treating physician will also need to monitor a patient’s blood numbers more closely during treatment to evaluate whether the treatment is safe and, later, whether it is working. The medications used to treat LGL leukemia are called Immunosuppressives. They are used to decrease the survival of immune cells like lymphocytes. Treatment usually takes 4-6 months to show a stable improvement of low blood counts.

The three immunosuppressives that are used in LGL leukemia are methotrexate, cyclosporine A and cyclophosphamide. They are all manufactured under several brand names, so care should be taken to check that recommended treatments fall into these three categories. When they are given in very high doses, methotrexate and cyclophosphamide are used as chemotherapeutic drugs, but they are used in much lower doses to act as immunosuppressives in LGL leukemia. Therefore, when used to treat LGLL they do not have the same side effects as they do as chemotherapeutics. It is important to note that online information about these agents generally only covers the side effects that are associated with chemotherapy. Although each medication can only be expected to work in 40-60% of patients individually (depending on the drug), about 90% of patients will respond to one of these three medications. For the remaining 10% of patients, several alternative therapies are available, but because they have been less well studied in the LGLL patient population, they are recommended on a case-by-case basis (Loughran and Lamy, 2011).

In addition to the therapies that help LGLL cells die off, there are supportive therapies that can help patients with LGLL. These therapeutics can help keep patients healthy so they need active treatment less infrequently and can keep their other blood cell numbers stable during treatment. These supportive medications include steroids, like prednisone, to help support the bone marrow in making normal cells, colony stimulating factors to support neutrophil numbers and transfusions to help increase red blood cell or platelet counts. There is also clinical and research data to support the use of supplements in LGLL patients. Vitamin D has been shown to have supportive effects in managing the effects of LGL leukemia and folate is also a common supportive agent, especially when patients are taking the immunosuppressive drug methotrexate.

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Clinical Trials and Studies

For more information about LGL leukemia contact the LGL Leukemia Program and Registry at the University of Virginia.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:

For information about clinical trials sponsored by private sources, contact:

For information about clinical trials conducted in Europe, contact:

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Cheon H, Xing JC, Moosic KB, Ung J, Chan V, Chung DS, Toro MF, Elghawy O, Wang JS, Hamele CE, Hardison RC, Olson TL, Tan SF, Feith D, Aakrosh R, Loughran T. Genomic Landscape of TCR Alpha-Beta and TCR Gamma-Delta T-Large Granular Lymphocyte Leukemia. Blood. 2022 Jan 11:blood.2021013164.

Olson TL, Cheon H, Xing JC, Olson KC, Paila U, Hamele CE, Neelamraju Y, Shemo BC, Schmachtenberg M, Sundararaman SK, Toro MF, Keller CA, Farber EA, Onengut-Gumuscu S, Garrett-Bakelman FE, Hardison RC, Feith DJ, Ratan A, Loughran TP. Frequent somatic TET2 mutations in chronic NK-LGL leukemia with distinct patterns of cytopenias. Blood. 2021 Aug 26;138(8):662-673.

Rivero A, Mozas P, Jiménez L, López-Guerra M, Colomer D, Bataller A, Correa J, Rivas-Delgado A, Bastidas G, Baumann T, Martínez-Trillos A, Delgado J, Giné E, Campo E, López-Guillermo A, Villamor N, Magnano L, Matutes E. Clinicobiological characteristics and outcomes of patients with T-cell large granular lymphocytic leukemia and chronic lymphoproliferative disorder of natural killer cells from a single institution. Cancers. 2021; 13(15):3900. https://doi.org/10.3390/cancers13153900

Lamy T, Moignet A, Loughran TP Jr. LGL leukemia: from pathogenesis to treatment. Blood. 2017 Mar 2;129(9):1082-1094.

Shah MV, Hook CC, Call TG and Go RS. A population-based study of large granular lymphocyte leukemia. Blood Cancer J. 2016 Aug 5;6(8): e455.

Dearden, C. Large granular lymphocytic leukaemia pathogenesis and management. British Journal of Haematology 2011; 152: 273-283.

Lamy T and Loughran TP. How I treat LGL leukemia. Blood 2011;117(10): 2764–2774.

Zhang R, Shah MV, Loughran TP Jr. The root of many evils: indolent large granular lymphocyte leukaemia and associated disorders. Hematol Oncol. 2010 Sep;28(3):105-17. doi: 10.1002/hon.917. PMID: 19645074; PMCID: PMC4377226.

Sokol L & Loughran TP. Large granular lymphocyte leukemia. Oncologist. 2006;11: 263–273.

Kanchan K. & Loughran TP. Antigen-driven clonal T cell expansion in disorders of hematopoiesis. Leukemia Research 2003; 27: 291–292.

Lamy T & Loughran TP. Clinical features of large granular lymphocyte leukemia. Seminars in Hematology 2003; 40:185-195.

Loughran T, Kadin M, Starkebaum G, Abkowitz JL, Clark EA, Disteche C, Lum LG & Slichter SJ. Leukemia of large granular lymphocytes: association with clonal chromosomal abnormalities and autoimmune neutropenia, thrombocytopenia and haemolytic anemia. Annals of Internal Medicine 1985; 102: 169–175.


University of Virginia LGL Program Website: LGL Leukemia Registry | UVA Health

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