Rareshare would like to acknowledge Dr. Thomas P. Loughran, Jr., Director of the University of Virginia Cancer Center for reviewing this content.

LGLL is currently diagnosed in about 0.2-0.72 people in 1 million persons every year. It equally affects both men and women and it is more frequent in older adults, with 60 being the average age at diagnosis. LGLL makes up 2 to 5 % of all chronic lymphoproliferative disorders in the U.S. and 5-6% of all cases in the Asian population. 

The exact cause of LGLL is currently unknown, but there are three features that are more common in individuals diagnosed with this type of leukemia: autoimmune diseases, other lymphomas or cancers, and mutations in the STAT3 gene.

Autoimmune disorders, such as rheumatoid arthritis and lupus, occur with about 30% of cases of LGLL. This could indicate that LGLL itself is an autoimmune disorder. An autoimmune disease describes when the body’s immune system targets important processes or tissues and causes harm to itself. The immune system releases antibodies that target foreign substances called antigens to mark them for destruction by the body. Autoantibodies are antibodies that target something created in the body and can disrupt normal processes. In the case of LGLL, this autoimmune response could be targeting normal T- and NK- white blood cells.

Additionally, about 25-30% of individuals with LGLL also have other types of lymphomas or cancer, meaning that their LGLL could be linked to other cancers in the body.

Recently, research aimed at finding the genetic cause of LGLL found mutations or alterations in the STAT3 and STAT5B genes in 40% of the patients analyzed. STAT3 is what is known as an oncogene; when it is activated and unregulated it can cause cells to grow out of control which can cause cancer. Although these results have been confirmed in additional cohorts or groups of patients, it is important to keep in mind that STAT3 alterations are not the only cause of LGLL. 

While it is more common that people diagnosed with LGLL have symptoms, about one third of these individuals do not experience adverse symptoms and are diagnosed based on abnormal blood cell counts during a blood test. Symptoms of large granular lymphocytic leukemia are often linked to decreased numbers of red and white blood cells in the bloodstream. Such symptoms that may indicate a diagnosis can include: 

• Below-normal concentration of neutrophils, a type of white cell (chronic neutropenia) - causes frequent infections

• Decrease in the number of red blood cells (anemia) occurs in about half of patients

• Fever, fatigue, and flu-like symptoms indicating an infection

• Night sweats

• Unintended weight loss

• Enlargement of the spleen (splenomegaly) occurs in 25 to 50 percent of patients

• Enlargement of the liver (hepatomegaly) rarely occurs

• Swollen lymph nodes (lymphadenopathy) rarely occurs

Rheumatoid arthritis and lupus occur on a higher than average percentage in people diagnosed with LGLL.

The diagnosis is established by finding an increased number of large granular lymphocytes (LGL) which are clonal. Clonal means that all the LGL are originated from the same original abnormal LGL cell that slowly copies itself exactly over and over again. Determination of an increased number of LGL can be made by examining a blood sample under the microscope. Flow cytometry in conjunction with a CBC (complete blood count) can also be used to quantitate the number of LGL and also determine whether the LGL are of T cell or NK cell origin. Clonality in the T cell form of LGLL is evidenced by finding clonal rearrangement of the T cell receptor gene. Each T cell presents a different and unique T cell receptor gene due to a process known as rearrangement. If the excess of LGL all have the same T cell receptor gene, that means that they are clonal, i.e. that they derived from the same original T cell. It is difficult to determine clonality in patients with the NK type of LGLL as there is no test available to detect clonal NK cells. The diagnosis of LGLL then can be readily established by these blood studies so that an initial marrow aspirate/biopsy is not usually needed. Marrow studies then are reserved for specific indications outside of the usual diagnostic workup. Genetic testing for alterations in the STAT3 gene could also be performed but the clinical relevance of this test is part of ongoing research studies.

Blood samples are taken for determination of LGL count and clonality. Tests to establish diagnosis would include a CBC (complete blood count) and differential, review of the peripheral blood smear (the examination of the blood under the microscope), flow cytometry, and T cell receptor gene rearrangement. In the vast majority of patients, a marrow aspirate/biopsy is not needed to establish the diagnosis. 

If there are no symptoms, then it is not always necessary to treat this disease. Treatment is advised in the case of symptomatic anemia, severe neutropenia or moderate neutropenia with recurrent infections.

The treatment of LGLL is based on what is called immunosuppressive therapy, a treatment that lowers the activity of the body’s immune system.

Immunosuppresive drugs used to treat LGLL include single agent methotrexate, oral cyclophosphamide and cyclosporine. In a minority of patients, resistance can arise to these treatments making them no longer effective. When this occurs, purine analogues or anti-CD52 antibody (Alemtuzumab) can be used. The illness is a chronic disease and immunosuppressive therapies can improve the blood counts. Unfortunately, however, there is no known cure at this time.

Most of the patients present with a chronic slow-growing LGLL. Some patients may not have many symptoms and not need treatment for some time. There are patients that never need therapy. The prognosis varies from person to person depending on the severity of the symptoms but overall there is not a significant effect on the lifespan.

On very rare occasions, LGLL can present as an acute fast-growing leukemia. This is an aggressive disease that is resistant to therapy. In particular patients with an NK type of LGLL need to be distinguished from the acute NK leukemias, that occur primarily in the Far East.

LGL Leukemia Patient Registry

The LGL Leukemia Patient Registry at the University of Virginia is currently the only national registry for patients with known or suspected LGL leukemia.  Patients enroll by giving informed consent and can then donate specimens to help advance research of the disease.  More information about the Registry can be found by clicking on this link: https://cancer.uvahealth.com/cancers-we-treat/specialty-programs-clinics/lgl-leukemia/lgl-leukemia-registry

To contact the LGL Leukemia Registry Coordinator, please call 434-243-8431

Additional LGL Leukemia Information

If you would like to view Podcasts, find patient support resources, or read lay person’s educational content about LGL leukemia, click on this link:  https://cancer.uvahealth.com/cancers-we-treat/specialty-programs-clinics/lgl-leukemia/Learn-About-LGL-Leukemia

www.lls.org/leukemia/large-granular-lymphocytic-leukemia

www.hopkinsmedicine.org/kimmel_cancer_center/centers/bone_marrow_failure_disorders/large_granular_leukemia.html

Koskela, H. L., et al. (2012). "Somatic STAT3 mutations in large granular lymphocytic leukemia." N Engl J Med 366(20): 1905-1913.

Lamy, T. and T. P. Loughran, Jr. (2011). "How I treat LGL leukemia." Blood 117(10): 2764-2774.

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

Neff, J. L., et al. (2013). "Distinguishing T-cell Large Granular Lymphocytic Leukemia from Reactive Conditions: Laboratory Tools and Challenges in Their Use." Surg Pathol Clin 6(4): 631-639.

Oshimi, K. (2017). "Clinical Features, Pathogenesis, and Treatment of Large Granular Lymphocyte Leukemias." Intern Med 56(14): 1759-1769.

Shah, M.V., Hook C.C., Call T.G., Go R.S. (2016). "A population-based study of large granular lymphocyte leukemia." Blood Cancer J. 6(8):e455.

https://my.clevelandclinic.org/health/body/23342-lymphocytes