Introduction:
Sizeable granular lymphocytosis is also known as large granular lymphocytic leukemia. In this disorder, white blood cells called lymphocytes are part of the immune system and help fight infections. The leukemia condition presents with enlarged lymphocytes that contain granules that can be visualized in the microscope. There are three forms of the disorder. T-cell and natural killer cell types are slow growing, whereas the third type is aggressive. B-cells fight bacteria and viruses that invade the body. T-cells attack harmful cells like cancer. When there is abnormal production of these cells, their cellular function is disrupted.
What Are Large Granular Lymphocytes?
In this type, the lymphocytes are enlarged with round or kidney-shaped nuclei, broad cytoplasm, and azurophilic granules (which contain antimicrobial protein). They are commonly found in peripheral blood and form 10 to 15 percent of mononuclear cells (cells that have a single nucleus). Many of these lymphocytes are natural killer cells, whereas few are T-cells. The expansion of these cells is found in disorders such as T-cell large granular lymphocytosis leukemia, a chronic lymphoproliferative disorder of natural killer cells, and aggressive natural killer cell leukemia.
What Is the Incidence of Large Granular Lymphocytic Leukemia?
The incidence of the disease is 2 to 5 percent of all chronic lymphocytic disorders. It affects men and women with equal frequency. The age at which the disorder is diagnosed is among the elderly above 60 years of life. Although, few cases were diagnosed among younger patients.
What Is the Cause of Developing Large Granular Lymphocytic Leukemia?
Patients with autoimmune disorders like rheumatoid arthritis have an increased risk of developing significant granular lymphocytosis. Individuals with lymphoma (lymphatic system cancer) or other forms of cancer have an increased risk of developing the disorder. Most patients who develop this disorder have a mutation in STAT3 (signal transducer and activator of transcription 3) and STAT5B genes important for cell immunity and determining how cells multiply and divide.
How Can Large Granular Lymphocytic Leukemia Affect the Body?
The disorder is a form of chronic lymphocytic leukemia in which T-cells and natural killer cells mutate to form abnormal cells that prevent bone marrow from producing normal blood cells. Individuals affected by this disorder have a low neutrophil count that can increase their susceptibility to infection. The patients may also develop a lower red blood cell count as their production is disrupted.
What Are the Signs and Symptoms of Large Granular Lymphocytosis?
Some patients with this disease do not develop symptoms and are often diagnosed during a blood test.
- Variation in blood cell count.
- Reduction in red blood cell formation (red cell aplasia).
- Reduction in neutrophil level (neutropenia).
- A lower level of red blood cells and hemoglobin in the blood (anemia). Few patients develop severe anemia and may require a blood transfusion. A few patients develop hemolytic anemia (destruction of blood cells faster than replacement).
- Recurrent infections and fever can be caused by bacterial infection. The infection can develop in the skin, throat, and perirectal areas, which may develop into sepsis (the body's extreme response to infection). Oral aphthous ulcer (lesions developing in the mouth's soft tissue) formation is common.
- Night sweats.
- Unexpected weight loss.
- Spleen enlargement occurs in half of the patients due to infections or anemia.
- In rare instances, liver enlargement is seen.
- Lymph nodes can become swollen.
- Fatigue is the most common symptom that can develop due to anemia.
- Individuals with this disorder have a low lymphocyte count.
How to Diagnose Large Granular Lymphocytosis?
The suspected patient's blood is examined under a microscope to detect abnormality.
- Complete blood count and differential count are used to analyze blood cells and determine the type of blood cells.
- The microscope is required for examining peripheral blood smears to determine blood cells. The lymphocyte count may appear normal or reduced. However, there is a more significant number of abnormal cells that can be detected in this disease.
- Flow cytometry can identify the type of sizeable granular lymphocytosis that can be T-cell or natural killer cell. It can also be used to examine cell features.
- Immunophenotyping is a technique by which blood or tissues are analyzed for markers on the cell surfaces.
- T-cell receptor gene rearrangement analyses are blood or bone marrow test. The test helps the doctor identify problems in the gene responsible for abnormal T-cell functioning.
- Genetic testing for mutation in STAT3 and STAT5 genes.
- Bone marrow aspiration or biopsy is required for diagnosis confirmation. The test can also be used to rule out other disorders such as immunodeficiency, rheumatoid arthritis (inflammation of joints), myelodysplasia (a disorder caused by poorly formed blood cells), and myeloid mutations (a disease affecting bone marrow).
How to Treat Large Granular Lymphocytic Leukemia?
Individuals with both forms of significant granular lymphocytosis require similar treatment. During the early stage of the disease, a wait-and-watch approach is used. The patients are advised to undergo blood tests every few months, and the symptoms are monitored. Treatment is started if the patients develop moderate to severe neutropenia, transfusion-related anemia, or autoimmune conditions. Such patients are provided with immunosuppressive therapy or steroids. Low doses of Methotrexate, Cyclophosphamide, and Cyclosporine may be administered.
Supportive Therapy
Patients who develop anemia or neutropenia are treated with granulocyte colony-stimulating factor. The treatment does not cure the underlying disease but improves the symptoms. However, the treatment is ineffective in all patients and can cause exacerbation of splenomegaly and joint problems.
First Line Therapy
Methotrexate, Cyclophosphamide, and Cyclosporine A form the first line of therapy. The therapy must be provided for at least four months to obtain visible results. Methotrexate is suitable for neutropenic patients as it reduces the body's immune response and slows the growth of cancer cells. Oral Cyclophosphamide is preferred for anemic patients due to the damage caused by the drug on the DNA (deoxyribonucleic acid) of cancer cells that inhibits cell copying. If the primary therapy fails, alternating treatment with Methotrexate or Cyclophosphamide is administered, or treatment with Cyclosporine A is initiated. Cyclosporine A acts by preventing the immune system from attacking normal cells.
Second Line Therapy
When the primary line of treatment fails, Alemtuzumab drug is provided for refractory patients. The drugs act by stimulating the immune system to attack cancer cells. There are ongoing studies to analyze its effectiveness in treating the disease. Other treatment options such as the use of purine analogs (an anticancer drug similar to purine compound), combined therapy (a combination of drugs is used), immunotherapy (treatment in which the immune system is suppressed), and target therapy are being used with varying efficiency.
Conclusion:
Large granular lymphocytic leukemia is a rare form of blood cancer. The disease causes the enlargement of lymphocytes and granule formation. These cells multiply fast with impaired function leading to repeated infections. Studies are ongoing to establish treatment options for the disorder. Currently, combined drugs at low doses are being administered to slow the disease rates.
