Indolent T-Cell Large Granular Lymphocyte Leukemia

Indolent T-Cell Large Granular Lymphocyte Leukemia

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Bone, Muscle, & Joint
Digestive Health
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Contributed byKrish Tangella MD, MBAApr 07, 2018

What are the other Names for this Condition? (Also known as/Synonyms)

  • Indolent T-Cell LGL Leukemia
  • Large Granular Lymphocyte Leukemia, Indolent T-Cell type
  • LGLL, Indolent T-Cell type

What is Indolent T-Cell Large Granular Lymphocyte Leukemia? (Definition/Background Information)

  • Indolent T-Cell Large Granular Lymphocyte Leukemia is the most common form of large granular lymphocyte leukemia, a type of blood cancer. It is typically seen in middle-aged and older adults
  • Large granular lymphocyte (LGL) leukemia represents a type of lymphoproliferative disorder. Lymphoproliferative disorders are disorders in which there is uncontrolled production of (excess) lymphocytes that occurs due to several reasons
  • It should be noted that in some individuals, a short-term increase in large granular lymphocyte numbers may be seen in association with a variety of conditions including viral infections, autoimmune disorders, and non-lymphoid malignancies. In such cases, the increase is usually reactive in nature and non-malignant. Such short-term increase should not be misdiagnosed as Indolent T-Cell LGL Leukemia
  • The cause of Indolent T-Cell Large Granular Lymphocyte Leukemia is generally not known, although some research scientists believe that it is due to abnormal autoimmune responses, or initiated by certain viral infections
  • Indolent T-Cell Large Granular Lymphocyte Leukemia does not present with symptoms in over 30% of the patients. In others, it can cause signs and symptoms that include fever, weight loss, and appetite loss, reduced blood cell counts with a variety of symptoms, and swollen spleen and/or liver
  • In case no symptoms are observed, the healthcare provider may choose to follow a ‘wait and watch’ approach. In individuals who present symptoms, Indolent T-Cell Large Granular Lymphocyte Leukemia is typically treated using chemotherapy, blood transfusions, and other supportive measures
  • In general, the prognosis of Indolent T-Cell Large Granular Lymphocyte Leukemia is good with adequate treatment, in most of the individuals

General information on lymphocytes:

  • Lymphocytes are the main white blood cells found in the lymph, which is the fluid of the lymphatic system; just as blood is the fluid of the circulatory system. Lymphocytes are made in bone marrow, and can develop into either B-cells or T-cells
  • Large granular lymphocytes (LGLs) are present in peripheral blood in normal adults. The LGLs usually constitute 10-15% of the mononuclear cells in peripheral blood and they fight infections
  • Lymph results from filtration of blood as it travels to and from tissues. Lymph is colorless because it lacks red blood cells; instead, it contains lymphocytes. It is central to the immune system
  • There are 3 different kinds of lymphocytes:
    • T-lymphocytes or T cells: They help combat infections and abnormalities within the cells (cell-mediated immunity). They fight viruses and cancerous cells
    • B-lymphocytes or B cells: They produce antibodies that are bodily defense proteins, which target foreign invaders outside the cells (humoral immunity). They fight bacterial cells, cell fragments, and other immunogenic elements
    • Natural killer cells or NK cells: They perform diverse functions related to both cell-mediated and humoral immunity. They also scout for cancer cells, a process called immune surveillance
  • Large granular lymphocyte leukemias can be of T-cell type or NK-cell type

Who gets Indolent T-Cell Large Granular Lymphocyte Leukemia? (Age and Sex Distribution)

  • Indolent T-Cell Large Granular Lymphocyte Leukemia is the most common form of large granular lymphocyte leukemia (85% of all LGL leukemias belong to this type)
  • The condition is generally seen during middle-age and older age (average age around 60 years)
  • Both males and females are equally affected (male-female ratio is 1:1)
  • It can occur worldwide and all racial and ethnic groups may be affected

What are the Risk Factors for Indolent T-Cell Large Granular Lymphocyte Leukemia? (Predisposing Factors)

No specific risk factors have been identified for Indolent T-Cell Large Granular Lymphocyte Leukemia. However, the following conditions have been associated with Indolent T-Cell LGL Leukemia:

  • Sjogren’s syndrome
  • Systemic lupus erythematosus (SLE)
  • Hashimoto’s thyroiditis

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Indolent T-Cell Large Granular Lymphocyte Leukemia? (Etiology)

The exact cause of Indolent T-Cell Large Granular Lymphocyte Leukemia is unknown. However, blood tests indicate positive results for the presence of human T-cell lymphotropic virus (HTLV).

  • Some researchers believe that it is due to an abnormal autoimmune response or one that is initiated by certain viral infections
  • Some believe that LGL leukemia is a persistent autoimmune disorder

Many cases of Indolent T-Cell LGL Leukemia have a normal karyotype. Only, less than 10% of the individuals show chromosomal abnormalities that may include:

  • Inversion of 12p
  • Inversion of 14q
  • Deletion of 5q
  • Trisomy of chromosome 3
  • Trisomy of chromosome 8
  • Trisomy of chromosome 14

Also, the presence of a clonal population of T-cells as evidenced by TCR-β/γ (T-cell receptor-beta/gamma) gene rearrangement is essential for a diagnosis.

What are the Signs and Symptoms of Indolent T-Cell Large Granular Lymphocyte Leukemia?

Indolent T-Cell Large Granular Lymphocyte Leukemia is asymptomatic in about 33% of the individuals. In others, the following signs and symptoms may be noted:

  • ‘B’ symptoms that may include fever, night sweats, and weight loss, is seen in 20-40% of the individuals
  • Cytopenia (blood cell count reduction), which consists of the following:
    • Decreased red blood cells (anemia), causing fatigue, pale skin, and shortness of breath
    • Decreased white blood cells (leukopenia or leukocytopenia), causing an increased risk for infections. It is seen in 20-40% of the individuals
    • Decrease in platelet numbers (thrombocytopenia), resulting in easy bruising, prolonged bleeding, bleeding from the gums or nose, and presence of blood in stool
  • Rheumatoid arthritis (RA) in 33% of the individuals (25-35% incidence rate), which can result in stiffening of joints, joint and muscular pain, tiredness, etc.
  • Mild-moderate splenomegaly, or enlarged spleen, in 20-50% individuals
  • Hepatomegaly, or enlarged liver, in 10-20% individuals

Unlike other types (aggressive T-cell variant and aggressive NK-cell type) of LGL leukemia, where enlargement of the lymph nodes is seen; in the indolent type, enlarged lymph nodes (lymphadenopathy) are not usually noted.

How is Indolent T-Cell Large Granular Lymphocyte Leukemia Diagnosed?

Tests and procedures that could help in the diagnosis of Indolent T-Cell Large Granular Lymphocyte Leukemia include:

  • A thorough physical examination and a complete medical history
  • Assessment of presenting symptoms
  • Blood tests that may include:
    • Complete blood cell count (CBC)
    • Absolute large granular lymphocytes count on peripheral blood
    • Liver function blood test (LFT)
    • Lactate dehydrogenase (LDH) blood test
    • Blood culture, on a case-by-case basis, to rule-out any infections
    • Rheumatoid factor blood test
    • Antinuclear antibodies (ANA) test
    • Immunoglobulin studies
    • Anti-neutrophil antibodies blood tests
    • Southern blot techniques
  • Molecular studies on peripheral blood and/or bone marrow specimen
  • Polymerase chain reaction (PCR) test: It is used to measure the presence of certain biomarkers in blood or bone marrow cells. The test is ultrasensitive and detects extremely low amounts of biomarkers remaining in blood, which can be missed by cytogenetic methods, such as FISH, karyotype, or flow cytometry. PCR allows a more sensitive follow-up of patients in remission and can help determine whether additional treatment is necessary
    • Blood tests, such as PCR techniques and southern blot techniques, are used to determine T-cell receptor (TCR) gene rearrangement clonality
    • In Indolent T-Cell LGL Leukemia, TCR-β/γ gene rearrangement is noted
  • Flow cytometric analysis on peripheral blood and/or bone marrow specimen: Flow cytometry to identify cells as they flow through an instrument, called a flow cytometer. Flow cytometry measures the number and percentage of cells in a blood/bone marrow sample, and cell characteristics such as size, shape, and the presence of biomarkers on the cell surface. This method helps to sub-classify the condition and to detect residual levels of disease after treatment. This tool may help in diagnosing relapse and restart treatment as needed. Flow cytometric analysis shows the following phenotype of the tumor cells: CD3+, TCRαβ, CD8+, CD57+, and CD16+
  • CT scan of the abdomen
  • Fluorescence in situ hybridization (FISH): It is a test performed on the blood or bone marrow cells to detect chromosome changes (cytogenetic analysis) in blood cancer cells. The test helps in identifying genetic abnormalities that may not be evident with an examination of cells under a microscope
  • Immunophenotyping to identify a specific type of cell in a sample, which can help determine the best treatment course to be followed
  • Bone marrow aspiration and biopsy is performed and sent to a laboratory for a pathological examination, to determine if the bone marrow is involved. Sometimes, the pathologist may perform special studies, which may include immunohistochemical stains, histochemical stains, molecular testing, and very rarely electron microscopic studies. However, a bone marrow biopsy is not needed in the early stages of the condition
  • Differential diagnoses, to eliminate other conditions, such as Felty syndrome (that presents rheumatoid arthritis, neutropenia and splenomegaly), are often considered, before arriving at a definitive diagnosis

A definitive diagnosis of Indolent T-Cell LGL Leukemia is arrived at by a combination of blood tests, special molecular studies, and analysis of symptoms.

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

Note:

  • In some cases, a transient increase in the number of large granular lymphocytes (LGLs) are often seen in a variety of conditions such as viral infections, autoimmune disorders, non-lymphoid malignancies, and solid organ transplantation
  • In such cases, the increase is usually reactive in nature and non-malignant. Besides, by usually treating the underlying condition, a decrease in LGLs is noted
  • However, if there are persistent increases in LGLs, diagnostic work-ups or additional studies should be performed to rule out large granular lymphocyte leukemia

What are the possible Complications of Indolent T-Cell Large Granular Lymphocyte Leukemia?

The complications due to Indolent T-Cell Large Granular Lymphocyte Leukemia may include:

  • Severe bleeding
  • Severe anemia requiring blood transfusions
  • Severe leucopenia leading to recurrent infections
  • Organ (liver or spleen) dysfunction
  • Pure red cell aplasia (PRCA) observed in 10-20% patients

There may be complications related to chemotherapy used in treating the condition, which may include:

  • Side effects such as dizziness, vomiting, appetite loss, mouth ulcers, and hair loss
  • By damaging healthy cells, the individual is more open or vulnerable to secondary infections
  • The treatment can also cause infertility in men and women. Hence, measures to protect the individual’s fertility must be considered, before starting chemotherapy

How is Indolent T-Cell Large Granular Lymphocyte Leukemia Treated?

The healthcare provider may recommend a ‘wait and watch’ approach for asymptomatic Indolent T-Cell Large Granular Lymphocyte Leukemia, after a diagnosis of the condition is established. In individuals with symptoms, the treatment of Indolent T-Cell LGL Leukemia may involve the following measures:

  • Chemotherapy: This approach uses a combination of drugs to kill the cancerous cells and can be used in patients, for all stages of the tumor
    • There can be severe side effects including fatigue, nausea, hair loss, anemia, elevated risk of infection, and drug-specific reactions
    • Many lymphomas can be resistant to chemotherapy. It can also damage healthy cells
    • Chemotherapy can be administered as a pill, liquid, shot, or intravenously
  • Targeted treatment with monoclonal antibody

Note: Men and women in child-bearing age would greatly benefit from counseling regarding fertility issues. Some chemotherapy agents can cause infertility in both men and women. There can be permanent damage to the testicles and ovaries, harming their ability to produce sperms or ova. In men, sperm banking can be considered before initiating therapy. In women, in many cases, due to urgency of starting chemotherapy, it is often difficult to perform ovum banking. However, if there is sufficient time prior to chemotherapy, ovum banking may be performed. The healthcare provider may help assess the risk-benefit analysis, depending upon each individual’s specific circumstances.

  • Immunosuppressive therapy
  • Prednisone therapy - treatment with steroids on a case-by-case basis may be undertaken
  • Administration of hematopoietic growth factors to treat decreased blood counts
  • Blood transfusion
  • If spleen is enlarged, then a surgical removal of the spleen (splenectomy) may be considered
  • Supportive treatment: Anti-nausea medications and antibiotics may be used as supportive therapy. In combination with other treatment measures, these can help combat the symptoms of immunodeficiency

Autologous and allogeneic stem cell transplant may be considered on a case-by-case basis, especially in younger individuals. Stem cell transplantations have resulted in cure in some individuals.

  • Stem cell transplantation: This procedure involves the transplantation of healthy blood-forming stem cells into the body. The procedure is also called hematopoietic progenitor cell transplantation. Stem cells can be collected from the bone marrow, circulating (peripheral) blood, and umbilical cord blood. It may either involve an autologous stem cell transplantation, where stem cells are harvested from individuals before treatment and transplanted back into the patient after treatment, or involve an allogeneic stem cell transplantation, where stem cells donated by another matching person (usually a brother or sister) is used, if the condition recurs after stem cell transplant using one’s own cell. This is called as allogeneic stem cell transplant
  • Bone marrow transplantation: Typically, systemic cases may be treated by administering high doses of chemotherapy or radiotherapy. But, high doses of chemotherapy drugs will also damage the bone marrow, preventing it from making any blood cells. Hence, before starting high-dose chemotherapy, the physicians may take out some of the patient’s bone marrow and freeze/preserve it. Collecting the bone marrow is called a bone marrow harvest. The bone marrow is then stored. After high dose chemotherapy or radiation, the bone marrow is thawed and injected back into patient through a drip (transfusion). This is called an autologous bone marrow transplant. Sometimes bone marrow donated by another matching person (usually a brother or sister) is used, if the condition recurs following transplant using one’s own cell. This is called as allogeneic bone marrow transplant

Allogeneic bone marrow and allogeneic stem cell transplants may have more side effects and complications, and this treatment may not be suitable for every individual. If allogeneic transplants come from a healthy donor with no malignant cells, then the chances of recurrence of the condition may be reduced.

The healthcare provider will determine the best course of treatment depending on one’s individual circumstances. Also, follow-up care with regular screening and check-ups are important post-treatment.

Note: In some cases, a short-term increase in LGL count is observed due to the presence of certain underlying conditions. In such cases, treating the underlying condition normally resolves the abnormal increase in LGL numbers.

How can Indolent T-Cell Large Granular Lymphocyte Leukemia be Prevented?

Currently, it is not possible to prevent Indolent T-Cell Large Granular Lymphocyte Leukemia. However, controlling certain factors may help lower one’s general risk for the condition.

  • Healthy diet and exercise, as well as avoidance of unnecessary exposure to chemicals, may help decrease its risk
  • Avoiding smoking
  • Using appropriate protective gear while working with X-rays or other radioactive sources
  • In order to avoid a relapse, or be prepared for a recurrence, the entire diagnosis, treatment process, drugs administered, etc. should be well-documented and follow-up measures initiated

Regular medical screening at periodic intervals with blood tests, scans, and physical examinations, are mandatory. Often several years of active vigilance are crucial and necessary.

What is the Prognosis of Indolent T-Cell Large Granular Lymphocyte Leukemia? (Outcomes/Resolutions)

  • The prognosis of Indolent T-Cell Large Granular Lymphocyte Leukemia is generally good in a majority of the individuals. Individuals, who do not show symptoms, have better prognosis than those who present symptoms
  • In general, the prognosis depends upon a set of several factors, which include:
    • Overall health of the individual: Individuals with overall excellent health have better prognosis compared with those with poor health
    • Individuals with bulky disease have a poorer prognosis
    • Involvement of vital organs may complicate the condition
    • Whether the condition is occurring for the first time, or is recurrent. Recurring conditions have worse prognosis compared to cases that do not recur 
    • Response to treatment: Conditions that respond to treatment have better prognosis compared to tumors that do not respond to treatment
    • Progression of the condition makes the outcome worse
  • An early diagnosis and prompt treatment of the condition generally yields better outcomes than a late diagnosis and delayed treatment
  • The combination chemotherapy drugs used, may have some severe side effects (such as cardio-toxicity). This chiefly impacts the elderly adults, or those who are already affected by other medical conditions. Tolerance to the chemotherapy sessions is a positive influencing factor

Additional and Relevant Useful Information for Indolent T-Cell Large Granular Lymphocyte Leukemia:

The following article link will help you understand leukemia and lymphoma:

http://www.dovemed.com/diseases-conditions/leukemia-and-lymphoma/

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Krish Tangella MD, MBA picture
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Krish Tangella MD, MBA

Pathology, Medical Editorial Board, DoveMed Team

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