Large granular lymphocytic leukaemia (LGLL) is characterised by an excessive production of certain white blood cells – large granular T-cell or natural killer (NK) lymphocytes – which infiltrate the bone marrow, spleen and liver.
The actual cause of LGLL is not completely understood, but recent studies have shown that the STAT3 (Signal Transducer and Activator of Transcription 3) gene has frequently undergone mutation in patients with LGLL.
LGLL is commonly associated with autoimmune diseases, particularly rheumatoid arthritis. The association is reinforced by the presence of rheumatoid factor, antinuclear antibodies and antineutrophil antibodies.
Given the chronic nature of T-cell LGLL and chronic NK-cell LGLL, these cancers are associated with a median overall survival of nine to ten years.
The aggressive variant of T-cell LGLL has a poor prognosis even with treatment. Patients with mild symptoms may have a better prognosis than those with severe symptoms at diagnosis. Patients who get an early diagnosis and rapid treatment generally fare better.
Aggressive NK-cell LGLL has a very poor prognosis because patients are shown to not respond to any of the treatments currently available.
What are the symptoms of LGLL?
The chronic T-cell and NK-cell variants of LGLL generally appear and progress slowly; therefore, there may be a few symptoms at the onset, including:
- Mild cytopenias (neutropenia, with or without anaemia)
- Presence of autoimmune diseases
- Elevated numbers of large granular lymphocyte T-cells or NK-cells in the blood
- Splenomegaly (enlarged spleen)
- Night sweats
- Oral sores
- Recurring infections
This variant presents suddenly and progresses rapidly. The most common features are:
- Wide range of cytopenias
- Hepatosplenomegaly (enlarged liver and spleen)
- Peripheral lymphadenopathy (enlarged lymph nodes around the body)
- Presence of Epstein-Barr virus infection
- Severe B symptoms:
- Unexplained weight loss
- Severe fatigue
- Fevers for at least two weeks without evidence of infection
- Drenching night sweats
How is LGLL diagnosed?
The diagnosis of LGLL, which requires evidence of an increase in T-cell or NK-cell LGLS together with supporting clinical symptoms, is based on the following tests:
- Morphology – A peripheral blood smear (examining blood samples under a microscope) will reveal the structure of the cells in the blood.
- Evidence of increased numbers of circulating LGLs greater than 0.5 x 109/L in peripheral blood usually lasting for more than six months will provide the diagnosis.
- Bone marrow aspiration and biopsy can also be used to confirm the diagnosis.
- Flow cytometry and immunophenotyping – Flow cytometry is a common technique used for immunophenotyping. It can separate different types of blood or bone marrow cells, and then identify and count them.
- LGLL is typically characterised by distinct immunophenotypic cell populations.
- T-cell LGLs are usually positive for CD3+/CD8+/CD57+/CD16+, which are characteristic of cytotoxic T-cells.
- NK-cell LGLs are commonly positive for CD2+/CD16+/CD56+, but negative for CD3.
- T-cell clonality – Genetic testing for evidence of T-cell clonality (genetically identical cancer cells) is needed to distinguish clonal cancer T-LGL leukaemia cells from normal T-LGL cells. This test is not useful for NK-LGL leukaemia cells which can make the diagnosis challenging in this situation.
How is LGLL treated?
There are no definite treatment regimens established for LGLL so far, because it is such a rare disorder. Treatment recommendations come mainly from experience of treating patients in small retrospective studies and case-series.
Treatment regimens for T-cell LGLL and NK-cell LGLL are virtually the same, although the more aggressive forms of T-cell LGLL and NK-cell LGLL tend not to respond to chemotherapy.
At present, first-line therapy consists of a single immunosuppressive oral agent such as low dose methotrexate, cyclophosphamide, or cyclosporin A. Treatment should be continued for at least four months prior to evaluating patients’ responses.
For patients who do not respond to first-line therapies, a number of drugs such as fludarabine, cladribine, and bendamustine have shown promise. However, they have only been tested in a small number of patients.
Combinations of chemotherapies such as cyclophosphamide, doxorubicin, vincristine, and prednisone, or chemotherapy regimens which include cytosine arabinoside, have not been effective in patients with chronic LGLL, and also have severe side effects. However, for patients with aggressive forms of LGLL, these drugs may be of benefit.
In patients with refractory LGLL, immunotherapy (therapy that uses the body’s own immune system to fight the cancer) may be helpful.
Alemtuzumab, which is a monoclonal antibody immunotherapy drug, can be considered when combined chemotherapies have not resulted in a response. However, the risk of opportunistic infections for patients need to be factored in with this treatment.
The monoclonal antibody rituximab has been used for patients where LGLL and rheumatoid arthritis co-exist. However, it is not generally considered an adequate treatment for LGLL.
A splenectomy (the removal of the spleen) is normally considered in patients with an enlarged spleen which is causing symptoms, or in patients with severe refractory cytopenias.
Treating an aggressive form of T-cell LGLL
Some patients with T-cell LGLL suffer from a rare aggressive form of the disease which has a very poor prognosis. In aggressive and refractory LGLL, chemotherapy combinations have not shown to be successful, which has suggested the possibility of haematopoietic stem cell transplantation, given its success in other leukaemias.
Treating an aggressive form of NK-cell LGLL
For patients with aggressive NK-cell LGLL, initial treatment with L-asparaginase, either alone or in combination with other chemotherapies, followed by an allogeneic stem cell transplant is considered to be the best option. L-asparaginase is an enzyme which breaks down asparagine in the body, an amino acid used by the body to make proteins. Normal cells can make asparagine for themselves, but cancer cells cannot and therefore they cannot survive.
Research has identified that involvement of STAT, JAK and RAS genes in patients which LGL and the connection of LGLL with autoimmune disorders. Different specific inhibitors of the pathways involved have been tested to discover new treatments:
- OPB-31121 – a STAT inhibitor which has a significant anticancer effect on human leukaemia cells in the laboratory by inhibiting STAT3 and STAT5.
- Tofacitinib citrate – a specific JAK inhibitor which has shown good results for patients with refractory rheumatoid arthritis.
- Tipifarnib – a farnesyltransferase inhibitor has shown improvement in bone marrow haematopoiesis in the laboratory.
- BNZ-1 – a selective inhibitor of the cytokines, interleukin-2 (IL2) and IL15, was shown to safely decrease T-regulatory cells and NK-cells while not affecting white blood cells in a phase 1 trial.
Questions to ask your medical team about LGLL
We understand going through a blood cancer through journey can be difficult. It may help to talk to a close friend or relative about how you are feeling. Here are some questions that may be useful to ask your doctor.
- How would I know if I had LGLL?
- What tests will I need to have?
- What will the tests show?
- How long will the results take?
- How rare is LGLL?
- What sort of treatment will I need?
- How long will my treatment last?
- What will the side effects be?
- Is there anything I should or shouldn’t eat?
- Will I be able to go back to work?
- Where can I get help with claiming benefits and grants?
- Where can I get help dealing with my feelings?
More information on LGLL can be found in our free information booklet.
You can download the booklet on our information pages.
If you would like a hard copy version of this booklet, please contact our support team on firstname.lastname@example.org or call our freephone helpline on 08088 010 444 (Monday – Friday 8:30am – 5:30pm)
Published date: January 2019 Review date: January 2021