Large granular lymphocytic Leukemia C91.7

The term "T-cell leukemia with large granular lymphocytes" LGL, summarizes a spectrum of rare lymphoproliferative disorders of T-lymphocytes and natural killer cells.

Characteristic of T-cell leukemias with large granular lymphocytes (LGL) is neutropenia and/or anemia with evidence of enlarged lymphocytes characterized by conspicuous granules. The T-cell leukemias with large granular lymphocytes are often associated with autoimmune diseases such as rheumatoid arthritis ( Felty syndrome is an important differential diagnosis - Steinway SN et al 2014).

Two types of LGL leukaemia are distinguished:

• the somewhat more frequent T-cell LGL leukemia
• and
• the less common NK-cell LGL leukaemia.

Both types can be chronic (slow growing) or aggressive (fast growing).

The incidence of T-cell LGL and NK-cell LGL leukemia is between 2 and 5% of all chronic lymphoproliferative disorders. The annual incidence is reported to be 1:250,000/year.

LGL leukemia affects both men and women.

LGL leukemias are thought to result from chronic antigen stimulation that promotes long-term cell survival by activating survival signaling pathways and suppressing pro-apoptotic signaling. These include Jak-Stat, Map kinases, Pi3k/Akt, sphingolipid, and IL-15/Pdgf signaling pathways(Steinway SN et al. 2014).

The average age at diagnosis is 60 years. Less than 25% of patients are younger than 50 years.

2/3 of patients diagnosed with chronic T-cell and NK-cell LGL leukemia present with symptoms at the time of diagnosis. These are:

Neutropenia, anemia, and/or thrombocytopenia, and moderate lymphocytosis.

Furthermore, the following symptoms may occur:

• Recurrent infections
• Fever
• Night sweats
• Unintentional weight loss
• Splenomegaly (in 25 to 50% of patients)
• Hepatomegaly (rare)
• Lymphadenopathy (rare)
• Peripheral neuropathy (Saini NY et al 2018).

Complicating comorbidities:

• Autoimmune diseases (such as rheumatoid arthritis) are diagnosed before the onset of LGL leukemia in about 20% of cases.

Blood count

Bone marrow puncture

Flow cytometry (differentiation of lymphocytes - T cells?/ NK cells?)

Diagnosis is based on the detection of NK cell LGL lymphocytosis, a characteristic immune phenotype and confirmation of clonality by analysis of rearrangements in the TCRbeta and TCRgamma genes.

Differential diagnosis must exclude diseases with proliferation of CD56-positive cells and diseases with reactive LGL proliferation (solid tumors, connective tissue diseases, hemophagocytosis syndromes, idiopathic thrombocytopenic purpura, non-Hodgkin lymphoma (see there) and viral infections).

An important and difficult differential diagnosis is chronic lymphoproliferative disorder of NK cells (CLPD-NK).

If T-cell LGL leukemia is associated with rheumatoid arthritis, differentiation from Felty's syndrome (rheumatoid arthritis, neutropenia and splenomegaly, see there) may be difficult.

LGL leukemia is usually chronic and indolent, but in rare cases it can take an aggressive course (Steinway SN et al 2014).

T-cell LGL leukemia (T-LGL) is the most common LGL disease in the Western world. Despite its indolent course, the disease is often associated with marked neutropenia, and its pathogenesis is multifactorial, involving both humoral and cytotoxic mechanisms.

Patients with aggressive T-cell or NK-cell LGL leukemia may experience enlargement of the liver and spleen (hepatosplenomegaly), fever, unintentional weight loss, and night sweats. The aggressive T-cell and NK-cell LGL leukemias are refractory to therapy.

The therapies are analogous to acute lymphoblastic leukemia (ALL). Induction chemotherapy followed by consolidation and stem cell transplantation at the time of first remission may be an option.

1. Pontikoglou C et al. (2011) Pathophysiologic mechanisms and management of neutropenia associated with large granular lymphocytic leukemia. Expert Rev Hematol 4:317-328.
2. Saini NY et al (2018) Large granular lymphocytic leukemia-associated peripheral neuropathy. Ann Hematol 97:1501-1504.
3. Steinway SN et al (2014) The pathogenesis and treatment of large granular lymphocyte leukemia. Blood Rev 28: 87-94.