How I Treat LGL Leukemia (Thierry Lamy, Thomas P. Loughran)

Large granular lymphocyte (LGL) leukemia is a very rare disease which was first described in 1985, and is characterized by clonal expansion of cytotoxic T or NK cells. Cytotoxic cells are a part of the immune system responsible for killing certain cells such as foreign cells, cancer cells and cells infected with viruses. In LGL leukemia, these cytotoxic cells are not dying off as they normally would (a process known as apoptosis), and this can disrupt the balance of other types of blood cells.

The most common features of LGLL are neutropenia or anemia; rheumatoid arthritis (RA) and other autoimmune diseases are also frequently seen in conjunction with LGLL. There is no cure for LGLL, which is usually an indolent, or chronic disease. Most patients eventually need treatment because of severe or symptomatic neutropenia (low neutrophil count), anemia (low red blood cells), or RA. Treatment consists of immunosuppressive therapy. Most patients will have a normal life span. The exception are the few who die of neutropenia-associated sepsis – a life threatening complication of infection. LGLL is diagnosed by establishing increased numbers of the clonal LGL.This is done with advanced bloodwork known as flow cytometry, and sometimes a bone marrow biopsy if the bloodwork is inconclusive. Indications for treatment include:
1. severe neutropenia (absolute neutrophil count (ANC) < 500);
2. moderate neutropenia (ANC >500) symptomatic from recurrent infections;
3. symptomatic or transfusion-dependent anemia;
4. associated autoimmune conditions requiring therapy, most often RA.

Patients are evaluated for treatment response using periodic blood counts and clinical assessments. Based on blood count results 4 months after starting therapy, we determine if there has been a complete hematologic response, a partial hematologic response, or treatment failure. There is no standard treatment for patients with LGL leukemia. Immunosuppressive therapy remains the foundation of treatment, including single agents methotrexate (MTX), oral cyclophosphamide, and cyclosporine (CyA).

Stem cell transplantation has no role in therapy for LGL leukemia. MTX (10 mg/m2) taken weekly, with or without prednisone, is the initial choice for patients with neutropenia. For LGL patients with anemia, MTX on the same schedule is the choice of one author (T.P.L.), whereas cyclophosphamide at 100 mg orally daily is the first choice of the other author (T.L.). The patient is evaluated after 4 months.

In case of failure of the primary therapy, cyclophosphamide (100 mg orally daily) is initiated by one of the authors (T.P.L.); the second author (T.L.) also chooses cyclophosphamide for neutropenia patients but uses CyA for anemic patients. CyA is not used much by one author (T.P.L.) and is reserved for patients failing both MTX and cyclophosphamide. Both MTX and CyA are maintained indefinitely if well tolerated by the patient. Cyclophosphamide is limited to 6-12 months due to bladder toxicity and mutagenesis.

For patients who fail these treatments, purine analogs and Campath are considered. Splenectomy (removal of the spleen) is also an option for such patients. As there is currently no cure for LGL leukemia, newer treatments are needed. Enrollment in clinical trials is encouraged. Participation in the US national LGL Leukemia Registry or the French LGL Registry is welcomed.

Synopsis is courtesy of Laura Pinyuh, member of LGL Leukemia Support

Thierry Lamy, Thomas P. Loughran; How I treat LGL leukemia. Blood 2011; 117 (10): 2764–2774. doi: https://doi.org/10.1182/blood-2010-07-296962