Alemtuzumab (Campath) to Treat T-Large Granular Lymphocyte Leukemia

T Cell Large Granular Lymphocyte (T-LGL) lymphoproliferative disorders are a heterogeneous group of uncommon diseases which may involve a monoclonal or oligoclonal T cell population, which bear characteristic surface markers corresponding to activated cytotoxic (CD3+, CD8+) lymphocytes. They are often associated with quite severe neutropenia, anemia, and thrombocytopenia, which may be life-threatening. There is some evidence that the abnormal cytotoxic lymphocyte population may cause the cytopenias by suppressing hematopoiesis, although the mechanism is unclear. Immunosuppressive therapy has been shown to improve the cytopenias of T-LGL leukemia, however the long-term use of the commonly used agents often lead to significant toxicity in the older patients which are affected by this disease.

Alemtuzumab (Campath[R]) is currently approved as second line agent in patients with chronic lymphocytic leukemia (CLL) and has been used successfully in the treatment of certain autoimmune disorders. In the Hematology Branch, Campath is currently being investigated in two bone marrow failure syndromes: aplastic anemia and myelodysplasia. Cytopenia(s) is an important characteristic of patients with T-LGL leukemia, often being the indication for immunosuppressive therapy. Our preliminary experience with Campath indicates that it is well tolerated, among the elderly patients.

Therefore, we propose this pilot, Phase II, single agent, study which will evaluate the efficacy and safety of alemtuzumab (Campath[R]), an immunosuppressive drug, in subjects with T-LGL leukemia. Commercially available Alemtuzumab (Campath[R]) will be administered off label at 10 mg per day by intravenous infusion for 10 days total. Subjects who do not show a response to initial Campath or relapse may receive a second cycle of drug after the 3-month time point.

The primary end point of the study is the response rate at three months, defined as improvement in cytopenia(s). Secondary endpoints will include relapse-free survival, response at 6 months, life threatening toxicity, reduction in the number of abnormal T-LGL clone, response to second cycle of Campath, and overall survival.

• INCLUSION CRITERIA:

Clinical history supportive of the diagnosis of T-LGL leukemia (i.e. a history of cytopenias with peripheral blood morphologic evidence of LGLs)

Immunophenotypic studies of peripheral blood showing an increased population of T-LGLs (suggested by staining with CD3+, CD8+ and CD16+ or CD57+) or gammadelta T cells

Restricted or clonal rearrangement of the T-cell receptor by PCR AND one or more of the following:

Severe neutropenia (less than 500 neutrophils/microliter); OR

Severe thrombocytopenia (less than 20,000 platelets/microliter), or moderate thrombocytopenia (less than 50,000 platelets/microliter) with active bleeding; OR

Symptomatic anemia with a hemoglobin less than 9 g/dL or red blood cell transfusion requirement of greater than 2 units/month for two months prior to initiation of Campath

Ages 18-85 (both inclusive)

Exclusion criteria

A reactive LGL lymphocytosis to a viral infection

Serologic evidence of HIV infection

Infection not adequately responding to appropriate therapy

Previous immunosuppressive therapy with alemtuzumab

History of carcinoma that is not considered cured (excluding non-melanoma skin carcinoma)

Moribund status or concurrent hepatic, renal, cardiac, neurologic, pulmonary, infectious, or metabolic disease of such severity that it would preclude the subject's ability to tolerate protocol therapy or that death within 7-10 days is likely

Current pregnancy or unwilling to take oral contraceptives or refrain from pregnancy if of childbearing potential

Not able to understand the investigational nature of the study or give informed consent.