Alemtuzumab (Campath ) to Treat T-Large Granular Lymphocyte Leukemia
Alemtuzumab (Campath ) to Treat T-Large Granular Lymphocyte Leukemia
This study will examine the use of alemtuzumab (Campath ) in patients with T cell large
 granular lymphocytic leukemia (T-LGL). Patients with T-LGL often have reduced white blood
 cells, red blood cells and platelets, and increased numbers of abnormal cells called large
 granular lymphocytes (LGLs). Patients may have recurrent infections, anemia, or abnormal
 bleeding. Campath destroys specific parts of the abnormal LGLs, which interfere with the
 production of normal blood cells. This study will determine whether Campath can increase
 blood counts and reduce the number of abnormal LGLs in patients and will examine the side
 effects of the drug.

 Patients 18 to 85 years of age with T-LGL leukemia may be eligible for this study.
 Participants undergo the following procedures:

 Before starting Campath treatment

 -  Medical history and physical examination, blood tests, electrocardiogram (ECG).

 -  Echocardiogram (heart ultrasound) and 24-hour Holter monitoring (continuous ECG
 recording).

 -  Bone marrow biopsy: About a tablespoon of bone marrow is withdrawn through a needle
 inserted into the hipbone. The procedure is done using local anesthetic.

 -  Placement of central line, if needed: An intravenous line (tube) is placed into a major
 vein in the chest. It can stay in the body and be used for the entire treatment period.
 The line is used to give chemotherapy or other medications, including antibiotics and
 blood transfusions, and to collect blood samples. The line is usually placed under local
 anesthesia in the radiology department or the operating room.

 -  Apheresis: A catheter (plastic tube) is placed in a vein in each arm. Blood is drawn
 from one vein and run through a cell-separating machine, where the white blood cells are
 collected and saved. The remaining blood is transfused back to the patients through the
 vein in the other arm.

 During Campath treatment

 -  Campath therapy: After a small test dose, patients receive10 daily infusions of Campath
 , each of which lasts about 2 hours. The first few infusions are given at the NIH
 Clinical Center so that the patient can be monitored closely.

 -  Induction therapy: Aerosolized pentamadine, valacyclovir and other medicines are given
 to protect against or treat various infections that commonly affect patients with
 suppressed immune systems.

 -  Whole blood or platelet transfusions, if needed, and injections of growth factors, if
 needed.

 -  Blood tests and check of vital signs (temperature, pulse, blood pressure) every day
 during treatment. Echocardiogram and 24-hour Holter monitor after the last dose of
 Campath .

 Follow-up evaluations after Campath treatment ends

 -  Blood tests at home or at NIH (weekly for the first 3 months, then every other week
 until 6 months, then annually for 5 years

 -  Echocardiogram at NIH (at 3 months only)

 -  Bone marrow biopsy at NIH (at 6 and 12 months, then as clinically indicated)

 -  One repeat apheresis collection for laboratory studies.
T Cell Large Granular Lymphocyte (T-LGL) lymphoproliferative disorders are a heterogeneous
 group of uncommon diseases which may involve a polyclonal or a monoclonal 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, in particular 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 aAlemtuzumab (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.