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

Study Overview
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Brief Summary
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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 Bone marrow biopsy: About a tablespoon of bone marrow is withdrawn through a needle inserted into the hipbone.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.

Detailed Description
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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.

Official Title
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Treatment of T-Large Granular Lymphocyte (T-LGL) Lymphoproliferative Disorders With Alemtuzumab (Campath)

Conditions
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T-LGL Lymphoproliferative Disorders

Intervention / Treatment
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* Biological: Alemtuzumab (Campath)


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Alemtuzumab in patients with T cell large granular lymphocytic leukemia (T-LGL)<br>Alemtuzumab (Campath) will be administered at 10 mg/dose IV for 10 days as an infusion over 2 hours. | Biological: Alemtuzumab (Campath)<br>* Alemtuzumab (Campath) will be administered at 10 mg/dose IV for 10 days as an infusion over 2 hours.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Hematological Response After Three Months of Alemtuzumab | The primary endpoint was hematologic response at three months after treatment. A complete response (CR) was defined as normalization of all affected lineages, and a partial response (PR) was defined in neutropenic subjects as 100% increase in the ANC to >500/µL, and in those with anemia, any increase in hemoglobin of 2 g/dL or more observed in at least two serial measurements 1 week apart and sustained for one month or more without exogenous growth factors support or transfusions. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants That Are Red Blood Cell and/or Platelet Transfusion-Independent | Number of participants that are red blood cell and/or platelet Transfusion-Independent following Alemtuzumab | 3 months | 
| Participants Overall Survival After Alemtuzumab Infusion | Participants overall survival after Alemtuzumab infusion for cell large granular lymphocytic leukemia (T-LGL) at month 3. | 3 months | 
| Number of Participants That Experienced a Life-Threatening Toxicity | Number of participants that experienced a Life-Threatening Toxicity (grade >/= 4) as defined by Common toxicity Criteria (CTC) version 2.0. The CTC 2.0 is a set of criteria for the standardized classification of adverse effects. Adverse events are graded accordingly: 0 = No adverse event or within normal limits 1 = Mild adverse event 2 = Moderate adverse event 3 = Severe and undesirable adverse event 4 = Life-threatening or disabling adverse event 5 = Death related to adverse event | 12 months | 
| Number of Participants That Are Relapse-free Survival Following Campath Infusion. | Number of participants that are Relapse-free survival following Campath infusion. Relapse is defined as a fall in peripheral blood counts to 50% the values obtained during the response period. | Month 12 | 
| Number of Participants With Molecular Response to Campath | Number of Participants with Molecular Response to Campath. Molecular Response to Campath is defined as disappearance of the clonal population of T-LGL | Up to Month 12 | 
| Participant Response at 6 Months | Participant response at 6 months following Alemtuzumab. A complete response (CR) was defined as normalization of all affected lineages, and a partial response (PR) was defined in neutropenic subjects as 100% increase in the ANC to >500/µL, and in those with anemia, any increase in hemoglobin of 2 g/dL or more observed in at least two serial measurements 1 week apart and sustained for one month or more without exogenous growth factors support or transfusions. | 6 months | 
| Participants Response to a Second Cycle of Campath | Participants Response to a second cycle of Campath. A complete response (CR) was defined as normalization of all affected lineages, and a partial response (PR) was defined in neutropenic subjects as 100% increase in the ANC to >500/µL, and in those with anemia, any increase in hemoglobin of 2 g/dL or more observed in at least two serial measurements 1 week apart and sustained for one month or more without exogenous growth factors support or transfusions. | 12 months | 
| Number of Participants With Clone Size Improvements | Number of participants with clone size improvements following Alu | Up to 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neutropenia, Monoclonal Antibody Therapy, Anti-CD52, T-LGL Leukemia, LGL Leukemia, Leukemia