Alemtuzumab and Rituximab in Treating Patients With High-Risk, Early-Stage Chronic Lymphocytic Leukemia

Study Overview
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Brief Summary
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RATIONALE: Monoclonal antibodies, such as alemtuzumab and rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Giving alemtuzumab together with rituximab may kill more cancer cells. PURPOSE: This phase II trial is studying the side effects and how well giving alemtuzumab together with rituximab works in treating patients with high-risk, early-stage chronic lymphocytic leukemia.

Detailed Description
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OBJECTIVES: Primary Determine the rate of complete and overall response to alemtuzumab and rituximab in patients with high-risk, early-stage chronic lymphocytic leukemia. Determine the toxicity of this regimen in these patients. Secondary Determine the overall survival and time to progression of patients treated with this regimen. Determine time to response and duration of response in patients treated with this regimen. Correlate prognostic markers 11q-, 17p-, unmutated VH gene, and CD38+ with clinical outcome. Determine response to this regimen using an expanded definition of response that includes minimal residual disease detected by sensitive flow cytometry in patients in complete clinical remission and single rearranged IgVH gene detected by polymerase chain reaction in patients with no monoclonal population on flow cytometry. Correlate in vitro response with clinical outcome in patients treated with this regimen. Determine if alemtuzumab and rituximab are synergistic in vitro. Determine the mechanism of action of this regimen in vitro. Determine the effect of this regimen on immune function. Monitor T-lymphocyte, natural killer cell, and monocyte number during and after treatment in these patients. Serially evaluate T-lymphocyte immunophenotype and function in patients treated with this regimen. Monitor recovery of humoral immunity by serial serum protein electrophoresis, immunofixation electrophoresis, and immunoglobulin quantification. OUTLINE: Dose-escalation (week 1): Patients receive rituximab IV on day 1 and escalating doses of alemtuzumab subcutaneously (SC) on days 3-5 in week 1. Treatment (weeks 2-5): Patients receive alemtuzumab SC on days 1-3 (at the highest dose administered during week 1) and rituximab IV on day 3 in weeks 2-5 in the absence of disease progression or unacceptable toxicity. Patients undergo blood collection at baseline and periodically during study treatment for pharmacokinetic and prognostic biomarker (11q-, 17p-, unmutated IgVH, and CD38 expression by flow cytometry and fluorescent in-situ hybridization) studies. Immune function (CDR3 T-cell receptor by reverse transcriptase-polymerase chain reaction) and in vitro and in vivo response are also examined. After completion of study therapy, patients are followed periodically for 5 years. PROJECTED ACCRUAL: A total of 33 patients will be accrued for this study.

Official Title
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Antibody Therapy With Alemtuzumab and Rituximab for Initial Treatment of High Risk Chronic Lymphocytic Leukemia

Conditions
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Leukemia

Intervention / Treatment
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* Drug: Alemtuzumab
* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: * Diagnosis of B-cell chronic lymphocytic leukemia (CLL) - Early-stage, biologically high-risk disease defined by the following criteria: Rai stage 0-II (does not meet standard NCI-sponsored Working Group criteria for treatment) Clinical and phenotypic features manifested in the peripheral blood, including the following: Minimum threshold peripheral blood lymphocyte count of > 5,000/mm³ Small-to-moderate peripheral blood lymphocytes with ≤ 55% prolymphocytes Monoclonality of B lymphocytes by immunophenotypic evaluation, demonstrating co-expression of CD19, CD5, and CD23 antigens, surface expression of CD20 and CD52, and B-cell monoclonal population defined by light-chain exclusions Poor prognosis demonstrated by ≥ 1 of the following high-risk parameters: Unmutated human immunoglobulin variable region heavy chain (IgVH) gene and CD38 expression (≥ 30% cells positive on flow cytometry) OR unmutated IgVH ZAP-70 expression (≥ 20% cells positive on flow cytometry) = 11q- = 17p- PATIENT CHARACTERISTICS: ECOG performance status 0-2 Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Creatinine ≤ 1.5 times upper limit of normal (ULN) Total bilirubin ≤ 3.0 times ULN OR direct bilirubin ≤ 1.5 times ULN AST ≤ 3.0 times ULN (unless due to hemolysis or CLL) Hemoglobin ≥ 9.0 g/dL No New York Heart Association class III-IV heart disease No myocardial infarction within the past month No uncontrolled infection No active HIV infection No evidence of autoimmune hemolytic anemia, immune thrombocytopenia, or pure red blood cell aplasia No other active primary malignancy requiring treatment or limiting survival to less than 2 years PRIOR CONCURRENT THERAPY: No prior treatment for CLL Prior corticosteroids allowed No prior radiotherapy More than 4 weeks since prior major surgery

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Alemtuzumab + Rituximab<br>Alemtuzumab 30mg Monday, Wednesday, and Friday x 5 weeks, Rituximab 375/mg/m2 IV weekly (Wednesday) x 4 weeks (weeks 2-5) | Drug: Alemtuzumab<br>* 30 mg Monday, Wednesday, and Friday x 5 weeks<br>Drug: Rituximab<br>* 375mg/m2 IV weekly (Wednesday) x 4 weeks (weeks 2-5)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed Response, Defined as Objective Complete Remission or Partial Remission for a Duration of at Least 2 Months | Confirmed response is defined as a > 50% decrease in clinical symptoms from baseline and recovery from blood counts. | Up to 6 months | 
| Number of Participants With Treatment Related Adverse Events | Adverse events (AE) that are classified as either possibly, probably, or definitely related to study treatment according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE version 3.0). The maximum grade for each type of AE will be recorded for each patient. Grade refers to the severity of the AE.> > Grade 1: Mild AE, Grade 2: Moderate AE, Grade 3: Severe AE, Grade 4: Life-threatening or disabling AE, Grade 5: Death related AE | Weekly for first 6 weeks, then monthly for 6 months, then at 9 and 12 months post registration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Response | Calculated from the date of registration until the first date at which the patient's objective status was classified as a response. In patients who do not achieve a response, time to response will be censored at the patient's last evaluation date. Response is defined the same way as in the response primary outcome measure. | Registration to first response (up to 5 years) | 
| Duration of Response | Duration of response is calculated from the date of documented response until the date of progression in the subset of patients who respond to treatment. In patients who have not yet progressed, duration of response will be censored at the patient's last evaluation date. | Up to 5 years | 
| Survival | Survival is calculated from the date of registration to the date of death due to any cause. In patients who are still alive, survival will be censored at the last date when the patient was known to be alive. | Death or last follow-up (up to 5 years) | 
| Time to Disease Progression | Calculated from date of registration to date of disease progression. In patients that have not progressed, time to disease progression will be censored at the patient's last evaluation date. | Time from registration to progression (up to 5 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage 0 chronic lymphocytic leukemia, stage I chronic lymphocytic leukemia, stage II chronic lymphocytic leukemia, B-cell chronic lymphocytic leukemia