Cyclophosphamide and Total Body Irradiation in Treating Patients Who Are Undergoing an Autologous Peripheral Stem Cell Transplant For Chronic Lymphocytic Leukemia

Study Overview
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Brief Summary
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RATIONALE: Giving chemotherapy before a peripheral stem cell transplant stops the growth of cancer cells by stopping them from dividing or killing them. Giving colony-stimulating factors, such as G-CSF, and certain chemotherapy drugs, helps stem cells move from the bone marrow to the blood so they can be collected and stored. Chemotherapy or radiation therapy is then given to prepare the bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy and radiation therapy. PURPOSE: This phase II trial is studying how well giving cyclophosphamide together with total-body irradiation works in treating patients who are undergoing an peripheral stem cell transplant for chronic lymphocytic leukemia.

Detailed Description
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OBJECTIVES: Primary Determine the safety and feasibility of autologous peripheral blood stem cell transplantation in patients with chronic lymphocytic leukemia treated with cyclophosphamide and total-body irradiation. Secondary Determine the safety, feasibility, and efficacy of combination therapy comprising dexamethasone, carmustine, cytarabine, etoposide, and melphalan (Dexa-BEAM) and filgrastim (G-CSF) mobilization in patients treated with this regimen. Determine the efficacy of ex-vivo graft purging in patients treated with this regimen. Determine the incidence of complete clinical and molecular remissions in patients treated with this regimen. Determine the progression-free survival of patients treated with this regimen. OUTLINE: This is a multicenter, open-label, nonrandomized study. Cytoreductive treatment: Patients undergo 2-4 courses of cytoreductive treatment, preferably following the fludarabine and cyclophosphamide (FC) protocol. Stem cell mobilization: Patients achieving a complete remission (CR) or partial remission (PR) and stable blood counts undergo stem cell mobilization comprising dexamethasone, carmustine, cytarabine, etoposide, melphalan (Dexa-BEAM), and filgrastim (G-CSF). Patients with an adequate number of mobilized cells undergo stem cell collection. Patients with CR or very good PR proceed to myeloablative therapy. Myeloablative therapy: Patients undergo total-body irradiation on day -4 and receive cyclophosphamide IV on days -4 and -3. Autologous peripheral blood stem cell transplantation (PBSCT): Patients undergo autologous PBSCT on day 0. After completion of study, patients are followed periodically. PROJECTED ACCRUAL: A total of 150 patients will be accrued for this study.

Official Title
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Pivotal Study for High Dose Therapy and Autologous Stem Cell Transplantation in Early Stages of CLL

Conditions
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Chronic Lymphocytic Leukemia

Intervention / Treatment
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* Biological: filgrastim
* Drug: carmustine
* Drug: cyclophosphamide
* Drug: cytarabine
* Drug: dexamethasone
* Drug: etoposide
* Drug: fludarabine phosphate
* Drug: melphalan
* Procedure: bone marrow ablation with stem cell support
* Procedure: peripheral blood stem cell transplantation
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Patients with chronic lymphocytic leukemia, meeting 1 of the following criteria: Binet stage B or C disease Binet stage A disease and at high risk for disease progression, defined as the following: Non-nodular marrow infiltration or lymphocyte doubling time < 12 months Thymidine kinase > 7.0 U/L or ß-2-microglobulin > 3.5 mg/L Polymerase chain reaction-amplifiable clonal CDRIII rearrangement of the IgV_H PATIENT CHARACTERISTICS: ECOG performance status 0-1 No concurrent disease resulting in major organ dysfunction PRIOR CONCURRENT THERAPY: No prior combination therapy comprising melphalan, dexamethasone, carmustine, cytarabine, and etoposide (DEXA-Beam) No more than 1 prior chemotherapy regimen No prior chemotherapy regimen longer than 6 months in duration

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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: High dose therapy + autologous PBSCT<br>Cytoreductive treatment: (preferentially) FC (2-4 cycles) Mobilization: Dexa-BEAM + G-CSF (1-2 cycles) Myeloablation: fractionated TBI (e.g. 6x2Gy) + Cyclophosphamide (2 x 60 mg/kg; d -4 to -3) autologous peripheral blood stem cell transplantation (PBSCT) (d 0) | Biological: filgrastim<br> <br> Drug: carmustine<br> <br> Drug: cyclophosphamide<br> <br> Drug: cytarabine<br> <br> Drug: dexamethasone<br> <br> Drug: etoposide<br> <br> Drug: fludarabine phosphate<br> <br> Drug: melphalan<br> <br> Procedure: bone marrow ablation with stem cell support<br> <br> Procedure: peripheral blood stem cell transplantation<br> <br> Radiation: radiation therapy<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of autologous peripheral stem cell transplantation (PBSCT) as measured by a treatment-related mortality of < 5% at 12 months following transplant |  |  | 
| Feasibility of PBSCT as measured by > 50% of included patients proceeding to transplant |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of mobilization comprising dexamethasone, carmustine, cytarabine, etoposide, and melphalan (Dexa-BEAM) as measured by a treatment-related mortality of < 5% before transplant phase |  |  | 
| Efficacy of Dexa-BEAM mobilization as measured by the amount of CD34+ cells > 4x10e6/kg at harvest |  |  | 
| Complete clinical remissions by NIH criteria at 3 months following transplant |  |  | 
| Molecular remissions by CDR3 PCR at 3 months following transplant |  |  | 
| Progression-free survival by NIH criteria at 5 years from study entry |  |  | 

 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, stage III chronic lymphocytic leukemia, stage IV chronic lymphocytic leukemia, refractory chronic lymphocytic leukemia