Rituximab and Combination Chemotherapy in Treating Patients With Newly Diagnosed Waldenstrom's Macroglobulinemia

Study Overview
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Brief Summary
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RATIONALE: Monoclonal antibodies, such as rituximab, can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. Drugs used in chemotherapy work in different ways to stop cancer cells from dividing so they stop growing or die. Combining rituximab with combination chemotherapy may kill more cancer cells. PURPOSE: This phase II trial is studying how well giving rituximab together with combination chemotherapy works in treating patients with newly diagnosed Waldenstrom's macroglobulinemia.

Detailed Description
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OBJECTIVES: Determine the response rate of patients with newly diagnosed Waldenstrom's macroglobulinemia treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. Determine the associated toxic effects of this regimen, specifically the frequency of febrile neutropenia, in these patients. Determine the progression-free survival of patients treated with this regimen. Correlate baseline cytogenetic features and gene expression profiles with response in patients treated with this regimen. OUTLINE: This is a pilot, multicenter study. Patients receive rituximab intravenously (IV) over approximately 4 hours, cyclophosphamide IV over 5-30 minutes, doxorubicin IV over 5-15 minutes, and vincristine IV over 1 minute on day 1. Patients also receive oral prednisone on days 1-5. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually for 5 years. ACTUAL ACCRUAL: A total of 16 patients were accrued for this study.

Official Title
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Phase II Pilot Study Of Rituximab Plus CHOP In Patients With Newly Diagnosed Waldenstrom's Macroglobulinemia

Conditions
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Lymphoma

Intervention / Treatment
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* Biological: rituximab
* Drug: cyclophosphamide
* Drug: Doxorubicin
* Drug: Prednisone
* Drug: Vincristine


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Diagnosis of Waldenstrom's macroglobulinemia confirmed by the presence of the following: Bone marrow lymphoplasmacytosis with: > 10% lymphoplasmacytic cells OR aggregates or sheets of one of the following: lymphocytes, plasma cells or lymphoplasmacytic cells on the bone marrow biopsy (measured within 4 weeks prior to registration) Measurable disease defined as a quantitative immunoglobulin M (IgM) monoclonal protein of > 1,000 mg/dL obtained within 4 weeks prior to registration Cluster of differentiation 20 (CD20) positive stain of bone marrow or lymph node samples obtained < 8 weeks prior to registration Impaired bone marrow function due to infiltration by lymphoplasmacytic lymphoma, defined by 1 of the following: Hemoglobin no greater than 11 g/dL Serum viscosity level relative to water of at least 4.0 centipoise Absolute neutrophil count at least 1,000/mm^3 Platelet count at least 75,000/mm^3 Bilirubin no greater than 3.0 mg/dL Aspartate aminotransferase (AST) no greater than 3 times upper limit of normal Creatinine no greater than 3.0 mg/dL Age of 18 and over ECOG (Eastern Cooperative Oncology Group) performance status 0-1 Must be symptomatic with 1 of the following: Clinically significant anemia (hemoglobin no greater than 11 g/dL) Bulky lymphadenopathy Symptoms attributable to hyperviscosity (e.g., nose bleeding, gingival bleeding, or retinal hemorrhage) History of heart disease allowed only if 1 of the following is demonstrated by echocardiography, multigated acquisition scan (MUGA), exercise MUGA, or coronary catheterization: Ejection fraction of at least 45% Normal fractional shortening of the left ventricle Must have been tested for hepatitis B surface antigen within 2 weeks of registration Negative pregnancy test Fertile patients must use effective contraception EXCLUSION CRITERIA: Prior treatment for Waldenstrom's macroglobulinemia Prior anti-CD20 therapy Concurrent steroids exceeding 10 mg prednisone (or equivalent) per day Prior irradiation if less than 4 weeks had elapsed prior to registration and the date of last treatment Prior anthracyclines Prior malignancy except curatively treated basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, or other cancer curatively treated with surgery alone and from which patient has been disease free for at least 5 years Active heart disease Pregnant or nursing Myocardial infarction within the past 3 months Congestive heart failure Symptomatic ventricular arrhythmia

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rituximab + CHOP<br>Rituximab 375 mg/m2 day 1 of a 21-day cycle, followed by: Cyclophosphamide 750 mg/m2 Doxorubicin 50 mg/m2 Vincristine 1.4 mg/m2 and Prednisone 100 mg/m2 daily | Biological: rituximab<br>* Rituximab is given intravenously. The initial rate is 50 mg/hr for the 1st hour. If no toxicity, the rate may be escalated in 50 mg/hr increments at 30-minute intervals to a maximum of 400 mg/hr. If the first dose is well tolerated, the initial rate for subsequent dose is 100 mg/hr, increased in 100 mg/hr increments at 30-minute intervals, not to exceed 400 mg/hr. If the patient experiences fever and rigors, the antibody infusion is discontinued. The severity of the side effects should be evaluated. If the symptoms improve, the infusion is continued initially at half the previous rate. Following the antibody infusion, the intravenous line should be maintained for medications as needed. If there are no complications after one hour of observation, the intravenous line may be discontinued.<br>* Other names: NSC# 687451;Drug: cyclophosphamide<br>* Cyclophosphamide will be given at a dosage of 750 mg/m² intravenously on day 1 of each cycle (1 cycle =21 days) for 6 cycles. Dose is based on surface area calculated based on actual body weight. The drug should be administered as a rapid IV infusion over 5 to 30 minutes.<br>* Other names: Neosar;Drug: Doxorubicin<br>* Doxorubicin will be given intravenously at a dosage of 50 mg/m² on day 1 of each cycle for 6 cycles (1 cycle =21 days). Dose is based on surface area calculated based on actual body weight. Doxorubicin should be administered as a continuous infusion into tubing of a freely flowing intravenous line for 5 -15 minutes. Avoid extravasation.<br>* Other names: ADR;Drug: Prednisone<br>* Prednisone will be administered at 100 mg/m² orally, days 1-5 of each cycle for 6 cycles (1 cycle =21 days). Dose is based on surface area calculated based on actual body weight.<br>* Other names: Liqui-Pred;Drug: Vincristine<br>* Vincristine will be administered 1.4 mg/m² intravenously (Maximum dose = 2.0 mg) on day 1 of each cycle for 6 cycles (1 cycle =21 days). Dose is based on surface area calculated based on actual body weight. Given as IV push over 1 minute, using extravasation precautions.<br>* Other names: LCR;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response to Treatment | Objective response assessed using standard myeloma response criteria. Objective response is defined as a > 50% reduction in the quantitative IgM or M-Spike levels from baseline levels. Response must be documented by two measurements separated by at least 3 weeks. | Every 3 months if patient is < 2 years from study entry, every 6 months if patient is 2-5 years from study entry, every 12 months if patient is 6-10 years from study entry | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CHOP, Waldenstrom macroglobulinemia, Rituximab