Early or Delayed Fludarabine and Rituximab in Treating Patients With Previously Untreated Chronic Lymphocytic Leukemia

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as fludarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as 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 fludarabine together with rituximab may kill more cancer cells. Sometimes the cancer may not need treatment until it progresses. In this case, observation may be sufficient. It is not yet known whether giving fludarabine together with rituximab early is more effective than giving fludarabine and rituximab after observation in treating chronic lymphocytic leukemia. PURPOSE: This randomized phase III trial is studying fludarabine and rituximab to compare how well they work when given early or after observation in treating patients with previously untreated chronic lymphocytic leukemia.

Detailed Description
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OBJECTIVES: Primary To determine if early treatment with chemoimmunotherapy comprising fludarabine phosphate and rituximab extends the time to second treatment in patients with genetically high-risk (unmutated IgV_H), asymptomatic, previously untreated chronic lymphocytic leukemia (CLL). To determine the time to disease progression that would warrant second treatment. To determine overall survival. Secondary To measure the proportion of patients with asymptomatic, previously untreated CLL who have mutated and unmutated IgV_H genes. To determine the differences in acute and chronic toxicity of administering chemoimmunotherapy early to patients with genetically high-risk CLL compared to waiting until symptoms develop. To determine the effect of select pretreatment clinical and biological characteristics (such as interphase cytogenetic abnormalities, ZAP-70 expression, and p53 dysfunction [primary and secondary]) on response, time to second treatment, and overall survival of patients with genetically high-risk CLL randomized to early treatment. To determine the effect of select pretreatment clinical and biological characteristics (such as interphase cytogenetic abnormalities, ZAP-70 expression, and p53 dysfunction) on response, time to first and second treatments, and overall survival of patients with genetically high-risk CLL randomized to standard treatment (observation until symptoms occur). To describe the natural history of patients with genetically low-risk (mutated IgV_H genes), asymptomatic, previously untreated CLL, in terms of time to initial treatment, response, progression, and survival. To determine the effect of select pretreatment characteristics on time to first treatment, response, progression, and survival of patients with genetically low-risk CLL. To correlate patterns of resistance that emerge in patients with unmutated IgV_H genes who have relapsing or refractory CLL following receipt of chemoimmunotherapy with clonal evolution, including acquisition of high-risk karyotype abnormalities, p53 mutations, p53 dysfunction (primary and secondary), altered mRNA and protein expression related to treatment resistance, DNA mutations, microRNA gene expression, and methylation changes. To determine whether highly sensitive flow cytometry negativity at completion of therapy in patients randomized to early treatment is an effective surrogate marker for prolonged time to second treatment, overall survival, and other clinical benefits. To collect demographic data on familial CLL in newly diagnosed patients participating on this study. OUTLINE: This is a multicenter study. Genetically high-risk disease: Patients are stratified according to age (< 50 years vs 50 to 70 years vs > 70 years) and presence of the high-risk genetic feature [del(11)(q22.3) or del(17)(p13.1)] by FISH (yes vs no). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive rituximab IV over 4 hours on days 1, 3, and 5 of week 1 and then on day 1 of weeks 5, 9, 13, 17, and 21. Patients also receive fludarabine phosphate IV over 30 minutes on days 1-5 of weeks 1, 5, 9, 13, 17, and 21. After completion of chemoimmunotherapy, patients are followed every 3 months until disease progression. At the time of disease progression, patients receive retreatment with chemoimmunotherapy as above or another treatment regimen. Arm II: Patients are followed every 3 months until disease progression. At the time of disease progression, patients receive rituximab and fludarabine phosphate as in arm I. Patients are then followed every 3 months until second disease progression. Patients with a second disease progression receive retreatment with chemoimmunotherapy as above or another treatment regimen. Genetically low-risk disease: Patients are followed every 3 months until disease progression. At the time of disease progression, patients receive rituximab and fludarabine phosphate as in arm I. Patients are then followed every 3 months until second disease progression. Patients with a second disease progression receive retreatment with chemoimmunotherapy as above or another treatment regimen. Patients undergo blood sample collection periodically for correlative studies. After finishing treatment, patients are followed periodically.

Official Title
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A Phase III Intergroup CLL Study of Asymptomatic Patients With Untreated Chronic Lymphocytic Leukemia Randomized to Early Intervention Versus Observation With Later Treatment in the High Risk Genetic Subset With IGVH Unmutated Disease

Conditions
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Leukemia

Intervention / Treatment
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* Biological: rituximab
* Drug: fludarabine phosphate


Participation Criteria
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Eligibility Criteria
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Eligibility Criteria for Pre-Registration: Patients must be within 6 months of the initial flow cytometric confirmation of B-cell chronic lymphocytic leukemia (CLL). This interval begins with the initial flow cytometric confirmation of disease. Clinical and immunophenotypic evidence of CLL including: 2.1 An absolute lymphocytosis of > 5,000/μL Morphologically, the lymphocytes must appear mature with < 55% prolymphocytes. Local institution lymphocyte phenotype must reveal a predominant B-cell monoclonal population sharing a B-cell marker (CD19, CD20, CD23) with the CD5 antigen, in the absence of other pan-T-cell markers. Additionally, the B-cells must be monoclonal with regard to expression of either κ or λ and have surface immunoglobulin expression of low density. Patients with bright surface immunoglobulin levels must have CD23 coexpression and absence of t(11;14) on interphase cytogenetics or have negative tumor protein staining for cyclin D1. 2.2 Staging - Patients must be in the low category (i.e., only stages 0 or I) of the modified three-stage Rai staging system as described in the protocol. Patients should not have evidence of active disease as demonstrated by any of the following criteria: Splenomegaly and/or massive/progressive lymphadenopathy that would require therapy Presence of weight loss > 10% over the preceding 6 month period Grade 2 or 3 fatigue Fevers > 100.5°F or night sweats for greater than 2 weeks without evidence of infection Progressive lymphocytosis with an increase of > 50% over a 2 month period or an anticipated doubling time of less than 6 months. Prior Treatment: No prior therapy for CLL including corticosteroids for autoimmune complications that have developed since the initial diagnosis of CLL. Age ≥ 18 years Performance Status 0 - 1. No HIV disease. Due to alterations in host immunity, patients known to have HIV infection may not be enrolled. Non-pregnant and non-nursing. Due to the unknown teratogenic potential of chemotherapy, pregnant or nursing women may not be enrolled. Women and men of reproductive potential should agree to use an effective means of birth control. Required Initial Laboratory Values: Creatinine ≤ 1.5 x upper limit of normal Eligibility Criteria for Registration (to Low-Risk Cohort or High-Risk Cohort Randomization between Early Intervention Versus Observation with Later Treatment) Successful determination of IgVH mutational status by reference laboratory. Absence of progression of CLL, i.e., absence of the following: Progressive splenomegaly and/or lymphadenopathy on two independent measures spaced two weeks apart. If one assessment notes progression, this should be repeated prior to re-registration. Development of anemia (hemoglobin < 11 g/dL) or thrombocytopenia (platelets < 100,000/μL). Progressive lymphocytosis with an increase of > 50% over a 2 month period or an anticipated doubling time of less than 6 months. Symptoms referable to CLL, including weight loss > 10% over the preceding 6 month period; grade 2 or 3 fatigue; or fevers > 100.5°F and/or night sweats for greater than 2 weeks without evidence of infection. Required Laboratory Value: Creatinine ≤ 1.5 x upper limit of normal

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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive rituximab IV over 4 hours on days 1, 3, and 5 of week 1 and then on day 1 of weeks 5, 9, 13, 17, and 21. Patients also receive fludarabine phosphate IV over 30 minutes on days 1-5 of weeks 1, 5, 9, 13, 17, and 21. After completion of chemoimmunotherapy, patients are followed every 3 months until disease progression. At the time of disease progression, patients receive retreatment with chemoimmunotherapy as above or another treatment regimen. | Biological: rituximab<br>* Given IV over 4 hours<br>Drug: fludarabine phosphate<br>* Given IV over 30 minutes<br>|
| Active Comparator: Arm II<br>Patients are followed every 3 months until disease progression. At the time of disease progression, patients receive rituximab and fludarabine phosphate as in arm I. Patients are then followed every 3 months until second disease progression. Patients with a second disease progression receive retreatment with chemoimmunotherapy as above or another treatment regimen. | Biological: rituximab<br>* Given IV over 4 hours<br>Drug: fludarabine phosphate<br>* Given IV over 30 minutes<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Second Treatment in High Risk Patients | Kaplan-Meier analysis was conducted to estimate the distribution of time from randomization to second treatment or death whichever comes first. Events were defined as the start of second treatment or death. Patients who had not experienced one of these defined events of interest were censored at their last known follow-up. | Up to 72 months | 
| Disease-Free Survival in High Risk Patients | Kaplan-Meier analysis was conducted to estimate disease free survival defined as:> Arm A: Time from randomization until Second Treatment (first relapse) or death whichever comes first. Events were defined as the start of second treatment or death. Patients who had not experienced one of these defined events of interest were censored at their last known follow-up.> Arm B: Time from randomization until First Treatment (first relapse) or death whichever comes first. Events were defined as the start of first treatment or death. Patients who had not experienced one of these defined events of interest were censored at their last known follow-up. | Up to 72 months | 
| Overall Survival (OS) for High Risk Patients | Kaplan-Meier analysis was conducted to estimate the distribution of time from randomization to death from any cause. Estimates were not stratified. Patients who did not experience this primary outcome had their survival times censored at their last follow-up. | Up to 72 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Mutated and Unmutated IgVH Genes | Number of patients with mutated and unmutated IgVH genes are reported below. | Once at baseline | 
| Overall Survival in Low Risk Patients | Overall survival in low risk patients (registration to first treatment or death)> • Events were defined as death from any cause. Low risk Patients who were alive were censored at their last known follow-up. | Up to 72 months | 
| Time to First Treatment Survival in Low Risk Patients | Time to First Treatment Survival in low risk patients (registration to first treatment or death)> • Events were defined as the start of first treatment or death from any cause. Patients who didn't receive their first treatment were censored at their last known follow-up. | Up to 72 months | 

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