This study will assess the effect of maintenance treatment with rituximab in comparison with observation period (no treatment), in participants with progressive B-cell CLL who have had previous first-line induction treatment with rituximab, cladribine and cyclophosphamide (RCC regimen). After 6 months of RCC induction therapy, participants will be randomized either to receive maintenance treatment with rituximab or to receive no treatment (observation only) for 96 weeks. Participants completing maintenance/observation period will be followed-up for approximately 3 years.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
128
Cladribine will be adminiatered at a dose of 0.12 mg/kg/day as IV infusion on Days 2-4 of each 28-day cycle during induction phase.
Cyclophosphamide will be administred at a dose of 250 mg/m\^2/day as IV infusion over 15-30 minutes on Days 2-4 of each 28-day cycle during induction phase.
Rituximab will be administered at a dose of 375 mg/m\^2 as IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m\^2 as IV infusion on Day 1 of Cycles 2-6 during induction phase. Rituximab will be administered at a dose of 375 mg/m\^2 as IV infusion on Day 1 of each 12-week cycle during maintenance phase.
City Clinical Hospital #9
Minsk, Belarus
Medical University, Independent Public Clinical Hospital; Dept. of Hematology, SPSK
Bialystok, Poland
Szpital Uniwersytecki W Krakowie; Klinika Hematologii
Krakow, Poland
Medical University School; Dept. of Haematology
Lodz, Poland
Istytut Hematologii i Transfuzjologii; Hematologia
Warsaw, Poland
Medical Uni of Wroclaw; Hematology
Wroclaw, Poland
Percentage of Participants With Disease Progression (PD), Relapse, or Death Due to Any Cause Assessed According to the National Cancer Institute (NCI) Revised Guidelines for the Diagnosis and Treatment of Chronic Lymphocytic Leukemia (CLL)
PD occurred if any of the following events was observed: appearance of any new lesion, such as enlarged lymph nodes (greater than \[\>\]1.5 centimeters \[cm\]), splenomegaly, hepatomegaly, or other organ infiltrates; an increase of greater than or equal to (\>/=) 50 percent (%) in greatest determined diameter of any previous site; an increase in the previously noted enlargement of the liver or spleen by \>/=50%; an increase in the number of blood lymphocytes by \>/=50% with B-lymphocytes \>/=5000 per microliter (/mcL); transformation to a more aggressive histology; occurrence of cytopenia (neutropenia, anemia, or thrombocytopenia) attributable to CLL.
Time frame: From randomization to PD, Relapse, or death due to any cause (overall approximately 5 years)
Progression-Fee Survival (PFS) Assessed According to the NCI Revised Guidelines for the Diagnosis and Treatment of CLL
PFS was defined as the time from date of randomization to date of PD, relapse, or death due to any cause. Participants alive with no evidence of PD or relapse were censored at date of last clinical examination. PD occurred if any of the following events was observed: appearance of any new lesion, such as enlarged lymph nodes (\>1.5 cm), splenomegaly, hepatomegaly, or other organ infiltrates; an increase of \>/=50% in greatest determined diameter of any previous site; an increase in the previously noted enlargement of the liver or spleen by \>/=50%; an increase in the number of blood lymphocytes by \>/=50% with B-lymphocytes \>/=5000/mcL; transformation to a more aggressive histology; occurrence of cytopenia (neutropenia, anemia, or thrombocytopenia) attributable to CLL.
Time frame: From randomization to PD, relapse, or death due to any cause (overall approximately 5 years)
Percentage of Participants With CR or PR Assessed According to the NCI Revised Guidelines for the Diagnosis and Treatment of CLL
CR was achieved if participants met all of the following criteria \>/= 2 months after last treatment: no lymphadenopathy (Ly)/ hepatomegaly/ splenomegaly/constitutional symptoms; neutrophils \>1500/mcL, platelets (PL) \>100,000/mcL, hemoglobin (Hb) \>11.0 grams per deciliter (g/dL), bone marrow (BM) sample must be normocellular for age with lymphocytes \<30% of nucleated cells. PR: a reduction in Ly (decrease in lymph node size by \>/=50% compared to pre-treatment state, no increase in any lymph node, no new enlarged lymph node); a reduction of \>/=50% from pre-treatment state in the lymphocytes count, and in enlargement of the spleen or liver; any one of the following: neutrophils \>1500/mcL, PL \>100,000/mcL (or 50% improvement from baseline), Hb \>11.0 g/dL (or 50% improvement from baseline).
Time frame: 8 weeks after the last dose of rituximab during induction treatment (Week 29) and 12 weeks after the end of maintenance treatment or observation phase (Week 129)
Percentage of Participants With Minimal Residual Disease (MRD) According to Rawstron Criteria in Participants With CR or PR
MRD was defined by the presence of tumor cells in bone marrow, using 4-color flow cytometry of cluster of differentiation (CD)19/CD5/CD20/CD79b. MRD was assessed in participants who achieved CR or PR. CR: if participants met all of the following criteria \>/=2 months after last treatment: no Ly/ hepatomegaly/ splenomegaly/constitutional symptoms; neutrophils \>1500/mcL, PL \>100,000/mcL, Hb \>11.0 g/dL, BM sample must be normocellular for age with lymphocytes \<30% of nucleated cells. PR: a reduction in Ly; a reduction of \>/=50% from pre-treatment state in the lymphocytes count, and in enlargement of the spleen or liver; any one of the following: neutrophils \>1500/mcL, PL \>100,000/mcL (or 50% improvement from baseline), Hb \>11.0 g/dL (or 50% improvement from baseline).
Time frame: 8 weeks after the last dose of rituximab during induction treatment (Week 29) and 12 weeks after the end of maintenance treatment or observation phase (Week 129)
PFS Assessed According to the NCI Revised Guidelines for the Diagnosis and Treatment of CLL According to Clinical and Biochemical Factors
PFS: time from date of randomization to date of PD, relapse, or death from any cause. Participants alive with no evidence of PD or relapse were censored at date of last clinical examination. PD: appearance of any new lesion, such as enlarged lymph nodes (\>1.5 cm), splenomegaly, hepatomegaly, or other organ infiltrates; an increase of \>/=50% in greatest determined diameter of any previous site; an increase in previously noted enlargement of liver or spleen by \>/=50%; an increase in number of blood lymphocytes by \>/=50% with B-lymphocytes \>/=5000/mcL; transformation to a more aggressive histology; or occurrence of cytopenia attributable to CLL. Rai Stage: staging for CLL, based on lymphocyte, red blood cell and platelet counts and size of lymph nodes, spleen, and liver. Rai Stage I or II are intermediate risk CLL and Rai Stage III or IV are high risk CLL. This outcome measure assessed relationship between clinical markers and clinical outcome (PFS) after study treatment.
Time frame: From randomization to PD, relapse, or death due to any cause (overall approximately 5 years)
Percentage of Participants With CR or PR Assessed According to the NCI Revised Guidelines for the Diagnosis and Treatment of CLL According to Clinical and Biochemical Factors at Week 29
CR was achieved if participants met all of the following criteria \>/= 2 months after last treatment: no Ly/ hepatomegaly/ splenomegaly/constitutional symptoms; neutrophils \>1500/mcL, PL \>100,000/mcL, Hb \>11.0 g/dL, BM sample must be normocellular for age with lymphocytes \<30% of nucleated cells. PR: a reduction in Ly; a reduction of \>/=50% from pre-treatment state in the lymphocytes count, and in enlargement of the spleen or liver; any one of the following: neutrophils \>1500/mcL, PL \>100,000/mcL (or 50% improvement from baseline), Hb \>11.0 g/dL (or 50% improvement from baseline). Rai Stage: staging for CLL, based on lymphocyte, red blood cell and platelet counts and size of lymph nodes, spleen, and liver. Rai Stage I or II are intermediate risk CLL and Rai Stage III or IV are high risk CLL. This outcome measure assessed the relationship between clinical markers and clinical outcome (response) after study treatment.
Time frame: 8 weeks after the last dose of rituximab during induction treatment (Week 29)
Percentage of Participants With CR or PR Assessed According to the NCI Revised Guidelines for the Diagnosis and Treatment of CLL According to Clinical and Biochemical Factors at Week 129
CR was achieved if participants met all of the following criteria \>/=2 months after last treatment: no Ly/ hepatomegaly/ splenomegaly/constitutional symptoms; neutrophils \>1500/mcL, PL \>100,000/mcL, Hb \>11.0 g/dL, BM sample must be normocellular for age with lymphocytes \<30% of nucleated cells. PR: a reduction in Ly; a reduction of \>/=50% from pre-treatment state in the lymphocytes count, and in enlargement of the spleen or liver; any one of the following: neutrophils \>1500/mcL, PL \>100,000/mcL (or 50% improvement from baseline), Hb \>11.0 g/dL (or 50% improvement from baseline). Rai Stage: staging for CLL, based on lymphocyte, red blood cell and platelet counts and size of lymph nodes, spleen, and liver. Rai Stage I or II are intermediate risk CLL and Rai Stage III or IV are high risk CLL. This outcome measure assessed the relationship between clinical markers and clinical outcome (response) after study treatment.
Time frame: 12 weeks after the end of maintenance treatment or observation phase (Week 129)
Percentage of Participants With MRD According to Rawstron Criteria in Participants With CR or PR According to Clinical and Biochemical Factors at Week 29
MRD: the presence of tumor cells in bone marrow, using 4-color flow cytometry of CD19/CD5/CD20/CD79b. MRD was assessed in participants who achieved CR or PR. CR (\>/=2 months after last treatment): no Ly/ hepatomegaly/ splenomegaly/constitutional symptoms; neutrophils \>1500/mcL, PL \>100,000/mcL, Hb \>11.0 g/dL, BM sample must be normocellular for age with lymphocytes \<30% of nucleated cells. PR: a reduction in Ly; a reduction of \>/=50% from pre-treatment state in the lymphocytes count, and in enlargement of the spleen or liver; any one of the following: neutrophils \>1500/mcL, PL \>100,000/mcL (or 50% improvement from baseline), Hb \>11.0 g/dL (or 50% improvement from baseline). Rai Stage: staging for CLL, based on lymphocyte, red blood cell and platelet counts and size of lymph nodes, spleen, and liver. Rai Stage I or II are intermediate risk CLL and Rai Stage III or IV are high risk CLL. This outcome measure assessed relationship between clinical markers and MRD after study treatment.
Time frame: 8 weeks after the last dose of rituximab during induction treatment (Week 29)
Percentage of Participants With MRD According to Rawstron Criteria in Participants With CR or PR According to Clinical and Biochemical Factors at Week 129
MRD: the presence of tumor cells in bone marrow, using 4-color flow cytometry of CD19/CD5/CD20/CD79b. MRD was assessed in participants who achieved CR or PR. CR (\>/=2 months after last treatment): no Ly/ hepatomegaly/ splenomegaly/constitutional symptoms; neutrophils \>1500/mcL, PL \>100,000/mcL, Hb \>11.0 g/dL, BM sample must be normocellular for age with lymphocytes \<30% of nucleated cells. PR: a reduction in Ly; a reduction of \>/=50% from pre-treatment state in the lymphocytes count, and in enlargement of the spleen or liver; any one of the following: neutrophils \>1500/mcL, PL \>100,000/mcL (or 50% improvement from baseline), Hb \>11.0 g/dL (or 50% improvement from baseline). Rai Stage: staging for CLL, based on lymphocyte, red blood cell and platelet counts and size of lymph nodes, spleen, and liver. Rai Stage I or II are intermediate risk CLL and Rai Stage III or IV are high risk CLL. This outcome measure assessed relationship between clinical markers and MRD after study treatment.
Time frame: 12 weeks after the end of maintenance treatment or observation phase (Week 129)
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