Tolerance and Efficacy of Subcutanous Low Doses Rituximab for CLL Consolidation Treatment

Study Overview
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Brief Summary
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Chronic Lymphocytic Leukemia (CLL) is still an incurable disease. However recent advances have established correlation between the quality of the response (in particular achievement of negativity of minimal residual disease (MRD) and progression free and overall survival. That is why MRD negative complete remission (CR) is the current goal in CLL treatment. The association of Rituximab fludarabine cyclophosphamide leads to the best response rate with 52 to 72% CR in medically fit untreated CLL patients. MRD results in this setting are still preliminary and around 50%. However many other situations (unfit, elderly, relapse, haematological toxicity leading to early interruption of treatment…) are associated with much lower response rate that would be improved by consolidation treatment. Monoclonal antibodies are the treatment of choice for consolidation because of sparing marrow and targeting CLL cells. Alemtuzumab has been used for this purpose and results confirm improvement of CR and MRD negative responses but alemtuzumab induced immunodeficiency lead to unacceptable infectious complications. Rituximab monotherapy induces low response rate at standard dose regimen. This is at least partially due to shaving of CD20, mechanism by which CD20 is lost from the leukemic cells but these cells are not cleared. Using low doses of rituximab reduced shaving and allowed CLL cells clearance by the mononuclear phagocytic system. Such low doses of rituximab can be administered subcutaneously. The investigators then propose subcutaneous low dose rituximab in consolidation to CLL patients responding after induction but having not achieved MRD negative CR.

Detailed Description
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Objective(s) of the clinical study Main objective: - To improve the minimal residual disease (MRD) negative complete response (CR) rate after consolidation using subcutaneous low dose of rituximab Secondary objectives: Progression free survival, treatment free survival, overall survival, MRD follow-up, Safety Medico-economic study Quality of life study Immune functions study (ancillary study) Main assessment criteria: MRD negative CR rate, established by peripheral blood 4colour flow cytometry according to international consensus on CLL MRD study, at the end of the consolidation treatment. Experimental plan: Inclusion of patients after the evaluation of response to induction treatment according to NCI-ICLLWG criteria and MRD analysis (2 to 3 months after induction completion): patients having not achieved MRD negative CR. Consolidation treatment by subcutaneous rituximab given at 20 mg/m²/d thrice weekly during 12 weeks. Evaluation of the response 3 months after completion of the consolidation treatment. Subjects number: 35 patients will be needed to accept the hypothesis of an augmentation of CR with negative MRD >=40%, excluding the hypothesis that this rate is < 20%. This ensure us an alpha risk at 5% with a 80% power, taking into account that non evaluable patients will be < 5%. Brief description of the ancillary study: Immune functions study before and after consolidation treatment by rituximab

Official Title
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Phase II Study of Tolerance and Efficacy of Subcutanous Low Doses Rituximab Given as Consolidation Treatment to Chronic Lymphocytic Leukaemia (CLL) Patients Responding to Induction Therapy

Conditions
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Chronic Lymphocytic Leukemia

Intervention / Treatment
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* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: CLL (Matutes 4 or 5) in CR after induction treatment with negative MRD or PR age>18 performance status<=2 signed informed consent Exclusion Criteria: cytopenia other malignant affection HIV or HBV positive steroids treatment richter syndrome pregnant or breastfeeding women

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<br>Consolidation treatment with sub cutaneaous low doses of Rituximab | Drug: Rituximab<br>* Low doses of sub cutaneaous rituximab<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Residual disease | - minimal residual disease (MRD) negative complete response (CR) rate after consolidation using subcutaneous low dose of rituximab, from randomisation up to 3 month after the end of treatment | up to 3 month after the end of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| overall survival | time between inclusion and death | From date of inclusion until date of death, assessed up to 10 years | 
| Adverse events | Number and description of adverse events recorded according to the CTC-AE V4 | up to 3 months | 
| -Quality of life | -Quality of life study by QLQ-C30 | up to 3 months after the end of treatment | 
| Immune functions | NK, monocytes, CD8, and CD 20 expression on leucemic cells or B cells | up to 3 months after the end of treatment | 
| - Progression free survival | Time between inclusion and progression | up to time of progression assessed up to 10 years | 
| treatment free survival | time between end of treatment and restarting a new treatement | up to time of new treatment assessed up to 10 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MRD negative CR