Patient will receive either one infusion of rituximab IV and seven administrations of rituximab SC (experimental arm) or four infusions of rituximab IV (standard arm).

The hypothesis is that the use of rituximab by sub cutaneous route and the scheme of administration could:

• optimize rituximab exposure leading to improve response rate
• increase adaptative response and then improve long-term control disease.

Inclusion Criteria:

• Histologically confirmed follicular lymphoma CD20+ grade 1, 2 and 3a by biopsy within 4 months before signing informed consent

• Have a bone marrow biopsy within 4 months before the first study drug administration

• Have no prior therapy except surgery for diagnosis

• Aged 18 years or more with no upper age limit

• ECOG performance status 0-2

• Ann Arbor Stage II, III or IV

• Bi-dimensionally measurable disease defined by at least one single node or tumor lesion > 1.5 cm assessed by CT scan and/or clinical examination

• With low-tumor burden defined as:

  • Nodal or extra-nodal tumor mass with diameter less than 7 cm in its greater diameter
  • And involvement of less than 3 nodal or extra nodal sites with diameter greater than 3 cm
  • And absence of B symptoms
  • And no symptomatic splenomegaly
  • And no compression syndrome (ureteral, orbital, gastrointestinal…)
  • And no pleural or peritoneal serous effusion
  • And no cytopenia, with hemoglobin > 10 g/dL (6.25mmol/L) and absolute neutrophil count> 1.5 G/L and platelets > 100 G/L within 28 days before the randomization
  • And LDH < ULN within 28 days before the randomization
  • And β2 microglobulin < ULN within 28 days before the randomization

• Have signed an informed consent

• Must be covered by a social security system

Exclusion Criteria:

• Grade 3b follicular lymphoma
• Ann Arbor Stage I
• Seropositive for or active viral infection with hepatitis B virus (HBV) HBs Ag positive HBs Ag negative, anti-HBs antibody positive and/or anti-HBc antibody positive and detectable viral DNA

Note:

Patients who are HBs Ag negative, anti-HBs positive and/or anti-HBc positive but viral DNA negative are eligible Patients who are seropositive due to a history of hepatitis B vaccine are eligible

• Known seropositive for, or active viral infection with hepatitis C virus (HCV)
• Known seropositive for, or active viral infection with Human Immunodeficiency Virus (HIV)
• Any of the following laboratory abnormalities within 28 days before the randomization:

Total bilirubin or GGT or AST or ALT > 3 ULN. Calculated creatinine clearance (Cockcroft and Gault formula) < 60 mL /min

• Presence or history of CNS involvement by lymphoma
• Prior history of malignancies other than lymphoma (except for basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or breast) unless the subject has been free of the disease for ≥ 3 years
• Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form.
• Patient with mental deficiency preventing proper understanding of the informed consent and the requirements of treatment.
• Adult under law-control
• Adult under tutelage
• Contraindication to use rituximab or known sensitivity or allergy to murine products
• Pregnant or lactating females.
• Concomitant disease requiring prolonged use of corticosteroids or corticosteroids administration for lymphoma within 28 days before the first study drug administration.
• Male and female patients of childbearing potential who cannot or do not wish to use an effective method of contraception, during the study treatment and for 12 months thereafter.