Inclusion Criteria:

• 18 years < age < 75 years
• Pathologically confirmed low grade, follicular, B cell lymphoma (WHO Classification Follicular grades 1 and 2
• Failed at least first line chemotherapy with any standard anthracycline containing regimen (see appendix C for definition of treatment failure)
• Frozen biopsy material obtained at relapse or disease progression should be available for central pathology review and molecular biology studies
• The lymphoma must be CD20 positive (on the biopsy material obtained at relapse or disease progression)
• At least one measurable lesion one nodal or extranodal lesion
• WHO performance status grade 0 or 1
• Bulky disease at study entry according to the GELF criteria: Nodal or extranodal single mass > 7cm in its greatest diameter; systemic B-symptoms; increased LDH and beta 2 microglobulinemia (> 3mg/L); involvement of at least 3 nodal sites, each with a diameter of greater than 3 cm; splenic enlargement with margin below the umbilical line or cranio caudal diameter of greater than 20 cm; compression syndrome (ureteral, orbital, gastrointestinal), or pleural or peritoneal serous effusion.
• Patient information and written informed consent

Exclusion Criteria:

• Evidence of histological transformation to diffuse large B-cell lymphoma
• > 2 prior treatment regimen
• Chemotherapy, or other experimental anticancer treatment during the 4 weeks before inclusion
• Any radiation therapy to the index lesion(s) during the 4 weeks before inclusion
• Autologous stem cell transplant during the 3 months before inclusion
• Prior treatment including fludarabine and / or mitoxantrone and / or rituximab or contra-indication to one of these products
• Unless exempted by the Responsible Investigator, as lymphoma related: serum creatinine >2 x Institutional Upper Limit of Normal (IULN), total bilirubin >2 x IULN or AST (SGOT) >2 x IULN, alkaline phosphatase >2 x IULN
• Low bone marrow function: absolute neutrophil count < 1500/mm3 and platelet < 100 x 109/L at study entry (unless bone marrow infiltration)
• Clinically significant cardiac disease, as defined by history of symptomatic ventricular arrhythmias, congestive heart failure or myocardial infarction within 12 months of study entry
• Evidence of symptomatic CNS disease
• Known positivity for HIV, HBs antigen or hepatitis C
• Pregnant or lactating women. Women of childbearing potential, and all men, unwilling to take appropriate contraceptive measures during and for at least 6 months after cessation of therapy
• Patients considered for an autologous or allogenic stem transplant at time of primary treatment failure or relapse according to the rules of the respective centers
• Any uncontrolled serious non malignant condition or infection which would likely compromise the study objectives
• Previous evolutive malignancy within 5 years of study entry, with the exception of non-melanoma skin tumors or stage 0 (in situ) cervical carcinoma
• Major surgery within 4 weeks prior to enrollment, unless patient has recovered from all treatment related toxicity
• Patient under tutelage.