Fludarabine, Mitoxantrone and Rituximab in Relapsed or Primary Failing Advanced Follicular Non-Hodgkin's Lymphoma

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 Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria: Nodal or extranodal single mass \> 7cm in its greatest diameter; systemic B-symptoms; increased lactate dehydrogenase (LDH) and beta 2 macroglobulinemia (\> 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 aspartate aminotransferase (AST) \>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 central nervous system disease
* Known positivity for HIV, hepatitis Bs 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.