Fludarabine,Cyclophosphamide and Rituximab Followed by Zevalin for Non-Follicular Indolent Lymphomas. (Z0105)

Inclusion Criteria:

• Patients with a lymphoma refractory to front-line chemotherapy, not including fludarabine, or in first relapse after chemotherapy not including fludarabine, not suitable for high-dose chemotherapy supported by auto or allogeneic bone marrow transplantation.
• Histologically-confirmed small lymphocytic (SLL), lymphoplasmacytic (LPL) and marginal zone (MZL) lymphomas.
• All prior chemotherapy, including corticosteroids, had to have been completed > 4 weeks before study treatment; < 25% of active bone marrow irradiated previously; no prior bone marrow transplantation.
• Age: 18-70 years
• ECOG- performance status: 0-2.
• No allergy to mouse proteins.
• CD20 positive B cell lymphoma.
• Ann Arbor stage III or IV disease with bidimensionally measurable disease in at least one site which has not irradiated, including any adenopathy or mass that could be measured during a physical examination or that was > 5 cm on a computed tomographic scan (CT). In the event of splenomegaly or hepatomegaly, extension 5 cm below the costal margin was considered evidence of measurable disease. Osteoblastic bone lesions, ascites and pleural effusion are not considered measurable disease.
• Tumor involvement in the marrow<25% before treatment with Zevalin.
• Acceptable hematologic status within one week prior study start: Hb>9g/dL, white blood count >3x10^9/L, absolute neutrophil count >1.5x10^9/L, platelets >100x10^9/L.
• Written informed consent prior to any study specific screening procedures, with the understanding that the patient has the right to withdraw from that study at any time, without prejudice.
• Patients willing and able to comply with the protocol for the duration of the study.
• Patients, if sexually active, must agree to be using effective contraception for the entire treatment period and for 1 year following treatment. Women, of child-bearing potential, must have a negative pregnancy test.

Exclusion Criteria:

• Histologies other than those included
• History of malignancy other than squamous cell carcinoma, basal cell carcinoma of the skin or carcinoma in situ of cervix within the last 5 years.
• Major surgery, other than diagnostic surgery, within the last 4 weeks.
• Presence of malignant ascites or pleural effusions.
• Evidence of CNS involvement. Patients with a history of uncontrolled seizures, central nervous system disorders or psychiatric disability judged by the investigator to be clinically significant and adversely affecting compliance to study drugs.
• Clinically significant cardiac disease (e.g. congestive heart failure, symptomatic coronary artery disease, cardiac arrhythmias not well controlled with medication, or myocardial infarction within the last 6 months, NYHA class III or IV heart disease), abnormal liver function tests, not disease related, within 1 week prior to study start (serum bilirubin >2 mg/dL; ALAT >2.5 x upper normal limit; alkaline phosphatase >2.5xupper normal limit), abnormal renal function, not disease related (serum creatinine >2.0 mg/dL), active opportunistic infections.
• Serum positivity for HIV, HBsAg and HCV except for those with no sign of active viral replication, assessed by HCV-RNA and HBV-DNA. This latter group of patients can be enrolled in the study, but they will receive lamivudine prophylaxis and bimonthly evaluation of HbSAg, HbCAb and HBV-DNA will be provided.