ReBeL study: A randomized phase I/II trial of lenalidomide and rituximab with or without bendamustine in patients ≥ 18 years with relapsed follicular lymphoma. A HOVON/GLSG study.

1. Relapsed FL grade 1, 2, 3a;

2. Ann Arbor stage II-IV at relapse;

3. The lymphoma at relapse must be CD20+. To establish this, and to exclude transformation to aggressive lymphoma, a biopsy at relapse is strongly recommended;

4. A maximum of three prior treatment regimens (patients that have had a prior allogeneic SCT are excluded; prior autologous SCT (if > 1 year ago) is allowed);

5. Subjects must have an indication for treatment based on one or more of the following criteria:

A. Involvement of at least 3 nodal sites, each with a diameter > 3 cm;

B. Symptomatic splenomegaly;

C. Bulky disease at study entry according to the GELF criteria: nodal or extranodal mass (except spleen) > 7 cm in its greatest diameter;

D. B-symptoms (absence or presence of fever and/or night sweats and/or unexplained loss of 10% of body weight or more in the 6 months preceding diagnosis);

E. Hb < 10 g/dl (6.2 mmol/l) (if caused by bone marrow infiltration and not otherwise explained);

F. Thrombocytopenia: platelets < 100x109/l caused by bone marrow infiltration;

G. Organ compression syndrome (e.g. hydronephrosis caused by lymphadenopathy);

H. Pleural/peritoneal effusion;

I. Symptomatic extranodal manifestations.

6. Measurable disease as defined in appendix C (patients with only bone marrow involvement are therefore not eligible);

7. Age ≥ 18 years;

8. Able to adhere to the study visit schedule and other protocol requirements;

9. WHO performance status of 0-2;

10. Laboratory test results within these ranges: absolute neutrophil count ≥ 1.5x 109/l, platelet count ≥ 100x 109/l, creatinin clearance ≥ 50 ml/min, total bilirubin ≤ 30 µmol/l (1,75 mg/dl), AST & ALT ≤ 3x ULN;

11. Females of childbearing potential must have a negative serum or urine pregnancy test within 10 - 14 days prior to and again within 24 hours of starting lenalidomide treatment;

12. Patients must be willing and capable to use adequate contraception during the therapy (all men, all pre-menopausal women). Patients must be able to adhere to the requirements of the Lenalidomide Pregnancy Prevention Risk Management Plan;

13. Written informed consent.

1. Rituximab-refractory patients (definition: progression during or within 6 months after rituximab containing immunochemotherapy or rituximab maintenance treatment);

2. Clinical or histologic signs of transformation;

3. Prior allogeneic SCT;

4. Prior autologous SCT less than one year ago;

5. Any prior use of lenalidomide or bendamustine;

6. Concurrent use of other anti-cancer agents or treatments;

7. Use of any other experimental drug or therapy within 28 days of baseline;

8. Hepatitis B sAg positive, Hepatitis C positive and/or HIV positive patients;

9. Patients with uncontrolled autoimmune hemolytic anemia (AIHA) or autoimmune thrombocytopenia (ITP);

10. Active fungal, bacterial, and/or viral infection;

11. Pregnant or breast-feeding females (lactating females must agree not to breast feed while taking lenalidomide);

12. Known hypersensitivity and/or serious adverse reactions to lenalidomide or similar drugs;

13. Intolerance of exogenous protein administration, or known allergy to murine products;

14. Uncontrolled hyperthyroidism or hypothyroidism;

15. Neuropathy ≥ grade 2 at time of inclusion;

16. Clinically symptomatic severe cardiac dysfunction (NYHA III-IV);

17. Clinically symptomatic severe pulmonary dysfunction;

18. Severe neurologic or psychiatric diseases.