Study of Mosunetuzumab Plus Lenalidomide Compared to Anti-CD20 Anti-body + Chemotherapy in Follicular Lymphoma FLIPI2-5

Inclusion Criteria:

1. 1. Patient with histologically proven previously untreated CD20+ follicular lymphomagrade 1, 2, or 3a (including patient watched during up to 10 years after initialdiagnosis) as assessed by the investigators according to the WHO 2016classification12, or classical follicular lymphoma according to the WHO 2022classification13. Diagnostic tissue must be available for central pathology review,exploratory endpoints and secondary data use.

2. FLIPI 2-5.

3. All Ann Arbor stages (including stage I if FLIPI ≥ 2).

4. Must need treatment as evidenced by at least one of the following criteria:

4.1. Bulky disease defined as one of the following: 4.1.1. a nodal or extranodalmass/lesion > 70 mm in its largest diameter or, 4.1.2. involvement of at least 3different nodal or extranodal sites (each with a diameter greater than > 30 mm) 4.2.Presence of at least one of the following B symptoms within the prior 6 months: 4.2.1. fever (> 38°C) of unclear etiology 4.2.2. night sweats 4.2.3. weight lossgreater than 10% 4.3. Symptomatic splenomegaly 4.4. Symptomatic lesion: 4.4.1.painful lesion and/or 4.4.2. any compressive syndrome (for example, but notrestricted to- ureteral, orbital, gastrointestinal) 4.5. Any one of the followingcytopenias due to lymphoma: 4.5.1. hemoglobin < 10g/dL (6.25 mmol/L) 4.5.2.platelets <100 x 109/L, or 4.5.3. absolute neutrophil count (ANC) < 1.5 x 109/L 4.6.Pleural or peritoneal serous effusion (irrespective of cell content) 4.7. Abnormalbiological prognostic parameters: (item not applicable for Germany) 4.7.1. β2microglobulin > ULN or 4.7.2. LDH > ULN

5. At least one bi-dimensionally measurable nodal lesion, defined as > 15 mm in itslongest dimension, or at least one bi-dimensionally measurable extra nodal lesion,defined as > 10 mm in its longest dimension (and FDG-avid lesion).

6. Participant who understood and voluntarily signed and dated an informed consentprior to any study-specific assessments/procedures.

7. Must be ≥ 18 years old at the time of signing the informed consent form (ICF).

8. ECOG performance status 0 to 2.

9. Estimated minimum life expectancy of 3 months.

10. Adequate hematological function within 28 days prior to randomization, including:

10.1. Absolute neutrophil count (ANC) ≥ 1 x 109/L 10.2. Platelet count ≥ 75 x 109/L,or ≥ 30 x 109/L if bone marrow infiltration or splenomegaly 10.3. Hemoglobin ≥ 8.0g/dL (5 mmol/L) unless related to bone marrow infiltration or splenomegaly.Transfusion is allowed before starting treatment (no required window)

11. Normal laboratory values:

11.1. Measured or estimated creatinine clearance ≥ 40mL/min calculated byinstitutional standard method (MDRD or Cockcroft-Gault 11.2. AST or ALT ≤ 2.5 x theupper limit of normal (ULN), except in patients with documented liver or pancreaticinvolvement by lymphoma ≤ 5 x ULN 11.3. Serum total bilirubin ≤ 1.5 x ULN (or ≤ 3 xULN for patients with Gilbert syndrome), except in patients with documented liver orpancreatic involvement by lymphoma ≤ 3 x ULN

12. LVEF within normal range (i.e. > 50% as evaluated by Transthoracic Echocardiographyor > 45% as evaluated by isotopic method (MUGA scan).

13. Participants should be able to receive adequate prophylaxis and/or therapy forthromboembolic events (aspirin, low molecular weight heparin or direct oralanticoagulants). Patients with a curative anticoagulation therapy can be enrolled. A patient withdeep vein thrombosis due to compressive syndrome is eligible if a curativeanticoagulation therapy has been started at least 1 week before initiating studytreatment: low molecular weight heparin possible at treatment onset, then directoral anticoagulants according to local practices.

14. Must be able to adhere to the study visit schedule and other protocol requirements.

15. No more applicable following SM#14

16. Negative HIV test before randomization, with the following exception: Patients with a positive HIV test before randomization are eligible provided theyare stable on antiretroviral therapy for at least 4 weeks, have a CD4 count ≥ 200/uL, have an undetectable viral load, and have not had a history of opportunisticinfection attributable to AIDS within the last 12 months.

17. For women of childbearing potential (WOCBP) :

• must have a negative result for pregnancy test (highly sensitive serum) within 7 days before randomization and within 7 days before initiation of studytreatment.

• must agree to abstain from becoming pregnant or breastfeeding, and agree to usehighly effective contraceptive methods during study participation, and for atleast 28 days after the final dose of lenalidomide (if applicable), 3 monthsafter the final dose of mosunetuzumab and tocilizumab (if applicable), 12months after the final dose of CHOP (if applicable), 6 months after the finaldose of bendamustine (if applicable), 12 months after the final dose ofrituximab (if applicable), and 18 months after the final dose of obinutuzumab (if applicable).

18. For men with a female partner of childbearing potential or pregnant female partner,men must remain abstinent or use a condom during the treatment period (includingperiods of treatment interruption), and for at least 07 days after the final dose oflenalidomide (if applicable), 2 months after the final dose of tocilizumab (ifapplicable), 6 months after the final dose of CHOP (if applicable), 3 months afterthe final dose of bendamustine (if applicable), 12 months after the final dose ofrituximab (if applicable), and 3 months after the final dose of obinutuzumab (ifapplicable). Men must also agree to refrain from donating sperm from the first dayof treatment until at least 7 days after the final dose of lenalidomide (ifapplicable), 2 months after the final dose of tocilizumab (if applicable), 6 monthsafter the final dose of CHOP (if applicable), 3 months after the final dose ofbendamustine (if applicable), 12 months after the final dose of rituximab (ifapplicable), and 3 months after the last dose of obinutuzumab (if applicable).

19. Participant covered by any social security system (France).

20. Participant who understands and speaks one of the country official languages, unlesslocal regulation authorizes independent translators.

Exclusion criteria:

1. Grade 3b follicular lymphoma according to the WHO 2016 classification12, orfollicular large B-cell lymphoma according to the WHO 2022 classification13

2. Suspicion or clinical evidence of transformed lymphoma at enrollment by investigatorassessment. Examples: patients with high or intermediate high SUV (>20) in any nodal orextranodal site particularly in the bones (vertebrae etc) unless biopsy proven to begenuine FL grade 1,2, 3A ; and/or discordant (e.g. SUV doubled) with SUV of othersites including the biopsy site.; and/or LDH > 2.5 x ULN in a context of rapidlyprogressive disease, etc. Please contact the Coordinating Investigator / Sponsor todiscuss such cases or if there is any doubt before considering enrolment.

3. Prior localized radiotherapy for the FL.

4. Prior history of another lymphoma.

5. Uncontrolled symptomatic pleural or serous effusion requiring urgent treatment (within one week of finding). Participants may only be enrolled after Coordinatinginvestigator / sponsor approval once confirmed participant is durably asymptomaticafter adequate pleural/serous drainage or only if an efficient drainage device (e.g.pleurX™) is in place before randomization.

6. Uncontrolled symptomatic ureterohydronephrosis resulting in renal failure.Participants with adequate management i.e. ureteral catheter or double J stentallowing renal failure control are eligible only if urinary catheter is in placebefore randomization.

7. Presence or history of symptomatic or threatening lymphomatous epidural/nerve rootlesion, even such participants whose disease is controlled by short course ofsteroids are NOT eligible.

8. Use of any standard or experimental anti-cancer drug therapy within 45 days of thestart (Day 1) of study treatment.

9. Any contraindication to any drug contained in the study treatment control arms or inthe Auxiliary Medicinal Products (AxMPs)

10. Systemic immunosuppressive medications (including, but not limited to,cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosisfactor agents) and corticosteroids on the long run with the following exceptions:inhaled steroids for asthma, topical steroids, or replacement or stresscorticosteroids during the study at any time. Participants who require lymphomasymptom control during screening may receive corticosteroid < or = 1mg/kg/dayprednisone or equivalent for a maximum of 10 days prior to first dose of studytreatment

11. Received a live, attenuated vaccine within 4 weeks before the first dose of studytreatment, or in whom it is anticipated that such a live attenuated vaccine will berequired during the study period or within 6 months after the final dose of studytreatment.

12. Major surgery (excluding surgical documentation of FL) within 28 days prior tosigning informed consent.

13. Seropositive for or active viral infection with hepatitis B virus (HBV):

• HBsAg positive

• HBsAg negative, anti-HBs positive and/or anti-HBc positive and detectable viralDNA (Patients who are HBsAg negative, anti-HBs positive and/or anti-HBcpositive but viral DNA negative are eligible. They should be treated andperform testing at regular interval described in section Anti infectiousprophylaxis; Patients who are seropositive due to a history of hepatitis Bvaccine (anti-HBs positive) are eligible).

14. Known seropositive for, or active infection hepatitis C virus (HCV) (Patients whoare positive for HCV antibody with a negative viral RNA are eligible).

15. Known or suspected hypersensitivity to biopharmaceuticals produced in CHO cells orany component of the mosunetuzumab, anti-CD20 mAb, tocilizumab, lenalidomideformulation, including mannitol; or to any of the excipients.

16. History of solid organ transplantation or allogeneic stem cell transplant (SCT).

17. Active autoimmune disease requiring treatment.

18. History of autoimmune disease, including, but not limited to, myasthenia gravis,myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,inflammatory bowel disease, vascular thrombosis associated with antiphospholipidsyndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome,multiple sclerosis, vasculitis, uveitis, or glomerulonephritis.

• Participants with a history of autoimmune-related hypothyroidism on a stabledose of thyroid replacement hormone may be eligible.

• Participants with controlled Type 1 diabetes mellitus who are on an insulinregimen are eligible for the study.

• Participants with a remote history of, or well-controlled autoimmune disease,with a treatment-free interval from immunosuppressive therapy for 12 months maybe eligible after review and discussion with the Coordinating investigator.

19. Participants with any active infection such as known active bacterial, viral (including SARS-CoV-2), fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds), known or suspected chronic activeEpstein-Barr virus (EBV) infection are excluded.

20. Evidence of any significant, concomitant disease that could affect compliance withthe protocol or interpretation of results, including, but not limited to:

• significant cardiovascular disease [e.g., Objective Class C or D heart diseases (cf. Classes of Heart Failure | American Heart Association), myocardialinfarction within the previous 6 months, unstable arrhythmia, or unstableangina)

• significant pulmonary disease (such as obstructive pulmonary disease or historyof bronchospasm)

• clinically significant history of liver disease, including viral or otherhepatitis, or cirrhosis

• current or past history of central nervous system (CNS) disease, such asstroke, epilepsy, CNS vasculitis, or neurodegenerative disease. Participantswith a history of stroke who have not experienced a stroke or transientischemic attack in the past 1 year and have no residual neurologic deficits asjudged by the investigator are allowed. Participants with a history of epilepsywho have had no seizures in the past 2 years with or without anti-epilepticmedications can be eligible.

21. History of confirmed progressive multifocal leukoencephalopathy (PML).

22. Known or suspected history of hemophagocytic lymphohistiocytosis (HLH).

23. History of erythema multiforme, Grade ≥3 rash, or blistering rash following priortreatment with immunomodulatory derivatives.

24. History of interstitial lung disease (ILD), drug-induced pneumonitis, and autoimmunepneumonitis.

25. Active malignancy other than the one treated in this research. Prior history ofmalignancies unless the patient has been free of the disease and therapy for ≥ 3years. However, patients with a single occurrence of the following conditions thathave been treated with curative intent are eligible:

• Localized non-melanoma skin cancer.

• Carcinoma in situ of the cervix.

• Carcinoma in situ of the breast.

• Incidental histologic finding of prostate cancer (T1a or T1b as per Tumor NodeMetastasis [TNM] staging system) or prostate cancer.

26. Presence or history of CNS or meningeal involvement by lymphoma.

27. Pregnant, planning to become pregnant or lactating WOCBP.

28. Any significant medical conditions, including the presence of laboratory abnormalityor psychiatric illness which places the patient at unacceptable risk if he/she wereto participate in the study, and likely to interfere with participation in thisclinical study (according to the investigator's decision) or which confounds theability to interpret data from the study.

29. Person deprived of his/her liberty by a judicial or administrative decision.

30. Person hospitalized without consent.

31. Adult person under legal protection.

32. Patients with absolute lymphocyte count > 20 G/L before randomization. Participantscirculating lymphoma cell≥ 5 G/L must be discussed with the Sponsor beforerandomization.

NB: for 29-31., if there is an individual benefit for such patients, an Ethics Committee will have to be informed case by case.