Inclusion Criteria:

1. Participant who understood and voluntarily signed and dated an informed consent form prior to any trial-specific assessments/procedures being conducted

2. Must be able to adhere to the trial visit schedule and other protocol requirements

3. Age between ≥ 18 years and < 80 years at the time of signing the informed consent form (ICF)

4. Cumulative Illness Rating Score (CIRS) ≤ 6

5. CD20+, untreated and documented CLL or SLL, with a Royal Marsden Hospital (RMH) or Matutes Score > 3. For SLL a detectable clone with a CLL phenotype in the peripheral blood is a prerequisite for trial participation.

6. Presence of TP53 abnormalities (either 17p deletion by FISH and/or TP53 mutations) according to ERIC recommandations.17

7. Participant requiring treatment according to 2018 iwCLL guidelines 18

8. Presence of measurable disease (absolute lymphocyte count > 5,000/μL, palpable or measurable lymph node ≥1.5cm on imaging, or bone marrow involvement

9. ECOG performance status 0 to 2

10. Adequate hematopoietic function within 7 days before the participant's enrollment

    • ANC ≥ 1 G/L
    • And Platelets ≥ 50 G/L
    • And Hemoglobin ≥ 8 g/dL

    Note: Platelets and/or red blood cells transfusions may be administered during screening to meet this requirement

11. Adequate renal function defined by a Creatinine Clearance ≥ 50 ml/min calculated according to MDRD or CKD-EPI or Cockcroft-Gault (using actual body weight).

12. Adequate liver function, as indicated by a total bilirubin <1.5 x ULN, AST and ALT <3 x ULN value, unless directly attributed to the participant's CLL/SLL or to Gilbert's Syndrome (the ULN is based on institutional values)

13. The participant must have been vaccinated against pneumococcal (< 5 years) and SARS-CoV-2 (< 1 year) with at least 21 days between the last vaccination and the participant's enrollment

14. Woman of childbearing potential (WOCBP):

    • should have a negative result for pregnancy test (minimum sensitivity of 25 mIU/mL, urine or serum), within 28 days prior the participant's enrollment
    • should agree to use 1 form of highly effective method of contraception from the time of screening until at least 12 months after the final dose of epcoritamab, or at least 3 months after the final dose of ibrutinib or at least 30 days after the final dose of venetoclax, whichever is the longest

15. Woman should agree to abstain from breastfeeding during trial participation and at least 4 months after the last study treatment administration

16. Woman should agree to perform further pregnancy testing monthly

17. Woman should agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the entire trial, until 12 months after the last administration of study treatment.

18. Man of reproductive potential should agree to use an acceptable method of birth control during treatment and until at least 12 months after the final dose of epcoritamab, 3 months after the final dose of ibrutinib and 30 days after the final dose of venetoclax (see section 15.7.3 Acceptable birth control methods). Men should agree not to donate sperm during the entire trial and until 12 months after the last administration of study treatment.

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

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

21. Life expectancy > 6 months

Exclusion Criteria:

1. Any prior CLL or SLL-specific therapies, even including rituximab used for autoimmune cytopenias.

2. Clinically significant cardiovascular disease including the following:

   1. Myocardial infarction within 6 months prior to ICF signature
   2. Unstable angina within 3 months prior to ICF signature
   3. NYHA class III or IV heart failure
   4. Uncontrolled hypertension
   5. History of clinically significant arrhythmias (including sustained ventricular tachycardia, ventricular fibrillation, or torsades de pointes).
   6. QTcF > 480 msec using the Fridericia formula
   7. History of Mobitz II second- or third-degree heart block without permanent pacemaker
   8. LVEF <50% as determined by echocardiography or multiple uptake gated acquisition (MUGA) scan

3. Child-Pugh liver cirrhosis.

4. Clinical evidence for Central Nervous System involvement by CLL

5. History of ongoing or confirmed Progressive Multifocal Leukoencephalopathy (PML).

6. Active autoimmune disease or other disease requiring permanent immunosuppressive treatment including steroids therapy > 20mg daily of prednisone dose or equivalent within 15 days prior participant's enrollment

7. Active, uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura, requiring steroid therapy with > 20 mg daily of prednisone dose or equivalent within 15 days prior participant's enrollment

8. Any prior history of Richter transformation or DLBCL

9. Active malignancy other than the one treated in this trial. Prior history of malignancies unless the participant has been free of the disease for ≥ 2 years.

   However, participants with the following history /conditions that have been treated with a curative intent are allowed:

   1. Non-invasive basal cell or epidermoid carcinoma (non melanoma)
   2. In situ carcinoma of the cervix
   3. In situ carcinoma of the breast
   4. Incidental histologic finding of prostate cancer (T1a or T1b) using the tumor, nodes, metastasis [TNM] clinical staging system Woman with adjuvant endocrine therapy (I.e., hormonotherapy) after breast cancer treatment can be enrolled if hormonotherapy was started for ≥ 2 years

10. History of stroke or intracranial hemorrhage within 6 months prior to ICF signature.

11. Major surgery anticipated before the ICF signature

12. Known bleeding disorders

13. Active Hepatitis C Virus (HCV) infection (RNA PCR-positive). Participants who received treatment for HCV infection that was intended to eradicate the virus may participate if hepatitis C RNA levels are undetectable

14. Active Hepatitis B Virus (HBV) infection (DNA PCR-positive). Participants with evidence of prior HBV infection but who are PCR-negative are permitted in the trial but should receive prophylactic antiviral therapy during the entire treatment with active monitoring of viral load in the blood

15. Known history of seropositivity for HIV infection

16. Known or suspected hypersensitivity or anaphylaxis to trial intervention(s) including active substance or to any of the excipients.

17. Requires treatment with warfarin, other vitamin K antagonists, or dual antiplatelet therapy

18. Requires treatment with a strong cytochrome CYP3A4 inhibitor/inducer

19. Vaccinated with live, attenuated vaccines within 6 months of enrollment

20. Participation in another clinical study who would compromise the participation to the current study.

21. Use of any standard or experimental anti-cancer drug therapy within 28 days or 5 half-lives (whichever is shorter) before the participant's enrollment

22. Any prior therapy with a bispecific antibody targeting CD3 and CD20

23. Prior allogeneic stem cells or autologous transplant.

24. Pregnant, planning to become pregnant or lactating woman

25. Any significant medical conditions, or laboratory abnormality or psychiatric illness likely to interfere with participation in this clinical trial (according to the investigator's decision)

26. Ongoing active bacterial, viral, fungal, mycobacterial, parasitic or other infection requiring systemic treatment (excluding prophylactic treatment) at the time of enrollment or within the previous 2 weeks prior to the first dose of trial drug, including COVID-19 infection and participants with positive cytomegalovirus PCR.

27. Participant deprived of their liberty by a judicial or administrative decision

28. Participant hospitalized without consent

29. Adult participant under legal protection