Evaluation of Risk-Adapted and MRD-Driven Strategy for Untreated Fit Patients With Intermediate Risk Chronic Lymphocytic Leukemia

Inclusion Criteria:

* Age 18 years or older.
* Immunophenotypically confirmed CLL (according to IWCLL guidelines, RMH score 4-5 or RMH 3 providing CD200high and CD20low), excluding small lymphocytic lymphoma without lymphocytosis.
* Indication for treatment according to the 2018 IWCLL criteria and clinically measurable disease.
* Risk stratification: no criteria characterizing low-risk or high-risk groups.
* Patient with unmutated status
* Absence of 17p deletion and/or TP53 mutation.
* Performance status ECOG \< 2.
* CIRS (Cumulative Illness Rating Scale) ≤ 6.
* Eligibility for fludarabine, cyclophosphamide and rituximab combination (FCR) and for ibrutinib and venetoclax therapy.
* Adequate hepatic function per local laboratory reference range as follows:
* Aspartate transaminase (AST) and alanine transaminase (ALT) \< 3.0 x ULN
* Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin).
* No prior treatment for CLL (chemotherapy, radiotherapy, immuno-therapy) except steroids for less than 1 month.
* Willingness to accept highly effective methods of contraception for the duration of therapy and 12 months thereafter.
* Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin \[β-hCG\]) or urine pregnancy test at Screening.
* Signed (or their legally-acceptable representatives must sign) an informed consent document indicating that they understand the purpose of and procedures required for the study, including biomarkers, and are willing to participate in the study.

Exclusion Criteria:

* Patients with IGHV mutated (except VH3-21/subset #2) with normal karyotype and/or del 13q without TP53 mutation ie low risk patients.
* Patients del 17p and or TP53 mutation ie high risk patients.
* CLL without active disease according to IWCLL 2008 criteria.
* Known HIV seropositivity.
* Evidence of other clinically significant uncontrolled condition(s) including, but not limited to:
* Uncontrolled and/or active systemic infection (viral, bacterial or fungal)
* Chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment. Note: subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface (HBs) antigen negative, anti-HBs antibody positive and anti-hepatitis B core (HBc) antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) may participate.
* Active and uncontrolled autoimmune cytopenia, including autoimmune hemolytic anemia (AIHA) (isolated positive DAT is not an exclusion criteria) and idiopathic thrombocytopenic purpura (ITP).
* Life expectancy \< 6 months.
* Patient refusal to perform the bone marrow biopsy for evaluation points.
* Active second malignancy currently requiring treatment (except basal cell carcinoma, in situ endometrial carcinoma and incidental prostate carcinoma) and/or less than 5 years CR after breast cancer.
* Concurrent severe diseases which exclude the administration of therapy.
* heart insufficiency NYHA grade III/IV, LEVF \< 50% and or RF \<30%, myocardial infarction within the past 6 months prior to study.
* severe chronic obstructive lung disease with hypoxemia.
* severe diabetes mellitus.
* hypertension difficult to control.
* impaired renal function with creatinine clearance \< 50 ml/min according the formula of Cockcroft and Gault.
* Treatment with any of the following within 7 days prior to the first dose of study drug:
* steroid therapy for anti-neoplastic intent.
* A significant history of renal, neurologic, psychiatric, endocrine, metabolic, immunologic, cardiovascular, or hepatic disease that, in the opinion of the investigator, would adversely affect the patient's participation in this study or interpretation of study outcomes.
* Major surgery within 30 days prior to the first dose of study treatment.
* History of prior other malignancy that could affect compliance with the protocol or interpretation of results, with the exception of the following:
* curatively treated basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma in situ of the cervix at any time prior to study.
* other cancers not specified above that have been curatively treated by surgery and/or radiation therapy from which patient is disease-free for ≥ 5 years without further treatment.
* Contraindication to the use of Rituximab.
* Contraindication to the use of Venetoclax.
* Contraindication to the use of Ibrutinib.
* Pregnant or breastfeeding women.
* Adult under law-control.
* Fertile male and female patients who cannot or do not wish to use an effective method of contraception, during and for 12 months after the final treatment used for the purposes of the study.
* No affiliation to social security.