The evidence base in support of fixed-duration, first-line approaches in medically fit patients with CLL is clearly strengthening, whether through combining targeted agents with immunochemotherapy or through chemotherapy-free combinations. The long-term PB MRD response rates with the investagators fixed-duration (15-month) immunochemotherapy approach remain the best to date, even compared to the new targeted agent combinations of ibrutinib-venetoclax or obinutuzumab-venetoclax.

The investigators' phase 2 ICLL07 trial in previously untreated fit CLL patients with a fixed-duration immunochemotherapy approach (with 4 cycles of FC-obinutuzumab and chemosparing strategy) carries a low risk for short and long term toxicities which still exist, including cardiac toxicities probably related to BTK inhibitors, moreover, two patients experienced treatment related myelodysplastic syndrome or acute myeloid leukemia beyond the end of treatment. Follow-up at 5,5 years from treatment start showed a persistent PB MRD benefit beyond end of treatment, high survival rates, and low long term toxicity with no difference in the durability of MRD response between the mutated and unmutated IGHV patients.

The investigators aim to explore the safety and efficacy of a fixed duration strategy combining a new BTK inhibitor with a favorable safety profile and a limited number of ICT courses.

The main goals and concerns are:

i) to ensure deep response and long lasting MRD ii) to reduce the duration of BTKi exposure and the risk of clonal evolution with the appearance of deleterious mutations iii) to limit the risk of hematopoietic secondary cancers (MDS/AML) by excluding patients in whom clonal hematopoiesis of undetermined potential (CHIP) is detected before inclusion and decreasing the number of courses of chemotherapy to 3 cycles. Moreover, patients with TP53 abnormalities will be excluded with a lower cut off (1% versus 10% in the previous studies) iv) to limit the risk of BTKi toxicity by using a non-covalent BTKi

Inclusion Criteria:

• Immunophenotypically confirmed CLL according to IWCLL 2018 guidelines
• Binet stage C or Binet stage A and B with active disease could be considered for inclusion according to IWCLL 20108 for initiation of treatment.
• Absence of Del(17p) and TP53 mutation in NGS (cut off 1%)
• ECOG performance status 0-2
• CIRS (Cumulative Illness Rating Scale) ≤ 6
• Adequate coagulation: defined as activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) and prothrombin (PT) or (international normalized ratio (INR) not greater than 1.5 x ULN
• Calculated creatinine clearance ≥ 30 ml/min according to Cockcroft/Gault Formula: (140 - age) × body weight (kg) × 0.85 (if female) serum creatinine (mg/dL) × 72
• Adequate liver function:
• Aspartate aminotransferase (AST)/alanine aminotransferase or (ALT) ≤ 3 × the ULN or ≤ 5 × ULN with documented liver involvement,
• Total bilirubin ≤ 1.5 × ULN or ≤ 3 × ULN with documented liver involvement and/or Gilbert's Disease"
• Adequate hematology values:
• absolute neutrophil count ≥ 0.75 x 109/L,
• platelet count ≥ 50 x 109/L (accordance to the coordinator if linked to the disease),
• Hemoglobin ≥ 80g/L Notes: Hgb and platelets: independent of transfusions within 7 days of Screening assessment. ANC: independent of growth factor support within 7 days of Screening assessment. Criteria must be met on C1D1 without transfusion/G-CSF within 7 days of assessment
• Prior vaccination to the SARS-Cov-2 virus and SARS-CoV-2 PCR testing (if clinically indicated) and negative result before study treatment administration at each treatment cycle
• The patient is able to take oral medications
• Signed written informed consent
• Willing or able to participate in all required study evaluations and procedures.
• Ability to understand the purpose and risks of the study and to provide a signed and dated informed consent form and authorization to use protected health information (in accordance with national and local subject privacy regulations)

Exclusion Criteria:

1. Presence of Clonal hematopoiesis of indetermined potential or CHIP (To define patients with CHIP: Presence of a myeloid mutation (whatever the mutation) with a VAF >2% in the granular fraction

2. Binet stage A without active disease according to IWCLL 20108 criteria

3. Life expectancy < 6 months

4. Current or past history or presence of clinically relevant disorder affecting the central nervous system (CNS)

5. Patient with history of confirmed progressive multifocal leukoencephalopathy (PML)

6. Evidence of other clinically significant uncontrolled condition(s) including, but not limited to:

   - Uncontrolled and/or active systemic infection (viral, bacterial or fungal): Known history of human immunodeficiency virus, serologic status reflecting active hepatitis B virus or hepatitis C virus infection, any uncontrolled active systemic infection along with subjects who are ongoing anti-infective treatment and subjects who have received vaccination with a live attenuated vaccine within 4 weeks before the first dose of study treatment

   1. Subjects who are hepatitis B core antibody (anti-HBc) positive and who are hepatitis B surface antibody (anti-HBs) negative will need to have a negative hepatitis B virus PCR result before enrollment. Those who are hepatitis B surface antigen (HBsAg) positive or hepatitis B virus PCR positive will be excluded.

   2. Subjects who are hepatitis C virus antibody positive will need to have a negative hepatitis C virus PCR result before enrollment. Those who are hepatitis C virus PCR positive will be excluded

      • Known active cytomegalovirus (CMV) infection. Unknown or negative status are eligible.
      • Active and uncontrolled autoimmune cytopenia, including autoimmune hemolytic anemia (AIHA) (isolated positive DAT is not an exclusion criteria) and idiopathic thrombocytopenic purpura (ITP).

7. Concomitant disease requiring prolonged use of corticosteroids (> 1 month)

8. Patients treated by vitamin K antagonist or dual antiaggregant or anticoagulants (coumadin, warfarin)

9. History of bleeding diathesis (e.g. hemophilia or von Willebrand disease)

10. Prior solid organ transplantation

11. Concurrent severe diseases that exclude the administration of therapy :

    • Heart insufficiency NYHA grade III/IV, LEVF LVEF < 50% and or RF < 30%, myocardial infarction within the past 6 months prior to study

    • Significant cardiovascular disease such as symptomatic arrhythmias (including atrial fibrillation), congestive heart failure, unstable angina or acute coronary syndrome within the past 2 months prior to randomization or myocardial infarction within 6 months of Screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional (Subjects with controlled, asymptomatic atrial fibrillation are allowed to enroll on study)

    • Prolongation of the QT interval corrected for heart rate (QTcF) > 470 msec. QTcF is calculated using Fridericia's Formula (QTcF): QTcF = QT/(RR0.33).

      • Correction of suspected drug-induced QTcF prolongation can be attempted at the investigator's discretion and only if clinically safe to do so with either discontinuation of the offending drug or switch to another drug not known to be associated with QTcF prolongation.
      • Correction for underlying bundle branch block (BBB) allowed

    • Severe chronic obstructive lung disease with hypoxemia

    • History of stroke or intra-cranial hemorrhage within the last 6 months

    • Severe diabetes mellitus

    • Uncontrolled hypertension

    • Impaired renal function with creatinine clearance < 30 ml/min according the formula of Cockroft and Gault

12. Patient who requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole (unless of separate dosing of pirtobrutinib capsules with antacids by at least 2 hours. Pirtobrutinib capsules should be taken 2 hours before an H2-receptor antagonist. Avoid co-administration of pirtobrutinib capsules with proton pump inhibitors).

13. Disease significantly affecting gastrointestinal function (malabsorption syndrome, stomach or small bowel resection)

14. Evidence for Richter syndrome

15. Treatment with any of the following within 7 days prior to the first dose of study drug: steroid therapy (see criteria 7 above) for anti-neoplastic intent.

16. A significant history of renal, neurologic, psychiatric, endocrine, metabolic, immunologic, cardiovascular, or hepatic disease that, in the investigator's opinion, would adversely affect the patient's participation in this study or interpretation of study outcomes.

17. Major surgery within 30 days prior to the first dose of study treatment.

18. 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.

19. Have a known hypersensitivity to any of the excipients of pirtobrutinib or to any intended study medications.

20. Persons deprived of their liberty by judicial or administrative decision, persons subject to a legal protection measure (guardianship, curatorship, legal protection), persons under psychiatric care

21. Treatment with another investigational agent or participating in another trial within 30 days prior to entering the study

22. No affiliate to social security

23. Currently pregnant (confirmed with positive pregnancy test) or breast feeding.

24. Women of Childbearing Potential (WOCBP) unless the following criteria are met- a negative pregnancy test is required for all WOCBP within 21 days before start of study intervention, followed by immediate highly effective contraception; further pregnancy testing will be performed monthly.

25. Fertile men or WOCBP unless the following criteria are met:

    Willing to use 2 methods of reliable contraception, including one highly effective contraceptive method (Pearl Index < 1) and one additional effective (barrier) method during study intervention and for 1 month after last pirtobrutinib dose (for WOCBP). Men must refrain from sperm donation during the study.

26. 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.

27. Lactation or plan to breastfeed during the study or within 1 week of the last dose of study treatment.