• Patient has provided written informed consent using the PIPOZA Patient Information and Consent Form (PICF)

• Confirmed diagnosis of CLL according to iwCLL 2018 criteria, also including CLL with atypical immunophenotype

• Prior systemic therapy, which must include zanubrutinib as the most recent prior line of therapy. Patients must have received at least one cycle (28 days) of zanubrutinib

• Patients must have an indication for second- or subsequent-line treatment in the opinion of the investigator as defined by iwCLL 2018 criteria, including:

‣ Where the original indication for treatment has not resolved with initial therapy and it is considered reasonable to initiate second-line treatment without waiting for formal disease progression to be manifest

⁃ Where the rate of disease progression is considered rapid, and initiation of subsequent therapy is considered acceptable before formal progression where there is substantial persisting disease burden

• Age 18 years of age or older at time of signing the PICF

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2

• Must have adequate bone marrow function, as defined below:

‣ Absolute neutrophil count \> 0.75 × 109/L; if marrow is known to be infiltrated by CLL, granulocyte-colony stimulating factor (G-CSF) support may be used to achieve eligibility criteria

⁃ Platelets ≥ 30 × 109/L independent of transfusions within 7 days prior to screening assessment

⁃ Haemoglobin ≥ 70 g/L independent of transfusions within 7 days prior to screening assessment

• Normal hepatic function defined as:

‣ Total bilirubin ≤ 1.5× upper limit of normal (ULN) or ≤ 3.0 x ULN with documented liver involvement and/or Gilbert's Disease

⁃ Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \< 3.0 × ULN or ≤ 5.0 × ULN with documented liver involvement

• Adequate renal function defined as creatinine clearance of \> 30 mL/minute calculated by Cockroft-Gault formula or using biochemical or nuclear medicine techniques

⁃ Ability to swallow tablets

⁃ Patients must have had a zanubrutinib washout period of at least 24 hours prior to the planned start date of pirtobrutinib on Day 1 Cycle 1

⁃ Prior treatment-related adverse events must have recovered to Grade ≤ 1 or pretreatment baseline with the exception of alopecia and Grade 2 peripheral neuropathy

⁃ Women of childbearing potential defined as not postmenopausal for at least 2 years or surgically sterile must have a negative serum pregnancy test documented within 14 days prior to planned started date of pirtobrutinib on Day 1 Cycle 1

⁃ Men with partners of childbearing potential or women of childbearing potential must agree to use a highly effective contraceptive method of birth control during study treatment and for at least 6 months following the last dose of study drug. Sperm donation is prohibited during the duration of participation in this study and for 6 months after the last dose of study drug. Acceptable methods of birth control are:

∙ Combined estrogen and progestin containing hormonal contraception associated with inhibition of ovulation given orally, intravaginally, or transdermally

‣ Progestin-only hormonal contraception associated with inhibition of ovulation given orally, by injection, or by implant

‣ Intrauterine device Intrauterine hormone-releasing system

‣ Bilateral tubal occlusion

‣ Vasectomised partner

‣ Sexual abstinence: Considered a highly effective method only if defined as refraining from heterosexual intercourse during an entire period of risk associated with the study treatment. The reliability of sexual abstinence needs will be evaluated in relation to the duration of the study and to the usual lifestyle of the patient

⁃ The patient understands the purpose of the trial and procedures required for the trial which includes compliance with the protocol requirements and restrictions listed in the PICF and in this protocol