A Study to Investigate the Sequencing Strategy of Pirtobrutinib After Disease Progression on First-line Acalabrutinib Treatment for Adult Participants With Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

To assess the efficacy and safety of pirtobrutinib in participants with CLL/SLL who have progressed on first-line treatment with acalabrutinib.

The purpose of this study is to assess the efficacy and safety of pirtobrutinib in participants with CLL/SLL who have progressed on first-line treatment with acalabrutinib. A subset of participants who have disease progression on pirtobrutinib will be retreated with acalabrutinib to assess whether relapsed CLL can be re-sensitized to a covalent irreversible BTK inhibitor such as acalabrutinib, and thereby, remain on treatment within the BTK inhibitor class rather than transition into another CLL/SLL treatment.

* The study duration for each participant will be up to 3 years in total.
* For participants who receive pirtobrutinib alone, the visit frequency will be approximately every month for the first 6 months. After that, the visit frequency will be reduced to one visit approximately every 3 months for the subsequent 12 months. The final part of the Treatment Phase has 2 visits in the space of 6 months. There is one visit to the site after the Treatment Phase.
* Participants who have disease progression on pirtobrutinib and go on to receive acalabrutinib retreatment will visit the site approximately once every month for the first 6 months. After that, the visit frequency will be reduced to 2 visits in the space of 6 months. There is one visit to the site after the Treatment Phase.

Eligibility Criteria:
Inclusion Criteria:

* Participant must be ≥ 18 at the time of signing the informed consent.
* Participants must have received acalabrutinib monotherapy as first-line treatment for CLL/SLL, have progressed per the iwCLL Criteria (Hallek et al 2018) and be eligible for second-line treatment by the same criteria.
* ECOG performance status of 0, 1, or 2.
* Adequate organ and BM function.
* Adequate coagulation, defined as aPTT or PTT and PT or INR not greater than 1.5 × ULN.
* Participants have a clearly defined, documented and accessible start date of their first line acalabrutinib monotherapy for CLL/SLL.
* Participants are eligible for the acalabrutinib retreatment phase only if they have progressed on pirtobrutinib monotherapy per iwCLL Criteria.

Exclusion Criteria:

* Major surgical procedure within 30 days before and not recovered adequately the first dose of study drug.
* Participants who experienced a major bleeding event or Grade ≥ 3 arrhythmia on prior treatment with a BTK inhibitor.
* History of bleeding diathesis (eg, hemophilia, von Willebrand disease).
* History of stroke or intracranial hemorrhage within 6 months before first dose of study drug.
* Significant cardiovascular disease.
* History of PML.
* Any active significant infection.
* HIV positive
* Active HBV or HCV infection.
* Active CNS involvement by lymphoma, leptomeningeal disease, or spinal cord compression.
* Active auto-immune cytopenia.
* History of prior or current malignancy.
* Requires or receiving therapeutic anticoagulation with warfarin or equivalent vitamin K antagonists.
* Received a live virus vaccination within 28 days of first dose of study drug.
* Requires treatment with a strong CYP3A inhibitor or inducer. The use of strong CYP3A inhibitors within 1 week or strong CYP3A inducers within 3 weeks of the first dose of study drug is prohibited.