Background: Outcomes remain poor for patients with relapsed/refractory chronic lymphocytic leukemia (CLL) after covalent Bruton tyrosine kinase inhibitor (cBTKi) therapy, particularly following prior BCL2 inhibitor exposure. Methods: Systematic review and pooled analysis of studies evaluating pirtobrutinib after prior cBTKi exposure. Results: Pooled overall response rate (ORR) was 72% (95% CI, 67–76%), with an ORR of 70% (95% CI, 60–79%) in patients previously exposed to both cBTKi and BCL2 inhibitor therapy. BRUIN CLL-321 demonstrated improved progression-free survival and time to next treatment versus investigator's choice. Pooled atrial fibrillation/flutter incidence was 3% (95% CI, 1–5%). Conclusions: Pirtobrutinib demonstrates meaningful clinical activity and favorable tolerability following prior covalent BTK inhibitor therapy, supporting its role as an important sequencing strategy in relapsed/refractory CLL.