Chronic Lymphocytic Leukemia (CLL) / Small Lymphocytic Lymphoma (SLL)

Evidence-based treatment sequencing for CLL/SLL, using TP53 aberration and IGHV mutational status to frame frontline selection between continuous covalent BTK inhibitor therapy and time-limited venetoclax + obinutuzumab, then non-cross-resistant class crossover at first relapse, with the non-covalent BTK inhibitor pirtobrutinib reserved for disease exposed to both a covalent BTK inhibitor and a BCL-2 inhibitor.

Frontline therapy selection framed by TP53 aberration and IGHV mutational status

• Continuous covalent BTK inhibitor → Covalent BTK inhibitor — acalabrutinib or zanubrutinib (ibrutinib alternative)
• Time-limited venetoclax + obinutuzumab → Venetoclax + obinutuzumab (fixed 12-month duration)

1L: Covalent BTK inhibitor — acalabrutinib or zanubrutinib (ibrutinib alternative)

Preferred continuous targeted therapy across risk groups and the frontline choice most strongly favored in TP53-aberrant and unmutated-IGHV disease, where chemoimmunotherapy is inadequate. Acalabrutinib and zanubrutinib are preferred over ibrutinib for their improved cardiac/tolerability profile; monitor for atrial fibrillation, hypertension, and bleeding.

• Progression or intolerance → First relapse or intolerance — crossover guided by the frontline class already received

1L: Venetoclax + obinutuzumab (fixed 12-month duration)

Preferred fixed-duration, chemotherapy-free frontline regimen delivering deep MRD-negative remissions (CLL14). Requires TLS risk stratification with ramp-up dosing, hydration, and rasburicase/allopurinol prophylaxis; obinutuzumab needs infusion-reaction premedication and HBV screening.

• Progression or intolerance → First relapse or intolerance — crossover guided by the frontline class already received

First relapse or intolerance — crossover guided by the frontline class already received

• Prior covalent BTK inhibitor → Venetoclax-based therapy (after prior covalent BTK inhibitor)
• Prior time-limited venetoclax → Covalent BTK inhibitor (after prior time-limited venetoclax)

2L: Venetoclax-based therapy (after prior covalent BTK inhibitor)

After progression/intolerance on a covalent BTK inhibitor, cross over to BCL-2 inhibition (venetoclax, typically with an anti-CD20 antibody). Apply TLS prophylaxis with ramp-up dosing. Recheck TP53/karyotype at relapse to inform prognosis and trial eligibility.

• Progression (now double-class-exposed) → Progression after exposure to both a covalent BTK inhibitor and a BCL-2 inhibitor

2L: Covalent BTK inhibitor (after prior time-limited venetoclax)

After progression following fixed-duration venetoclax + obinutuzumab, cross over to a covalent BTK inhibitor. Late relapse after time-limited therapy may also be re-treated with a venetoclax-based regimen, but switching class is the standard non-cross-resistant approach.

• Progression (now double-class-exposed) → Progression after exposure to both a covalent BTK inhibitor and a BCL-2 inhibitor

Progression after exposure to both a covalent BTK inhibitor and a BCL-2 inhibitor

• Prior covalent BTK + BCL-2 inhibitor exposure → Pirtobrutinib (non-covalent BTK inhibitor)
• Clinical trial / CAR-T → Clinical trial or cellular therapy (CAR-T)

3L+: Pirtobrutinib (non-covalent BTK inhibitor)

For patients with prior covalent BTK inhibitor AND BCL-2 inhibitor exposure, pirtobrutinib retains activity including against BTK C481 resistance mutations (BRUIN). Non-covalent binding restores BTK inhibition where covalent agents have failed.

• Subsequent progression → Clinical trial or cellular therapy (CAR-T)

3L+: Clinical trial or cellular therapy (CAR-T)

For multi-refractory (double-exposed) disease or Richter transformation, prioritize clinical-trial enrollment and evaluate CD19 CAR-T cell therapy and allogeneic transplant in appropriate candidates.