Selection of second-line therapy for chronic lymphocytic leukemia

Step 1: Evaluate exposure to prior therapies and response to therapy:
Initial therapy	Response to initial therapy	Preferred next treatment options
BTK inhibitor	Refractory	Venetoclax-based therapy
	Intolerant	Venetoclax-based therapy^* or Alternative BTK inhibitor (if no BTK mutation present)
Venetoclax plus obinutuzumab	Early progression	BTK inhibitor
	Late progression	Venetoclax-based therapy (if no BCL2 mutation present)^* or BTK inhibitor
Chemoimmunotherapy	Any	Venetoclax-based therapy^* or BTK inhibitor
Step 2: Consider adverse events and administration concerns of interest:
BTK inhibitor	Continuous therapy; increases the risk for bleeding, atrial fibrillation, and hypertension; other toxicities include fatigue, rash, infections, and myalgias/arthralgias; numerous drug interactions
Venetoclax plus obinutuzumab	Time-limited treatment; requires risk-based TLS prophylaxis and monitoring; most common toxicities include neutropenia, thrombocytopenia, anemia, diarrhea, nausea, upper respiratory tract infection, cough, musculoskeletal pain, fatigue, and edema; numerous drug interactions
Step 3: Consider patient characteristics impacting choice of therapy:
Venetoclax-based therapy preferred over BTK inhibitor	Cardiovascular disorders Uncontrolled hypertension Anticoagulation High risk for bleeding, low platelet counts
BTK inhibitor preferred over venetoclax-based therapy	Impaired creatinine clearance Strong CYP3A inhibitors

BTK: Bruton tyrosine kinase; TLS: tumor lysis syndrome.

* Venetoclax-based therapy and BTK inhibitors are equally acceptable next treatment options in this scenario.

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