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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	Early progression	Venetoclax-based therapy* OR BTK inhibitor
	Late progression	Venetoclax-based therapy* OR BTK inhibitor OR Repeat chemoimmunotherapy (less preferred)
Step 2: Consider adverse events and administration concerns of interest:
Ibrutinib	Continuous therapy; AEs include fatigue, rash, neutropenia, infections; hypertension; pneumonia; atrial fibrillation; bleeding; myalgia/arthralgia
Acalabrutinib	Continuous therapy; AEs include fatigue, rash, headache, diarrhea, infections; hypertension; atrial fibrillation; bleeding; pyrexia
Venetoclax plus obinutuzumab	Time-limited treatment; AEs include fatigue, rash, tumor lysis syndrome, neutropenia, diarrhea, infections
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; AEs: adverse effects.
* Venetoclax-based therapy and BTK inhibitors are equally acceptable next treatment options in this scenario.

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