Below are non-chemo treatment paths CLL patients can expect whether for first-time or follow-up therapy (as of 2023 per NCCN guidelines). Medicine names with a brief description are listed, followed by preferred CLL treatment paths. Treatment paths are separated by if the patient does or does not have chromosome 17 deletion (del[17p])/TP53 mutation.  

To get the most accurate care for your CLL, find your CLL specialist. Need help? Take a look at HealthTree’s CLL specialist directory to locate an expert near you. 

Non-Chemo Treatment Names and Descriptions 

• Venetoclax (Venclexta): BCL-2 inhibitor targeted therapy
  • Taken in tablets by mouth for ~12 months (previously untreated CLL) or ~24 months (previously treated CLL)
  • More info about venetoclax 
• Zanubrutinib (Brukinsa): Covalent BTK inhibitor targeted therapy 
  • Taken in tablets by mouth as needed 
  • More info about zanubrutinib and zanubrutinib for relapsed/refractory CLL
• Acalabrutinib (Calquence): Covalent BTK inhibitor targeted therapy 
  • Taken in tablets by mouth as needed
  • More info about acalabrutinib
• Obinutuzumab (Gazyva): Antibody targeted therapy 
  • Administered by infusion
  • More info about obinutuzumab
• Rituximab (Rituxan): Antibody targeted therapy 
  • Administered by infusion 
  • More info about rituximab
• Idelalisib (Zydelig): PI3K inhibitor targeted therapy 
  • Taken in tablets by mouth as needed 
  • More info about idelalisib
• Lenalidomide (Revlimid): Targeted therapy and immunotherapy 
  • Taken in tablets by mouth as needed
  • More info about lenalidomide 

Possible CLL Treatment Paths 

The following are all non-chemo treatment options. Chemotherapy is rarely used to treat CLL thanks to recent medical advances. 

Patient does not have del(17p)/TP53 mutation

First time being treated (one of the following): 

• Venetoclax with obinutuzumab 
• Zanubrutinib taken by itself 
• Alcalbrutinib with or without obinutuzumab 

Second and third-line regimens:

• If first treatment was a BTK inhibitor
  • Use venetoclax with rituximab
  • If the first BTK tried was not alcalabrutinib or zanubrutinib, then try one of those
• If first treatment was venetoclax alone
  • Use venetoclax with obinutuzumab if cancer had been in remission
  • Alcalabrutinib or zanubrutinib
• If first treatment was chemoimmunotherapy or immunotherapy 
  • Use venetoclax with rituximab 
  • Alcalabrutinib or zanubrutinib

If BTK inhibitors and venetoclax don’t work:

• Patients are advised to enroll in cellular therapy clinical trials like CAR T-cell therapy 
  • Recent data shows a high overall response rate (the % of patients in which the cancer is significantly reduced [ORR]) for cellular therapies. See here for more info about CAR T-cell therapy for relapsed/refractory and high-risk CLL 
• Doctor may discuss an allogeneic stem cell transplant
• Lenalidomide with or without rituximab
• Idelalisib with or without rituximab

Patient has del(17p)/TP53 mutation

First time being treated (one of the following): 

• Venetoclax with or without obinutuzumab
• Zanubrutinib taken by itself 
• Alcalbrutinib with or without obinutuzumab 

Second and third-line regimens for CLL with del(17p)/TP53 mutation:

• Venetoclax with rituximab or venetoclax alone 
• Zanubrutinib
• Alcalabrutinib 

If BTK inhibitors and venetoclax don’t work:

• High-risk CLL patients are advised to enroll in CAR T-cell therapy clinical trials 
  • Recent studies have shown promising treatment success for CAR T-cell therapy for relapsed/refractory and high-risk CLL

Commonly Asked Questions

Why are some medicines used in a combination? 

• Data has shown some medicines are more effective at reducing CLL cancer cells when used in combination with another type of treatment

What is a 17p deletion and a TP53 mutation? 

• 17p deletion [del(17p)] means a portion of chromosome 17 is deleted. If 17p is deleted, this also means the TP53 gene is deleted which contains instructions to build protein p53. P53 is used to repair damaged DNA and start the process for cells beyond repair to die 
• Sometimes chromosome 17 is not deleted, however, the TP53 gene in chromosome 17 is mutated causing it to not work as it should
• Tests your doctor will complete to check for del(17p)/TP53 mutation:
  • del(17p) - Fluorescence in situ hybridization (FISH) testing shows missing parts of chromosomes
  • TP53 mutation - DNA sequencing finds gene mutations