CLL patients may hear about several genetic deletions or mutations that used to be considered high-risk and associated with poor treatment outcomes when chemoimmunotherapy was used. Chemo is now rarely used to treat CLL thanks to recent medicine advances now using non-chemo targeted therapies. These targeted therapies include medicines like venetoclax (Venclexta) and BTK inhibitors like zanubrutinib (Brukinsa) and acalabrutinib (Calquence) to help reduce CLL cells in the body, leaving most other healthy cells alone. 

Doctors found that most CLL patients treated with these targeted therapies have a successful reduction in CLL cells with multiple-year remissions regardless if they do or don’t have the chemo-associated high-risk genetic features such as del(17p)/TP53 mutation, del(11q)/ATM mutation, unmutated IGHV, BIRC3, NOTCH1, and SF3B1.

Del(17p)/TP53 Mutation

One of the above genetic abnormalities that still has some impact on targeted therapy decisions is del(17p)/TP53 mutation. The TP53 gene (located on chromosome 17) is in charge of creating protein 53 (p53) which helps suppress cell tumor growth, helps repair cell DNA, and instructs cells beyond repair to die. If CLL patients have either a deletion or mutation of the TP53 gene, they may require treatment at the time of diagnosis as the CLL cells can multiply more quickly than CLL cells without the TP53 deletion/mutation. In the case of venetoclax, patients with del(17p)/TP53 mutation would be encouraged to pair the treatment with a monoclonal antibody obinutuzumab (Gazyva) instead of taking venetoclax alone. This is because doctors found that patients with this genetic abnormality who took venetoclax alone had shorter remission periods (the amount of time patients have little to no CLL signs/symptoms present after treatment) than patients without. Pairing venetoclax with the antibody medicine proved to be helpful in extending the amount of time in remission.

Are there CLL targeted therapy resistant genetic features?

CLL patients can receive tests like fluorescence in situ hybridization (FISH) to look for chromosome deletions and next-generation DNA sequencing to check for gene mutations. The results can provide insight into how the patient's CLL cells may react to targeted therapies. If patients have the below genetic deletions or mutations, they should consult with their CLL specialist to review treatment options in order to avoid trying therapies they are resistant to. 

BCL2 mutations (resistance to venetoclax) 

• G101V mutation
• D103Y mutation

BTK Inhibitors

• Covalent BTKis deletions/mutations (acalabrutinib, ibrutinib, and zanubrutinib)
  • C481 binding site mutation 
  • Gain-of-function mutations in PLCG2 (enable CLL cells to keep dividing outside of BTK control) 
  • del(8p) causing the deletion of TRAIL-R (ibrutinib resistance) 
  • BTK A428D and L528W
• Non-covalent BTKis deletions/mutations (pirtobrutinib and nemtabrutinib (ARQ531))
  • Gain-of-function mutations in PLCG2  
  • Mutations in the tyrosine kinase area of the BTK protein (L528W, A428D, M437R, V416L, T474I)

A study showed that a group of CLL patients who were previously treated with covalent BTKis (cBTKi) and then switched to a non-covalent BTKi (ncBTKi), 73% of the CLL patients after the ncBTKi treatment developed new BTK mutations (L528W, A428D, M437R, V416L, and/or T474I) leading to increased treatment resistance. 

Researchers are reviewing other possible genetic deletions and mutations that may influence the effectiveness of targeted therapies as well as are continuing to research further effective treatment options for CLL patients. 

CAR T-cell Therapy

If a CLL patient has a genetic abnormality that can cause targeted therapies to not work well, they may have the option to join a CAR T-cell therapy clinical trial. CAR T-cell therapy is currently FDA-approved for other types of blood cancers and is in the process of getting FDA-approved for CLL. The treatment helps enhance the patient’s own cancer-killing immune system T-cells and has shown promising results to reduce CLL cells for relapsed/refractory patients. See here for more information about CAR T for CLL.