CLL Genetic Features

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. Chemotherapy is now rarely used to treat CLL; thanks to recent medical advances, doctors are now using 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.

Genetic features of CLL cells can influence how the disease progresses. These factors may be added to future CLL staging systems. Two of the main genetic mutations doctors look for in CLL cells are: 

Del(17p)/TP53 Mutation

The TP53 gene located inside chromosome 17 codes for a protein called p53. P53 helps repair cell DNA, suppress tumors, and signal for cells beyond repair to die. If the TP53 gene is deleted or mutated (often written as del(17p)/TP53 mutation), the p53 protein does not work as it should, causing this type of CLL to progress more quickly than other forms of the disease. Up to 7% of untreated CLL patients have del(17p)/TP53 mutated CLL. Del(17p)/TP53 mutated CLL is more commonly seen in relapsed/refractory CLL. 

Also, del(17p)/TP53 mutated CLL was associated as a high-risk feature more when chemotherapy was used and less now with newer targeted therapies like BTK inhibitors and venetoclax. This gene alteration does have some implications despite targeted therapies, such as patients may need to start treatment closer to the time of diagnosis because of the fast progression of the disease and they may have less time in-between fixed-duration therapies than other forms of CLL.

Unmutated IGHV

Immunoglobulin Heavy Gene Mutation (IGHV): If the IGHV gene is mutated, the CLL cell is older and the disease typically progresses slowly. If IGHV is unmutated, the CLL cell is young and the disease may progress quickly. 

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.