Management of CLL that has progressed following ibrutinib

This study reviewed evidence on patients with chronic lymphocytic leukemia (CLL) that stop responding to ibrutinib (Imbruvica) therapy.

Tyrosine kinase inhibitor therapy is a targeted therapy that blocks signals needed for tumors to grow. This includes the Bruton tyrosine kinase inhibitor ibrutinib. Ibrutinib blocks a signal that keeps the CLL cell alive. This treatment is particularly effective in CLL that is hard to treat, such as when there are certain genetic abnormalities (mutations) due to CLL. However, some patients can stop responding to ibrutinib over time. 

Relapse on ibrutinib can come in two forms. CLL can either progress during treatment or it can transform into a more aggressive subtype of CLL. Two of such subtypes are known as large cell lymphoma and prolymphocytic leukemia. Transformation typically occurs within the first 2 years of therapy. In contrast, CLL progression almost never occurs during the first year of treatment.

Studies have reported various rates of average survival after CLL relapse. Some trials report survival of 3 to 5.7 months after ibrutinib treatment. In a more recent report, average survival after CLL relapse was 23 months. Number of previous therapies and having genetic abnormalities such as 17p deletion are risk factors for progression.

Novel treatments are being investigated for patients previously treated with ibrutinib. Venetoclax (Venclexta) is a newly developed therapy that blocks a protein called BCL2. One study reported a 70% overall response rate in patients resistant to ibrutinib. 45% of patients were negative for minimal residual disease (small number of leukemia cells that remain after treatment). However, the complete remission rate was only 2%. Other drugs currently under investigation include the targeted therapies duvelisib (INK-1197) and entospletinib (GS-9973).

The author concluded that ibrutinib resistance is an uncommon but growing problem. More studies are needed to examine those patients at risk of relapsing on ibrutinib and possible treatment strategies.