A move towards targeted therapies for CLL

This study reviewed evidence on the use of targeted therapies for chronic lymphocytic leukemia (CLL). Authors concluded that newly developed targeted therapies are an effective treatment option for CLL, including CLL that is difficult to treat.

Standard therapy for CLL usually involves a combination of chemotherapies and immunotherapies. Early studies are reporting promising results with newly developed targeted therapies for CLL. Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells with less harm to normal cells.

Monoclonal antibody therapy is a type of immunotherapy that blocks signals needed for tumors to grow. Rituximab (Rituxan) is a commonly used monoclonal antibody therapy. It is generally well-tolerated and often combined with other treatments. Idelalisib is another type of antibody therapy. Early studies have shown it to be effective for relapsed CLL. Kinase inhibitors (KIs), such as ibrutinib (Imbruvica) and idelalisib (Zydelig), block signals that keeps the CLL cell alive. KIs are especially effective in CLL that is hard to treat. Venetoclax (ABT-199) is a newly developed therapy that blocks a protein called BCL2. Inhibiting BCL2 may kill cancer cells and may make them more sensitive to other anticancer drugs.

The aim of this study was to review evidence on targeted therapies for CLL.

Some patients with newly diagnosed CLL with or without a genetic abnormality known as 17p deletion (making CLL harder to treat) are fit for chemo-immunotherapy. Studies have shown good effectiveness with FCR. This is a combination of rituximab with the chemotherapies fludarabine (Fludara) and cyclophosphamide (Cytoxan). Bendamustine (Treanda) or chlorambucil (Leukeran) with rituximab is an option for patients not fit for FCR.

An increasing number of options are available for those patients with CLL whose disease relapses or is resistant to initial treatment (refractory disease). Ibrutinib without any additional chemotherapy led to an 89% overall response rate in relapsed/refractory CLL. Another study involving 144 patients with the 17p deletion and an average of 2 prior therapies reported a response rate of 83% with ibrutinib therapy. At 2 years, 63% of patients were progression-free. No new serious side effects were reported with long-term follow-up.

One study examined idelalisib with rituximab in 210 patients who were not eligible for chemotherapy. Overall survival (proportion who have not died from any cause since treatment) was 92% at 12 months. This was compared to 80% when rituximab was combined with placebo (control drug with no active effect). However, there was a high rate of side effects.

Venetoclax was associated with a 79.7% overall response rate in 107 patients with 17p deletion. Serious side effects included low white and red blood cell counts and infection. Venetoclax with rituximab has been associated with a response rate of 86% for relapsed/refractory CLL. 51% of patients achieved a complete response. 82% of patients were progression-free at 2 years. The rate of side effects was considered acceptable.

The order that targeted therapies are administered may affect their effectiveness. Patients treated with ibrutinib first compared to idelalisib first had significantly longer time to disease progression. This applied to newly diagnosed CLL, refractory disease, and patients with the 17p deletion. After the first KI fails, the use of the alternative KI or venetoclax was superior to chemo-immunotherapy.

This study concluded that FCR should be offered as a first-line therapy to patients who are fit for chemo-immunotherapy. Targeted therapies such as idelalisib plus rituximab or venetoclax may be more suitable in relapsed/refractory CLL. For patients with 17p deletion, ibrutinib is a good treatment option, which can be combined with venetoclax.