Reviewing evidence on targeted therapies for CLL

This study reviewed recent evidence on newly developed 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. However, further trials are needed.

CLL is cancer of the blood and bone marrow. It is one of the most common types of leukemia in adults. 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.

Tyrosine kinase inhibitor therapy is a type of targeted therapy. These therapies inferfere with certain molecules that allow cancer cells to grow or spread. This includes the Bruton tyrosine kinase inhibitor ibrutinib (Imbruvica). Ibrutinib blocks a signal that keeps the CLL cell alive. This treatment is especially helpful in CLL that is hard to treat, such as when there are certain genetic abnormalities (mutations or deletions) due to CLL. Idelalisib (Zydelig) is another kinase inhibitor that blocks the protein PI3K. It is often used in patients after other treatments have already been tried. BCL2 inhibitor therapy is a cancer treatment that blocks a protein called BCL2. BCL2 inhibitor therapy may kill cancer cells and may make them more sensitive to other anticancer drugs. An example is the drug venetoclax (ABT-199).

The aim of this study was to review recent evidence from the CLL German Study Group on newly developed targeted therapies for CLL.

Ibrutinib, idelalisib and venetoclax have been associated with significantly improved survival for CLL patients with specific genetic abnormalities. These include patients with a deletion of the 17p chromosome and those with a mutation of the TP53 gene. The TP53 gene provides instructions for making a protein called tumor protein p53. These three new targeted therapies are the most important for the treatment of patients with 17p chromosome deletions and TP53 mutations. However, patients with these abnormalities still show significantly poorer treatment response compared to patients without these genetic abnormalities.

Both ibrutinib and idelalisib are generally well tolerated. Some mild side effects frequently reported with ibrutinib often affect the skin or the stomach and digestive system. Patients may also show signs of inflammation of the liver, colon, lungs as well as high blood pressure, irregular heart rate, and some bleeding events. Venetoclax has been associated with tumor lysis syndrome. This refers to a group of metabolic abnormalities that can happen when cancer treatment causes cancer cells to die quickly.

The combination of ibrutinib or idelalisib with a monoclonal antibody, such as rituximab, can improve effectiveness. One study involving 40 patients with high-risk disease reported a treatment response rate of 95% with ibrutinib and rituximab. Excessive CLL cells were cleared faster from the blood compared to ibrutinib alone. Only 8% of patients showed disease progression at 6 months following the combination therapy.

The combination of venetoclax with rituximab was examined in a study involving 48 CLL patients. 86% of patients responded to treatment. Of these, 41% were complete responses. Disease progression after response occurred in 12% of patients. Serious side effects mainly affected red and white blood cell counts occurring in 12 to 53% of patients. Obinutuzumab (Gazyva) is another antibody treatment being explored in combination with venetoclax Obinutuzumab combined with the chemotherapy chlorambucil has been associated with improved survival among elderly patients. It is also being looked at as part of the induction phase of sequential targeted therapy.

Current trials are examining the use of sequential targeted therapy. This will include 1 or 2 courses of mild chemotherapy to decrease tumor size (known as debulking). The second phase includes combination treatment with targeted therapies and/or antibodies for 6 to 12 months (known as induction). The final phase includes 1 year of treatment with a single antibody or targeted therapy (known as maintenance).

Authors concluded that newly developed targeted therapies are an effective treatment option for CLL, including CLL that is difficult to treat. Authors also advised that further trials are needed to examine the best treatment combinations and the order of therapies.