Targeted Therapy Dominates CLL Treatment Landscape

Targeted therapy is at the forefront of chronic lymphocytic leukemia (CLL) treatment. In many cases, targeted agents offer superior outcomes to chemotherapy, with more manageable side effects. Multiple targeted therapy options are available, and some choices depend on certain molecular markers.
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A sea change has occurred in the treatment of chronic lymphocytic leukemia (CLL), one in which upfront treatment with chemotherapy has been largely abandoned in favor of targeted therapies.

Unlike chemotherapy, which indiscriminately attacks cells, including cancer cells, targeted therapy homes on specific protein (targets) on or in CLL cells. These targeted therapies can take many forms, and their profile of side effects is much different from that of chemotherapy, making them more desirable in elderly patients with CLL or patients with comorbid conditions.

Targeted therapies have already shown better effectiveness than chemoimmunotherapy in patients with CLL. Chemoimmunotherapy such as the combination of fludarabine, cyclophosphamide, and rituximab, referred to as FCR, is often reserved for younger, fit patients with CLL, but this group constitutes only about 10% of all CLL cases, and even these patients may opt for targeted therapy given the risk for secondary malignancies with chemoimmunotherapy.

The targeted therapies consist of kinase inhibitors and monoclonal antibodies. They are often used in combination with chemotherapy to strengthen responses. In some cases, targeted agents are used together. An advantage to kinase inhibitors is that they are taken orally, whereas monoclonal antibodies must be infused over several hours.

Ibrutinib is approved for the treatment of CLL in patients who have not yet received treatment (first line), patients who have received at least 1 prior therapy, and those with a deletion in chromosome 17, which predicts a poor response to standard treatment. Survival with ibrutinib is superior to that with other drugs used, such as the chemotherapy drug chlorambucil.

Acalabrutinib is the most recent oral kinase inhibitor approved by the US Food and Drug Administration for the treatment of CLL and small lymphocytic lymphoma. Approval was based on 2 studies showing superior survival without disease progression in patients treated with acalabrutinib compared with other therapies, including the monoclonal antibody obinutuzumab and chlorambucil.

Idelalisib is an oral kinase inhibitor approved for the treatment of relapsed CLL in combination with rituximab. This combination proved better than rituximab alone on the end point of survival without disease progression.

Venetoclax is a targeted therapy that inhibits B-cell lymphoma regulator protein. It is used to treat patients with CLL who have a deletion in chromosome 17p who have received at least 1 prior therapy.

Monoclonal antibodies include ofatumumab, obinutuzumab, and duvelisib.

The side effects associated with chemotherapy can include anemia, which can increase the risk for infection; fatigue; diarrhea; nausea and vomiting; skin problems; and hair loss. Targeted agents have their own side effects. For example, hypertension and an increased risk for major adverse cardiovascular events are common side effects of ibrutinib. Atrial fibrillation (an abnormal heart beat) can also occur with ibrutinib in up to 10% of patients. With idelalisib, a decrease in blood neutrophils is a possibility, as well as increase in blood triglycerides, high blood sugar levels, an increase in certain blood liver enzymes, and fever. Anemia and a low white blood cell count are possible with venetoclax, as well as low levels of platelets and upper respiratory tract infection.

Monoclonal antibodies can sometimes cause allergic reactions during infusion.

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Last modified: December 9, 2019

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