Treatment options for patients with chronic lymphocytic leukemia, or CLL, have traditionally been limited to chemotherapies alone or alongside immunotherapies that modulate the patient’s immune response. For instance, the combined regimen known as FCR, for fludarabine, cyclophosphamide, and rituximab, was once a gold standard for patients with newly diagnosed CLL. However, chemotherapy-based regimens like FCR can be difficult for patients to tolerate, especially if they are older, unfit, or have other medical conditions such as kidney, heart, or lung diseases.
Newer therapies that better target cancer cells have been shown to have significant clinical efficacy and manageable safety profiles in treating CLL. Known as Bruton tyrosine kinase (BTK) inhibitors and BCL-2 inhibitors, these targeted therapies are becoming the preferred standard of care for most patients with newly diagnosed CLL, as well as for patients with relapsing or refractory disease. It should be noted that, although most patients show improved survival outcomes with these newer therapies, for some patients with specific types of CLL, such as those with immunoglobulin heavy chain (IGHV)-mutated CLL, chemotherapy with FCR remains the preferred regimen.
Ibrutinib, a BTK inhibitor, was the first targeted therapy approved for the treatment of CLL. In the RESONATE-2 clinical trial, researchers compared ibrutinib to chlorambucil, a chemotherapy agent, as first-line therapy in patients with newly diagnosed CLL who were aged ≥65 years. Five years after the start of the study, 70% of patients taking ibrutinib were alive with no cancer progression, whereas that number was only 12% for patients taking chlorambucil. Although ibrutinib is generally well tolerated, it is associated with an increased risk of cardiovascular side effects, including abnormal heart rhythms (atrial fibrillation) and bleeding.
Newer BTK inhibitors, such as acalabrutinib, have been associated with similar clinical efficacy with fewer risks of cardiovascular side effects. In the ELEVATE-TN trial, acalabrutinib combined with the immunotherapy obinutuzumab prevented CLL progression or death in about twice as many patients (93%) as did treatment with the chemotherapy chlorambucil plus obinutuzumab (47%). Notably, the numbers of patients with atrial fibrillation were low among those taking acalabrutinib.
Despite the benefits of targeted therapies, one advantage of chemotherapy-based regimens is that a patient only needs to take them for a limited time. For instance, a course of treatment may be only 6 cycles, or 6 months. However, for BTK inhibitors like ibrutinib and acalabrutinib, patients should continue taking the treatment indefinitely to prevent their disease from progressing.
An even newer treatment for CLL, the BCL-2 inhibitor venetoclax, has the benefits of being a targeted therapy and being used for only a limited amount of time. For patients with newly diagnosed CLL, venetoclax is given for 12 cycles, and for patients with relapsed or refractory CLL, venetoclax is given for up to 24 cycles, or 2 years. Safety and efficacy of venetoclax were evaluated in patients who had newly diagnosed CLL and other medical conditions in the CLL14 trial. Patients received either venetoclax plus obinutuzumab or chlorambucil plus obinutuzumab. Three years after the trial began, only approximately 18% of patients in the group receiving venetoclax showed progression of their disease or had died, compared with approximately 50% of patients having progression or dying in the group receiving chlorambucil.
Both BTK inhibitors and BCL-2 inhibitors have improved the number of quality medications available for treating CLL. To date, there are no clinical studies that have compared them head-to-head in patients with newly diagnosed CLL, so it is difficult to say whether one is better than another. Current and future studies are set to explore combinations of these already approved medications. In addition, exciting research continues on new therapies, including the BCL-2 inhibitor LOXO-305 and therapies derived from the patient’s own immune system (CAR T-cell therapies), which should further expand the treatment options for patients with CLL.
Astor L. The battle for the front line in CLL moves away from chemoimmunotherapy. Targeted Ther Oncol. 2020;9:73.