Two Drugs Show Efficacy against Common Form of Leukemia
Reports from two early-stage trials of new oral drugs provide hope for patients with high-risk chronic lymphocytic leukemia (CLL) that has returned after prior treatment.
Some patients with CLL, the most common type of leukemia in the United States, do well even without treatment, whereas others need chemotherapy to manage their disease.
Chemotherapy can keep the disease in check for years without symptoms or need for further treatment, but virtually all patients relapse. Ultimately, for most patients, there is no curative therapy.
Relapsed CLL becomes harder to treat as patients’ tumors acquire a number of genetic abnormalities. The loss of part of chromosome 17, referred to as deletion 17p, is common in CLL and strongly associated with resistance to chemotherapy. Patients whose tumors develop deletion 17p are considered to be at high risk of disease progression and have an expected survival of only a few years.
A More Selective BTK Inhibitor
Findings from a clinical trial led by John C. Byrd, M.D., of the Ohio State University, showed that the drug acalabrutinib was both safe and effective. Of the 61 patients with relapsed CLL enrolled in the trial, 95 percent had a complete or partial tumor response, including patients with deletion 17p. After a median of 14 months, one patient died of pneumonia and one patient developed treatment-resistant CLL.
Acalabrutinib blocks Bruton tyrosine kinase (BTK), a key switch in the signaling pathway required for the growth and survival of CLL cells. Acalabrutinib follows in the steps of ibrutinib (Imbruvica®), the first BTK inhibitor to be developed, which was approved by the Food and Drug Administration (FDA) in 2014 for some patients with CLL. While ibrutinib inhibits BTK and several other kinases, acalabrutinib is more selective, targeting BTK only.
“It’s very encouraging that there is a second BTK inhibitor that shows a very high rate of response in patients with CLL, even in those otherwise considered at high risk of treatment failure, and also has very good tolerability,” said Adrian Wiestner, M.D., an investigator at the National Heart, Lung, and Blood Institute, who studies CLL but was not involved in the trial.
Taken together with the larger clinical experience with ibrutinib, the findings validate that targeting BTK can improve the outlook for patients with CLL, providing an effective option compared with existing therapies, said Dr. Wiestner.
“The benefit of having different drugs that can hit the same target in a tumor cell is that, if one drug leads to intolerable side effects, the other can be used,” he continued. “Conceivably, in some situations, one of the drugs may be safer or more efficacious than the other. Thus, having a choice can make a very good situation even better.”
Strong Responses with Venetoclax
Promising findings from a study testing another new drug in patients with high-risk CLL were also published in NEJM and presented at ASH. Andrew W. Roberts, Ph.D., of the University of Melbourne in Australia, led a 116-patient phase II trial of the investigational drug venetoclax, in which nearly 80 percent of patients responded to the drug and, in about 85 percent of those patients, the responses lasted for a year or more. Common side effects included mild diarrhea and upper respiratory infections.
Venetoclax works in a different way than ibrutinib and acalabrutinib. The drug targets the BCL2 protein, which, among other things, regulates the process of cell death, or apoptosis. CLL cells tend to produce excessive amounts of BCL2, preventing apoptosis. By blocking BCL2 activity, venetoclax reactivates the normal process of apoptosis, leading to the death of CLL cells.
“The big step forward is that we now have different drugs that kill tumor cells in unique ways,” Dr. Wiestner said. “This offers the potential for combinations that can really deliver a two-pronged attack on the tumor cells and hopefully can be the building blocks for treatments that lead not only to long-term survival, but also to long-term treatment-free periods for patients with CLL.”
Source: National Cancer Institute