April 16, 2014
An alternative to chemo?
BY Scott Merville
A newly approved drug for the treatment of chronic lymphocytic leukemia (CLL), studied in clinical trials at MD Anderson, is showing significant promise. In February, the U.S. Food and Drug Administration granted accelerated approval of Imbruvica, for use in previously treated CLL patients.
"Ibrutinib produces durable responses in patients after other treatments have failed, and with very little toxicity. The main side effect is mild diarrhea that usually resolves over time," says Susan O'Brien, M.D., a professor in Leukemia who led the phase I clinical trial of the drug.
O’Brien and her MD Anderson colleagues were instrumental in bringing the drug, developed by Pharmacyclics, Inc., to clinical trial and helped solve a puzzle about ibrutinib’s initial effects, which appeared to be alarming. Today they continue advanced clinical trials, including a combination trial through MD Anderson’s Moon Shots Program.
"This is an exciting time for CLL, with ibrutinib and other drugs in clinical trials providing new approaches that move us away from reliance on chemotherapy combinations," O’Brien says. One important advantage is that ibrutinib does not suppress bone marrow production of normal blood cells such as red cells, platelets and infection-fighting white cells. CLL already does that, exposing patients to potentially lethal infections and to bleeding. Chemotherapy also can worsen this effect, known as myelosuppression.
Even successful drug regimens such as the fludarabine-cyclophosphamide-rituximab (FCR) combination, developed at MD Anderson and now considered the CLL standard of care, can be difficult for older patients to tolerate. Chemotherapy also raises a patient’s risk of developing other cancers later on.
"Our goal now is to eliminate the need for chemotherapy in treating CLL," says Michael Keating, M.D., professor in Leukemia.
Ibrutinib blocks Bruton’s tyrosine kinase (BTK), a vital component of B cell receptor signaling. In doing so, it disrupts a number of molecular signaling networks that are important for the survival and growth of CLL cells.
High response rates, stymied disease progression
In December, O’Brien reported on a clinical trial involving 140 CLL patients that showed ibrutinib alone produces complete or partial responses in 88% of patients who have had previous treatment, and 86% of those who have received the drug as initial therapy. At the 30-month mark, 76% remained on the drug and showed no sign of the disease progressing.
Combining the drug with the antibody rituximab boosted the response rate to 95% in a clinical trial led by Jan Burger, M.D., an associate professor in Leukemia. At 18 months, 78% of a 40-patient group showed no progression.
Driving CLL cells out of hiding
CLL develops slowly and often is monitored for years before high white blood cell counts and other indicators point to the need for treatment.
Alarmingly, patients who enrolled early in the phase I trial showed an increase in their white blood counts after taking ibrutinib. "That’s normally a sign of disease progression that would result in the patient being taken off the drug," O’Brien says.
But there were offsetting clinical observations that discouraged jumping to conclusions.
"CLL cells accumulate in the lymph nodes, so these patients have a lot of swelling, especially around the neck," O’Brien explains. Just as the white cell counts rose, bloated lymph nodes began to retreat and patients reported feeling better. Eventually, white counts began to fall.
Burger conducted laboratory studies that illuminated what was going on.
"Ibrutinib flushes the leukemia cells out of the bone marrow, lymph node and spleen into the bloodstream where they lose the support they get from surrounding tissue and slowly die," Burger says. "CLL cells generally are long-lived, even without survival signals."
It can take months for blood counts and bone marrow involvement to return to normal as the interrupted growth signaling caused by ibrutinib slowly takes its toll. Some patients who lack certain genetic mutations in their CLL cells respond more rapidly.
CLL Moon Shot advances the cause
So far, ibrutinib has led to few complete remissions. The drug tamps down CLL, but so far doesn’t cure it, Burger reports. However, complete response rates are increasing in the group of patients taking the ibrutinib/rituximab combination. O’Brien suspects that, over time, more complete remissions will emerge as the ibrutinib slowly destroys CLL cells and patients are followed longer.
New drugs are in the pipeline. Idelalisib blocks a different molecular pathway called PI3K. O’Brien co-led a clinical trial of the drug combined with rituximab, compared with rituximab alone, for heavily pretreated CLL patients who were not eligible for chemotherapy combinations.
The combination was so superior that the clinical trial was halted in October after an early data analysis.
CLL was chosen as one of MD Anderson’s moon shots, a program to dramatically reduce cancer deaths, starting with six efforts that target eight cancers. Burger leads a new combination trial launched in December that compares ibrutinib to ibrutinib plus rituximab in 208 previously treated CLL patients.
Genomic analyses of patients’ CLL cells will be done before and during treatment and at the point of resistance, when it develops, to reveal how the disease changes during treatment.
Burger and colleagues are trying to stay ahead of CLL by studying cases where the leukemia became resistant to ibrutinib. "We'll need to identify and understand these mechanisms so we can develop ways to defeat resistance as it arises."