Idelalisib Bolsters CLL Regimen

Idelalisib (Zydelig; Gilead) increases the effectiveness of a drug combination commonly used against relapsed or refractory chronic lymphocytic leukemia (CLL), new research shows.

Bendamustine (Treanda; Cephalon) is a form of chemotherapy, and rituximab (Rituxan; Genentech) is an immunotherapy that targets the CD20 receptor on B cells. The combination of the two has been a standard second-line treatment for CLL and a less toxic first-line alternative to regimens containing the chemotherapeutic fludarabine (Fludara; Genzyme). A team led by Andrew Zelenetz, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, NY, performed a phase III trial to determine if they could improve the effectiveness of the combination by incorporating idelalisib, an inhibitor of PI3Kδ.

The 416 patients with relapsed or refractory CLL in the study received bendamustine and rituximab along with either idelalisib or a placebo. The trial began in 2012, but in 2015 it was stopped early because the patients treated with idelalisib were faring so much better.

Although neither group had reached its median overall survival, patients in the idelalisib group were 45% less likely to die than were the patients in the placebo group. In addition, progression-free survival for the idelalisib patients was 23 months, versus 11 months for the placebo patients. “That's a meaningful benefit,” says Zelenetz, who presented the results at the American Society of Hematology's 57th Annual Meeting in Orlando, FL, in December.

Patients treated with idelalisib had higher rates of some side effects. For instance, 63.3% developed neutropenia and fever, compared with 41.5% of the patients in the control group. Zelenetz notes that the patients who received idelalisib didn't develop more infections, suggesting that the neutropenia wasn't clinically significant.

Several choices for treating relapsed or refractory CLL are now available. For instance, the FDA in 2014 approved idelalisib and rituximab for patients who are eligible to take rituximab alone. That same year, ibrutinib (Imbruvica; Pharmacyclics and Janssen Biotech) also received approval as a monotherapy.

However, there's still a need for the trio of idelalisib, bendamustine, and rituximab, Zelenetz says. Patients who take ibrutinib have to remain on the drug for the rest of their lives, and the combination could provide an alternative for patients who aren't willing to make that commitment or who develop resistance. “If the plan is to give bendamustine and rituximab, the addition of idelalisib will improve outcomes,” Zelenetz says.

“This adds an option” for treatment of CLL, says Anthony Mato, MD, of the University of Pennsylvania in Philadelphia, who wasn't connected to the research. However, he says, “the addition of idelalisib to an immuno-chemotherapy backbone does increase toxicity, which also needs to be considered.”

“It's very clear from this presentation that if you add idelalisib to bendamustine and rituximab, you do better than on bendamustine and rituximab alone,” says Susan O'Brien, MD, of the University of California, Irvine. The next question researchers need to answer, she says, is whether patients could do just as well without bendamustine. –Mitch Leslie