Zydelig Yields High Responses in Older Patients with Newly Diagnosed CLL, SLL

This past summer Zydelig (idelalisib) was approved for several recurrent B-cell cancers, such as chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). New data shows the drug also creates a response in older patients newly diagnosed with CLL or SLL.

Nearly 90 percent of patients enrolled in the phase 2 study demonstrated a partial response, Andrew D. Zelenetz, vice chair of Medicine for Medical Informatics at Memorial Sloan Kettering Cancer Center.

As expected, lymphocytosis, which is when the body produces a high lymphocyte count, was evident in the early months of treatment with Zydelig, peaking at two to three months, but was rarely associated with symptoms and slowly normalized. Zydelig is a targeted, highly selective, small-molecule inhibitor of PI3K delta, which inhibits homing and retention of malignant B cells in lymphoid tissues, reducing B-cell survival.

Zelenetz described the massive lymphocytosis that occurs with Zydelig, and how it’s a function of the way it works. PI3K delta resides downstream of many signaling pathways, including one responsible for directing the CLL cell to a microenvironment, so in essence, the malignant cell gets “lost.”

“It’s as if you close the garage door on an electric car and the car can’t get back in and get charged. If it doesn’t get charged, it dies. The cells come out of the garage, they can’t get back in because they can’t find their way back, and they’re in the circulation,” he said. “That’s why the [lymphocyte] count goes up. But it’s transient because those cells are doomed. Some of these patients go up to a couple hundred thousand cells and even with that, they never have symptoms. We see massive lymphocytosis with this agent without clinical consequences.”

The phase 2, single-arm, open-label study was an extension of another study that evaluated the response rate of Zydelig when combined with Rituxan (rituximab) in 64 previously untreated older patients with CLL or SLL. The overall response rate in that trial was 97 percent, and the complete response rate was 19 percent, but the role of Rituxan in the regimen was not clear, other than to reduce the increase in lymphocyte count observed with Zydelig.

“We wanted to know if rituximab was doing anything other than dealing with the lymphocytosis expected with idelalisib,” said Zelenetz. For this reason, a second cohort of 41 patients was enrolled and treated with Zydelig monotherapy. We wanted to see if we could get similar efficacy results without the rituximab.”

Drug interruption for side effects was common, but most patients were able to restart therapy at the original dose and continue therapy without another interruption. Of 38 evaluable patients, 47 percent had a partial response, and 40 percent had a partial response with lymphocytosis, for an overall response rate of 87 percent. The median time to response was 1.9 months.

Tolerability of monotherapy was good, he said, with side effects expected with PIK3- δ inhibitors such as diarrhea, pneumonitis and rash, “but about at the same level as we saw them in the combination study,” he said. “They occur a little more so upfront than we see in the relapsed/refractory setting. There is increasing evidence that these are immune-mediated, so it’s not surprising that in a more immune intact host, you’ll see a little more of these side effects.” Serious diarrhea/colitis occurred in 10 percent of patients, with additional cases of pneumonia, cellulitis, dyspnea and fever.