Andrew D. Zelenetz, MD, PhD
Idelalisib monotherapy shows activity in treatment-naïve patients ≥65 years with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), with nearly 90% of patients enrolled in a phase II study demonstrating a partial response, reported Andrew D. Zelenetz, MD, PhD, at the 2014 ASH Annual Meeting.
As expected, lymphocytosis was evident in the early months of treatment with idelalisib monotherapy, peaking at 2 to 3 months, but was rarely associated with symptoms and slowly normalized.
A targeted, highly selective, small-molecule inhibitor of phosphoinositide 3-kinase (PI3K)-δ, idelalisib inhibits homing and retention of malignant B cells in lymphoid tissues, reducing B cell survival. Zelenetz described the massive lymphocytosis that occurs with idelalisib, and how it’s a function of the way it works. PI3K-δ resides downstream of many signaling pathways. One of the critical signaling pathways is CXCR4 CXCR 5, because this receptor binds CXCL12. As such, it is responsible for directing the CLL cell to a microenvironment.
“If you prevent CXCR4 CXCR5 from detecting CXCL12, the cell becomes lost,” he explained. “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. 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 II, single-arm, open-label study was an extension of Study 101-08, which evaluated the response rate of idelalisib when combined with rituximab in 64 previously untreated patients with CLL or SLL ≥65 years. The overall response rate in that trial was 97%, and the complete response rate was 19%, but the role of rituximab in the regimen was not clear, other than to reduce the increase in lymphocyte count observed with idelalisib.
“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 idelalisib monotherapy (150 mg twice daily). Ninety-three percent of the patients enrolled had CLL, and 7% had SLL.
“We wanted to see if we could get similar efficacy results without the rituximab,” he said.
Thirty-eight of the 41 patients (93%) completed 8 weeks of therapy, and treatment is ongoing in 76% (as of September 22, 2014). Ten percent of patients discontinued: 5% discontinued due to an adverse event, 4% withdrew consent, and 1% died.
The mean idelalisib exposure was 5.4 months (median: 6.0 months). Eighty-eight percent had exposure ≥2 months, 85% for ≥3 months, 70% for ≥4 months, and 54% for ≥6 months. 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; a few patients restarted therapy at 100 mg after interruption.
Of 38 evaluable patients, 47% had a partial response, and 40% had a partial response with lymphocytosis, for an overall response rate of 87%. The median time to response was 1.9 months. “We found out that rituximab had nothing to do with the nodal response,” said Zelenetz, vice chair of Medicine for Medical Informatics at Memorial Sloan Kettering Cancer Center.
Mean progression-free survival (PFS) at 9 months was 83%; the median PFS has not been reached.
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% of patients, pneumonia in 7%, cellulitis in 7%, dyspnea in 5% and pyrexia in 3%.
Zelenetz AD, Lamanna N, Kipps TJ, et al. A phase II study of idelalisib monotherapy in previously untreated patients ≥65 years with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Presented at: 2014 ASH Annual Meeting; December 6-9, 2014; San Francisco, CA. Abstract 1986.
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