NEW YORK (FRONTLINE MEDICAL NEWS) – Safety issues with idelalisib, a first-in-class PI3K delta inhibitor, are an important concern in patients with chronic lymphocytic leukemia – particularly those aged 65 years and younger, according to Steven Coutre, MD.

Findings from the second interim analysis of the pivotal trial for idelalisib as reported at the 2014 annual meeting of the American Society of Hematology ( Sharman J., et al. Abstract 330 ) and a recent update from an open-label extension represent the longest reported follow-up of idelalisib-treated patients to date. Those analyses showed substantial progression-free and overall survival advantages with idelalisib plus rituximab vs. placebo plus rituximab (progression-free survival in the latest update was 19.4 vs. 7.3 months, respectively; hazard ratio 0.25), said Dr. Coutre, professor of medicine at Stanford (Calif.) University.

“Still, even with that report, the follow-up on that initial study was relatively short, and I think it really underreports some of the safety issues of the toxicities that we see,” he said at an international congress on hematologic malignancies.

To further investigate those safety issues, Dr. Coutre and his colleagues performed an integrated analysis of eight clinical trials, including the pivotal trial. That analysis found idelalisib to be efficacious, but significant toxicities were noted, “particularly in younger less heavily-pretreated patients. [Idelalisib] should not be used as frontline therapy … and I don’t think it will be developed in the future as frontline therapy,” Dr. Coutre said.

“At least in the relapse setting, idelalisib plus rituximab is a choice for all of our patients, but it has to be a considered choice; you have to put it in the context of other therapies that the patients have available to them and make a decision based on your individual patient.”

In the analysis, Dr. Coutre and his colleagues found numerous adverse events occurring in 15% or more of idelalisib-treated patients. These included diarrhea/colitis – with median onset at 7.1 months – in 37% who received monotherapy and 40% who received combination therapy (grade 3 or greater diarrhea/colitis in 11% and 17%, respectively), and pneumonia in 13% and 18% of patients (grade 3 or greater in 11% and 14%, respectively), Dr. Coutre said.

Transaminitis – which was observed early in the studies, usually within the first 8 weeks of treatment – also was common, occurring in 50% and 47% of those with monotherapy and combination therapy, respectively (grade 3 or greater, 16% and 13%, respectively).

Pneumonitis occurred in about 3% of patients, and usually within the first 6 months of therapy.

“So that’s sort of where things were until earlier this year when we learned from several ongoing studies, very important studies in both previously treated patients with low-grade lymphomas and previously untreated patients, that there was a further problem – and that is a difference in mortality,” he said.

Patients in many of these studies, including all of those where it was being used for previously untreated patients, were taken off the drug because of this finding.

“As a result of further analysis of these studies, there’s a new safety label indication,” he said.

Of note, in another idelalisib study reported at ASH 2015 an age-related toxicity concern emerged.

“Idelalisib was used for previously untreated patients. But the distinction here is that for the first time it was being used in younger patients – patients under the age of 65,” he said, noting that severe transaminitis occurred in a significant number of the younger patients.

More than half (52%) of patients had grade 3 or greater hepatotoxicity and all 7 subjects aged 65 years and younger required systemic steroids for toxicities.

Age was found in the study to be a significant risk factor for early hepatotoxicity.

“We’re finally starting to understand the mechanisms behind this, or at least the likely mechanisms, and this seems to be immune mediated,” he said, adding, “you see a lymphocytic infiltrate on liver biopsies, you see a lymphocytic colitis in patients who receive idelalisib.”

Typically, toxicities in these patients can be managed with corticosteroids, but in some cases of severe toxicity even steroids seem to be insufficient, he said.

Further, rapid recurrence is often seen upon re-exposure to the drug, especially with respect to hepatotoxicity, he added.

Preclinical data from mouse models supports this mechanism.

“And importantly [those models] demonstrated a decrease in regulatory T cells in patients treated with idelalisib,” he said.

Dr. Coutre reported consulting for Abbvie, Celgene, Gilead, Janssen, and Pharmacyclics.