Death, Adverse Events Reported in Patients Taking Idelalisib (Zydelig) With Other Drugs

European regulators examine trial findings

In Europe, pharma regulators have started a review into the safety of the leukemia drug idelalisib (Zydelig, Gilead Sciences) because of concerns over serious adverse events, including deaths, according to a Reuters report. The review was prompted by an increased rate of adverse events, mostly involving infections, seen in three clinical trials that tested the drug in combination with other cancer medications, the European Medicines Agency (EMA) said.

The EMA announced that it would review data from the studies to determine whether the findings had any consequences for the approved use of idelalisib. In the meantime, patients taking the drug should be carefully monitored for signs of infections, the agency said.

In the U.S., idelalisib is approved for the treatment of:

  • Relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab (Rituxan, Genentech) in patients for whom rituximab alone would be considered appropriate therapy because of other co-morbidities
  • Relapsed follicular B-cell non-Hodgkin lymphoma in patients who have received at least two prior systemic therapies
  • Relapsed small lymphocytic lymphoma in patients who have received at least two prior systemic therapies

The U.S. safety data for idelalisib were derived from 218 subjects with relapsed CLL who received up to eight doses of rituximab with or without idelalisib 150 mg twice daily. The median duration of exposure to idelalisib was five months. Serious adverse events were reported in 54 (49%) subjects treated with idelalisib plus rituximab. The most frequent serious adverse events reported for subjects treated with idelalisib included pneumonia (17%), pyrexia (9%), sepsis (8%), febrile neutropenia (5%), and diarrhea (5%). Adverse events that led to the discontinuation of idelalisib occurred in 11 (10%) subjects. The most common adverse events that led to treatment discontinuations were hepatotoxicity and diarrhea/colitis.

In a subset of 110 subjects treated with idelalisib plus rituximab, the most common infection-related adverse events included sepsis (8%), sinusitis (8%), bronchitis (6%), and urinary tract infection (5%).

Idelalisib is an inhibitor of PI3Kδ kinase, which is expressed in normal and malignant B cells. Idelalisib induced apoptosis and inhibited proliferation in cell lines derived from malignant B cells and in primary tumor cells. Idelalisib inhibits several signaling pathways in cells, including B-cell receptor signaling and CXCR4 and CXCR5 signaling, which are involved in the trafficking and homing of B cells to lymph nodes and bone marrow. The treatment of lymphoma cells with idelalisib resulted in the inhibition of chemotaxis and adhesion, and reduced cell viability.

Sources: Reuters; March 11, 2015; and Zydelig Prescribing Information; July 2014.