Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity.

Abstract

Idelalisib is a small-molecule inhibitor of PI3Kδ with demonstrated efficacy for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL). To evaluate idelalisib as front-line therapy, we enrolled 24 subjects in a phase 2 study consisting of 2 months of idelalisib monotherapy followed by 6 months of combination therapy with idelalisib and the anti-CD20 antibody ofatumumab. After a median follow-up period of 14.7 months, hepatotoxicity was found to be a frequent and often severe adverse event. A total of 19 subjects (79%) experienced either grade ≥1 ALT or AST elevation during the study, and 13 subjects (54%) experienced grade ≥3 transaminitis. The median time to development of transaminitis was 28 days, occurring before ofatumumab introduction. Younger age and mutated immunoglobulin heavy chain status were significant risk factors for the development of hepatotoxicity. Multiple lines of evidence suggest that this hepatotoxicity was immune mediated. A lymphocytic infiltrate was seen on liver biopsy specimens taken from 2 subjects with transaminitis, and levels of the proinflammatory cytokines CCL-3 and CCL-4 were higher in subjects experiencing hepatotoxicity. All cases of transaminitis resolved either by holding the drug, initiating immunosuppressants, or both, and rates of recurrent toxicity were lower in patients taking steroids when idelalisib was reinitiated. A decrease in peripheral blood regulatory T cells was seen in patients experiencing toxicity on therapy, which is consistent with an immune-mediated mechanism. These results suggest that caution should be taken as drugs within this class are developed for CLL, particularly in younger patients who have not received prior disease-specific therapy. This study was registered at www.clinicaltrials.gov as #NCT02135133.

• Authors: Benjamin L Lampson, Siddha N Kasar, Tiago R Matos, Elizabeth A Morgan, Laura Rassenti, Matthew S Davids, David C Fisher, Arnold S Freedman, Caron A Jacobson, Philippe Armand, Jeremy S Abramson, Jon E Arnason, Thomas J Kipps, Joshua Fein, Stacey Fernandes, John Hanna, Jerome Ritz, Haesook T Kim, Jennifer R Brown
• Journal: Blood (Blood) Vol. 128 Issue 2 Pg. 195-203 (07 14 2016) ISSN: 1528-0020 [Electronic] United States
• PMID: 27247136 (Publication Type: Clinical Trial, Journal Article)
• Copyright: © 2016 by The American Society of Hematology.

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Immunoglobulin Heavy Chains
• Purines
• Quinazolinones
• ofatumumab
• idelalisib

Topics

• Age Factors
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal (administration & dosage, adverse effects)
• Antibodies, Monoclonal, Humanized
• Chemical and Drug Induced Liver Injury (blood, genetics, immunology)
• Female
• Hepatitis, Autoimmune (blood, genetics, immunology)
• Humans
• Immunoglobulin Heavy Chains (blood, genetics, immunology)
• Leukemia, Lymphocytic, Chronic, B-Cell (blood, drug therapy, genetics, immunology)
• Liver (immunology, metabolism, pathology)
• Male
• Middle Aged
• Mutation
• Purines (administration & dosage, adverse effects)
• Quinazolinones (administration & dosage, adverse effects)