title: 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.affiliation: Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Benjamin L
authors.identifier: 0000-0002-6033-3363
authors.initials: BL
authors.lastname: Lampson
authors.affiliation: Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Siddha N
authors.initials: SN
authors.lastname: Kasar
authors.affiliation: Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Tiago R
authors.initials: TR
authors.lastname: Matos
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA;
authors.forename: Elizabeth A
authors.identifier: 0000-0001-5880-9337
authors.initials: EA
authors.lastname: Morgan
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of California, San Diego, La Jolla, CA; CLL Research Consortium, Moores UCSD Cancer Center, La Jolla, CA;
authors.forename: Laura
authors.initials: L
authors.lastname: Rassenti
authors.affiliation: Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; CLL Research Consortium, Moores UCSD Cancer Center, La Jolla, CA;
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Davids
authors.affiliation: Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: David C
authors.initials: DC
authors.lastname: Fisher
authors.affiliation: Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Arnold S
authors.initials: AS
authors.lastname: Freedman
authors.affiliation: Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Caron A
authors.initials: CA
authors.lastname: Jacobson
authors.affiliation: Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Philippe
authors.initials: P
authors.lastname: Armand
authors.affiliation: Center for Lymphoma, Massachusetts General Hospital Cancer Center, Boston, MA;
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Abramson
authors.affiliation: Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, MA; and.
authors.forename: Jon E
authors.initials: JE
authors.lastname: Arnason
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of California, San Diego, La Jolla, CA; CLL Research Consortium, Moores UCSD Cancer Center, La Jolla, CA;
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kipps
authors.affiliation: Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Joshua
authors.identifier: 0000-0001-5441-1516
authors.initials: J
authors.lastname: Fein
authors.affiliation: Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; CLL Research Consortium, Moores UCSD Cancer Center, La Jolla, CA;
authors.forename: Stacey
authors.initials: S
authors.lastname: Fernandes
authors.affiliation: Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: John
authors.initials: J
authors.lastname: Hanna
authors.affiliation: Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Jerome
authors.identifier: 0000-0001-5526-4669
authors.initials: J
authors.lastname: Ritz
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: Haesook T
authors.identifier: 0000-0003-4889-6849
authors.initials: HT
authors.lastname: Kim
authors.affiliation: Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; CLL Research Consortium, Moores UCSD Cancer Center, La Jolla, CA;
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Brown
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000235:genetics / Q000276:immunology; D005260:Female; D019693:Hepatitis, Autoimmune / Q000097:blood / Q000235:genetics / Q000276:immunology; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000097:blood / Q000235:genetics / Q000276:immunology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011687:Purines / Q000008:administration & dosage / Q000009:adverse effects; D052999:Quinazolinones / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007143:Immunoglobulin Heavy Chains; D011687:Purines; D052999:Quinazolinones; C527517:ofatumumab; C552946:idelalisib