idelalisib and Chemical-and-Drug-Induced-Liver-Injury

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.

Topics: Age Factors; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Chemical and Drug Induced Liver Injury; Female; Hepatitis, Autoimmune; Humans; Immunoglobulin Heavy Chains; Leukemia, Lymphocytic, Chronic, B-Cell; Liver; Male; Middle Aged; Mutation; Purines; Quinazolinones

The PI3K/AKT signaling pathway is one of the most frequently activated signaling networks in human cancers and has become a valuable target in anticancer therapy. However, accumulating reports suggest that adverse effects such as severe liver injury and inflammation may accompany treatment with pan-PI3K and pan-AKT inhibitors. Our prior work has demonstrated that activation of the PI3K/AKT pathway has a protective role in Fas- or TNFα-induced hepatocytic cell death and liver injury. We postulated that PI3K or AKT inhibitors may exacerbate liver damage via the death factor-mediated hepatocyte apoptosis. In this study we found that several drugs targeting PI3K/AKT either clinically used or in clinical trials sensitized hepatocytes to agonistic anti-Fas antibody- or TNFα-induced apoptosis and significantly shortened the survival of mice in in vivo liver damage models. The PI3K or AKT inhibitors promoted Fas aggregation, inhibited the expression of cellular FLICE-inhibitory protein S and L (FLIP

Topics: Aminopyridines; Animals; Antibodies; Apoptosis; CASP8 and FADD-Like Apoptosis Regulating Protein; Chemical and Drug Induced Liver Injury; Hep G2 Cells; Hepatocytes; Humans; Imidazoles; Liver; Male; Mice, Inbred BALB C; Mice, Inbred C57BL; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Purines; Quinazolinones; Tumor Necrosis Factor-alpha

Idelalisib is a phosphatidylinositol 3-kinase inhibitor highly selective for the delta isoform that has shown good efficacy in treating chronic lymphocytic leukemia and follicular lymphoma. In clinical trials, however, idelalisib was associated with rare, but potentially serious liver and lung toxicities. In this study, we used the Collaborative Cross (CC) mouse population to identify genetic factors associated with the drug response that may inform risk management strategies for idelalisib in humans. Eight male mice (4 matched pairs) from 50 CC lines were treated once daily for 14 days by oral gavage with either vehicle or idelalisib at a dose selected to achieve clinically relevant peak plasma concentrations (150 mg/kg/day). The drug was well tolerated across all CC lines, and there were no observations of overt liver injury. Differences across CC lines were seen in drug concentration in plasma samples collected at the approximate Tmax on study Days 1, 7, and 14. There were also small but statistically significant treatment-induced alterations in plasma total bile acids and microRNA-122, and these may indicate early hepatocellular stress required for immune-mediated hepatotoxicity in humans. Idelalisib treatment further induced significant elevations in the total cell count of terminal bronchoalveolar lavage fluid, which may be analogous to pneumonitis observed in the clinic. Genetic mapping identified loci associated with interim plasma idelalisib concentration and the other 3 treatment-related endpoints. Thirteen priority candidate quantitative trait genes identified in CC mice may now guide interrogation of risk factors for adverse drug responses associated with idelalisib in humans.

Topics: Animals; Antineoplastic Agents; Biomarkers; Bronchoalveolar Lavage Fluid; Chemical and Drug Induced Liver Injury; Chromosome Mapping; Dose-Response Relationship, Drug; Liver Function Tests; Lung Injury; Mice, Inbred Strains; MicroRNAs; Oxidative Stress; Phosphatidylinositol 3-Kinase; Polymorphism, Single Nucleotide; Protein Kinase Inhibitors; Purines; Quantitative Trait Loci; Quinazolinones; Risk Factors; Species Specificity; Toxicogenetics

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers; Chemical and Drug Induced Liver Injury; Female; Humans; Liver Function Tests; Male; Middle Aged; Purines; Quinazolinones; Waldenstrom Macroglobulinemia