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.

Figure 1

Transaminitis is frequent and severe in subjects receiving idelalisib monotherapy. (A) An index case of idelalisib-related transaminitis. (B) The fraction of subjects experiencing an ALT elevation of the indicated grade at the indicated time. (C) Swim plot of the indicated toxicities of grade ≥2 at the time that they were first experienced by subjects enrolled in the trial. Other toxicities include one subject with grade 3 rash and 1 subject with grade 3 oral ulcers.

Figure 2

Clinical factors are associated with the development of early hepatotoxicity. (A) Significant difference in age at enrollment between subjects who experienced no toxicity on trial and those who experienced early hepatotoxicity (P = .02, Mann-Whitney U test). (B) Receiver-operating characteristic (ROC) curves for mutated (M) IGHV status, age ≤65 years, or a combination of the two for predicting the occurrence of early hepatotoxicity.

Figure 3

Tissue biopsies and response to steroids suggest an immune-mediated cause for hepatotoxicity. (A) Liver biopsy specimens taken from a normal patient, an otherwise healthy patient with CLL, and a subject with persistent transaminitis after discontinuation of idelalisib. Liver biopsy specimens from patients with CLL demonstrate lymphoid aggregates on hematoxylin and eosin staining (composed of CD20⁺ B cells, data not shown) as well as increased CD3⁺ T cells scattered throughout the parenchyma that are increased in number and activation (as assessed by perforin staining) in a subject on idelalisib. (B) A duodenal biopsy specimen from a subject with diarrhea on idelalisib reveals an activated (perforin-positive) CD8⁺ lymphocytic infiltrate, which is not present in a control sample taken from a subject without CLL. (C) Transaminase levels over time for a subject who, after an unsuccessful attempt at idelalisib reintroduction, was successfully reintroduced to the drug while on steroids.

Figure 4

Increased inflammatory cytokine levels and decreased regulatory T-cell levels are associated with the development of toxicities while on idelalisib. (A) Serum CCL-3 and (B) CCL-4 levels in subjects at various time points on idelalisib therapy. Baseline values indicated in red are subjects who experienced toxicity at day ∼28, and blue represents subjects who did not experience early hepatotoxicity. Open symbols represent levels drawn when subjects have held idelalisib for 3 to 9 days due to toxicity; closed symbols represent samples drawn while subjects remain on idelalisib. (C) Percentage of CD4⁺ T cells that are FoxP3⁺CD25^hi regulatory T cells in subjects on idelalisib. (D) Percentage of CD4⁺ T cells that are CD3⁺CD4⁺ FoxP3⁺CD25^hi regulatory T cells in subjects on idelalisib, stratified by toxicity. At baseline, values indicated in red are subjects who experienced toxicity at day ∼28, blue symbols are subjects who did not experience toxicity, and purple symbols are subjects who experienced delayed toxicity and thus contributed data points to the no toxicity group at day ∼28 and the toxicity group at day ∼130.