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

Abstract

• Idelalisib as upfront therapy for CLL caused an early hepatotoxicity in a subset of primarily younger patients with IGHV-mutated disease.• Multiple lines of evidence suggest that this adverse effect is immune mediated, perhaps through inhibition of regulatory T cells.Idelalisib is a small-molecule inhibitor of PI3Kd 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. (Blood. 2016;128(2):195-203)

Improving T-cell expansion and function for adoptive T-cell therapy using ex vivo treatment with PI3Kδ inhibitors and VIP antagonists

“…The rationale for using these agents was previous data from our laboratory showing enhancement of CD8 T-cell dependent anticancer immunity in peptide antagonist to vasoactive intestinal peptide (VIPhyb)-treated mice 13,14 and reports of autoimmunity after stopping PI3K d inhibitor (idelalisib) in lymphoma and chronic lymphocytic leukemia (CLL) patients. [15][16][17] To test this hypothesis, we studied blood samples from healthy volunteers, DLBCL patients prior to treatment, and samples from DLBCL patients who had received multiple courses of cytotoxic treatment. Of note, lymphoma patients who had received prior treatment had a significantly higher proportion of CD27 2 CD28…”

Combinations of idelalisib with rituximab and/or bendamustine in patients with recurrent indolent non-Hodgkin lymphoma

“…Idelalisib administered to CLL patients frontline is associated with frequent immune-mediated hepatotoxicity. Lampson et al 29 noted that as median age and number of prior therapies increased, the frequency of immune-mediated AEs with idelalisib decreased.…”

Idelalisib at the Crossroads of B-Cell Lymphoproliferative Disorders.

“…The delayed time to onset, the immune cell infiltrate in biopsies of affected organs (such as the colonic mucosa) and abatement of toxicity with immunosuppressants have all supported the unique immunological toxicity pattern of idelalisib. 31 Affected CLL patients had depressed Treg functionality at baseline and lost marker of Treg activation after idelalisib therapy. 31 On the other hand, previous studies 32 disclosed that CD4+CD25+ T cells were elevated in inflammatory bowel disease (IBD) suggesting a partial role of activated T cell response in the disease pathophysiology.…”

“…31 Affected CLL patients had depressed Treg functionality at baseline and lost marker of Treg activation after idelalisib therapy. 31 On the other hand, previous studies 32 disclosed that CD4+CD25+ T cells were elevated in inflammatory bowel disease (IBD) suggesting a partial role of activated T cell response in the disease pathophysiology. Thus, the conclusion that CD4+CD25+ regulatory T cells may play a key role in the immunopathogenesis of IBD 32 shall be further searched for the immunitymediated colitis associated with the idelalisib as well.…”