Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity
Mené sur 24 patients atteints d'une leucémie lymphocytaire chronique récidivante/réfractaire, cet essai de phase II évalue la toxicité hépatique d'un traitement comportant l'idélalisib seul pendant 2 mois, puis en combinaison avec l'ofatumumab pendant 6 mois (durée médiane de suivi : 14,7 mois)
Idelalisib as up-front 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 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 II study consisting of two months of idelalisib monotherapy followed by six months of combination therapy with idelalisib and the anti-CD20 antibody ofatumumab. After a median follow-up of 14.7 months, hepatotoxicity was found to be a frequent and often severe adverse event. Nineteen subjects (79%) experienced either grade ≥1 ALT or AST elevation during the study, with 13 subjects (54%) experiencing grade ≥ 3 transaminitis. The median time to development of transaminitis was 28 days, occurring before ofatumumab introduction. Younger age and mutated immunoglobulin heavy chain (IGHV) 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 biopsies taken from two subjects with transaminitis, and levels of the pro-inflammatory 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 re-initiated. 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. (ClinicalTrials.gov identifier: NCT02135133)