The double significance of idelalisib immune-related toxicity

In this issue of Leukemia & Lymphoma WagnerJohnston et al. [1] reported an intriguing post-hoc analysis of three registrational trials of idelalisib in indolent non-Hodgkin lymphoma (iNHL) and chronic lymphocytic leukemia (CLL) patients, investigating the potential relationship between the most relevant immune-related adverse events (irAEs), namely grade 3 diarrhea/colitis and alanine/aspartate transaminase (AST/ALT) elevation, and improved treatment outcome. The first-in-class PI3Kd inhibitor idelalisib has been approved in 2014 in combination with rituximab for the treatment of patients with relapsed or refractory CLL based on the phase III 116/117 study [2], and as monotherapy in follicular lymphoma (FL) and small lymphocytic lymphoma after two prior lines of therapy based on the phase II 101–09 study [3]. Idelalisib selectively inhibits the p110d isoform of PI3K catalytic subunit, which is predominantly expressed in lymphoid cells. As a result, idelalisib blocks a wide variety of pro-survival B-cell receptormediated signals that converge on the PI3K-AKTmTOR and BTK pathways, which are critical for B-cells survival [4]. Moreover, idelalisib disrupts the response of malignant B-cells to a wide range of cytokines, chemokines and adhesion molecules in the tumor microenvironment [5]. Despite initial excitement due to its significant activity also in patients with high-risk features, for instance TP53 deletion/mutation, unmutated IGHV or complex karyotype in CLL and double chemoand rituximab-refractoriness or early progression within 24months in FL [6], an extensive use of idelalisib has been significantly hampered by the emergence of unique treatment-related toxicities, which require appropriate management with frequent dose interruptions, reductions and discontinuations [7]. Importantly, the main treatment-emergent adverse events occurring during idelalisib dosing, namely diarrhea/colitis, ALT/AST elevation, rash and pneumonitis, were recognized to share a common immune-mediated mechanism, as suggested by the evidence of increased CD8þ T-cells infiltrates within both liver sinusoids and intestinal mucosa at histopathological examination of liver and colonic biopsies in patients with persistent transaminitis or diarrhea, respectively [8]. Interestingly, the rate of these events typically increases in the upfront setting and in younger patients, possibly reflecting a more intact immune-system [8]. Considering the frequent occurrence of grade 3 diarrhea/colitis (19%-26) and AST/ALT elevation (11–14%), which substantially contributed to dose interruptions ( 1 in nearly 50%, 2 in 34% of patients [9]), reductions and discontinuations, one can logically expect that the outcome of patients experiencing irAEs would result basically worst due to less time on drug. Surprisingly, the joined analysis of nearly 400 patients treated with idelalisib within 3 registrational trials (283 with CLL and 125 with iNHL, including 72 with FL) performed by Wagner-Johnston et al. [1] pointed out the opposite result, suggesting even an improved outcome for these subgroups of patients. In details, patients who experienced grade 3 diarrhea/ colitis displayed a significantly higher overall response rate (ORR) with respect to the remaining ones across all subgroups (iNHL, FL and CLL), while a trend toward a better progression-free survival (PFS) and a significantly improved overall survival (OS) were detected only in CLL patients. Further, grade 3 AST/ALT elevation was associated with significantly higher ORR in FL