1. Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity
by Benjamin L. Lampson, Siddha N. Kasar, Tiago R. Matos, Elizabeth A. Morgan, Laura Rassenti, Matthew S. Davids, David C. Fisher, Arnold S. Freedman, Caron A. Jacobson, Philippe Armand, Jeremy S. Abramson, Jon E. Arnason, Thomas J. Kipps, Joshua Fein, Stacey Fernandes, John Hanna, Jerome Ritz, Haesook T. Kim, and Jennifer R. Brown
Blood
Volume 128(2):
July 14, 2016
©2016 by American Society of Hematology

2. Transaminitis is frequent and severe in subjects receiving idelalisib monotherapy.
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.
Benjamin L. Lampson et al. Blood 2016;128:
©2016 by American Society of Hematology

3. Clinical factors are associated with the development of early hepatotoxicity.
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.
Benjamin L. Lampson et al. Blood 2016;128:
©2016 by American Society of Hematology

4. Tissue biopsies and response to steroids suggest an immune-mediated cause for hepatotoxicity.
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.
Benjamin L. Lampson et al. Blood 2016;128:
©2016 by American Society of Hematology

5. Increased inflammatory cytokine levels and decreased regulatory T-cell levels are associated with the development of toxicities while on idelalisib.
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+CD25hi regulatory T cells in subjects on idelalisib. (D) Percentage of CD4+ T cells that are CD3+CD4+ FoxP3+CD25hi 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.
Benjamin L. Lampson et al. Blood 2016;128:
©2016 by American Society of Hematology