Open AccessA T cell inflammatory phenotype is associated with autoimmune toxicity of the PI3K inhibitor duvelisib in chronic lymphocytic leukemia
Author(s) -
Deepti Gadi,
Alec Griffith,
Svitlana Tyekucheva,
Zixu Wang,
Vanessa Rai,
Alexander R. Vartanov,
Emily M. Thrash,
Stacey M. Fernandes,
Timothy Z. Lehmberg,
Brandon Lee,
Stephen P. Martindale,
John-Hanson Machado,
Oreofe O. Odejide,
Philippe Armand,
David C. Fisher,
Jon Arnason,
Matthew S. Davids,
James A. Lederer,
Jennifer R. Brown
Publication year - 2021
Publication title -
leukemia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.539
H-Index - 192
eISSN - 1476-5551
pISSN - 0887-6924
DOI - 10.1038/s41375-021-01441-9
Subject(s) - chronic lymphocytic leukemia , medicine , chemoimmunotherapy , immunology , cd8 , toxicity , cytotoxic t cell , fludarabine , leukemia , context (archaeology) , cyclophosphamide , immune system , biology , chemotherapy , biochemistry , in vitro , paleontology
Several PI3Kδ inhibitors are approved for the therapy of B cell malignancies, but their clinical use has been limited by unpredictable autoimmune toxicity. We have recently reported promising efficacy results in treating chronic lymphocytic leukemia (CLL) patients with combination therapy with the PI3Kδγ inhibitor duvelisib and fludarabine cyclophosphamide rituximab (FCR) chemoimmunotherapy, but approximately one-third of patients develop autoimmune toxicity. We show here that duvelisib FCR treatment in an upfront setting modulates both CD4 and CD8 T cell subsets as well as pro-inflammatory cytokines. Decreases in naive and central memory CD4 T cells and naive CD8 T cells occur with treatment, while activated CD8 T cells, granzyme positive Tregs, and Th17 CD4 and CD8 T cells all increase with treatment, particularly in patients with toxicity. Cytokines associated with Th17 activation (IL-17A and IL-21) are also relatively elevated in patients with toxicity. The only CLL feature associated with toxicity was increased priming for apoptosis at baseline, with a significant decrease during the first week of duvelisib. We conclude that an increase in activated CD8 T cells with activation of Th17 T cells, in the context of lower baseline Tregs and greater CLL resistance to duvelisib, is associated with duvelisib-related autoimmune toxicity.