Journal
LEUKEMIA
Volume 36, Issue 3, Pages 723-732Publisher
SPRINGERNATURE
DOI: 10.1038/s41375-021-01441-9
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Funding
- NIH [RO1 CA 213442, U01AI138318, P30AR070253, P30AR069625]
- Verastem Oncology
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Combination therapy with the PI3K delta gamma inhibitor duvelisib and chemoimmunotherapy shows promising efficacy in treating CLL patients, but approximately one-third of patients develop autoimmune toxicity. The treatment modulates CD4 and CD8 T cell subsets as well as pro-inflammatory cytokines, resulting in an increase in activated CD8 T cells and Th17 T cells.
Several PI3K delta 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 PI3K delta gamma 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.
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