Duvelisib inhibition of chemokines in patients with CLL (DUO study) and iNHL (DYNAMO study)

David T. Weaver, Kam Sprott, Jonathan Pachter, NgocDiep Le, Matthew Steven Davids, Marco Montillo, Árpád Illés, Gabriel Etienne, Julio Delgado, Bryone Kuss, Constantine Tam, Fritz Offner, Scott Lunin, Francesc Bosch, Peter Hillmen, Nicole Lamanna, Stephan Stilgenbauer, Pier Luigi Zinzani, Ian W. Flinn, Jennifer R. Brown

Research output: Contribution to journalMeeting Abstractpeer-review


Background: Duvelisib (IPI-145) (DUV) is an oral dual inhibitor of phosphoinositide 3-kinase (PI3K)-δ and PI3K-γ being developed to treat B-cell malignancies. PI3K-δ inhibition directly targets proliferation and survival of malignant leukemia and lymphoma cells, while PI3K-γ inhibition modulates the tumor microenvironment (TME) through key support cells, including tumor-associated macrophages, nurse-like stroma and T cells, and via soluble factors stimulating tumor growth, survival and migration. The Phase 3 DUO study in relapsed/refractory (RR) CLL/SLL and the Phase 2 DYNAMO study in RR iNHL both met their primary endpoints (Flinn, ASH 2017; Zinzani EHA 2017). Methods: DUO (NCT02004522) pts were randomized to DUV (n = 160) or ofatumumab (OFA) (n = 159). DYNAMO (NCT01882803) pts (n = 129) received DUV. Serum from baseline and C2D1 was used for correlative studies of 24 chemokines, cytokines and serum factors. Bonferroni-Holm adjustment for multiple comparisons was applied. Results: In DUO, CCL1, CCL17, CXCL9, CXCL10, CXCL11, and IL-10 were reduced in pts treated with DUV (median % inhibition = 43.8%) but not in those treated with OFA (p≤0.0009). Eight chemokines were reduced in both treatment arms, but the level of reduction was significantly greater for DUV pts (median % inhibition, DUV 64.6% vs OFA 26.8%; p≤0.001). Many of the chemokines inhibited following DUV treatment are associated with the TME, including TNFα, IL-10, IL2Rα, IL12P40, CCL1, CCL17, CCL19, CXCL9, CXCL10, CXCL11, and CXCL13. In DYNAMO, 13 corresponding chemokines were also inhibited (p≤0.008), including TME factors. Reductions occurred rapidly (by C2D1) in both studies. In DUO, there was a correlation between duration of response and reduction (highest quartile) of the following chemokines: CCL17 (19.4 mo. Q4 vs 10.4 mo. Q1-3), CXCL11 (14.9 mo. Q4 vs 10.9 mo. Q1-3) IL-6 (16.6 mo. Q4 vs 10.9 mo. Q1-3), TRAIL (24 mo. Q4 vs 10.3 mo. Q1-3), VEGF_D (24 mo. Q4 vs 10.9 mo. Q1-3), TPO (14.9 mo. Q4 vs 10.9 mo. Q1-3). Conclusions: Pts with CLL and iNHL treated with DUV monotherapy showed significant reduction of chemokines potentially derived from the tumor cells and TME. Further investigation of the effects of DUV on TME pharmacodynamic markers is warranted.
Original languageEnglish
Pages (from-to)12048
Number of pages1
JournalJournal of Clinical Oncology
Issue numberS15
Publication statusPublished - Jun 2018
Externally publishedYes


  • Duvelisib Inhibition
  • CLL (Duo Study)
  • iNHL (DYNAMO study)


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