TY - JOUR
T1 - Duvelisib inhibition of chemokines in patients with CLL (DUO study) and iNHL (DYNAMO study)
AU - Weaver, David T.
AU - Sprott, Kam
AU - Pachter, Jonathan
AU - Le, NgocDiep
AU - Davids, Matthew Steven
AU - Montillo, Marco
AU - Illés, Árpád
AU - Etienne, Gabriel
AU - Delgado, Julio
AU - Kuss, Bryone
AU - Tam, Constantine
AU - Offner, Fritz
AU - Lunin, Scott
AU - Bosch, Francesc
AU - Hillmen, Peter
AU - Lamanna, Nicole
AU - Stilgenbauer, Stephan
AU - Zinzani, Pier Luigi
AU - Flinn, Ian W.
AU - Brown, Jennifer R.
PY - 2018/6
Y1 - 2018/6
N2 - 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.
AB - 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.
KW - Duvelisib Inhibition
KW - CLL (Duo Study)
KW - iNHL (DYNAMO study)
U2 - 10.1200/JCO.2018.36.15_suppl.12048
DO - 10.1200/JCO.2018.36.15_suppl.12048
M3 - Meeting Abstract
SN - 0732-183X
VL - 36
SP - 12048
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - S15
ER -