Davids MS, Brown JR. Targeting the B Cell Receptor Pathway in Chronic Lymphocytic Leukemia. Leuk Lymphoma. 2012;53:2362–2370.

Article  CAS  Google Scholar 

Lampson BL, Kasar SN, Matos TR, Morgan EA, Rassenti L, Davids MS, et al. Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity. Blood. 2016;128:195–203.

Article  CAS  Google Scholar 

Sharman JP, Coutre SE, Furman RR, Cheson BD, Pagel JM, Hillmen P, et al. Final results of a randomized, phase iii study of rituximab with or without idelalisib followed by open-label idelalisib in patients with relapsed chronic lymphocytic leukemia. J Clin Oncol. 2019;37:1391–402.

Article  CAS  Google Scholar 

Davids MS, Fisher DC, Tyekucheva S, McDonough M, Hanna J, Lee B, et al. A phase 1b/2 study of duvelisib in combination with FCR (DFCR) for frontline therapy for younger CLL patients. Leukemia. 2021;35:1064–72.

Article  CAS  Google Scholar 

Hoellenriegel J, Meadows SA, Sivina M, Wierda WG, Kantarjian H, Keating MJ, et al. The phosphoinositide 3’-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia. Blood. 2011;118:3603–12.

Article  CAS  Google Scholar 

Lannutti BJ, Meadows SA, Herman SE, Kashishian A, Steiner B, Johnson AJ, et al. CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood. 2011;117:591–4.

Article  CAS  Google Scholar 

Ali K, Soond DR, Pineiro R, Hagemann T, Pearce W, Lim EL, et al. Inactivation of PI(3)K p110delta breaks regulatory T-cell-mediated immune tolerance to cancer. Nature. 2014;510:407–11.

Article  CAS  Google Scholar 

Dong S, Harrington BK, Hu EY, Greene JT, Lehman AM, Tran M, et al. PI3K p110delta inactivation antagonizes chronic lymphocytic leukemia and reverses T cell immune suppression. J Clin Investig. 2019;129:122–36.

Article  Google Scholar 

Kaneda MM, Messer KS, Ralainirina N, Li H, Leem CJ, Gorjestani S, et al. PI3Kgamma is a molecular switch that controls immune suppression. Nature. 2016;539:437–42.

Article  CAS  Google Scholar 

Balakrishnan K, Peluso M, Fu M, Rosin NY, Burger JA, Wierda WG, et al. The phosphoinositide-3-kinase (PI3K)-delta and gamma inhibitor, IPI-145 (Duvelisib), overcomes signals from the PI3K/AKT/S6 pathway and promotes apoptosis in CLL. Leukemia. 2015;29:1811–22.

Article  CAS  Google Scholar 

Dong S, Guinn D, Dubovsky JA, Zhong Y, Lehman A, Kutok J, et al. IPI-145 antagonizes intrinsic and extrinsic survival signals in chronic lymphocytic leukemia cells. Blood. 2014;124:3583–6.

Article  CAS  Google Scholar 

Peluso M, Faia K, Winkler D, Sharma S, Patel N, White K, et al. Duvelisib (IPI-145) inhibits malignant B-cell proliferation and disrupts signaling from the tumor microenvironment through mechanisms that are dependent on PI3K-delta and PI3K-gamma. Haematologica. 2015;100:124.

Google Scholar 

Vanhaesebroeck B, Perry MWD, Brown JR, Andre F, Okkenhaug K. PI3K inhibitors are finally coming of age. Nat Rev Drug Discov. 2021;20:741–69.

Article  CAS  Google Scholar 

Flinn IW, Hillmen P, Montillo M, Nagy Z, Illes A, Etienne G, et al. The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL. Blood. 2018;132:2446–55.

Article  CAS  Google Scholar 

Gadi D, Griffith A, Tyekucheva S, Wang Z, Rai V, Vartanov A, et al. A T cell inflammatory phenotype is associated with autoimmune toxicity of the PI3K inhibitor duvelisib in chronic lymphocytic leukemia. Leukemia. 2022;36:723–32.

Article  CAS  Google Scholar 

Gadi D, Griffith A, Wang Z, Tyekucheva S, Rai V, Fernandes SM, et al. Idelalisib reduces regulatory T cells and activates T helper 17 cell differentiation in relapsed refractory patients with chronic lymphocytic leukaemia. Br J Haematol. 2022;197:207–11.

Article  CAS  Google Scholar 

Lampson BL, Kim HT, Davids MS, Abramson JS, Freedman AS, Jacobson CA, et al. Efficacy results of a phase 2 trial of first-line idelalisib plus ofatumumab in chronic lymphocytic leukemia. Blood Adv. 2019;3:1167–74.

Article  CAS  Google Scholar 

Brown JR, Zelenetz A, Furman R, Lamanna N, Mato A, Montillo M, et al. Risk factors for grade 3/4 transaminase elevation in patients with chronic lymphocytic leukemia treated with idelalisib. Leukemia. 2020;34:3404–7.

Article  CAS  Google Scholar 

Matos TR, Lampson BL, Hirakawa M, Kasar S, Fernandes SM, Brown JR, et al. Altered expression of functional proteins in CD4 regulatory T cells during therapy with idelalisib. Blood. 2015;126:1735.

Article  Google Scholar 

Carey CD, Gusenleitner D, Lipschitz M, Roemer MGM, Stack EC, Gjini E, et al. Topological analysis reveals a PD-L1-associated microenvironmental niche for Reed-Sternberg cells in Hodgkin lymphoma. Blood. 2017;130:2420–30.

Article  CAS  Google Scholar 

Keskin DB, Anandappa AJ, Sun J, Tirosh I, Mathewson ND, Li S, et al. Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial. Nature. 2019;565:234–9.

Article  CAS  Google Scholar 

Gadi D, Kasar S, Griffith A, Chiu P, Tyekucheva S, Rai V, et al. Imbalance in T cell subsets triggers the autoimmune toxicity of PI3K inhibitors in CLL. Blood. 2019;134:1745.

Article  Google Scholar 

Winkler DG, Faia KL, DiNitto JP, Ali JA, White KF, Brophy EE, et al. PI3K-delta and PI3K-gamma inhibition by IPI-145 abrogates immune responses and suppresses activity in autoimmune and inflammatory disease models. Chem Biol. 2013;20:1364–74.

Article  CAS  Google Scholar 

Coutre S, Barrientos J, Brown JR, De Vos S, Furman RR, Keating MJ, et al. Safety of idelalisib in B-cell malignancies: Integrated analysis of eight clinical trials. ASCO Meeting Abstr. 2015;33:e18030.

Google Scholar 

Jain P, Javdan M, Feger FK, Chiu PY, Sison C, Damle RN, et al. Th17 and non-Th17 interleukin-17-expressing cells in chronic lymphocytic leukemia: delineation, distribution, and clinical relevance. Haematologica. 2012;97:599–607.

Article  CAS  Google Scholar 

Okkenhaug K, Bilancio A, Farjot G, Priddle H, Sancho S, Peskett E, et al. Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice. Science. 2002;297:1031–4.

Article  CAS  Google Scholar 

Chellappa S, Kushekhar K, Munthe LA, Tjonnfjord GE, Aandahl EM, Okkenhaug K, et al. The PI3K p110delta isoform inhibitor idelalisib preferentially inhibits human regulatory T cell function. J Immunol. 2019;202:1397–405.

Article  CAS  Google Scholar 

Maharaj K, Powers JJ, Achille A, Mediavilla-Varela M, Gamal W, Burger KL, et al. The dual PI3Kdelta/CK1epsilon inhibitor umbralisib exhibits unique immunomodulatory effects on CLL T cells. Blood Adv. 2020;4:3072–84.

Article  CAS  Google Scholar 

Steinbach EC, Kobayashi T, Russo SM, Sheikh SZ, Gipson GR, Kennedy ST, et al. Innate PI3K p110delta regulates Th1/Th17 development and microbiota-dependent colitis. J Immunol. 2014;192:3958–68.

Article  CAS  Google Scholar 

Sherry B, Jain P, Chiu PY, Leung L, Allen SL, Kolitz JE, et al. Identification and characterization of distinct IL-17F expression patterns and signaling pathways in chronic lymphocytic leukemia and normal B lymphocytes. Immunol Res. 2015;63:216–27.

Article  CAS  Google Scholar 

Gopal AK, Kahl BS, de Vos S, Wagner-Johnston ND, Schuster SJ, Jurczak WJ, et al. PI3Kdelta inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370:1008–18.

Article  CAS  Google Scholar 

Wagner-Johnston ND, Sharman J, Furman RR, Salles G, Brown JR, Robak T, et al. Idelalisib immune-related toxicity is associated with improved treatment response. Leuk Lymphoma. 2021;62:2915–20.

Article  CAS  Google Scholar