The Role of PI3K Inhibition in Lymphoid Malignancies
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Purpose of Review
The outcome of patients with lymphoid malignancies has markedly improved in recent years which is likely due to a combination of advances in supportive care, and therapeutic options. In this article, we will provide an overview over the role PI3-kinase signalling, one of the most important dysregulated pathways in cancer, and its successful inhibition in lymphoma.
PI3-kinase inhibitors have shown remarkable activity in an increasing subset of patients with non-Hodgkin lymphomas. The first drug to be approved was idelalisib for patients with relapsed/refractory follicular lymphoma and CLL/SLL as monotherapy, or in combination with rituximab, respectively. After an initial setback related to increased toxicity including deaths observed in several upfront studies, there has been a resurgence in interest in this pathway following the promising efficacy of second-generation PI3K inhibitors including in patients with T cell lymphomas.
PI3K inhibition continues to be an invaluable tool in the therapy of patients with lymphoid malignancies if managed cautiously. Preclinical models are helpful in predicting possible side effects and identifying new lymphoma subtypes that may be susceptible to this class of agents. The future will likely involve rationally designed combinatorial approaches to deepen the response rate and prevent the emergence of resistance.
KeywordsPI3-kinase B cell receptor Tumor microenvironment Lymphoma Follicular lymphoma T cell lymphoma CLL
Compliance with Ethical Standards
Conflict of Interest
Gottfried von Keudell has received consulting honoraria from Genentech, Pharmacyclics, and Bayer.
Alison J. Moskowitz has received research support from Seattle Genetics, Merck, Bristol-Myers Squibb, and Incyte. In addition, she has received honorarium from Kyowa Hakko Kirin Pharma, Miragen Therapeutics, Takeda Pharmaceuticals, ADC Therapeutics, Seattle Genetics, Cell Medica, Bristol-Myers Squibb, and Erytech Pharma.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
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- 28.Smith SM, Pitcher BN, Jung SH, Bartlett NL, Wagner-Johnston N, Park SI, et al. Safety and tolerability of idelalisib, lenalidomide, and rituximab in relapsed and refractory lymphoma: the Alliance for Clinical Trials in Oncology A051201 and A051202 phase 1 trials. Lancet Haematol. 2017;4(4):e176–e82.PubMedPubMedCentralGoogle Scholar
- 33.Patnaik A, Appleman LJ, Tolcher AW, Papadopoulos KP, Beeram M, Rasco DW, et al. First-in-human phase I study of copanlisib (BAY 80-6946), an intravenous pan-class I phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors and non-Hodgkin’s lymphomas. Ann Oncol. 2016;27(10):1928–40.PubMedPubMedCentralGoogle Scholar
- 34.• Dreyling M, Morschhauser F, Bouabdallah K, Bron D, Cunningham D, Assouline SE, et al. Phase II study of copanlisib, a PI3K inhibitor, in relapsed or refractory, indolent or aggressive lymphoma. Ann Oncol. 2017;28(9):2169–78 The results of this phase II study were the basis for the approval of copanlisib for patients with relapsed/refractory follicular lymphoma. PubMedPubMedCentralGoogle Scholar
- 35.Dreyling M, Santoro A, Mollica L, Leppa S, Follows GA, Lenz G, et al. Long-term efficacy and safety from the copanlisib CHRONOS-1 study in patients with relapsed or refractory indolent B-cell lymphoma. Blood. 2018;132.Google Scholar
- 37.• Flinn IW, Miller CB, Ardeshna KM, Tetreault S, Assouline SE, Mayer J, et al. DYNAMO: a phase II study of duvelisib (IPI-145) in patients with refractory indolent non-Hodgkin lymphoma. J Clin Oncol. 2019;37(11):912–22 The results of this study were the basis for the approval of duvelisib for patients with relapsed/refractory follicular lymphoma. PubMedGoogle Scholar
- 38.• 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(23):2446–55 The results of this study were the basis for the approval of duvelisib for patients with relapsed/refractory CLL. PubMedPubMedCentralGoogle Scholar
- 41.Sato A, Kayama H, Shojima K, Matsumoto S, Koyama H, Minami Y, et al. The Wnt5a-Ror2 axis promotes the signaling circuit between interleukin-12 and interferon-gamma in colitis. Sci Rep-Uk. 2015;5.Google Scholar
- 42.Burris HA, Flinn IW, Patel MR, Fenske TS, Deng CC, Brander DM, et al. Umbralisib, a novel PI3K delta and casein kinase-1 epsilon inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: an open-label, phase 1, dose-escalation, first-in-human study. Lancet Oncol. 2018;19(4):486–96.PubMedGoogle Scholar
- 43.Nastoupil LJ, Lunning MA, Vose JM, Schreeder MT, Siddiqi T, Flowers CR, et al. Tolerability and activity of ublituximab, umbralisib, and ibrutinib in patients with chronic lymphocytic leukaemia and non-Hodgkin lymphoma: a phase 1 dose escalation and expansion trial. Lancet Haematol. 2019;6(2):E100–E9.PubMedGoogle Scholar
- 45.Soumerai JD, Pagel JM, Jagadeesh D, Salman HS, Kenkre VP, Asch AS, et al. Initial results of a dose escalation study of a selective and structurally differentiated PI3K delta inhibitor, ME-401, in relapsed/refractory (R/R) follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). J Clin Oncol. 2018;36(15).Google Scholar
- 46.Zelenetz AD, Soumerai JD, Jagadeesh D, Reddy N, Stathis A, Asch AS, et al. Preliminary safety and efficacy results with an intermittent schedule of the PI3k delta inhibitor ME-401 alone or in combination with rituximab for B-cell malignancies. Blood. 2018;132.Google Scholar
- 50.Di Leo A, Johnston S, Lee KS, Ciruelos E, Lonning PE, Janni W, et al. Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2018;19(1):87–100.PubMedGoogle Scholar
- 51.Baselga J, Im SA, Iwata H, Cortes J, De Laurentiis M, Jiang Z, et al. Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(7):904–16.PubMedPubMedCentralGoogle Scholar
- 53.Younes A, Berdeja JG, Patel MR, Flinn I, Gerecitano JF, Neelapu SS, et al. Safety, tolerability, and preliminary activity of CUDC-907, a first-in-class, oral, dual inhibitor of HDAC and PI3K, in patients with relapsed or refractory lymphoma or multiple myeloma: an open-label, dose-escalation, phase 1 trial. Lancet Oncol. 2016;17(5):622–31.PubMedPubMedCentralGoogle Scholar
- 55.Horwitz SM, Koch R, Porcu P, Oki Y, Moskowitz A, Perez M, Myskowski P, Officer A, Jaffe JD, Morrow SN, Allen K, Douglas M, Stern H, Sweeney J, Kelly P, Kelly V, Aster JC, Weaver D, Foss FM, Weinstock DM Activity of the PI3K-delta,gamma inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma. Blood. 2018;131(8):888–898.PubMedPubMedCentralGoogle Scholar
- 56.Horwitz SM, Moskowitz AJ, Jacobsen ED, Mehta-Shah N, Khodadoust MS, Fisher DC, et al. The combination of duvelisib, a PI3K-δ,γ inhibitor, and romidepsin is highly active in relapsed/refractory peripheral T-cell lymphoma with low rates of transaminitis: results of parallel multicenter, phase 1 combination studies with expansion cohorts. Blood. 2018;132(Suppl 1):683.Google Scholar