Clinical use of PI3K inhibitors in B-cell lymphoid malignancies: today and tomorrow

References

• Young RM, Staudt LM. Targeting pathological B cell receptor signalling in lymphoid malignancies. Nat Rev Drug Discov. 2013;12:229–243.
   PubMed Web of Science ®Google Scholar
• Friedberg JW, Sharman J, Sweetenham J, et al. Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood. 2010;115:2578–2585.
   PubMed Web of Science ®Google Scholar
• Flinn IW, Bartlett NL, Blum KA, et al. A phase II trial to evaluate the efficacy of fostamatinib in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Eur J Cancer. 2016;54:11–17.
   PubMed Web of Science ®Google Scholar
• Ansell SM, Tang H, Kurtin PJ, et al. Temsirolimus and rituximab in patients with relapsed or refractory mantle cell lymphoma: a phase 2 study. Lancet Oncol. 2011;12:361–368.
   PubMed Web of Science ®Google Scholar
• Witzig TE, Reeder CB, LaPlant BR, et al. A phase II trial of the oral mTOR inhibitor everolimus in relapsed aggressive lymphoma. Leukemia. 2011;25:341–347.
   PubMed Web of Science ®Google Scholar
• Hess G, Herbrecht R, Romaguera J, et al. Phase III study to evaluate temsirolimus compared with investigator’s choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J Clin Oncol. 2009;27:3822–3829.
   PubMed Web of Science ®Google Scholar
• Ringshausen I, Schneller F, Bogner C, et al. Constitutively activated phosphatidylinositol-3 kinase (PI-3K) is involved in the defect of apoptosis in B-CLL: association with protein kinase Cδ. Blood. 2002;100:3741–3748.
   PubMed Web of Science ®Google Scholar
• Brown JR. The PI3K pathway: clinical inhibition in chronic lymphocytic leukemia. Semin Oncol. 2016;43:260–264.
   PubMed Web of Science ®Google Scholar
• Limon JJ, Fruman DA. Akt and mTOR in B cell activation and differentiation. Front Immunol. 2012;3:1–12.
   PubMed Web of Science ®Google Scholar
• Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet. 2006;7:606–619.
   PubMed Web of Science ®Google Scholar
• Bartalucci N, Guglielmelli P, Vannucchi AM. Rationale for targeting the PI3K/Akt/mTOR pathway in myeloproliferative neoplasms. Clin Lymphoma Myeloma Leuk. 2013;13:S307–S309.
   PubMedGoogle Scholar
• Polivka J Jr., Janku F. Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway. Pharmacol Ther. 2014;142:164–175.
   PubMed Web of Science ®Google Scholar
• Gao Y, Yuan CY, Yuan W. Will targeting PI3K/Akt/mTOR signaling work in hematopoietic malignancies? Stem Cell Investig. 2016;3:31–31.
   PubMedGoogle Scholar
• Curran E, Smith SM. Phosphoinositide 3-kinase inhibitors in lymphoma. Curr Opin Oncol. 2014;26:469–475.
   PubMed Web of Science ®Google Scholar
• Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. Oncogene. 2008;27:5497–5510.
   PubMed Web of Science ®Google Scholar
• Pauls SD, Lafarge ST, Landego I, et al. The phosphoinositide 3-kinase signaling pathway in normal and malignant B cells: activation mechanisms, regulation, and impact on cellular functions. Front Immunol. 2012;3:1–20.
   PubMed Web of Science ®Google Scholar
• Bauer TM, Patel MR, Infante JR. Targeting PI3 kinase in cancer. Pharmacol Ther. 2015;146:53–60.
   PubMed Web of Science ®Google Scholar
• Geuna E, Roda D, Rafii S, et al. Complications of hyperglycaemia with PI3K-AKT-mTOR inhibitors in patients with advanced solid tumours on phase I clinical trials. Br J Cancer. 2015;113:1541–1547.
   PubMed Web of Science ®Google Scholar
• Crouthamel MC, Kahana JA, Korenchuk S, et al. Mechanism and management of AKT inhibitor-induced hyperglycemia. Clin Cancer Res. 2009;15:217–225.
   PubMed Web of Science ®Google Scholar
• Hutter G, Zimmermann Y, Zoellner A, et al.  Mode of action of different PI3K-inhibitors in mantle cell lymphoma. Haematologica. 2016 Jun;101(supplement 1):271-271.
   Google Scholar
• Zydelig healthcare providers page [Internet]. Gilead Sci. 2016. Available from: http://zydelig.com/hcp/#
   Google Scholar
• Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370:1008–1018.
   PubMed Web of Science ®Google Scholar
• Flinn IW, Kahl BS, Leonard JP, et al. Idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase-δ, as therapy for previously treated indolent non-Hodgkin lymphoma. Blood. 2014;123:3406–3413.
   PubMed Web of Science ®Google Scholar
• Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370:997–1007.
   PubMed Web of Science ®Google Scholar
• Jones JA, Robak T, Wach M, et al. Updated results of a phase III randomized, controlled study of idelalisib in combination with ofatumumab for previously treated chronic lymphocytic leukemia (CLL). J Clin Oncol. 2016;34(suppl). abstr 7515. Available from: http://meetinglibrary.asco.org/content/163777-176.
   Google Scholar
• Kahl BS, Spurgeon SE, Furman RR, et al. A phase 1 study of the PI3Kd inhibitor idelalisib in patients with relapsed/refractory mantle cell lymphoma (MCL). Blood. 2015;123:3398–3406.
   Web of Science ®Google Scholar
• Barr PM, Saylors GB, Spurgeon SE, et al. Phase 2 study of idelalisib and entospletinib: pneumonitis limits combination therapy in relapsed refractory CLL and NHL. Blood. 2016;127:2411–2415.
   PubMed Web of Science ®Google Scholar
• Cheah CY, Nastoupil LJ, Neelapu SS, et al. Letter: lenalidomide, idelalisib, and rituximab are unacceptably toxic in patients with relapsed/refractory indolent lymphoma. Blood. 2015;125:3357–3359.
   PubMed Web of Science ®Google Scholar
• Smith SM, Pitcher B, Jung S, et al. Unexpected and serious toxicity observed with combined idelalisib, lenalidomide and rituximab in relapsed/refractory B cell lymphomas: alliance A051201 and A051202. Blood. 2014;124(3091):LP–3091.
   Google Scholar
• Zelenetz AD, Robak T, Coiffier B, et al. Idelalisib plus bendamustine and rituximab (BR) is superior to BR alone in patients with relapsed/refractory chronic lymphocytic leukemia: results of a phase 3 randomized double-blind placebo-controlled study. Blood. 2015;126:LBA5.
   Google Scholar
• Important drug warning (Gilead). Decreased overall survival and increased risk of serious infections in patients receiving ZYDELIG (idelalisib). [cited 2016 Aug16]. Available from: http://zydelig.com/Content/pdf/Zydelig-Safety-Info-FINAL.pdf.
   Google Scholar
• Lampson BL, Kasar SN, Matos TR, et al. Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity. Blood. 2016;128:195–204.
   PubMed Web of Science ®Google Scholar
• Cheah CY, Fowler NH. Idelalisib in the management of lymphoma. Blood. 2016;128:331–337.
   PubMed Web of Science ®Google Scholar
• Coutre S, Barrientos JC, Brown JR, et al. Safety of idelalisib in B-cell malignancies: integrated analysis of eight clinical trials.  J Clin Oncol 33, 2015 (suppl; abstr e18030). Available from: http://meetinglibrary.asco.org/content/152238-156
   Google Scholar
• O’Connor OA, Flinn IW, Lunning M, et al. Long-term follow-up of the next generation PI3Kδ inhibitor TGR-1202 demonstrates safety and high response rates in NHL: integrated-analysis of TGR-1202 monotherapy and combined with ublituximab. Haematologica. 2016 Jun;101(supplement 1):102–103.
   Google Scholar
• Davids MS, Kim HT, Nicotra A, et al. Preliminary results of a phase I/Ib study of ibrutinib in combination with TGR-1202 in patients with relapsed/refractory CLL or MCL.  Haematologica. 2016 Jun;101(supplement 1):102–103.  433-433.
   Google Scholar
• Burris HA, Patel MR, Brander DM, et al. TGR-1202, a novel once daily PI3Kδ inhibitor, demonstrates clinical activity with a favorable safety profile, lacking hepatotoxicity, in patients with chronic lymphocytic leukemia and B-Cell lymphoma. Blood. 2014;124(1984):LP–184.
   Google Scholar
• Burris HA, Flinn I, Lunning MA, et al. Long-term follow-up of the next generation PI3Kδ inhibitor TGR−1202 demonstrates a differentiated safety profile and high response rates in CLL and NHL: integrated-analysis of TGR-1202 monotherapy and combined with ublituximab. J Clin Oncol 34, 2016 (suppl; abstr 7512). Available from: http://meetinglibrary.asco.org/content/167448-176.
   Google Scholar
• Mato A, Burris III HA, Flinn IW, et al. Long-term follow-up of the next generation PI3Kδ inhibitor TGR−1202 demonstrates a differentiated safety profile and high response rates in CLL: integrated-analysis of TGR-1202 monotherapy and combined with ublituximab. Haematologica. 2016 Jun;101 (supplement 1):50-51.
   Google Scholar
• Nastoupil L, Lunning MA, Vose JM, et al. The chemotherapy-free triplet of ublituximab, TGR-1202, and ibrutinib is safe and highly active in relapsed B-cell malignancies. Hematol Oncol. 2015;33:100–180.
   Google Scholar
• Mahadevan D, Pauli EK, Cutter K, et al. A phase I trial of TGR-1202, a next generation once daily PI3K-delta inhibitor in combination with obinutuzumab plus chlorambucil, in patients with chronic lymphocytic leukemia. Blood. 2015;126(2942):LP–2942.
   Google Scholar
• DUETTS: duvelisib trials in hematologic malignancies webpage [Internet]. [cited 2016 Sep 20]. Available from: http://www.duettsprogram.com/
   Google Scholar
• O’Brien S, Patel M, Kahl BS, et al. Duvelisib (IPI-145), a PI3K-δ,γ inhibitor, is clinically active in patients with relapsed/refractory chronic lymphocytic leukemia. Blood. 2014;124:3334.
   Web of Science ®Google Scholar
• Davids MS, Kim HT, Gilbert E, et al. Preliminary results of a phase Ib study of duvelisib in combination with FCR (dFCR) in previously untreated, younger patients with CLL. Blood. 2015;126:4158.
   Web of Science ®Google Scholar
• Flinn IW, Cherry M, Maris M, et al. Combination trial of duvelisib (IPI-145) with bendamustine, rituximab, or bendamustine/rituximab in patients with lymphoma or chronic lymphocytic leukemia. Blood. 2015;126:3928.
   Web of Science ®Google Scholar
• Horwitz SM, Porcu P, Flinn I, et al. Duvelisib (IPI-145), a phosphoinositide-3-kinase-δ,γ inhibitor, shows activity in patients with relapsed/refractory T-cell lymphoma. Blood. 2014;124:803.
   PubMed Web of Science ®Google Scholar
• Casulo C, Jacobsen ED, Van Eygen K, et al. Preliminary safety, pharmacokinetics, and pharmacodynamics of duvelisib plus rituximab or obinutuzumab in patients with previously untreated CD20+ follicular lymphoma. J Clin Oncol 34, 2016 (suppl; abstr e19052). Available from: http://meetinglibrary.asco.org/content/165191-176.
   Google Scholar
• Fowler NH, Pearlberg J, Brail LH, et al. FRESCO: a phase 2, randomized study of duvelisib plus rituximab vs R-CHOP in patients with relapsed/refractory follicular lymphoma who have progressed within 24 months of receiving an alkylator-based chemotherapy regimen. J Clin Oncol 34, 2016 (suppl; abstr TPS7578). Available from: http://meetinglibrary.asco.org/content/165190-176
   PubMedGoogle Scholar
• Duvelisib hits endpoint but misses expectations in phase II iNHL study [Internet]. [cited 2016 Sep 20]. Available from: http://www.onclive.com/web-exclusives/duvelisib-hits-endpoint-but-misses-expectations-in-phase-ii-inhl-study
   Google Scholar
• CHRONOS trials: ongoing clinical trials with copanlisib [Internet]. [cited 2016 Sep 20]. Available from: http://www.chronostrials.com/#copanlisibtrials
   Google Scholar
• Dreyling MH, Morschhauser F, Bron D, et al. Preliminary results of a phase II study of single agent bay 80-6946, a novel PI3K inhibitor, in patients with relapsed/refractory, indolent or aggressive lymphoma. Blood. 2013;122:87.
   Web of Science ®Google Scholar
• Cunningham D, Zinzani PL, Assouline SE, et al. Results of the mantle cell lymphoma subset from a phase 2a study of copanlisib, a novel PI3K inhibitor, in patients with indolent and aggressive lymphoma. Blood. 2015;126:3935.
   Web of Science ®Google Scholar
• Kim RD, Alberts SR, Renshaw FG, et al. Phase 1 dose escalation study of copanlisib (BAY 80-6946) in combination with gemcitabine or gemcitabine-cisplatin in advanced cancer patients. J Clin Oncol 32:5s, 2014 (suppl; abstr 2610). Available from: http://meetinglibrary.asco.org/content/130773-144.
   Google Scholar
• Younes A, Salles G, Bociek RG, et al. An open-label phase II study of buparlisib (BKM120) in patients with relapsed and refractory diffuse large B-cell lymphoma, mantle cell lymphoma or follicular lymphoma. Blood. 2014;124(1718):LP–1718.
   Google Scholar
• Younes A, Salles G, Martinelli G, et al. An open-label phase II study of buparlisib (BKM120) in patients with relapsed and refractory diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL) and follicular lymphoma (FL). Blood. 2015;126:1493.
   Web of Science ®Google Scholar
• Wen PY, Yung WKA, Mellinghoff IK, et al. Phase II trial of the phosphatidyinositol-3 kinase (PI3K) inhibitor buparlisib (BKM120) in recurrent glioblastoma. J Clin Oncol 32:5s, 2014 (suppl; abstr 2019). Available from: http://meetinglibrary.asco.org/content/126737-144.
   Google Scholar
• Soulieres D, Faivre SJ, Mesia R, et al. BERIL-1: a phase II, placebo-controlled study of buparlisib (BKM120) plus paclitaxel in patients with platinum-pretreated recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). J Clin Oncol. 2016;34:1–2.
   PubMedGoogle Scholar
• Shih KC, Chowdhary SA, Becker KP, et al. A phase II study of the combination of BKM120 (buparlisib) and bevacizumab in patients with relapsed/refractory glioblastoma multiforme (GBM). J Clin Oncol 33, 2015 (suppl; abstr 2065). Available from: http://meetinglibrary.asco.org/content/152051-156.
   Google Scholar
• Armstrong AJ, Halabi S, Healy P, et al. Phase II trial of the PI3 kinase inhibitor BKM120 with or without enzalutamide in men with metastatic castration resistant prostate cancer (mCRPC). ASCO Meet Abstr. 2015;33:5025.
   Google Scholar
• Durrant ST, Nagler A, Vannucchi AM, et al. An open-label, multicenter, 2-arm, dose-finding, phase 1b study of the combination of ruxolitinib and buparlisib (BKM120) in patients with myelofibrosis: results from HARMONY study. Blood. 2015;126:827.
   PubMed Web of Science ®Google Scholar
• Maddocks KJ, Cohen JB, Christian BA, et al. A phase I study of BKM120 (buparlisib) and rituximab in patients with relapsed or refractory B-cell non-Hodgkins lymphoma (NHL). Blood. 2015;126:5114.
   Google Scholar
• Lanasa MC, Glenn M, Mato AR, et al. First-in-human study of AMG 319, a highly selective, small molecule inhibitor of PI3Kδ, in adult patients with relapsed or refractory lymphoid malignancies. Blood. 2013;122:678.
   Web of Science ®Google Scholar
• Kater AP, Tonino SH, Kersten MJ, et al. Interim analysis of dose-escalation stage of a phase 1b study evaluating safety and pharmacology of GS-9820, a second-generation, selective, PI3Kd-inhibitor in recurrent lymphoid malignancies. Blood. 2013;122(2881):LP–2881.
   Google Scholar
• Carlo-Stella C, Delarue R, Barde PJ, et al. A dose escalation study of RP6530, a novel dual PI3K delta/gamma inhibitor, in patients with relapsed/refractory hematologic malignancies. Blood. 2015;126:1495.
   Google Scholar
• Stark A-K, Sriskantharajah S, Hessel EM, et al. PI3K inhibitors in inflammation, autoimmunity and cancer. Curr Opin Pharmacol. 2015;23:82–91.
   PubMed Web of Science ®Google Scholar
• Patton DT, Garçon F, Okkenhaug K. The PI3K p110delta controls T-cell development, differentiation and regulation. Biochem Soc Trans. 2007;35:167–171.
   PubMed Web of Science ®Google Scholar
• Weidner A-S, Panarelli NC, Geyer JT, et al. Idelalisib-associated colitis: histologic findings in 14 patients. Am J Surg Pathol. 2015;39:1661–1667.
   PubMed Web of Science ®Google Scholar
• Patton DT, Garden OA, Pearce WP, et al. Cutting edge: the phosphoinositide 3-kinase p110 delta is critical for the function of CD4+CD25+Foxp3+ regulatory T cells. J Immunol. 2006;177:6598–6602.
   PubMed Web of Science ®Google Scholar
• Pongas G, Cheson BD. PI3K signaling pathway in normal B cells and indolent B-cell malignancies. Semin Oncol. 2016;43:647–654.
   PubMed Web of Science ®Google Scholar
• Luo CT, Liao W, Dadi S, et al. Graded Foxo1 activity in Treg cells differentiates tumour immunity from spontaneous autoimmunity. Nature. 2016;529:532–536.
   PubMed Web of Science ®Google Scholar
• Roychoudhuri R, Clever D, Li P, et al. BACH2 regulates CD8+ T cell differentiation by controlling access of AP-1 factors to enhancers. Nat Immunol. 2016;17:851–860.
   PubMed Web of Science ®Google Scholar
• Roychoudhuri R, Eil RL, Clever D, et al. The transcription factor BACH2 promotes tumor immunosuppression. J Clin Invest. 2016;126:599–604.
   PubMed Web of Science ®Google Scholar
• Brown JR, Byrd JC, Coutre SE, et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110 d, for relapsed/refractory chronic lymphocytic leukemia. Blood. 2014;123:3390–3397.
   PubMed Web of Science ®Google Scholar