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Review

Novel synthetic drugs currently in clinical development for chronic lymphocytic leukemia

&
Pages 1249-1265 | Received 27 Jun 2017, Accepted 22 Sep 2017, Published online: 03 Oct 2017

References

  • Hallek M, Cheson B, Catovsky D et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) updating the National Cancer Institute-Working Group (NCI-WG) 1996 guidelines Blood 2008;111:5446–5456.
  • Eichhorst B, Robak T, Montserrat E, et al. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26:v78–v84.
  • Gribben JG. How I treat CLL up front. Blood. 2010;115:187–197.
  • Satram-Hoang S, Reyes C, Hoang KQ, et al. Treatment practice in the elderly patient with chronic lymphocytic leukemia—analysis of the combined SEER and Medicare database. Ann Hematol. 2014;93:1335–1344.
  • Dicker F, Herholz H, Schnittger S, et al. The detection of TP53 mutations in chronic lymphocytic leukemia independently predicts rapid disease progression and is highly correlated with a complex aberrant karyotype. Leukemia. 2009;23:117–124.
  • Zenz T, Gribben JG, Hallek M, et al. Risk categories and refractory CLL in the era of chemoimmunotherapy. Blood. 2012;119:4101–4107.
  • Bottcher S, Ritgen M, Fischer K, et al. Minimal residual disease quantification is an independent predictor of progression-free and overall survival in chronic lymphocytic leukemia: a multivariate analysis from the randomized GCLLSG CLL8 trial. J Clin Oncol. 2012;30:980–988.
  • Thompson PA, Tam CS, O’Brien SM, et al. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood. 2016;127:303–309.
  • Robak T, Stilgenbauer S, Tedeschi A. Front-line treatment of CLL in the era of novel agents. Cancer Treat Rev. 2017;53:70–78.
  • Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010;376:1164–1174.
  • Fischer K, Bahlo J, Fink AM, et al. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016;127:208–215.
  • Thompson M, Brander D, Nabhan C, et al. Minimal residual disease in chronic lymphocytic leukemia in the era of novel agents: a review. JAMA Oncol. 2017 Jul;27. DOI:10.1001/jamaoncol.2017.2009
  • Eichhorst B, Fink AM, Bahlo J, et al. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016;17:928–942.
  • Hillmen P, Robak T, Janssens A, et al. Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial. Lancet. 2015;385:1873–1883.
  • Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370:1101–1110.
  • Byrd JC, Furman RR, Coutre SE, et al. Targeting Bruton tyrosine kinase with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369:32–42.
  • Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 370:997–1007.
  • Niiro H, Clark EA. Regulation of B-cell fate by antigen-receptor signals. Nat Rev Immunol. 2002;2:945–956.
  • Minden MD, Ubelhart R, Schneider D, et al. Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signalling. Nature. 2012;489:309–312.
  • Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373:2425–2437.
  • Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 2016;17:768–778.
  • Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374:311–322.
  • Venclyxto S [cited 2017 Mar 17]. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004106/WC500218800.pdf ( accessed March 2017).
  • Tai YT, Chang BY, Kong SY, et al. Bruton tyrosine kinase inhibition is a novel therapeutic strategy targeting tumor in the bone marrow microenvironment in multiple myeloma. Blood. 2012;120:1877–1887.
  • Wu J, Liu C, Tsui ST, et al. Second-generation inhibitors of Bruton tyrosine kinase. J Hematol Oncol. 2016;9:80.
  • Tam C, Grigg AP, Opat S, et al. The BTK inhibitor, BGB-3111, is safe, tolerable, and highly active in patients with relapsed/refractory B-cell malignancies: initial report of a phase 1 first-in-human trial. Blood. (ASH Annual Meeting Abstracts). 2015;126:Abstract 832.
  • Na L, Zhijian S, Ye L, et al. BGB-3111 is a novel and highly selective Bruton’s tyrosine kinase (BTK) inhibitor. Cancer Res. 2015;75:Abstract 2597.
  • Walter HS, Rule SA, Dyer MJ, et al. A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies. Blood. 2016;127:411–419.
  • Walter HS, Jayne S, Rule SA, et al. Long-term follow-up of patients with CLL treated with the selective Bruton’s tyrosine kinase inhibitor ONO/GS-4059. Blood. 2017;129:2808–2810.
  • Yasuhiro T, Sawada W, Klein C, et al. Anti-tumor efficacy study of the Bruton’s tyrosine kinase (BTK) inhibitor, ONO/GS-4059, in combination with the glycoengineered type II anti-CD20 monoclonal antibody obinutuzumab (GA101) demonstrates superior in vivo efficacy compared to ONO/GS-4059 in combination with rituximab. Leuk Lymphoma. 2017;58:699–707.
  • Brown JR, Harb WA, Hill BT, et al. Phase I study of single-agent CC-292, a highly selective Bruton’s tyrosine kinase inhibitor, in relapsed/refractory chronic lymphocytic leukemia. Haematologica. 2016;101:e295–e298.
  • Sanford DS, Wierda WG, Burger JA, et al. Three newly approved drugs for chronic lymphocytic leukemia: incorporating ibrutinib, idelalisib, and obinutuzumab into clinical practice. Clin Lymphoma Myeloma Leuk. 2015;15:385–391.
  • Aalipour A, Advani RH. Bruton tyrosine kinase inhibitors: a promising novel targeted treatment for B cell lymphomas. Br J Haematol. 2013;163:436–443.
  • Woyach JA, Furman RR, Liu TM, et al. Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014;370:2286–2294.
  • Davids MS, Brown JR. Ibrutinib: a first in class covalent inhibitor of Bruton’s tyrosine kinase. Future Oncol. 2014;10:957–967.
  • Niemann CU, Herman SE, Maric I, et al. Disruption of in vivo chronic lymphocytic leukemia tumor-microenvironment interactions by ibrutinib - findings from an investigator initiated phase 2 study. Clin Cancer Res. 2016;22:1572–1582.
  • Honigberg LA, Smith AM, Sirisawad M, et al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci U S A. 2010;107:13075–13080.
  • Byrd JC, Furman RR, Coutre SE, et al. Three-year follow-up of treatment naïve and previously treated patients with CLL and SLL receiving single agent ibrutinib. Blood. 2015;125:2497–2506.
  • Burger JA, Keating MJ, Wierda WG, et al. Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study. Lancet Oncol. 2014;15:1090–1099.
  • Jain P, Keating MJ, Wierda WG, et al. Long-term follow-up of treatment with ibrutinib and rituximab in patients with high-risk chronic lymphocytic leukemia. Clin Cancer Res. 2017;23:2154–2158.
  • Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371:213–223.
  • Chanan-Khan A, Cramer P, Demirkan F, et al. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol. 2016;17:200–211.
  • De Weerdt I, Koopmans SM, Kater AP, et al. Incidence and management of toxicity associated with ibrutinib and idelalisib: a practical approach. Haematologica. 2017 Aug 3; pii: haematol.2017.164103. DOI:10.3324/haematol.2017.164103
  • Tran PN, O’Brien S. The safety of Bruton’s tyrosine kinase inhibitors for the treatment of chronic lymphocytic leukemia. Expert Opin Drug Saf. 2017Jun;23:1–10. DOI:10.1080/14740338.2017.1344213
  • O’Brien SM, Furman RR, Coutre SE, et al. Five-year experience with single-agent ibrutinib in patients with previously untreated and relapsed/refractory chronic lymphocytic leukemia/small lymphocytic leukemia. Blood. 2016;128:33.
  • Shanafelt TD, Parikh SA, Noseworthy PA, et al. Atrial fibrillation in patients with chronic lymphocytic leukemia (CLL). Leuk Lymphoma. 2017;58:1630–1639.
  • Thompson PA, Levy V, Tam CS, et al. Atrial fibrillation in CLL patients treated with ibrutinib. An international retrospective study. Br J Haematol. 2016;175:462–466.
  • Wu J, Zhang M, Liu D. Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor. J Hematol Oncol. 2016;9:21.
  • Byrd JC, Harrington B, O’Brien S, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374:323–332.
  • Patel V, Balakrishnan K, Bibikova E, et al. Comparison of acalabrutinib, a selective Bruton tyrosine kinase inhibitor, with ibrutinib in chronic lymphocytic leukemia cells. Clin Cancer Res. 2017;23:3734–3743.
  • Herman SE, Montraveta A, Niemann CU, et al. The Bruton tyrosine kinase (BTK) inhibitor acalabrutinib demonstrates potent on-target effects and efficacy in two mouse models of chronic lymphocytic leukemia. Clin Cancer Res. 2017;23:2831–2841.
  • Wu J, Zhang M, Liu D. Bruton tyrosine kinase inhibitor ONO/GS-4059: from bench to bedside. Oncotarget. 2017;8:7201–7207.
  • Yasuhiro T, Yoshizawa T, Shingo Hotta S, et al. ONO-4059, a novel oral Bruton’s tyrosine kinase (Btk) inhibitor that demonstrates potent pharmacodynamic activity through phosphorylated Btk (P-Btk) inhibition, in addition to effective anti-tumour activity in a TMD-8 (DLBCL) xenograft model. Cancer Res. 2013;73(8 Supplement):Abstract 2452.
  • Arnason JE, Jennifer R, Brown JR. B cell receptor pathway in chronic lymphocytic leukemia: specific role of CC-292. Immunotargets Ther. 2014;3:29–38.
  • Evans EK, Tester R, Aslanian S, et al. Inhibition of Btk with CC-292 provides early pharmacodynamic assessment of activity in mice and humans. J Pharmacol Exp Ther. 2013;346:219–228.
  • Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer. 2002;2:489–501.
  • Vanhaesebroeck B, Guillermet-Guibert J, Graupera M, et al. The emerging mechanisms of isoform-specific PI3K signalling. Nat Rev Mo Cell Biol. 2010;11:329–341.
  • Vanhaesebroeck B, Welham MJ, Kotani K, et al. P110delta, a novel phosphoinositide 3-kinase in leukocytes. Proc Natl Acad Sci USA. 1997;94:4330–4335.
  • So L, Fruman DA. PI3K signalling in B- and T-lymphocytes: new developments and therapeutic advances. Biochem J. 2012;442:465–481.
  • Lannutti BJ, Meadows SA, Herman SE, et al. CAL-101, a p110 selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood. 2011;117:591–594.
  • Brown JR, Byrd JC, Coutre SE, et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110delta, for relapsed/refractory chronic lymphocytic leukemia. Blood. 2014;123:3390–3397.
  • Jones JA, Robak T, Brown JR, et al. Results of a phase 3 randomised, controlled study evaluating the efficacy and safety of idelalisib in combination with ofatumumab for previously treated chronic lymphocytic leukemia. Lancet Hematol. 2017;4:e114–e126.
  • Zelenetz AD, Barrientos JC, Brown JR, et al. Idelalisib in combination with bendamustine and rituximab improves overall survival in patients with relapsed/refractory CLL – interim results of a phase 3 randomized placebo-controlled trial. Lancet Oncol. 2017;18:297–311.
  • Coutre S, Barrientos JC, Brown JR, et al. Safety of idelalisib in B-cell malignancies: integrated analysis of eight clinical trials. ASCO Meeting Abstracts. 2015;33(15_suppl):e18030.
  • Coutré SE, Barrientos JC, Brown JR, et al. Management of adverse events associated with idelalisib treatment: expert panel opinion. Leuk Lymphoma. 2015;56:2779–2786.
  • 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;128:195–203.
  • European Medicines Agency. EMA reviews cancer medicine Zydelig. 11 March 2016. [cited 2017 May 17]. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2016/03/WC500203235.pdf.
  • [cited 2017 May 16]. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm490618.htm.
  • O’Connor OA, Flinn IW, Patel MR, et al. TGR-1202, a novel once daily PI3K-delta inhibitor, demonstrates clinical activity with a favorable safety profile in patients with CLL and B-cell lymphoma. Blood (ASH Annual Meeting Abstracts). 2015;126:Abstract 4154.
  • Matthew A, Lunning MA, Vose J, et al. Ublituximab + TGR-1202 demonstrates activity and a favorable safety profile in relapsed/refractory B-cell NHL and high-risk CLL: phase I results. Blood (ASH Annual Meeting Abstracts). 2015;126:Abstract 1538.
  • 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 (ASH Annual Meeting Abstracts). 2013;122:Abstract 2881.
  • Morschhauser F, Bron D, Bouabdallah K, 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 (ASH Annual Meeting Abstracts). 2013;122:Abstract 87.
  • Patnaik A, Appleman LJ, Tolcher AW, 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;10:1928–1940.
  • Chen SS, Ham S, Rai KR, et al. Dual inhibition of PI3K-delta and gamma by duvelisib (IPI-145) impairs CLL B- and T-cell migration, survival and proliferation in a murine xenograft model using primary chronic lymphocytic leukemia cells. Blood (ASH Annual Meeting Abstracts). 2015;126:Abstract 1753.
  • Vangapandu HV, Jain N, Gandhi V. Duvelisib: a phosphoinositide-3 kinase δ/γ inhibitor for chronic lymphocytic leukemia. Expert Opin Investig Drugs. 2017;26:625–632.
  • Balakrishnan K, Peluso M, Fu M, 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;29:1811–1822.
  • O’Brien S, Patel M, Kahlet BS, et al. Duvelisib (IPI-145), a PI3K-δ,γ inhibitor, is clinically active in patients with relapsed/refractory chronic lymphocytic leukemia. Blood (ASH Annual Meeting Abstracts). 2014;124:Abstract 3334.
  • Siddiqi T, Rosen ST. Novel biologic agents for non-Hodgkin lymphoma and chronic lymphocytic leukemia-part 2: adoptive cellular immunotherapy, small-molecule inhibitors, and immunomodulation. Oncology. 2015;29:299–308.
  • 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 (ASH Annual Meeting Abstracts). 2014;124:Abstract 1984.
  • Maharaj KK, Powers J, Fonseca R, et al. Differential regulation of human T-cells by TGR-1202, a novel PI3Kδ inhibitor. Cancer Res. 2016;76(14 Supplement):Abstract 545.
  • Liu N, Rowley BR, Bull CO, et al. BAY 80-6946 is a highly selective intravenous PI3K inhibitor with potent p110α and p110δ activities in tumor cell lines and xenograft models. Mol Cancer Ther. 2013;12:2319–2330.
  • Göckeritz E, Kerwien S, Baumann M, et al. Efficacy of phosphatidylinositol-3 kinase inhibitors with diverse isoform selectivity profiles for inhibiting the survival of chronic lymphocytic leukemia cells. Int J Cancer. 2015;137:2234–2242.
  • Maira S-M, Pecchi S, Huang A, et al. Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor. Mol Cancer Therap. 2012;11:317–328.
  • Bohnacker T, Prota AE, Beaufils F, et al. Deconvolution of buparlisib’s mechanism of action defines specific PI3K and tubulin inhibitors for therapeutic intervention. Nat Commun. 2017;9(8):14683.
  • Bashash D, Safaroghli-Azar A, Delshad M, et al. Inhibitor of pan class-I PI3K induces differentially apoptotic pathways in acute leukemia cells: shedding new light on NVP-BKM120 mechanism of action. Int J Biochem Cell Biol. 2016;79:308–317.
  • Oppermann S, Lam AJ, Tung S, et al. Janus and PI3-kinases mediate glucocorticoid resistance in activated chronic leukemia cells. Oncotarget. 2016;7:72608–72621.
  • Amrein L, Shawi M, Grenier J, et al. The phosphatidylinositol-3 kinase I inhibitor BKM120 induces cell death in B-chronic lymphocytic leukemia cells in vitro. Int J Cancer. 2013;133:247–252.
  • Ragon BK, Kantarjian H, Jabbour E, et al. Buparlisib, a PI3K inhibitor, demonstrates acceptable tolerability and preliminary activity in a phase I trial of patients with advanced leukemias. Am J Hematol. 2017;92:7–11.
  • Maira SM, Stauffer F, Brueggen J, et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther. 2008;7:1851–1863.
  • Choudhary GS, Al-Harbi S, Mazumder S, et al. MCL-1 and BCL-xL-dependent resistance to the BCL-2 inhibitor ABT-199 can be overcome by preventing PI3K/AKT/mTOR activation in lymphoid malignancies. Cell Death Dis. 2015;6:e1593.
  • Yamamoto N, Fujiwara Y, Tamura K, et al. Phase Ia/Ib study of the pan-class I PI3K inhibitor pictilisib (GDC-0941) administered as a single agent in Japanese patients with solid tumors and in combination in Japanese patients with non-squamous non-small cell lung cancer. Invest New Drugs. 2017;35:37–46.
  • Sarker D, Ang JE, Baird R, et al. First-in-human phase I study of pictilisib (GDC-0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors. Clin Cancer Res. 2015;21:77–86.
  • Vlahos CJ, Matter WF, Hui KY, et al. A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J Biol Chem. 1994;269:5241–5248.
  • 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.
  • Brown JR, Davids MS, Rodon J, et al. Phase I trial of the pan-PI3K inhibitor pilaralisib (SAR245408/XL147) in patients with chronic lymphocytic leukemia (CLL) or relapsed/refractory lymphoma. Clin Cancer Res. 2015;21:3160–3169.
  • Brown JR, Hamadani M, Arnason J, et al. SAR245409 monotherapy in relapsed/refractory follicular lymphoma: preliminary results from the phase II ARD12130 study. Blood (ASH Annual Meeting Abstracts). 2013;122:Abstract 86.
  • Ashkenazi A, Fairbrother WJ, Leverson JD, et al. From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors. Nat Rev Drug Discov. 2017;16:273–284.
  • Opydo-Chanek M, Gonzalo O, Marzo I. Multifaceted anticancer activity of BH3 mimetics: current evidence and future prospects. Biochem Pharmacol. 2017;136:12–23.
  • Roberts AW, Seymour JF, Brown JR, et al. Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of navitoclax in patients with relapsed or refractory disease. J. Clin. Oncol. 2012;30:488–496.
  • Roberts AW, Advani RH, Kahl BS, et al. Phase 1 study of the safety, pharmacokinetics, and antitumour activity of the BCL2 inhibitor navitoclax in combination with rituximab in patients with relapsed or refractory CD20+ lymphoid malignancies. Br J Haematol. 2015;170:669–678.
  • O’Brien SM, Claxton DF, Crump M, et al. Phase I study of obatoclax mesylate (GX15-070), a small molecule pan-Bcl-2 family antagonist, in patients with advanced chronic lymphocytic leukemia. Blood. 2009;113:299–305.
  • Seymour F, Roberts A, Carney DA, et al. Phase II study of navitoclax (ABT-263) safety and efficacy in patients with relapsed or refractory chronic lymphocytic leukemia (CLL): interim results. Haematologica. 2011;96(s2):Abstract227.
  • Majid A, Tsoulakis O, Walewska R, et al. BCL2 expression in chronic lymphocytic leukemia: lack of association with the BCL2 938A>C promoter single nucleotide polymorphism. Blood. 2008;111:874–877.
  • Seymour JF, Ma S, Brander DM, et al. Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study. Lancet Oncol. 2017;18:230–240.
  • Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm495253.htm [ Accessed May 2016].
  • Jones J, Choi MY, et al. Venetoclax activity in CLL patients who have relapsed after or are refractory to ibrutinib or idelalisib. Blood. 2016;128:Abstract637.
  • Fischer K, Al-Sawaf O, Fink AM, et al. Venetoclax and obinutuzumab in chronic lymphocytic leukemia. Blood. 2017;129:2702–2705.
  • Lampson BL, Davids MS. The development and current use of BCL-2 inhibitors for the treatment of chronic lymphocytic leukemia. Curr Hematol Malig Rep. 2017;12:11–19.
  • Fischer K, Fink AM, Bishop H, et al. Results of the safety run-in phase of CLL14 (BO25323): A prospective, open-label, multicenter randomized phase III trial to compare the efficacy and safety of obinutuzumab and venetoclax (GDC-0199/ABT-199) with obinutuzumab and chlorambucil in patients with previously untreated CLL and coexisting medical conditions. Blood (ASH Annual Meeting Abstracts). 2015;126:Abstract 496.
  • Oltersdorf T, Elmore SW, Shoemaker AR, et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005;435:677–681.
  • Vogler M, Weber K, Dinsdale D, et al. Different forms of cell death induced by putative BCL2 inhibitors. Cell Death Differ. 2009;16:1030–1039.
  • Van Delft MF, Wei AH, Mason KD, et al. The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell. 2006;10:389–399.
  • Kojima K, Duvvuri S, Ruvolo V, et al. Decreased sensitivity of 17p-deleted chronic lymphocytic leukemia cells to a small molecule BCL-2 antagonist ABT-737. Cancer. 2012;118:1023–1031.
  • Kipps TJ, Eradat H, Grosicki S, et al. A phase 2 study of the BH3 mimetic BCL2 inhibitor navitoclax (ABT-263) with or without rituximab, in previously untreated B-cell chronic lymphocytic leukemia. Leuk Lymphoma. 2015;56:2826–2833.
  • Goard CA, Schimmer AD. An evidence-based review of obatoclax mesylate in the treatment of hematological malignancies. Core Evid. 2013;8:15–26.
  • Robak T, Blonski JZ, Robak P. Antibody therapy alone and in combination with targeted drugs in chronic lymphocytic leukemia. Semin Oncol. 2016;43:280–290.
  • Kwok M, Rawstron AC, Varghese A, et al. Minimal residual disease is an independent predictor for 10-year survival in CLL. Blood. 2016;128:2770–2773.
  • Robak T. Ibrutinib in chronic lymphocytic leukaemia: alone or in combination? Lancet Oncol. 2016;17:129–131.
  • Flinn I, Moreno C, Gill DS, et al. Randomized, multicenter, open-label, phase 3 study of the BTK inhibitor ibrutinib in combination with obinutuzumab vs. chlorambucil in combination with obinutuzumab in patients with treatment-naïve CLL/SLL (PCYC- 1130): iLLUMINATE. J Clin Oncol. 2015;33(suppl):AbstractTPS7095.
  • Deng J, Isik E, Fernandes SM, et al. Bruton’s tyrosine kinase inhibition increases BCL-2 dependence and enhances sensitivity tovenetoclax in chronic lymphocytic leukemia. Leukemia. 2017 Feb 14. DOI:10.1038/leu.2017.32
  • Bojarczuk K, Siernicka M, Dwojak M, et al. B-cell receptor pathway inhibitors affect CD20 levels and impair antitumor activity of anti-CD20 monoclonal antibodies. Leukemia. 2014;28:1163–1167.
  • Skarzynski M, Niemann CU, Lee YS, et al. Interactions between ibrutinib and anti-CD20 antibodies: competing affects on the outcome of combination therapy. Clin Cancer Res. 2016;22:86–95.

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