Abstract
Over the last years, targeted anti-cancer therapy with small-molecule inhibitors and antibodies moved to the forefront as a strategy to treat hematological cancers. These novel agents showed outstanding effects in treatment of patients, often irrespective of their underlying genetic features. However, evolution and selection of subclones with continuous treatment leads to disease relapse and resistance toward these novel drugs. Venetoclax (ABT-199) is a novel, orally bioavailable small-molecule inhibitor for selective targeting of B-cell lymphoma 2 (BCL2). Venetoclax is in clinical development and shows high efficacy and safety in particular in the treatment of chronic lymphocytic leukemia (CLL), but preliminarily also in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). The most important and impressive outcomes of venetoclax treatment include a rapid induction of apoptosis and drastic reduction of the tumor bulk within a few hours after administration. Venetoclax was approved by the FDA and EMA in 2016 for patients with previously treated CLL with del(17p13) and patients failing B cell receptor signaling inhibitors (EMA only), on the basis of a single-arm phase II trial demonstrating a tremendous response rate of 79% with complete remission in 20% of cases and an estimated 1-year progression-free survival of 72%. This review focuses on the mode of action, the preclinical models, and outcomes from various clinical trials with venetoclax in different hematologic cancers as well as future development.
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References
Abulwerdi F et al (2014) A novel small-molecule inhibitor of mcl-1 blocks pancreatic cancer growth in vitro and in vivo. Mol Cancer Ther 13:565–75
Agarwal SK, Hu B, Chien D, Wong S, Salem A (2016) Evaluation of Rifampin’s transporter inhibitory and CYP3A inductive effects on the pharmacokinetics of venetoclax, a BCL-2 inhibitor: results of a single- and multiple-dose study. J Clin Pharmacol 56:1335–1343
Agarwal SK et al (2017) Effect of ketoconazole, a strong CYP3A inhibitor, on the pharmacokinetics of venetoclax, a BCL-2 inhibitor, in patients with non-Hodgkin lymphoma. Br J Clin Pharmacol 83:846–854
Albershardt TC et al (2011) Multiple BH3 mimetics antagonize antiapoptotic MCL1 protein by inducing the endoplasmic reticulum stress response and up-regulating BH3-only protein NOXA. J Biol Chem 286:24882–24895
Alford SE et al (2015) BH3 inhibitor sensitivity and Bcl-2 dependence in primary acute lymphoblastic leukemia cells. Cancer Res 75:1366–1375
Anderson MA et al (2016) The BCL2 selective inhibitor venetoclax induces rapid onset apoptosis of CLL cells in patients via a TP53-independent mechanism. Blood 127:3215–3224
Bai L et al (2014) BM-1197: a novel and specific Bcl-2/Bcl-xL inhibitor inducing complete and long-lasting tumor regression in vivo. PLoS ONE 9:e99404
Balakrishnan K, Burger JA, Wierda WG, Gandhi V (2009) AT-101 induces apoptosis in CLL B cells and overcomes stromal cell-mediated Mcl-1 induction and drug resistance. Blood 113:149–153
Bentz M et al (2000) t(11;14)-positive mantle cell lymphomas exhibit complex karyotypes and share similarities with B-cell chronic lymphocytic leukemia. Genes, Chromosom Cancer 27:285–294
Beroukhim R et al (2010) The landscape of somatic copy-number alteration across human cancers. Nature 463:899–905
Boise LH et al (1993) bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell 74:597–608
Brown JR et al (2015) Obatoclax in combination with fludarabine and rituximab is well-tolerated and shows promising clinical activity in relapsed chronic lymphocytic leukemia. Leuk Lymphoma 56:3336–3342
Byrd JC et al (2015) Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood 125
Byrd JC et al (2014) Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 371:213–223
Cahill N, Rosenquist R (2013) Uncovering the DNA methylome in chronic lymphocytic leukemia. Epigenetics 8:138–148
Cairo MS, Bishop M (2004) Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol 127:3–11
Cervantes-Gomez F et al (2015) Pharmacological and protein profiling suggests venetoclax (ABT-199) as optimal partner with ibrutinib in chronic lymphocytic leukemia. Clin Cancer Res 21:3705–3715
Cheson BD et al (2017) Tumor lysis syndrome in chronic lymphocytic leukemia with novel targeted agents. Oncologist 22:1283–1291
Choo EF et al (2014) The role of lymphatic transport on the systemic bioavailability of the BCL-2 protein family inhibitors navitoclax (ABT-263) and ABT-199. Drug Metab Dispos 42:207–212
Cimmino A et al (2005) miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci 102:13944–13949
Cohen NA et al (2012) A competitive stapled peptide screen identifies a selective small molecule that overcomes MCL-1-dependent leukemia cell survival. Chem Biol 19:1175–1186
Cramer P et al (2017) Bendamustine (B), followed by obinutuzumab (G) and venetoclax (A) in patients with chronic lymphocytic leukemia (Cll): Cll2-bag trial of the german CLL study group (GCLLSG). Hematol Oncol 35:25–27
Crombie J, Davids MS (2017) Venetoclax for the treatment of patients with chronic lymphocytic leukemia. Futur Oncol 13:1223–1232
Datta SR et al (2002) Survival factor-mediated BAD phosphorylation raises the mitochondrial threshold for apoptosis. Dev Cell 3:631–643
Davids MS, Roberts AW, Seymour JF, Pagel JM, Kahl BS, Wierda WG, Puvvada S, Kipps TJ, Anderson MA, Salem AH, Dunbar M, Zhu M, Peale F, Ross JA, Gressick L, Desai M, Kim SY, Verdugo M, Humerickhouse RA, Gordon GB, Gerecitano JF (2017) Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-hodgkin lymphoma. J Clin Oncol 35(8):826–833
Deeks ED (2016) Venetoclax: first global approval. Drugs 76:979–987
DiNardo C et al (2015) A phase 1b study of venetoclax (ABT-199/GDC-0199) in combination with decitabine or azacitidine in treatment-naive patients with acute myelogenous leukemia who are ≥ to 65 years and not eligible for standard induction therapy. Blood 126
Fernandez HF et al (2009) Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med 361:1249–1259
Fischer K et al (2015) 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 w…. Blood 126
Fischer U et al (2015) Genomics and drug profiling of fatal TCF3-HLF − positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options. Nat Genet 47:1020–1029
Fresquet V, Rieger M, Carolis C, Garcia-Barchino MJ, Martinez-Climent JA (2014) Acquired mutations in BCL2 family proteins conferring resistance to the BH3 mimetic ABT-199 in lymphoma. Blood 123:4111–4119
Frismantas V et al (2017) Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia. Blood 129:e26–e37
Gandhi L et al (2011) Phase I study of navitoclax (ABT-263), a novel Bcl-2 family inhibitor, in patients with small-cell lung cancer and other solid tumors. J Clin Oncol 29:909–916
Gibson CJ, Davids MS (2015) BCL-2 antagonism to target the intrinsic mitochondrial pathway of apoptosis. Clin Cancer Res 21:5021–5029
Gibson L et al (1996) bcl-w, a novel member of the bcl-2 family, promotes cell survival. Oncogene 13:665–675
Gratiot-Deans J, Merinot R, Nurezt G, Turkau LA (1994) Bcl-2 expression during T-cell development: early loss and late return occur at specific stages of commitment to differentiation and survival. 91, 10685–10689
Hanada M, Delia D, Aiello A, Stadtmauer E, Reed JC (1993) bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leukemia. Blood 82:1820–1828
Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674
Howard SC, Jones DP, Pui C-H (2011) The tumor lysis syndrome. N Engl J Med 364:1844–1854
Huber H, Edenhofer S, Estenfelder S, Stilgenbauer S (2017) Profile of venetoclax and its potential in the context of treatment of relapsed or refractory chronic lymphocytic leukemia. Onco Targets Ther 10:645–656
Inohara N, Ding L, Chen S, Núñez G (1997) Harakiri, a novel regulator of cell death, encodes a protein that activates apoptosis and interacts selectively with survival-promoting proteins Bcl-2 and Bcl-X(L). EMBO J 16:1686–1694
Inoue-Yamauchi A et al (2017) Targeting the differential addiction to anti-apoptotic BCL-2 family for cancer therapy. Nat Commun 8:16078
Kaefer A et al (2014) Mechanism-based pharmacokinetic/pharmacodynamic meta-analysis of navitoclax (ABT-263) induced thrombocytopenia. Cancer Chemother Pharmacol 74:593–602
Khaw SL et al (2014) Both leukaemic and normal peripheral B lymphoid cells are highly sensitive to the selective pharmacological inhibition of prosurvival Bcl-2 with ABT-199. Leukemia 28:1207–1215
Khaw SL et al (2016) Venetoclax responses of pediatric ALL xenografts reveal sensitivity of MLL-rearranged leukemia. Blood 128:1382–1395
Kipps TJ et al (2015) 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 56:2826–2833
Konopleva M et al (2016) Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov 6:1106–1117
Korsmeyer SJ et al (2000) Pro-apoptotic cascade activates BID, which oligomerizes BAK or BAX into pores that result in the release of cytochrome c. Cell Death Differ 7:1166–1173
Kotschy A et al (2016) The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature 538:477–482
Kumar SK et al (2015) Safety and efficacy of venetoclax (ABT-199/GDC-0199) monotherapy for relapsed/refractory multiple myeloma: phase 1 preliminary results. Blood 126
Lam LT et al (2017) Vulnerability of small-cell lung cancer to apoptosis induced by the combination of BET bromodomain proteins and BCL2 inhibitors. Mol Cancer Ther 16:1511–1520
Lee JH et al (2004) Inactivating mutation of the pro-apoptotic geneBID in gastric cancer. J Pathol 202:439–445
Leonard JT et al (2016) Targeting BCL-2 and ABL/LYN in Philadelphia chromosome-positive acute lymphoblastic leukemia. Sci Transl Med 8, 354ra114-354ra114
Lessene G et al (2013) Structure-guided design of a selective BCL-XL inhibitor. Nat Chem Biol 9:390–397
Li CJ et al (2016) Novel Bruton’s tyrosine kinase inhibitor Bgb-3111 demonstrates potent activity in mantle cell lymphoma. Blood 128
Liu-Dumlao T, Kantarjian H, Thomas DA, O’Brien S, Ravandi F (2012) Philadelphia-positive acute lymphoblastic leukemia: current treatment options. Curr Oncol Rep 14:387–394
Meijerink JP et al (1998) Hematopoietic malignancies demonstrate loss-of-function mutations of BAX. Blood 91:2991–2997
Merino R, Ding L, Veis DJ, Korsmeyer SJ, Nuñez G (1994) Developmental regulation of the Bcl-2 protein and susceptibility to cell death in B lymphocytes. EMBO J 13:683–691
Miyashita T, Reed JC (1995) Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 80:293–299
Monni O et al (1997) BCL2 overexpression associated with chromosomal amplification in diffuse large B-cell lymphoma. Blood 90
Moreau P et al (2017) Promising efficacy and acceptable safety of venetoclax plus bortezomib and dexamethasone in relapsed/refractory MM. Blood blood-2017-06-788323. https://doi.org/10.1182/blood-2017-06-788323
Motoyama N et al (1995) Massive cell death of immature hematopoietic cells and neurons in Bcl-x-deficient mice. Science 267:1506–1510
NCT01794507. A study evaluating ABT-199 in multiple myeloma subjects who are receiving bortezomib and dexamethasone as standard therapy—full text view—ClinicalTrials.gov
NCT02391480. A study evaluating the safety and pharmacokinetics of ABBV-075 in subjects with cancer—full text view—ClinicalTrials.gov
NCT02755597. A study evaluating venetoclax (ABT-199) in multiple myeloma subjects who are receiving bortezomib and dexamethasone as standard therapy—full text view—ClinicalTrials.gov
NCT02758665. Trial of ibrutinib plus venetoclax plus obinutuzumab in patients with CLL (CLL2-GiVe)-full text view-ClinicalTrials.gov
NCT02987400. Combination of obinutuzumab and venetoclax in relapsed or refractory DLBCL—full text view—ClinicalTrials.gov
NCT03112174. Study of ibrutinib combined with venetoclax in subjects with mantle cell lymphoma (SYMPATICO)—full text view—ClinicalTrials.gov
NCT03181126 & AbbVie. A study of venetoclax in combination with navitoclax and chemotherapy in subjects with relapsed acute lymphoblastic leukemia—full text view—ClinicalTrials.gov
NCT03236857. A study of the safety and pharmacokinetics of venetoclax in pediatric and young adult patients with relapsed or refractory malignancies—full text view—ClinicalTrials.gov
NCT03314181. A study of combination therapy with venetoclax, daratumumab and dexamethasone (with and without bortezomib) in subjects with relapsed or refractory multiple myeloma—full text view—ClinicalTrials.gov
Nguyen M et al (2007) Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis. Proc Natl Acad Sci 104:19512–19517
Niederst MJ, Engelman JA (2013) Bypass mechanisms of resistance to receptor tyrosine kinase inhibition in lung cancer. Sci Signal 6, re6
O’Brien SM et al (2005) Phase I to II multicenter study of oblimersen sodium, a Bcl-2 antisense oligonucleotide, in patients with advanced chronic lymphocytic leukemia. J Clin Oncol 23:7697–7702
O’Brien S et al (2009) 5-year survival in patients with relapsed or refractory chronic lymphocytic leukemia in a randomized, phase III trial of fludarabine plus cyclophosphamide with or without oblimersen. J Clin Oncol 27:5208–5212
O’Connor L et al (1998) Bim: a novel member of the Bcl-2 family that promotes apoptosis. EMBO J 17:384–395
Oda E et al (2000) Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science 288:1053–1058
Oltersdorf T et al (2005) An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435:677–681
Opferman JT et al (2003) Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1. Nature 426:671–676
Opferman JT et al (2005) Obligate role of anti-apoptotic MCL-1 in the survival of hematopoietic stem cells. Science 307:1101–1104
Pan R et al (2014) Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia. Cancer Discov 4:362–375
Park D et al (2013) Novel small-molecule inhibitors of Bcl-XL to treat lung cancer. Cancer Res 73:5485–5496
Perillo B, Sasso A, Abbondanza C, Palumbo G (2000) 17beta-estradiol inhibits apoptosis in MCF-7 cells, inducing bcl-2 expression via two estrogen-responsive elements present in the coding sequence. Mol Cell Biol 20:2890–2901
Pui C-H et al (2015) Clinical utility of sequential minimal residual disease measurements in the context of risk-based therapy in childhood acute lymphoblastic leukaemia: a prospective study. Lancet Oncol 16:465–474
Punnoose EA et al (2016) Expression profile of BCL-2, BCL-XL, and MCL-1 predicts pharmacological response to the BCL-2 selective antagonist venetoclax in multiple myeloma models. Mol Cancer Ther 15:1132–1144
Reed JC, Stein C, Subasinghe C, Haldar S, Croce CM, Yum S, Cohen J (1990) Antisense-mediated inhibition of BCL2 protooncogene expression and leukemic cell growth and survival: comparisons of phosphodiester and phosphorothioate oligodeoxynucleotides. Cancer Res 50:6565–6570
Rinkenberger JL, Horning S, Klocke B, Roth K, Korsmeyer SJ (2000) Mcl-1 deficiency results in peri-implantation embryonic lethality. Genes Dev 14:23–27
Roberts AW et al (2012) 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 30:488–496
Roberts AW et al (2016) Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med 374:311–322
Roberts AW, Stilgenbauer S, Seymour JF, Huang DCS (2017) Venetoclax in patients with previously treated chronic lymphocytic leukemia. Clin Cancer Res 23:4527–4533
Robertson LE, Plunkett W, McConnell K, Keating MJ, McDonnell TJ (1996) Bcl-2 expression in chronic lymphocytic leukemia and its correlation with the induction of apoptosis and clinical outcome. Leukemia 10:456–459
Rudin CM et al (2012) Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer. Clin Cancer Res 18:3163–3169
Seymour JF, Kipps TJ, Eichhorst BF, Hillmen P, D’Rozario JM, Assouline S, Owen CJ, Gerecitano J, Robak T, De la Serna J, Jaeger U, Cartron G, Montillo M, Humerickhouse R, Elizabet APK. Venetoclax plus rituximab is superior to bendamustine plus rituximab in patients with relapsed/refractory chronic lymphocytic leukemia—results from pre-planned interim analysis of the randomized phase 3 murano study. ASH Abstract 2017 (2017)
Seymour JF et al (2017) Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study. Lancet Oncol 18:230–240
Souers AJ et al (2013) ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med 19:202–208
Stilgenbauer S et al (2016) Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol 17:768–778
Sturm I et al (2000) Impaired BAX protein expression in breast cancer: mutational analysis of the BAX and the p53 gene. Int J Cancer 87:517–521
Tahir SK et al (2017) Potential mechanisms of resistance to venetoclax and strategies to circumvent it. BMC Cancer 17:399
Teh T-C et al (2017) Enhancing venetoclax activity in acute myeloid leukemia by co-targeting MCL1. Leukemia. https://doi.org/10.1038/leu.2017.243
Tolcher AW et al (2015) Safety, efficacy, and pharmacokinetics of navitoclax (ABT-263) in combination with erlotinib in patients with advanced solid tumors. Cancer Chemother Pharmacol 76:1025–1032
Tse C et al (2008) ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res 68:3421–3428
Tsujimoto Y, Cossman J, Jaffe E, Croce CM (1985) Involvement of the bcl-2 gene in human follicular lymphoma. Science 228:1440–1443
Vaillant F et al (2013) Targeting BCL-2 with the BH3 mimetic ABT-199 in estrogen receptor-positive breast cancer. Cancer Cell 24:120–129
van Delft MF et al (2006) The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell 10:389–399
Varadarajan S et al (2013a) Evaluation and critical assessment of putative MCL-1 inhibitors. Cell Death Differ 20:1475–1484
Varadarajan S et al (2013b) Sabutoclax (BI97C1) and BI112D1, putative inhibitors of MCL-1, induce mitochondrial fragmentation either upstream of or independent of apoptosis. Neoplasia 15:568–578
Veis DJ, Sentman CL, Bach EA, Korsmeyer SJ (1993) Expression of the Bcl-2 protein in murine and human thymocytes and in peripheral T lymphocytes. J. Immunol. 151:2546–2554
Vogler M, Dinsdale D, Dyer MJS, Cohen GM (2013) ABT-199 selectively inhibits BCL2 but not BCL2L1 and efficiently induces apoptosis of chronic lymphocytic leukaemic cells but not platelets. Br J Haematol 163:139–142
Wei MC et al (2000) tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c. Genes Dev 14:2060–2071
Weiss J, Gajek T, Köhler B, Haefeli W (2016) Venetoclax (ABT-199) might act as a perpetrator in pharmacokinetic drug-drug interactions. Pharmaceutics 8:5
Wilson WH et al (2010) Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity. Lancet Oncol 11:1149–1159
Woyach JA, Johnson AJ (2015) Targeted therapies in CLL: mechanisms of resistance and strategies for management. Blood 126
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Scheffold, A., Jebaraj, B.M.C., Stilgenbauer, S. (2018). Venetoclax: Targeting BCL2 in Hematological Cancers. In: Martens, U. (eds) Small Molecules in Hematology. Recent Results in Cancer Research, vol 212. Springer, Cham. https://doi.org/10.1007/978-3-319-91439-8_11
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