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Review

Pharmacodynamic considerations of small molecule targeted therapy for treating B-cell malignancies in the elderly

, PhD, , MD PhD & , MD PhD

Bibliography

  • Plawny L, Ries F. Emerging new anticancer biological therapies in 2013 (hematological malignancies). Curr Opin Oncol 2014;26:363–70
  • Robak T, Korycka A, Kasznicki M, et al. Purine nucleoside analogues for the treatment of haematological malignancies: pharmacology and clinical applications. Curr Cancer Drug Targets 2005;5(6):421–44
  • Cheson BD. Monoclonal antibody therapy of chronic lymphocytic leukemia. Best Pract Res Clin Haematol 2010;23:133–43
  • Robak T, Dmoszynska A, Solal-Celigny A, et al. Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia. J Clin Oncol 2010;28:1756–65
  • Goede V, Fischer K, Busch R, et al. Obituzumumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med 2014;370:1101–10
  • Wiestner A. Emerging role of kinase-targeted strategies in chronic lymphocytic leukemia. Blood 2012;20:4684–91
  • Seda V, Mraz M. B-cell receptor signaling and its crosstalk with other pathways in normal and malignant cells. Eur J Haematol 2015;94:193–205
  • Hurria A, Browner IS, Cohen HJ, et al. Senior adult oncology. J Natl Compr Cancer Netw 2012;10:162–209
  • Klotz U. Pharmacokinetics and drug metabolism in the elderly. Drug Metab Rev 2009;41:67–76
  • Shi S, Klotz U. Age-related changes in pharmacokinetics. Curr Drug Metab 2011;12:601–10
  • Linderman RD. Changes in renal function with aging. Implications for treatment. Drugs Aging 1992;2:423–31
  • Dai F, Chen Y, Huang L, et al. A novel synthetic small molecule YH-306 suppresses colorectal tumour growth and metastasis via FAK pathway. J Cell Mol Med 2015;19:383–95
  • Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 2013;369:32–42
  • Akinleye A, Awaru P, Furqan M, et al. Phosphatydyloinositol 3-kinase (PI3K) inhibitors as cancer therapeutics. J Hematol Oncol 2013;6:88
  • O’Brien S, Furman RR, Coutre SE, et al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol 2014;15:48–58
  • Brown JR, Byrd JC, Coutre SE, et al. Idelalisib, an inhibitor of phpsphatydyloinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia. Blood 2014;123:3390–7
  • Uckun FM, Qazi S. Bruton’s tyrosine kinase as a molecular target in treatment of leukemias and lymphomas as well as inflammatory disorders and autoimmunity. Expert Opin Ther Pat 2010;20:1457–70
  • Molica S. Progress in the treatment of elderly/unfit chronic lymphocytic leukemia patients: results of the German CLL-11 trial. Expert Rev Anticancer Ther 2015;15:9–15
  • Robak T. New horizons in the treatment of chronic lymphocytic leukemia. Acta Haematol Pol 2014;45:122–31
  • Hoellenriegel J, Coffey GP, Sinha U, et al. Selective, novel spleen tyrosine kinase (Syk) inhibitors suppress chronic lymphocytic leukemia B-cell activation and migration. Leukemia 2012;26:1576–83
  • Scarfo L, Ghia P. Reprogramming cell death: BCL2 family inhibition in hematological malignancies. Immunol Lett 2013;155:36–9
  • Blum W, Phelps MA, et al. Phase I clinical and pharmacokinetic study of novel schedule of flavopiridol in relapsed or refractory acute leukemias. Haematologica 2010;95:1098–105
  • Kojima K, Duvvuri S, Ruvolo V, et al. Decreased sensitivity of 17p-deleted chronic lymphocytic leukemia cells to small molecule BCL-2 antagonist ABT-737. Cancer 2012;118:1023–31
  • Hillmen P. Using the biology of chronic lymphocytic leukemia to choose treatment. Hematology Am Soc Hematol Educ Program 2011;2011:104–9
  • O’Brien S, Jones JA, Coutre S, et al. Efficacy and safety of ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic leukemia with 17p deletion: results from the Phase II RESONATE™-17 trial. Blood 2014;124:abstract 327
  • Byrd JC, Furman RR, Courte S, et al. The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib (PCI-32765) promotes high response rate, durable remission, and tolerable in treatment naive (TN) and ralapse or refractory (RR) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) patients including patients with high-risk (HR) disease: new and update results of 116 patients in phase Ib/II study. Blood 2012;120:abstract 189
  • Farooqui MZ, Valdez J, Martyr S, et al. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol 2015;16:169–76
  • Furaman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 2014;370:997–1007
  • McDermott J, Jimeno A. Ibrutinib for the treatment of chronic lymphocytic leukemia and mantle cell lymphoma. Drugs Today 2014;50:291–300
  • New FDA Approved Drugs for 2014/CenterWatch. Available from: www.centerwatch.com/drug-information/fda-approved-drugs/year/2014 [Last accessed on 2015.05.15]
  • Kuppers R. Mechanisms of B-cell lymphoma pathogenesis. Nat Rev Cancer 2005;5:251–62
  • Hagemann TL, Chen Y, Rosen FS, et al. Genomic organization of the Btk gene and exon scanning for mutations in patients with X-linked agammaglobulinemia. Hum Mol Genet 1994;3:1743–9
  • Honigberg LA, Smith AM, Sirisawad M, et al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and its efficacious in models of autoimmune disease and B-cell malignancies. PNAS 2010;107:13075–80
  • Afar DE, Park H, Howell BW, et al. Regulation of Btk by Src family tyrosine kinases. Mol Cell Biol 1996;16:3465–71
  • Pan Z, Scheerens H, Li S, et al. Discovery of Selective Irreversible Inhibitors for Bruton’s Tyrosine Kinase. Chem Med Chem 2007;2:58–61
  • BTK inhibitors-selleckchem.com. Available from: www.selleckchem.com [Last accessed on 2015.05.15]
  • Furnan RR, Cheng S, Lu P, et al. Ibrutinib resistance in chronic lymphocytic leukemia. N Engl J Med 2014;370:2352–4
  • Cheng S, Guo A, Lu P, et al. Functional characterization of BTKC481S mutation that confers ibrutinib resistance: exploration of alternative kinase inhibitors. Leukemia 2015;29:895–900
  • Rooij MFM, Kuil A, Geest CR, et al. The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Blood 2012;119:2590–4
  • Sukbuntherng J, Jejurkas P, Chan A, et al. Pharmacokinetics (PK) of ibrutinib in patients with chronic lymphocytic leukemia (CLL). J Clin Oncol 2013;abstract 7056
  • de Jong J, Sukbunthering J, Skee D, et al. Evaluation of the pharmacokinetics and food effect of oral ibrutinib in healthy subjects and chronic lymphocytic leukemia patients. Cancer Res 2014;74:abstract 4637
  • Wodarz D, Garg N, Komarova NL, et al. Kinetics of CLL cells in tissue and blood during therapy with the BTK inhibitor ibrutinib. Blood 2014;123:4132–5
  • Herman SEM, Mustafa RZ, Gyamfi JA, et al. Ibrutinib inhibits BCR and NF-kB signaling and reduces tumor proliferation in tissue-resident cells of patients with CLL. Blood 2014;123:3286–95
  • Cheng S, Ma J, Guo A, et al. BTK inhibition targets in vivo CLL proliferation through its effects on B-cell receptor signaling activity. Leukemia 2014;28:649–57
  • Advani RH, Buggy JJ, Sharman JP. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol 2013;31:88–94
  • Anantharaju A, Feller A, Chedid A. Aging liver. A Rev Gerontol 2002;48:343–53
  • Levade M, David E, Garcia C, et al. Ibrutinib treatment affects collagen and von Willebrand Factor-dependent platelet functions. Blood 2014;124:3991–5
  • McMullen JR, Boey EJ, Ooi JY, et al. Ibrutinib increases the risk of atrial fibrillation, potentially through inhibition of cardiac PI3K-Akt signaling. Blood 2014;124:3829–30
  • Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 2014;371:213–23
  • Danilov AV. Targeted therapy in chronic lymphocytic leukemia: past, present and future. Clin Ther 2013;35:1–17
  • Lee CS, Rattu MA, Kim SS. A review of novel, Bruton’s kinase inhibitor, ibrutinib. J Oncol Pharm Pract 2014; doi:10.1177/1078155214561281
  • Wang ML, Rule S, Martin P, et al. Targeting BTK with Ibrutinib in Relapsed or Refractory Mantle-Cell Lymphoma. N Engl J Med 2013;369:507–16
  • Burger JA, Keating WJ, Wierda WG, et al. The Btk inhibitor ibrutinib (PCI-32765) in combination with rituximab is well tolerated and display profound activity in high-risk chronic lymphocytic leukemia (CLL) patients. Blood 2012;120: Abstarct 87
  • Burger JA. Bruton’s tyrosine kinase (BTK) inhibitors in clinical trials. Curr Hematol Malig Rep 2014;9:44–9
  • Maddock K, Christian B, Jaglowski S, et al. A phase 1/1b study of rituximab, bendamustine and ibrutinib in patients with untreated and relapsed/refractory non-Hodgkin lymphoma. Blood 2015;125:242–8
  • Vij R, Chang BY, Berdeja JG, et al. Early Changes in Cytokines, Chemokines and Indices of Bone Metabolism in a Phase 2 Study of the Bruton Tyrosine Kinase (Btk) Inhibitor, Ibrutinib (PCI-32765) in Patients with Relapsed or Relapsed/Refractory Multiple Myeloma (MM). Blood 2012;120: Abstact 4039
  • Sivina M, Kreitman RJ, Arons E, et al. The Bruton tyrosine kinase inhibitor ibrutinb (PCI-32765) blocks hairy cell leukaemai survival, proliferation and B-cell receptor signaling: a new therapeutic approach. Br J Haematol 2014;166:177–88
  • Clinical trials. Available from: http:/clinicaltrials.gov [Last accessed on 2015.05.16]
  • Akinleye A, Chen Y, Mukhi N, et al. Ibrutinib and novel BTK inhibitors in clinical development. J Hematol Oncol 2013;6:59
  • Liu L, Di Paolo J, Barbosa J, et al. Antiarthritis effect of a novel Bruton’s tyrosine kinase (BTK) inhibitor in rat collagen-induced arthritis and mechanism-based pharmacokinetic/pharmacodynamic modeling: relationships between inhibition of BTK phosphorylation and efficacy. J Pharmacol Exp Ther 2011;338:154–63
  • Robak T, Robak E. Tyrosine kinase inhibitors as potential drugs for B-cell lymphoid malignancies and autoimmune disorders. Expert Opin Investig Drugs 2012;21:921–47
  • Salles GA, Karlin L, Rule S, et al. Phase I Study Of The Oral Btk Inhibitor ONO-4059 In Patients With Relapsed/Refractory and High Risk Chronic Lymphocytic Leukaemia (CLL). Blood 2012;122:abstract 676
  • Fegan C, Bagshawe J, Salles G, et al. The Bruton’s tyrosine kinase (BTK) inhibitor ONO-4059: promising single agent activity and well tolerated in patients with high risk chronic lymphocytic leukaemia (CLL). Blood 2014;124:abstract 3328
  • Dyer M, Hutchinson C, Rule S, et al. The Bruton’s tyrosine kinase (BTK) inhibitor ONO-4059: Single-agent activity in patients with relapsed and refractory non-GCB-DLBCL. J Clin Oncol 2014;32:abstract 8553
  • Brown J, Harb WA, Hill BT, et al. Phase 1 Study of single agent CC-292, a highly selective Bruton’s Tyrosine Kinase (BTK) inhibitor, in relapsed/refractory chronic lymphocytic leukemia (CLL) and B-cell non-hodgkin lymphoma (BNHL). Blood 2013;122:abstract 1630
  • Spurgeon SE, Coffey G, Fletcher LB, et al. The Selective Syk inhibitor P505-15 (PRT062607) inhibits B cell signaling and function in vitro and in vivo and augments the activity of fludarabine in chronic lymphocytic leukemia. J Pharmacol Exp Ther 2013;344:378–87
  • Baluom M, Grossbard EB, Mant T, et al. Pharmacokinetics of fosfamatinib, a spleen tyrosine kinase (SYK) inhibitor, in healthy human subjects following single and multiple oral dosing in three phase I studies. Br J Clin Pharmacol 2012;76:78–88
  • Small DS, Farid NA, Payne CD, et al. Effect of intrinsic and extrinsic factors on the clinical pharmacokinetics and pharmocodynamics of prasugrel. Clin Pharmacokinet 2010;49:777–98
  • Friedberg JW, Sharman J, Sweetenham J, et al. Inhibition of Syk with fosfamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood 2010;115:2578–85
  • Cheng S, Coffey G, Zhang XH, et al. SYK inhibition and response prediction in diffuse large B-cell lymphoma. Blood 2011;118:6342–52
  • Sharman J, Hawkins M, Kolibaba K, et al. An open-label phase 2 trial of entospletinib (GS-9973), a selective Syk inhibitor, in chronic lymphocytic leukemia. Blood 2015;125:2336–43
  • Barr PM, Saylors GB, Forbes Spurgeon SE, et al. Phase 2 trial of GS-9973, a selective syk inhibitor, and idelalisib (idela) in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). J Clin Oncol 2014;32:abstract 7059
  • Schnaiter A, Stilgenbauer S. Novel target treatment strategies for refractory chronic lymphocytic leukemia. Ther Adv Hem 2011;2:249–65
  • Lannutti B, Meadows SA, Herman SE, et al. CAL -101, a p110delta selective phosphatidyloinositol-3-kinase inhibitor for the treatment of B-cell malignancies inhibits PI3K signaling and cellular viability. Blood 2011;117:591–4
  • Awan FT, Byrd JC. New strategies in chronic lymphocytic leukemia: shifting treatment paradigms. Clin Cancer Res 2014;20:5869–74
  • Khan M, Saif A, Sandler S, et al. Idelalisib for the treatment of chronic lymphocytic leukemia. OSRN Oncology 2014;931858
  • Jin F, Robeson M, Zhou H, et al. The pharmacokinetics and safety of idelalisib in subjects with moderate or severe hepatic impairment. J Clin Oncol 2014;32:abstract 2592
  • Jin F, Robeson M, Zhou H, et al. Pharmacokinetics, Metabolism and Excretion Of Idelalisib. Blood 2013;122:abstract 5570
  • Jin F, Robeson M, Zhou H, et al. Evaluation of the effect of idalalisib on yhe QT/QTc interval in healthy subjects. Blood 2013;122:abstract 5573
  • Brown JR, Furman RR, Flinn I. Final results of a phase I study of idelalisib (GC-1101) a selective inhibitor of PI3Kδ, in patients with relapsed or refractory CLL. J Clin Oncol 2013;31:abstract 7003
  • Gopal AK, Kahl BS, de Vos S, et al. PI3K δ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med 2014;370:1008–18
  • Zelenetz AD, Lamanna N, Kipps TJ, et al. A phase 2 study of idelalisib monotherapy in previously untreated patients ≥ 65 years with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Blood 2014;124:abstract 1986
  • Burke R, Meadows S, Loriaux MM, et al. A potential therapeutic strategy for chronic lymphocytic leukemia by combining Idelalisib and GS-9973, a novel spleen tyrosine kinase (Syk) inhibitor. Oncotarget 2013;5:908–15
  • Barrientos JC, Coutre SE, et al. Long-term follow-up of a phase 1 trial of idelalisib (ZYDELIG®) in combination with bendamustine (B), bendamustine/rituximab (BR), fludarabine (F), chlorambucil (Chl), or chlorambucil/rituximab (ChlR) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). Blood 2014;124:abstract 3343
  • Sharman JP, Coutre SE, Furman RR, et al. Second Interim Analysis of a Phase 3 Study of Idelalisib (ZYDELIG®) Plus Rituximab (R) for Relapsed Chronic Lymphocytic Leukemia (CLL): Efficacy analysis in patient subpopulations with del(17p) and other adverse prognostic factors. Blood 2014;124:abstract 330
  • 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;28:1163–7
  • Yang Q, Modi P, Newcomb T, et al. Idelalisib: First-in-Class PI3K Delta Inhibitor for the Treatment of Chronic Lymphocytic Leukemia, Small Lymphocytic Leukemia, and Follicular Lymphoma. Clin Cancer Res 2015;21:1537–42
  • Keating GM. Idelalisib: a review of its use in chronic lymphocytic leukaemia and indolent non-Hodgkin’s lymphoma. Target Oncol 2015;10:145–51
  • Chang JE, Kahl BS. PI3-kinase inhibitors in chronic lymphocytic leukemia. Curr Hematol Malig Rep 2014;9:33–43
  • Peluso M, Faia K, Winkler D, et al. Duvelisib (IPI-145) Inhibits Malignant B-Cell Proliferation and Disrupts Signaling from the Tumor Microenvironment through Mechanisms That Are Dependent on PI3K-δ and PI3K-γ. Blood 2014;124:abstract 328
  • 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:abstract 3334
  • Flinn IW, Horowitz SM, Patel M, et al. Clinical safety and activity in a phase 1 trail of IPI-145, a potent inhibitor of phosphoinositide-3 kinase –gamma/delta in patients with advanced hematological malignancies. Blood 2012;120:abstract 3663
  • Horwitz SM, Flinn I, Patel MR, et al. Preliminary safety and efficacy of IPI-145, a potent inhibitor of phosphoinositide-3-kinase-δ,γ, in patients with relapsed/refractory lymphoma. J Clin Oncol 2013;31:abstract 8518
  • Dong S, Guinn D, Dubovsky JA, et al. IPI-145 antagonizes intrinsic and extrinsic survival signals in chronic lymphocytic leukemia cells. Blood 2014;124:3583–6
  • Porcu P, Flinn I, Kahl BS, et al. Clinical activity of duvelisib (IPI-145), a phosphoinositide-3-kinase-δ,γ inhibitor, in patients previously treated with ibrutinib. Blood 2014;124:abstract 3335
  • 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:abstract 2881
  • Younes A, Salles G, Bociek RG, et al. 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:abstract 1718
  • Chapman CM, Sun X, Roschewski M, et al. ON 01910.Na is selectively cytotoxic for Chronic Lymphocytic Leukemia cells through a dual mechanism of action involving PI3K/AKT inhibition and induction of oxidative stress. Clin Cancer Res 2012;18:1979–91
  • 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;12:2319–30
  • Dreyling M, 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:abstract 87
  • Dreyling M, Cunningham D, Bouabdallah K, et al. Phase 2A Study of Copanlisib, a Novel PI3K Inhibitor, in Patients with Indolent Lymphoma. Presented. Blood 2014;124:abstract 1701
  • 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 2014;32:abstract 2610
  • Wołowiec D, Benchaib M, Pernas P, et al. Expression of cell cycle regulatory proteins in chronic lymphocytic leukemias. Comparison with non-Hodgkin’s lymphomas and non-neoplastic lymphoid tissue. Leukemia 1995;9:1382–8
  • Wołowiec D, Ciszak L, Kosmaczewska A, et al. Cell cycle regulatory proteins and apoptosis in B-cell chronic lymphocytic leukemia. Haematologica 2001;86:1296–304
  • Sedlacek HH. Mechanism of action of flavopiridol. Critical Rev Oncol Hematol 2001;38:139–70
  • Lin TS, Fischer B, Brooker-McEldowney M, et al. Flavopiridol (alvocidib) in chronic lymphocytic leukemia. Hematol Meeting Rep 2008;2:112–19
  • Senderowicz AM. Flavopiridol: the first cyclin-dependent kinase inhibitor in human clinical trials. Invest New Drugs 1999;17:313–20
  • Stephens DM, Ruppert AS, Blum K, et al. Flavopiridol treatment of patients aged 70 or older with refractory or relapsed chronic lymphocytic leukemia is a feasible and active therapeutic approach. Hematologica 2012;97:423–7
  • Blachly JS, Byrd JC. Emerging drug profile: cyclin-dependent kinase inhibitors. Leuk Lymphoma 2013;54:2133–43
  • Johnson AJ, Yeh YY, Smith LL, et al. The novel cyclin-dependent kinase inhibitor dinaciclib (SCH727965) promotes apoptosis and abrogates microenvironmental cytokine protection in chronic lymphocytic leukemia. Leukemia 2012;26:2344–53
  • Jones JJ, Geyer S, Andritsos LA, et al. Dinaciclib (SCH 727965) and Ofatumumab for the Treatment of Relapsed and Refractory (R/R) Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL): Results of a Phase 1b/2 Study. Blood 2014;124:abstract 329
  • Reed JC, Kitada S, Takayama S, et al. Regulation of chemoresistance by the bcl-2 oncoprotein in non-Hodgkin’s lymphoma and lymphocytic leukemia cell lines. Ann Oncol 1994;5.61-5
  • Roberts AW, Seymour JF, Brown JR, et al. An ongoing phase 1/2a study of ABT-263: pharmacokinetics (PK), safety, and anti-tumor activity in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). Blood 2009;114:abstract 883
  • Ng SY, Davis MS. Selective BCL2 inhibition to treat chronic lymphocytic leukemia and non-Hodgki lymphoma. Clin Adv Hematol Oncol 2014;12:224–9
  • Vogler M, Dinsdale D, Dyer MJ, Cohen GM. ABT-199 selectively inhibits BCL2 but not BCL2L1 and efficiently induces apoptosis of chronic lymphocytic leukaemic cells but not platelets. Br J Haematol 2013;163:139–42
  • Seymour JF, Davids MS, Pagel JM, et al. Bcl-2 inhibitor ABT-199 (GDC- 0199) monotherapy shows anti-tumor activity including complete remissions in high-risk relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Blood 2013;122:abstract 872
  • Salles GA, Boyd TE, Morschhauser F, et al. Preliminary results of a phase 1b study (GO28440) combining GDC-0199 (ABT-199) with bendamustine/rituximab in patients with relapsed/refractory or previously untreated chronic lymphocytic leukemia. Blood 2014;124:abstract 3337
  • Wilson WH, O’Connor OA, Czuczman MS, et al. 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 2010;11:1149–59
  • Souers AJ, Leverson JD, Boghaert ER, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med 2013;19:202–8
  • Flinn I, Brunvand M, Dyer MJS, et al. Preliminary Results of a Phase 1b Study (GP28331) Combining GDC-0199 (ABT-199) and obinutuzumab in patients with relapsed/refractory or previously untreated chronic lymphocytic leukemia. Blood 2014;124:abstract 4687
  • Roberts AW, Ma S, Brander DM, et al. Determination of recommended phase 2 dose of ABT-199 (GDC-0199) combined with rituximab (R) in patients with relapsed/ refractory (R/R) chronic lymphocytic leukemia (CLL). Blood 2014;124:abstract 325
  • Cervantes-Gomez F, Lamothe B, Woyach JA, et al. Pharmacological and protein profiling suggest venetoclax (ABT-199) as optimal partner with ibrutinib in chronic lymphocytic leukemia. Cancer Res 2014; clincanres.2809.2014
  • 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;10:389–99
  • O’Brien SM, Claxton D, Crup 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
  • Rule S, Shah N, Salles GA, et al. A Phase I Study Of The Oral Btk Inhibitor ONO-4059 In Patients With Relapsed/Refractory B-Cell Lymphoma. Blood 2013;122:abstract 4397

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