Bruton’s tyrosine kinase inhibitors: first and second generation agents for patients with Chronic Lymphocytic Leukemia (CLL)

References

• Burger JA, Chiorazzi NB. cell receptor signaling in chronic lymphocytic leukemia. Trends Immunol. 2013 Dec;34:592–601. DOI:10.1016/j.it.2013.07.002. PubMed PMID: 23928062; PubMed Central PMCID: PMC3898793.
   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 Apr 1;115:2578–2585. PubMed PMID: 19965662; eng.
   PubMed Web of Science ®Google Scholar
• Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013 Jul 4;369:32–42.
   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 Jan 22;370:997–1007.
   PubMed Web of Science ®Google Scholar
• 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 Jul 20;107:13075–13080. PubMed PMID: 20615965; PubMed Central PMCID: PMC2919935. DOI:10.1073/pnas.1004594107
   PubMed Web of Science ®Google Scholar
• Ponader S, Burger JA. Bruton’s tyrosine kinase: from X-linked agammaglobulinemia toward targeted therapy for B-cell malignancies. J Clin Oncol. 2014 Jun 10;32:1830–1839. PubMed PMID: 24778403; eng. DOI:10.1200/JCO.2013.53.1046
   PubMed Web of Science ®Google Scholar
• Smith CI. From identification of the BTK kinase to effective management of leukemia. Oncogene. 2017 Apr;36:2045–2053. PubMed PMID: 27669440. DOI:10.1038/onc.2016.343
   PubMed Web of Science ®Google Scholar
• Advani RH, Buggy JJ, Sharman JP, et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol. 2013 Jan 1;31:88–94.
   PubMed Web of Science ®Google Scholar
• Brown JR, Byrd JC, Coutre SE, et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110delta, for relapsed/refractory chronic lymphocytic leukemia. Blood. 2014 May 29;123:3390–3397. PubMed PMID: 24615777; PubMed Central PMCID: PMC4123414. eng. DOI:10.1182/blood-2013-11-535047
   PubMed Web of Science ®Google Scholar
• Burger JA, Montserrat E. Coming full circle: 70 years of chronic lymphocytic leukemia cell redistribution, from glucocorticoids to inhibitors of B-cell receptor signaling. Blood. 2013 Feb 28;121:1501–1509. DOI:10.1182/blood-2012-08-452607
   PubMed Web of Science ®Google Scholar
• Ponader S, Chen SS, Buggy JJ, et al. The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Blood. 2012 Feb 2;119:1182–1189. PubMed PMID: 22180443; eng. DOI:10.1182/blood-2011-10-38641
   PubMed Web of Science ®Google Scholar
• Quiroga MP, Balakrishnan K, Kurtova AV, et al. B-cell antigen receptor signaling enhances chronic lymphocytic leukemia cell migration and survival: specific targeting with a novel spleen tyrosine kinase inhibitor, R406. Blood. 2009 Jul 30;114:1029–1037. PubMed PMID: 19491390; eng.
   PubMed Web of Science ®Google Scholar
• De Rooij MF, 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 Mar 15;119:2590–2594. PubMed PMID: 22279054. DOI:10.1182/blood-2011-11-390989
   PubMed Web of Science ®Google Scholar
• Hoellenriegel J, Meadows SA, Sivina M, et al. The phosphoinositide 3ʹ-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia [Clinical Trial Research Support, Non-U.S. Gov’t]. Blood. 2011 Sep 29;118:3603–3612. PubMed PMID: 21803855. DOI:10.1182/blood-2011-05-352492
   PubMed Web of Science ®Google Scholar
• Coutre SE, Furman RR, Flinn IW, et al. Extended treatment with single-agent ibrutinib at the 420 mg dose leads to durable responses in chronic lymphocytic leukemia/small lymphocytic lymphoma. Clin Cancer Res. 2017 Mar 01;23:1149–1155. PubMed PMID: 28073846. DOI:10.1158/1078-0432.CCR-16-1431
   PubMed Web of Science ®Google Scholar
• Byrd JC, Furman RR, Coutre SE, et al. Three-year follow-up of treatment-naive and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 2015 Apr 16;125:2497–2506. PubMed PMID: 25700432; PubMed Central PMCID: PMCPMC4400288. DOI:10.1182/blood-2014-10-606038
   PubMed Web of Science ®Google Scholar
• Maddocks KJ, Ruppert AS, Lozanski G, et al. Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia. JAMA Oncol. 2015 Apr 1;1:80–87. PubMed PMID: 26182309. DOI:10.1001/jamaoncol.2014.218
   PubMed Web of Science ®Google Scholar
• Woyach JA, Ruppert AS, Guinn D, et al. BTKC481S-Mediated resistance to ibrutinib in chronic lymphocytic leukemia. J Clin Oncol. 2017 May 01;35:1437–1443.
   PubMed Web of Science ®Google Scholar
• Lipsky AH, Farooqui MZ, Tian X, et al. Incidence and risk factors of bleeding-related adverse events in patients with chronic lymphocytic leukemia treated with ibrutinib. Haematologica. 2015 Dec;100:1571–1578. PubMed PMID: 26430171; PubMed Central PMCID: PMC4666333. DOI:10.3324/haematol.2015.126672
   PubMed Web of Science ®Google Scholar
• Bye AP, Unsworth AJ, Vaiyapuri S, et al. Ibrutinib inhibits platelet integrin alphaIIbbeta3 outside-in signaling and thrombus stability but not adhesion to collagen. Arterioscler Thromb Vasc Biol. 2015 Nov;35:2326–2335. PubMed PMID: 26359510. DOI:10.1161/ATVBAHA.115.306130
   PubMed Web of Science ®Google Scholar
• Levade M, David E, Garcia C, et al. Ibrutinib treatment affects collagen and von Willebrand factor-dependent platelet functions. Blood. 2014 Dec 18;124:3991–3995. PubMed PMID: 25305202. DOI:10.1182/blood-2014-06-583294
   PubMed Web of Science ®Google Scholar
• Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014 Jul 17;371:213–223. PubMed PMID: 24881631; PubMed Central PMCID: PMC4134521. DOI:10.1056/NEJMoa1400376
   PubMed Web of Science ®Google Scholar
• Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic Leukemia. N Engl J Med. 2015 Dec 17;373:2425–2437.
   PubMed Web of Science ®Google Scholar
• Wierda WG, Padmanabhan S, Chan GW, et al. Ofatumumab is active in patients with fludarabine-refractory CLL irrespective of prior rituximab: results from the phase 2 international study. Blood. 2011 Nov 10;118:5126–5129. PubMed PMID: 21856867; PubMed Central PMCID: PMC4916553. DOI:10.1182/blood-2011-04-348656
   PubMed Web of Science ®Google Scholar
• Wierda WG, Kipps TJ, Mayer J, et al. Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol. 2010 Apr 01;28:1749–1755. PubMed PMID: 20194866; PubMed Central PMCID: PMC4979101. DOI:10.1200/JCO.2009.25.3187
   PubMed Web of Science ®Google Scholar
• 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 Feb;17:200–211. PubMed PMID: 26655421. DOI:10.1016/S1470-2045(15)00465-9
   PubMed Web of Science ®Google Scholar
• Robak T. Ibrutinib in chronic lymphocytic leukaemia: alone or in combination? Lancet Oncol. 2016 Feb;17:129–131. PubMed PMID: 26655423. DOI:10.1016/S1470-2045(15)00519-7
   PubMed Web of Science ®Google Scholar
• Jain P, Thompson PA, Keating M, et al. Long-term outcomes for patients with chronic lymphocytic leukemia who discontinue ibrutinib. Cancer. 2017;123:2268–2273. n/a-n/a. DOI:10.1002/cncr.30596
   PubMed Web of Science ®Google Scholar
• Farooqui M, Valdez JSoto S, et al. Atrial fibrillation in cll/sll patients on ibrutinib. Blood. 2015;26:2933–2933.
   Google Scholar
• Thompson PA, Levy V, Tam CS, et al. Atrial fibrillation in CLL patients treated with ibrutinib. An international retrospective study. Br J Haematol. 2016 Nov;175:462–466. PubMed PMID: 27611233. DOI:10.1111/bjh.14324
   PubMed Web of Science ®Google Scholar
• Kamel S, Horton L, Ysebaert L, et al. Ibrutinib inhibits collagen-mediated but not ADP-mediated platelet aggregation [Research Support, Non-U.S. Gov’t]. Leukemia. 2015 Apr;29:783–787. PubMed PMID: 25138588. DOI:10.1038/leu.2014.247
   PubMed Web of Science ®Google Scholar
• McMullen JR, Boey EJH, Ooi JYY, et al. Ibrutinib increases the risk of atrial fibrillation, potentially through inhibition of cardiac PI3K-Akt signaling. Blood. 2014;124:3829–3830.
   PubMed Web of Science ®Google Scholar
• Barr PM, Brown JR, Hillmen P, et al. Impact of ibrutinib dose adherence on therapeutic efficacy in patients with previously treated CLL/SLL. Blood. 2017;129:2612–2615.
   PubMed Web of Science ®Google Scholar
• Lip GY, Nieuwlaat R, Pisters R, et al. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest. 2010 Feb;137:263–272. PubMed PMID: 19762550. DOI:10.1378/chest.09-1584
   PubMed Web of Science ®Google Scholar
• Woyach JA, Furman RR, Liu TM, et al. Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014 Jun 12;370:2286–2294. PubMed PMID: 24869598; PubMed Central PMCID: PMC4144824. DOI:10.1056/NEJMoa1400029
   PubMed Web of Science ®Google Scholar
• Burger JA, Landau DA, Taylor-Weiner A, et al. Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition [Article]. Nat Commun. 2016 05 20; online. 7:11589. DOI:10.1038/ncomms11589 http://www.nature.com/articles/ncomms11589#supplementary-information
   PubMed Web of Science ®Google Scholar
• Byrd JC, Harrington B, O’Brien S, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016 Jan 28;374:323–332. PubMed PMID: 26641137; PubMed Central PMCID: PMCPMC4862586 DOI:10.1056/NEJMoa1509981
   PubMed Web of Science ®Google Scholar
• 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 Jan 28;127:411–419. PubMed PMID: 26542378; PubMed Central PMCID: PMCPMC4731845. DOI:10.1182/blood-2015-08-664086
   PubMed Web of Science ®Google Scholar
• 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 Apr 04. PubMed PMID: 28377400. DOI:10.1182/blood-2017-02-765115.
   Web of Science ®Google Scholar
• Tam CS, Opat S, Cull G, et al. Twice daily dosing with the highly specific BTK inhibitor, Bgb-3111, achieves complete and continuous BTK occupancy in Lymph nodes, and is associated with durable responses in patients (pts) with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Blood. 2016;128:642–642.
   Web of Science ®Google Scholar
• Covey T, Barf T, Gulrajani M, et al. Abstract 2596: ACP-196: a novel covalent Bruton’s tyrosine kinase (Btk) inhibitor with improved selectivity and in vivo target coverage in chronic lymphocytic leukemia (CLL) patients. Cancer Res. 2015;75(15 Supplement):2596–2596. am2015-2596. DOI:10.1158/1538-7445
   Google Scholar
• Lynch TJ Jr., Kim ES, Eaby B, et al. Epidermal growth factor receptor inhibitor-associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist. 2007 May;12:610–621. PubMed PMID: 17522250. DOI:10.1634/theoncologist.12-5-610
   PubMed Web of Science ®Google Scholar
• Da Roit F, Engelberts PJ, Taylor RP, et al. Ibrutinib interferes with the cell-mediated anti-tumor activities of therapeutic CD20 antibodies: implications for combination therapy. Haematologica. 2015 Jan;100:77–86. PubMed PMID: 25344523; PubMed Central PMCID: PMCPMC4281316. DOI:10.3324/haematol.2014.107011
   PubMed Web of Science ®Google Scholar
• Khurana D, Arneson LN, Schoon RA, et al. Differential regulation of human NK cell-mediated cytotoxicity by the tyrosine kinase Itk. J Immunology. 2007 Mar;15(178):3575–3582. PubMed PMID: 17339454.
   Google Scholar
• Dubovsky JA, Beckwith KA, Natarajan G, et al. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes [Clinical Trial Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]. Blood. 2013 Oct 10:122:2539-49. PubMed PMID: 23886836; PubMed Central PMCID: PMC3795457. DOI: 10.1182/blood-2013-06-507947
   Web of Science ®Google Scholar
• Rajasekaran N, Sadaram M, Hebb J, et al. Three BTK-specific inhibitors, in contrast to ibrutinib, do not antagonize rituximab-dependent NK-cell mediated cytotoxicity. Blood. 2014;124:3118–3118.
   PubMed Web of Science ®Google Scholar
• Atkinson BT, Ellmeier W, Watson SP. Tec regulates platelet activation by GPVI in the absence of Btk. Blood. 2003 Nov 15;102:3592–3599. DOI:10.1182/blood-2003-04-1142
   PubMed Web of Science ®Google Scholar
• Hamazaki Y, Kojima H, Mano H, et al. Tec is involved in G protein-coupled receptor- and integrin-mediated signalings in human blood platelets. Oncogene. 1998 May 28;16:2773–2779. PubMed PMID: 9652744. DOI:10.1038/sj.onc.1201799
   PubMed Web of Science ®Google Scholar
• 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 Aug;346:219–228. PubMed PMID: 23709115. DOI:10.1124/jpet.113.203489
   PubMed Web of Science ®Google Scholar
• Harb WA, Hill BT, Gabrilove J, 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). Blood. 2013;122:1630–1630.
   Web of Science ®Google Scholar
• Li N, Sun Z, Liu Y, et al. Abstract 2597: BGB-3111 is a novel and highly selective Bruton’s tyrosine kinase (BTK) inhibitor. Cancer Res. 2015;75(15 Supplement):2597–2597.
   Google Scholar
• Binnerts ME, Otipoby KL, Hopkins BT, et al. Abstract C186: SNS-062 is a potent noncovalent BTK inhibitor with comparable activity against wild type BTK and BTK with an acquired resistance mutation. Mol Cancer Ther. 2015;14(12 Supplement 2):C186–C186.
   Google Scholar
• Neuman LL, Ward R, Arnold D, et al. First-in-human phase 1a study of the safety, pharmacokinetics, and pharmacodynamics of the noncovalent bruton tyrosine kinase (BTK) Inhibitor SNS-062 in healthy subjects. Blood. 2016;128:2032–2032.
   Web of Science ®Google Scholar
• 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;128:233–233.
   Web of Science ®Google Scholar
• Chen Q, Jain N, Ayer T, et al. Economic burden of chronic lymphocytic leukemia in the era of oral targeted therapies in the United States. J Clin Oncol. 2017;35:166–174. PubMed PMID: 27870563. DOI:10.1200/jco.2016.68.2856
   PubMed Web of Science ®Google Scholar
• 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 Oct 2;376:1164–1174. PubMed PMID: 20888994. DOI:10.1016/S0140-6736(10)61381-5
   PubMed Web of Science ®Google Scholar
• 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 Sep;15:1090–1099. PubMed PMID: 25150798; PubMed Central PMCID: PMCPMC4174348 DOI:10.1016/S1470-2045(14)70335-3
   PubMed Web of Science ®Google Scholar
• Kohrt HE, Sagiv-Barfi I, Rafiq S, et al. Ibrutinib antagonizes rituximab-dependent NK cell-mediated cytotoxicity. Blood. 2014 Mar 20;123:1957–1960. PubMed PMID: 24652965; PubMed Central PMCID: PMCPMC3962169. DOI:10.1182/blood-2014-01-547869
   PubMed Web of Science ®Google Scholar
• Davis C, Stepanchick E, Syed K, et al. Effects of ibrutinib on rituximab and GA-101 induced antibody-dependent cell cytotoxicity (ADCC) in lymphoma cells in vitro. Blood. 2014;124:3117–3117.
   Web of Science ®Google Scholar
• Mathews Griner LA, Guha R, Shinn P, et al. High-throughput combinatorial screening identifies drugs that cooperate with ibrutinib to kill activated B-cell–like diffuse large B-cell lymphoma cells. Proceedings of the National Academy of Sciences. 2014 February 11, 2014;111:2349-2354. doi: 10.1073/pnas.1311846111
   Google Scholar
• Brown JR, Barrientos JC, Barr PM, et al. The Bruton’s tyrosine kinease (BTK) inhibitor, ibrutinib, with chemoimmunotherapy in patients with chronic lymphocytic leukemia. Blood. 2015;125:2915–2922.
   PubMed Web of Science ®Google Scholar
• Davids MS, Kim HT, Brander DM, et al. Initial results of a multicenter, phase ii study of ibrutinib plus FCR (iFCR) as frontline therapy for younger CLL patients. Blood. 2016;128:3243–3243.
   Web of Science ®Google Scholar
• Thompson PA, Strati P, Keating M, et al. Early achievement of MRD-negativity in IGHV-mutated patients portends highly favorable outcomes after first-line treatment of CLL with fludarabine, cyclophosphamide and rituximab (FCR). Serial monitoring for minimal residual disease (MRD) in blood after achieving MRD-negativity predicts subsequent clinical relapse. Blood. 2016;128:232–232.
   Web of Science ®Google Scholar
• 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 Jan 21;127:303–309. PubMed PMID: 26492934; PubMed Central PMCID: PMCPMC4760129. DOI:10.1182/blood-2015-09-667675
   PubMed Web of Science ®Google Scholar
• Rossi D, Terzi-di-Bergamo L, De Paoli L, et al. Molecular prediction of durable remission after first line fludarabine-cyclophosphamide-rituximab in chronic lymphocytic leukemia [Journal Article]. Blood. 2015 August 14. [Epub ahead of print]. DOI:10.1182/blood-2015-05-647925.
   Web of Science ®Google Scholar
• 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 Jan 14;127:208–215. PubMed PMID: 26486789. DOI:10.1182/blood-2015-06-651125
   PubMed Web of Science ®Google Scholar
• Ramsay AG, Clear AJ, Fatah R, et al. Multiple inhibitory ligands induce impaired T-cell immunologic synapse function in chronic lymphocytic leukemia that can be blocked with lenalidomide: establishing a reversible immune evasion mechanism in human cancer. Blood. 2012 Aug 16;120:1412–1421. PubMed PMID: 22547582; PubMed Central PMCID: PMC3423779. DOI:10.1182/blood-2012-02-411678
   PubMed Web of Science ®Google Scholar
• Ramsay AG, Gribben JG. Immune dysfunction in chronic lymphocytic leukemia T cells and lenalidomide as an immunomodulatory drug. Haematologica. 2009 Sep;94:1198–1202. PubMed PMID: 19734414; PubMed Central PMCID: PMC2738710. eng.
   PubMed Web of Science ®Google Scholar
• Ramsay AG, Johnson AJ, Lee AM, et al. Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug. J Clin Invest. 2008 Jul;118:2427–2437. PubMed PMID: 18551193; PubMed Central PMCID: PMC2423865. DOI:10.1172/JCI35017
   PubMed Web of Science ®Google Scholar
• Brusa D, Serra S, Coscia M, et al. The PD-1/PD-L1 axis contributes to T-cell dysfunction in chronic lymphocytic leukemia. Haematologica. 2013 Jun;98:953–963. PubMed PMID: 23300177; PubMed Central PMCID: PMC3669453. eng. DOI:10.3324/haematol.2012.077537[pii]
   PubMed Web of Science ®Google Scholar
• Shanafelt TD, Ramsay AG, Zent CS, et al. Long-term repair of T-cell synapse activity in a phase II trial of chemoimmunotherapy followed by lenalidomide consolidation in previously untreated chronic lymphocytic leukemia (CLL) [Clinical Trial, Phase II Research Support, Non-U.S. Gov’t]. Blood. 2013 May 16;121:4137–4141. PubMed PMID: 23493782. DOI:10.1182/blood-2012-12-470005
   PubMed Web of Science ®Google Scholar
• Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012 Jun 28;366:2443–2454. PubMed PMID: 22658127; PubMed Central PMCID: PMC3544539. eng. DOI:10.1056/NEJMoa1200690
   PubMed Web of Science ®Google Scholar
• Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma [Clinical Trial, Phase I Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]. N Engl J Med. 2015 Jan 22;372(4):311–319. PubMed PMID: 25482239; PubMed Central PMCID: PMC4348009. DOI:10.1056/NEJMoa1411087
   PubMed Web of Science ®Google Scholar
• Sagiv-Barfi I, Kohrt HE, Burckhardt L, et al. Ibrutinib enhances the antitumor immune response induced by intratumoral injection of a TLR9 ligand in mouse lymphoma. Blood. 2015 Mar 26;125:2079–2086. PubMed PMID: 25662332; PubMed Central PMCID: PMC4375105. DOI:10.1182/blood-2014-08-593137
   PubMed Web of Science ®Google Scholar
• Sagiv-Barfi I, Kohrt HE, Czerwinski DK, et al. Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK. Proc Natl Acad Sci U S A. 2015 Mar 3;112:E966–72. PubMed PMID: 25730880; PubMed Central PMCID: PMC4352777. DOI:10.1073/pnas.1500712112
   PubMed Web of Science ®Google Scholar
• Long M, Beckwith KA, Do P, et al. Ibrutinib represents a novel class of immune modulating therapeutics that enhances the survival of activated t cells in vitro and in vivo through a non-BTK mediated mechanism. Blood. 2016;128:3238–3238.
   Web of Science ®Google Scholar
• Kondo K, Burger JA, Micheal K, et al. Ibrutinib can modulate the T cell response in chronic lymphocytic leukemia by reducing PD1/PDL1 Interactions. Blood. 2015;126(23):1737–1737.
   PubMed Web of Science ®Google Scholar
• Cimmino A, Calin GA, Fabbri M, et al. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci U S A. 2005 Sep 27;102:13944–13949. PubMed PMID: 16166262; PubMed Central PMCID: PMCPMC1236577. DOI:10.1073/pnas.0506654102
   PubMed Web of Science ®Google Scholar
• Robertson LE, Plunkett W, McConnell K, et al. Bcl-2 expression in chronic lymphocytic leukemia and its correlation with the induction of apoptosis and clinical outcome. Leukemia. 1996 Mar;10:456–459. PubMed PMID: 8642861.
   PubMed Web of Science ®Google Scholar
• Del Gaizo Moore V, Brown JR, Certo M, et al. Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737 [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]. J Clin Invest. 2007 Jan;117(1):112–121. PubMed PMID: 17200714; PubMed Central PMCID: PMC1716201. DOI:10.1172/JCI28281
   PubMed Web of Science ®Google Scholar
• 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 Feb;19:202–208. PubMed PMID: 23291630; eng.
   PubMed Web of Science ®Google Scholar
• Roberts AWMS, Brander D, Kipps TJ, et al. Venetoclax (ABT-199/GDC-0199 combined with rituximab induces deep responses in patients with relapsed/refractory chronic lymphocytic leukemia. Haematologica. 2015;100:S431.
   PubMed Web of Science ®Google Scholar
• Cervantes-Gomez F, Lamothe B, Woyach JA, et al. Pharmacological and protein profiling suggest ABT-199 as optimal partner with ibrutinib in chronic lymphocytic leukemia. Clin Cancer Res. 2015 March;31:2015. DOI:10.1158/1078-0432.ccr-14-2809
   Web of Science ®Google Scholar
• Bojarczuk K, Sasi BK, Gobessi S, et al. BCR signaling inhibitors differ in their ability to overcome Mcl-1–mediated resistance of CLL B cells to ABT-199. Blood. 2016;127:3192–3201.
   PubMed Web of Science ®Google Scholar
• Deng J, Isik E, Fernandes SM, et al. Bruton/’s tyrosine kinase inhibition increases BCL-2 dependence and enhances sensitivity to venetoclax in chronic lymphocytic leukemia [Original Article]. Leukemia. 2017 02 14. online. DOI:10.1038/leu.2017.32.
   Web of Science ®Google Scholar
• 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 Feb;18:230–240. PubMed PMID: 28089635; PubMed Central PMCID: PMCPMC5316338. DOI:10.1016/S1470-2045(17)30012-8
   PubMed Web of Science ®Google Scholar
• Jones JA, Woyach J, Awan FT, et al. Phase 1b results of a phase 1b/2 study of obinutuzmab, ibrutinib, and venetoclax in relapsed/refractory chronic lymphocytic leukemia (CLL). Blood. 2016;128:639–639.
   Web of Science ®Google Scholar