OncohematologyOncohematologyОнкогематология1818-83462413-4023Publishing House ABV Press26310.17650/1818-8346-2017-12-4-18-26HEMATOLOGIC MALIGNANCIES: DIAGNOSIS, TREATMENT, SUPPORTIVE CAREГЕМОБЛАСТОЗЫ: ДИАГНОСТИКА, ЛЕЧЕНИЕ, СОПРОВОДИТЕЛЬНАЯ ТЕРАПИЯEFFECTIVENESS OF VENETOСLAX IN THE TREATMENT OF CHRONIC LYMPHOCYTIC LEUKEMIA (LITERATURE REVIEW)ЭФФЕКТИВНОСТЬ ВЕНЕТОКЛАКСА В ТЕРАПИИ ХРОНИЧЕСКОГО ЛИМФОЛЕЙКОЗА (ОБЗОР ЛИТЕРАТУРЫ)StrugovV. V.СтруговВ. В.
Russian Federation

2 Akkuratova St, Saint Petersburg, 197341

Владимир Владимирович Стругов.

197341 Санкт-Петербург, ул. Аккуратова, 2

strugov@almazovcentre.ruStadnikE. A.СтадникЕ. А.
Russian Federation

2 Akkuratova St, Saint Petersburg, 197341

197341 Санкт-Петербург, ул. Аккуратова, 2

ZaritskeyA. Yu.ЗарицкийА. Ю.
Russian Federation

2 Akkuratova St, Saint Petersburg, 197341

197341 Санкт-Петербург, ул. Аккуратова, 2

Almazov National Medical Research CentreФГБУ «Национальный медицинский исследовательский центр им. В.А. Алмазова» Минздрава России08122017124182608022018080220182017https://oncohematology.abvpress.ru/ongm/article/view/263

Currently we are facing a revolution in therapy of chronic lymphocytic leukemia, related to the development of novel target drugs, which have markedly improved treatment results in all groups of patients. While inhibitors of Bruton’s tyrosine kinase (ibrutinib, acalabrutinib etc.) and phosphatidylinositol-3 kinase isoforms (idelalisib, umbralisib etc.) are currently in the spotlight, much less attention is paid to antiapoptotic protein inhibitors such as venetoclax. In this review we summarize the results of venetoclax clinical studies in CLL as monotherapy and in combinations. The drug is distinguished by a high rate of complete responses and minimal residual disease eradication in high risk CLL patients, as well as a favorable toxicity profile. This makes it an ideal component of non-genotoxic regimens, aimed at the cure of the disease.

В последние годы в терапии хронического лимфолейкоза (ХЛЛ) произошла революция, связанная с появлением новых таргетных препаратов, которые существенно улучшили результаты лечения всех групп больных ХЛЛ. При этом ингибиторы тирозинкиназы Брутона (ибрутиниб, акалабрутиниб и др.) и изоформ фосфатидилинозитол-3-киназы (иделалисиб, умбралисиб и др.) находятся на пике популярности, в то время как ингибиторам антиапоптотических белков (венетоклакс) уделяется незаслуженно мало внимания. В данном обзоре мы представляем результаты клинических исследований венетоклакса в монотерапии и комбинированных схемах при ХЛЛ. Отличительной чертой данного препарата является высокая частота достижения полных ответов и эрадикации минимальной остаточной болезни у пациентов с ХЛЛ высокого риска, а также хорошо контролируемый профиль токсичности, что делает его идеальным компонентом негенотоксичных режимов, нацеленных на полное излечение заболевания.

chronic lymphocytic leukemiavenetoclaxantiapoptotic protein Bcl-2хронический лимфолейкозвенетоклаксантиапоптотический белок Bcl-21. Souers A.J., Leverson J.D., Boghaert E.R. et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med 2013;19(2):202–8. DOI: 10.1038/nm.3048.PMID: 23291630.Souers A.J., Leverson J.D., Boghaert E.R. et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med 2013;19(2):202–8. DOI: 10.1038/nm.3048.PMID: 23291630.2. SPС (Special Product Characteristics) Venetoclax. Доступно по: www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&applno=208573.SPС (Special Product Characteristics) Venetoclax. Доступно по: www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&applno=208573.3. SPС (Special Product Characteristics) Venetoclax. Доступно по: www.ema. europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004106/WC500218800.pdf.SPС (Special Product Characteristics) Venetoclax. Доступно по: www.ema. europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004106/WC500218800.pdf.4. Delbridge A.R., Strasser A. The BCL-2 protein family, BH3-mimetics and cancer therapy. Cell Death Differ 2015;22(7): 1071–80. DOI: 10.1038/cdd.2015.50. PMID: 25952548.Delbridge A.R., Strasser A. The BCL-2 protein family, BH3-mimetics and cancer therapy. Cell Death Differ 2015;22(7): 1071–80. DOI: 10.1038/cdd.2015.50. PMID: 25952548.5. Cory S., Huang D.C., Adams J.M. The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene 2003;22(53): 8590–607. DOI: 10.1038/sj.onc.1207102. PMID: 14634621.Cory S., Huang D.C., Adams J.M. The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene 2003;22(53): 8590–607. DOI: 10.1038/sj.onc.1207102. PMID: 14634621.6. Hanada M., Delia D., Aiello A. et al. bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leukemia. Blood 1993;82(6):1820–8. PMID: 8104532.Hanada M., Delia D., Aiello A. et al. bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leukemia. Blood 1993;82(6):1820–8. PMID: 8104532.7. Cimmino A., Calin G.A., Fabbri M. et al. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci USA 2005;102(39):13944–9. DOI: 10.1073/pnas.0506654102. PMID: 16166262.Cimmino A., Calin G.A., Fabbri M. et al. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci USA 2005;102(39):13944–9. DOI: 10.1073/pnas.0506654102. PMID: 16166262.8. Del Gaizo Moore V., Brown J.R., Certo M. et al. Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737. J Clin Invest 2007;117(1):112–21. DOI: 10.1172/JCI28281. PMID: 17200714.Del Gaizo Moore V., Brown J.R., Certo M. et al. Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737. J Clin Invest 2007;117(1):112–21. DOI: 10.1172/JCI28281. PMID: 17200714.9. Seymour J.F., Roberts A.W., Carney D.A. et al. Phase 2 Study of navitoclax (ABT263) safety and efficacy in patients with relapsed or refractory chronic lymphocytic leukemia: interim results. Clin Lymphoma Myeloma Leuk 2011;11(2):258.Seymour J.F., Roberts A.W., Carney D.A. et al. Phase 2 Study of navitoclax (ABT263) safety and efficacy in patients with relapsed or refractory chronic lymphocytic leukemia: interim results. Clin Lymphoma Myeloma Leuk 2011;11(2):258.10. Anderson M.A., Deng J., Seymour J.F. et al. The BCL2 selective inhibitor venetoclax induces rapid onset apoptosis of CLL cells in patients via a TP53-independent mechanism. Blood 2016;127(25):3215–24. DOI: 10.1182/blood-2016-01-688796. PMID: 27069256.Anderson M.A., Deng J., Seymour J.F. et al. The BCL2 selective inhibitor venetoclax induces rapid onset apoptosis of CLL cells in patients via a TP53-independent mechanism. Blood 2016;127(25):3215–24. DOI: 10.1182/blood-2016-01-688796. PMID: 27069256.11. Salem A.H., Agarwal S.K., Dunbar M. et al. Effect of low- and high-fat meals on the pharmacokinetics of Venetoclax, a selective first-in-class BCL-2 inhibitor. J Clin Pharmacol 2016;56(11):1355–61. DOI: 10.1002/jcph.741. PMID: 27029823.Salem A.H., Agarwal S.K., Dunbar M. et al. Effect of low- and high-fat meals on the pharmacokinetics of Venetoclax, a selective first-in-class BCL-2 inhibitor. J Clin Pharmacol 2016;56(11):1355–61. DOI: 10.1002/jcph.741. PMID: 27029823.12. Salem A.H., Dunbar M., Agarwal S.K. Pharmacokinetics of venetoclax in patients with 17p deletion chronic lymphocytic leukemia. Anticancer Drugs 2017;28(8):911–4. DOI: 10.1097/CAD.0000000000000522. PMID: 28562380.Salem A.H., Dunbar M., Agarwal S.K. Pharmacokinetics of venetoclax in patients with 17p deletion chronic lymphocytic leukemia. Anticancer Drugs 2017;28(8):911–4. DOI: 10.1097/CAD.0000000000000522. PMID: 28562380.13. Jones A.K., Freise K.J., Agarwal S.K. et al. Clinical predictors of Venetoclax pharmacokinetics in chronic lymphocytic leukemia and non-Hodgkin’s lymphoma patients: a pooled population pharmacokinetic analysis. AAPS J 2016;18(5):1192–202. DOI: 10.1208/s12248-016-9927-9. PMID: 27233802.Jones A.K., Freise K.J., Agarwal S.K. et al. Clinical predictors of Venetoclax pharmacokinetics in chronic lymphocytic leukemia and non-Hodgkin’s lymphoma patients: a pooled population pharmacokinetic analysis. AAPS J 2016;18(5):1192–202. DOI: 10.1208/s12248-016-9927-9. PMID: 27233802.14. Agarwal S.K., Hu B., Chien D. et al. 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 2016;56(11):1335–43. DOI: 10.1002/jcph.730. PMID: 26953185.Agarwal S.K., Hu B., Chien D. et al. 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 2016;56(11):1335–43. DOI: 10.1002/jcph.730. PMID: 26953185.15. Roberts A.W., Davids M.S., Pagel J.M. et al. Targeting BCL2 with Venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med 2016;374(4):311–22. DOI: 10.1056/NEJMoa1513257. PMID: 26639348.Roberts A.W., Davids M.S., Pagel J.M. et al. Targeting BCL2 with Venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med 2016;374(4):311–22. DOI: 10.1056/NEJMoa1513257. PMID: 26639348.16. 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(6):768–78. DOI: 10.1016/S1470-2045(16)30019-5. PMID: 27178240.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(6):768–78. DOI: 10.1016/S1470-2045(16)30019-5. PMID: 27178240.17. Stilgenbauer S., Chyla B., Eichhorst B. et al.Venetoclax in relapsed/refractory chronic lymphocytic leukemia with 17P deletion: Outcome and minimal residual disease from the full population of the pivotal M13-982 trial. Haematologica 2017;102(Suppl 2):311–2. PMCID: PMC5492673.Stilgenbauer S., Chyla B., Eichhorst B. et al.Venetoclax in relapsed/refractory chronic lymphocytic leukemia with 17P deletion: Outcome and minimal residual disease from the full population of the pivotal M13-982 trial. Haematologica 2017;102(Suppl 2):311–2. PMCID: PMC5492673.18. Jones J., Mato A.R., Coutre S. et al. Preliminary results of a phase 2, OpenLabel Study of Venetoclax (ABT-199/GDC-0199) monotherapy in patients with chronic lymphocytic leukemia relapsed after or refractory to Ibrutinib or Idelalisib therapy. Blood 2015;126(23):715.Jones J., Mato A.R., Coutre S. et al. Preliminary results of a phase 2, OpenLabel Study of Venetoclax (ABT-199/GDC-0199) monotherapy in patients with chronic lymphocytic leukemia relapsed after or refractory to Ibrutinib or Idelalisib therapy. Blood 2015;126(23):715.19. Thijssen R., Slinger E., Weller K. et al. Resistance to ABT-199 induced by microenvironmental signals in chronic lymphocytic leukemia can be counteracted by CD20 antibodies or kinase inhibitors. Haematologica 2015;100(8):302–6. DOI: 10.3324/haematol. 2015.124560. PMID: 25957396.Thijssen R., Slinger E., Weller K. et al. Resistance to ABT-199 induced by microenvironmental signals in chronic lymphocytic leukemia can be counteracted by CD20 antibodies or kinase inhibitors. Haematologica 2015;100(8):302–6. DOI: 10.3324/haematol. 2015.124560. PMID: 25957396.20. Tse C., Shoemaker A.R., Adickes J. et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res 2008;68(9):3421–8. DOI: 10.1158/0008-5472.CAN-07-5836. PMID: 18451170.Tse C., Shoemaker A.R., Adickes J. et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res 2008;68(9):3421–8. DOI: 10.1158/0008-5472.CAN-07-5836. PMID: 18451170.21. Seymour J.F., Ma S., Brander D.M. et al. Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study. Lancet Oncol 2017;18(2):230–40. DOI: 10.1016/S1470-2045(17)30012-8. PMID: 28089635.Seymour J.F., Ma S., Brander D.M. et al. Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study. Lancet Oncol 2017;18(2):230–40. DOI: 10.1016/S1470-2045(17)30012-8. PMID: 28089635.22. Fischer K., Al-Sawaf O., Fink A.М. et al. Venetoclax and obinutuzumab in chronic lymphocytic leukemia. Blood 2017;129 (19):2702–5. DOI: 10.1182/blood-2017-01-761973. PMID: 28325865.Fischer K., Al-Sawaf O., Fink A.М. et al. Venetoclax and obinutuzumab in chronic lymphocytic leukemia. Blood 2017;129 (19):2702–5. DOI: 10.1182/blood-2017-01-761973. PMID: 28325865.23. Cervantes-Gomez F., Lamothe B., Woyach J.A. et al. Pharmacological and protein profiling suggests Venetoclax (ABT-199) as optimal partner with ibrutinib in chronic lymphocytic leukemia. Clin Cancer Res 2015;21(16):3705–15. DOI: 10.1158/1078-0432.CCR-14-2809. PMID: 25829398.Cervantes-Gomez F., Lamothe B., Woyach J.A. et al. Pharmacological and protein profiling suggests Venetoclax (ABT-199) as optimal partner with ibrutinib in chronic lymphocytic leukemia. Clin Cancer Res 2015;21(16):3705–15. DOI: 10.1158/1078-0432.CCR-14-2809. PMID: 25829398.24. Deng J., Isik E., Fernandes S.M. et al. Bruton’s tyrosine kinase inhibition increases BCL-2 dependence and enhances sensitivity to venetoclax in chronic lymphocytic leukemia. Leukemia 2017;31(10):2075–84. DOI: 10.1038/leu.2017.32. PMID: 28111464.Deng J., Isik E., Fernandes S.M. et al. Bruton’s tyrosine kinase inhibition increases BCL-2 dependence and enhances sensitivity to venetoclax in chronic lymphocytic leukemia. Leukemia 2017;31(10):2075–84. DOI: 10.1038/leu.2017.32. PMID: 28111464.25. Hillmen P., Rawstron A., Munir T. et al. The initial report of the bloodwise tap clarity study combining ibrutinib and venetoclax in relapsed, refractory cll shows acceptable safety and promising early indications of efficacy. Haematologica 2017;102(s2):1–882. Abstract S770.Hillmen P., Rawstron A., Munir T. et al. The initial report of the bloodwise tap clarity study combining ibrutinib and venetoclax in relapsed, refractory cll shows acceptable safety and promising early indications of efficacy. Haematologica 2017;102(s2):1–882. Abstract S770.26. Ghia P., Scarfò L., Coscia M. et al. MRD-guided approach for the combination of ibrutinib to venetoclax in relapsed/refractory patients with chronic lymphocytic leukemia (improve study). Hematol Oncol 2017;35(Suppl. S2):426–7. DOI: 10.1002/hon.2440_11.Ghia P., Scarfò L., Coscia M. et al. MRD-guided approach for the combination of ibrutinib to venetoclax in relapsed/refractory patients with chronic lymphocytic leukemia (improve study). Hematol Oncol 2017;35(Suppl. S2):426–7. DOI: 10.1002/hon.2440_11.27. Jones J.A., Woyach J., Awan F.T. 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(22):639.Jones J.A., Woyach J., Awan F.T. 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(22):639.28. Choudhary G., Al-Harbi S., Mazumder S. et al. MCL-1 and BCL-xL-dependent resistance to the BCL-2 inhibitor ABT199 can be overcome by preventing PI3K/AKT/mTOR activation in lymphoid malignancies. Cell Death Dis 2015;6:e1593. DOI: 10.1038/cddis.2014.525. PMID: 25590803.Choudhary G., Al-Harbi S., Mazumder S. et al. MCL-1 and BCL-xL-dependent resistance to the BCL-2 inhibitor ABT199 can be overcome by preventing PI3K/AKT/mTOR activation in lymphoid malignancies. Cell Death Dis 2015;6:e1593. DOI: 10.1038/cddis.2014.525. PMID: 25590803.29. Patel V., Balakrishnan K., Douglas M. et al. Duvelisib treatment is associated with altered expression of apoptotic regulators that helps in sensitization of chronic lymphocytic leukemia cells to venetoclax (ABT-199). Leukemia 2017;31(9): 1872–81. DOI: 10.1038/leu.2016.382. PMID: 28017967.Patel V., Balakrishnan K., Douglas M. et al. Duvelisib treatment is associated with altered expression of apoptotic regulators that helps in sensitization of chronic lymphocytic leukemia cells to venetoclax (ABT-199). Leukemia 2017;31(9): 1872–81. DOI: 10.1038/leu.2016.382. PMID: 28017967.30. Blunt M., Koehrer S., Dobson R. et al. The Dual Syk/JAK Inhibitor Cerdulatinib Antagonizes B-cell Receptor and Microenvironmental Signaling in Chronic Lymphocytic Leukemia. Clin Cancer Res 2017;23(9):2313–24. DOI: 10.1158/1078–0432.CCR-16-1662. PMID: 27697994.Blunt M., Koehrer S., Dobson R. et al. The Dual Syk/JAK Inhibitor Cerdulatinib Antagonizes B-cell Receptor and Microenvironmental Signaling in Chronic Lymphocytic Leukemia. Clin Cancer Res 2017;23(9):2313–24. DOI: 10.1158/1078–0432.CCR-16-1662. PMID: 27697994.31. Bojarczuk K., Sasi B., 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(25):3192–201. DOI: 10.1182/blood-2015-10-675009. PMID: 27095788.Bojarczuk K., Sasi B., 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(25):3192–201. DOI: 10.1182/blood-2015-10-675009. PMID: 27095788.32. Oppermann S., Ylanko J., Shi Y. et al. High-content screening identifies kinase inhibitors that overcome venetoclax resistance in activated CLL cells. Blood 2016;128 (7):934–47. DOI: 10.1182/blood-2015-12-687814. PMID: 27297795.Oppermann S., Ylanko J., Shi Y. et al. High-content screening identifies kinase inhibitors that overcome venetoclax resistance in activated CLL cells. Blood 2016;128 (7):934–47. DOI: 10.1182/blood-2015-12-687814. PMID: 27297795.33. Yecies D., Carlson N.E., Deng J., Letai A. Acquired resistance to ABT-737 in lymphoma cells that up-regulate MCL-1 and BFL-1. Blood 2010;115(16):3304–13. DOI: 10.1182/blood-2009-07-233304. PMID: 20197552.Yecies D., Carlson N.E., Deng J., Letai A. Acquired resistance to ABT-737 in lymphoma cells that up-regulate MCL-1 and BFL-1. Blood 2010;115(16):3304–13. DOI: 10.1182/blood-2009-07-233304. PMID: 20197552.34. Smit L.A., Hallaert D.Y., Spijker R. et al. Differential Noxa/Mcl-1 balance in peripheral versus lymph node chronic lymphocytic leukemia cells correlates with survival capacity. Blood 2007;109(4):1660–8. DOI: 10.1182/blood-2006-05-021683. PMID: 17038534.Smit L.A., Hallaert D.Y., Spijker R. et al. Differential Noxa/Mcl-1 balance in peripheral versus lymph node chronic lymphocytic leukemia cells correlates with survival capacity. Blood 2007;109(4):1660–8. DOI: 10.1182/blood-2006-05-021683. PMID: 17038534.35. Vogler M., Butterworth M., Majid A. et al. Concurrent up-regulation of BCL–XL and BCL2A1 induces approximately 1000-fold resistance to ABT-737 in chronic lymphocytic leukemia. Blood 2009;113 (18):4403–13. DOI: 10.1182/blood-2008-08-173310. PMID: 19008458.Vogler M., Butterworth M., Majid A. et al. Concurrent up-regulation of BCL–XL and BCL2A1 induces approximately 1000-fold resistance to ABT-737 in chronic lymphocytic leukemia. Blood 2009;113 (18):4403–13. DOI: 10.1182/blood-2008-08-173310. PMID: 19008458.36. Geest C.R., de Rooij M.F., Liu N. et al. Possible mechanisms of resistance to the novel BH3-mimetic ABT-199 in in vitro lymph node models of CLL – the role of Abl and Btk. Blood 2013;122(21):4188.Geest C.R., de Rooij M.F., Liu N. et al. Possible mechanisms of resistance to the novel BH3-mimetic ABT-199 in in vitro lymph node models of CLL – the role of Abl and Btk. Blood 2013;122(21):4188.37. Kurtova A.V., Balakrishnan K., Chen R. et al. Diverse marrow stromal cells protect CLL cells from spontaneous and druginduced apoptosis: development of a reliable and reproducible system to assess stromal cell adhesion-mediated drug resistance. Blood 2009;114(20):4441–50. DOI: 10.1182/blood-2009-07-233718. PMID: 19762485.Kurtova A.V., Balakrishnan K., Chen R. et al. Diverse marrow stromal cells protect CLL cells from spontaneous and druginduced apoptosis: development of a reliable and reproducible system to assess stromal cell adhesion-mediated drug resistance. Blood 2009;114(20):4441–50. DOI: 10.1182/blood-2009-07-233718. PMID: 19762485.38. Roberts A.W., Seymour J.F., Brown J.R. 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(5):488–96. DOI: 10.1200/JCO.2011.34.7898. PMID: 22184378.Roberts A.W., Seymour J.F., Brown J.R. 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(5):488–96. DOI: 10.1200/JCO.2011.34.7898. PMID: 22184378.39. Song T., Chai G., Liu Y. et al. Bcl-2 phosphorylation confers resistance on chronic lymphocytic leukaemia cells to the BH3 mimetics ABT-737, ABT-263 and ABT-199 by impeding direct binding. Br J Pharmacol 2016;173(3):471–83. DOI: 10.1111/bph.13370. PMID: 26493374.Song T., Chai G., Liu Y. et al. Bcl-2 phosphorylation confers resistance on chronic lymphocytic leukaemia cells to the BH3 mimetics ABT-737, ABT-263 and ABT-199 by impeding direct binding. Br J Pharmacol 2016;173(3):471–83. DOI: 10.1111/bph.13370. PMID: 26493374.40. Fresquet V., Rieger M., Carolis C. et al. Acquired mutations in BCL2 family proteins conferring resistance to the BH3 mimetic ABT-199 in lymphoma. Blood 2014;123 (26):4111–9. DOI: 10.1182/blood-2014-03-560284. PMID: 24786774.Fresquet V., Rieger M., Carolis C. et al. Acquired mutations in BCL2 family proteins conferring resistance to the BH3 mimetic ABT-199 in lymphoma. Blood 2014;123 (26):4111–9. DOI: 10.1182/blood-2014-03-560284. PMID: 24786774.41. Bodo J., Zhao X., Durkin L. et al. Acquired resistance to venetoclax (ABT199) in t(14;18) positive lymphoma cells. Oncotarget 2016;7(43):70000–10. DOI: 10.18632/oncotarget.12132. PMID: 27661108.Bodo J., Zhao X., Durkin L. et al. Acquired resistance to venetoclax (ABT199) in t(14;18) positive lymphoma cells. Oncotarget 2016;7(43):70000–10. DOI: 10.18632/oncotarget.12132. PMID: 27661108.42. Anderson M.A., Tam C., Lew T.E. et al. Clinicopathological features and outcomes of progression of CLL on the BCL2 inhibitor venetoclax. Blood 2017;129(25):3362–70. DOI: 10.1182/blood-2017-01-763003. PMID: 28473407.Anderson M.A., Tam C., Lew T.E. et al. Clinicopathological features and outcomes of progression of CLL on the BCL2 inhibitor venetoclax. Blood 2017;129(25):3362–70. DOI: 10.1182/blood-2017-01-763003. PMID: 28473407.43. Roberts A.W., Seymour J.F., Eichhorst B. et al. Pooled Multi-Trial Analysis of Venetoclax efficacy in patients with relapsed or refractory chronic lymphocytic leukemia. Blood 2016;128(22):3230.Roberts A.W., Seymour J.F., Eichhorst B. et al. Pooled Multi-Trial Analysis of Venetoclax efficacy in patients with relapsed or refractory chronic lymphocytic leukemia. Blood 2016;128(22):3230.44. Davids M., Jones J., Eradat H. et al. Modified Venetoclax dose ramp-up in select high-risk patients with chronic lymphocytic leukemia (CLL) with progression after B-cell Receptor pathway inhibitors (BCRi). Clin Lymphoma Myeloma Leuk 2017;17:302.Davids M., Jones J., Eradat H. et al. Modified Venetoclax dose ramp-up in select high-risk patients with chronic lymphocytic leukemia (CLL) with progression after B-cell Receptor pathway inhibitors (BCRi). Clin Lymphoma Myeloma Leuk 2017;17:302.45. Leverson J.D., Phillips D.C., Mitten M.J. et al. Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy. Sci Transl Med 2015;7(279):279ra40. DOI: 10.1126/scitranslmed.aaa4642. PMID: 25787766.Leverson J.D., Phillips D.C., Mitten M.J. et al. Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy. Sci Transl Med 2015;7(279):279ra40. DOI: 10.1126/scitranslmed.aaa4642. PMID: 25787766.