Venetoclax for the treatment of elderly or chemotherapy-ineligible patients with acute myeloid leukemia: a step in the right direction or a game changer?

References

• Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016 May 19;127(20):2391–2405.
   PubMed Web of Science ®Google Scholar
• National Comprehensive Cancer Network. Acute Myeloid Leukemia (version 2.2020). 2020 [Accessed on 2020 Aug 04]. Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/aml_blocks.pdf
   Google Scholar
• Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7–34.
   PubMed Web of Science ®Google Scholar
• Howlader N, Noone AM, Krapcho M, et al. SEER cancer statistics review, 1975–2016. National Cancer Institute, Bethesda, MD; 2019.
   Google Scholar
• Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017 Jan 26;129(4):424–447.
   PubMed Web of Science ®Google Scholar
• Fernandez HF, Sun Z, Yao X, et al. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med. 2009 Sep;24(361):1249–1259. .
   Google Scholar
• Medeiros B, Satram-Hoang S, Hurst D, et al. Big data analysis of treatment patterns and outcomes among elderly acute myeloid leukemia patients in the United States. Ann Hematol. 2015 Jul;94(7):1127–1138. .
   PubMed Web of Science ®Google Scholar
• Wang R, Zeidan AM, Halene S, et al. Health Care Use by Older Adults With Acute Myeloid Leukemia at the End of Life. J Clin Oncol. 2017;35(30):3417–3424. Oct 20. .
   PubMed Web of Science ®Google Scholar
• Zeidan AM, Podoltsev NA, Wang X, et al. Temporal patterns and predictors of receiving no active treatment among older patients with acute myeloid leukemia in the United States: A population-level analysis. Cancer. 2019 [Dec 1];125(23):4241–4251. .
   PubMed Web of Science ®Google Scholar
• Cashen AF, Schiller GJ, O'Donnell MR, et al. Multicenter, phase II study of decitabine for the first-line treatment of older patients with acute myeloid leukemia. J Clin Oncol. 2010 Feb 1;28(4):556–61
   Google Scholar
• Cortes JE, Heidel FH, Hellman A, et al. Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. Leukemia. 2019 Feb;33(2):379–389. .
   PubMed Web of Science ®Google Scholar
• Dombret H, Seymour JF, Butrym A, et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015 [Jul 16];126(3):291–299. .
   PubMed Web of Science ®Google Scholar
• Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol. 2010 Feb 1;28(4):562–569.
   PubMed Web of Science ®Google Scholar
• Kantarjian HF, Thomas XG, Dmoszynska A, et al. Multicenter, randomized, open-label, phase iii trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol. 2012 Jul 20;30(21):2670–2677.
   PubMed Web of Science ®Google Scholar
• Amadori S, Suciu S, Selleslag D, et al. Gemtuzumab ozogamicin versus best supportive care in older patients with newly diagnosed acute myeloid leukemia unsuitable for intensive chemotherapy: results of the randomized phase III EORTC-GIMEMA AML-19 trial. J Clin Oncol. 2016 Mar 20;34(9):972–979.
   PubMed Web of Science ®Google Scholar
• Burnett AK, Milligan D, Prentice AG, et al. A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer. 2007 Mar 15;109(6):1114–1124.
   PubMed Web of Science ®Google Scholar
• Dennis M, Hills RK, Russell NH, et al. An evaluation of 17 years of low dose cytarabine as therapy for AML patients not fit for intensive treatment, including patients with adverse cytogenetics, shows improving survival, potential underutilisation and highlights the need for new therapy. Blood. 2017 Dec 7;130(1):3874.
   Google Scholar
• Zeidan AM, Wang R, Wang X, et al. Clinical outcomes of older patients with AML receiving hypomethylating agents: a large population-based study in the United States. Blood Adv. 2020 May 20;4(10):2192–2201.
   PubMed Web of Science ®Google Scholar
• Lachowiez C, DiNardo CD, Konopleva M. Venetoclax in acute myeloid leukemia - current and future directions. Leuk Lymphoma. 2020 Jun;61(6):1313–1322.
   PubMed Web of Science ®Google Scholar
• Zaman S, Wang R, Gandhi V. Targeting the apoptosis pathway in hematologic malignancies. Leuk Lymphoma. 2014 Sep;55(9):1980–1992.
   PubMed Web of Science ®Google Scholar
• Pan R, Hogdal LJ, Benito JM, et al. Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid Leukemia. Cancer Discov. 2014 Mar;4(3):362–675. .
   PubMed Web of Science ®Google Scholar
• Konopleva M, Letai ABCL. 2 inhibition in AML: an unexpected bonus? Blood. 2018 Sep 6;132(10):1007–1012.
   PubMed Web of Science ®Google Scholar
• Pollyea DA, Amaya M, Strati P, et al. Venetoclax for AML: changing the treatment paradigm. Blood Adv. 2019 Dec 23;3(24):4326–4335.
   PubMed Web of Science ®Google Scholar
• Oltersdorf T, Elmore SW, Shoemaker AR, et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005 Jun 2;435(7042):677–681.
   PubMed Web of Science ®Google Scholar
• Tse C, Shoemaker AR, Adickes J, et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 2008 May 1;68(9):3421–3428.
   PubMed Web of Science ®Google Scholar
• 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 Dec;11(12):1149–1159. .
   PubMed Web of Science ®Google Scholar
• Zhu H, Almasan A. Development of venetoclax for therapy of lymphoid malignancies. Drug Des Devel Ther. 2017 Mar;9(11):685–694.
   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(2):202–208. .
   PubMed Web of Science ®Google Scholar
• Konopleva M, Contractor R, Tsao T, et al. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell. 2006 Nov;10(5):375–388. .
   PubMed Web of Science ®Google Scholar
• Chan SM, Thomas D, Corces-Zimmerman MR, et al. Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nat Med. 2015 Feb;21(2):178–184. .
   PubMed Web of Science ®Google Scholar
• Niu X, Zhao J, Ma J, et al. Binding of released Bim to Mcl-1 is a mechanism of intrinsic resistance to ABT-199 which can be overcome by combination with daunorubicin or cytarabine in AML cells. Clin Cancer Res. 2016 Sep 1;22(17):4440–4451.
   PubMed Web of Science ®Google Scholar
• Leverson JD, Sampath D, Souers AJ, et al. Found in translation: how preclinical research is guiding the clinical development of the BCL2-Selective inhibitor venetoclax. Cancer Discov. 2017 Dec;7(12):1376–1393. .
   PubMed Web of Science ®Google Scholar
• Teh TC, Nguyen NY, Moujalled DM, et al. Enhancing venetoclax activity in acute myeloid leukemia by co-targeting MCL1. Leukemia. 2018 Feb;32(2):303–312. .
   PubMed Web of Science ®Google Scholar
• Bogenberger JM, Kornblau SM, Pierceall WE, et al. BCL-2 family proteins as 5-Azacytidine-sensitizing targets and determinants of response in myeloid malignancies. Leukemia. 2014 Aug;28(8):1657–1665. .
   PubMed Web of Science ®Google Scholar
• Bogenberger JM, Delman D, Hansen N, et al. Ex vivo activity of BCL-2 family inhibitors ABT-199 and ABT-737 combined with 5-azacytidine in myeloid malignancies. Leuk Lymphoma. 2015 Jan;56(1):226–229. .
   PubMed Web of Science ®Google Scholar
• Pollyea DA, Stevens BM, Jones CL, et al. Venetoclax with azacitidine disrupts energy metabolism and targets leukemia stem cells in patients with acute myeloid leukemia. Nat Med. 2018 Dec;24(12):1859–1866. .
   PubMed Web of Science ®Google Scholar
• Jones CL, Stevens BM, D’Alessandro A, et al. Inhibition of amino acid metabolism selectively targets human leukemia stem cells. Cancer Cell. 2019 Feb 11;35(2):333–335.
   PubMed Web of Science ®Google Scholar
• Tsao T, Shi Y, Kornblau S, et al. Concomitant inhibition of DNA methyltransferase and BCL-2 protein function synergistically induce mitochondrial apoptosis in acute myelogenous leukemia cells. Ann Hematol. 2012 Dec;91(12):1861–1870. .
   PubMed Web of Science ®Google Scholar
• Lehmann C, Friess T, Birzele F, et al. Superior anti-tumor activity of the MDM2 antagonist idasanutlin and the Bcl-2 inhibitor venetoclax in P53 wild-type acute myeloid leukemia models. J Hematol Oncol. 2016 June 28;9(1):50.
   PubMedGoogle Scholar
• Pan R, Ruvolo V, Mu H, et al. Synthetic Lethality of Combined Bcl-2 Inhibition and P53 Activation in AML: mechanisms and Superior Antileukemic Efficacy. Cancer Cell. 2017 Dec 11;32(6):748–760.
   PubMed Web of Science ®Google Scholar
• Aimiuwu J, Wang H, Chen P, et al. RNA-dependent inhibition of ribonucleotide reductase is a major pathway for 5-azacytidine activity in acute myeloid leukemia. Blood. 2012 May 31;119(22):5229–5238.
   PubMed Web of Science ®Google Scholar
• Ghoshal K, Datta J, Majumder S, et al. 5-Aza-deoxycytidine induces selective degradation of DNA methyltransferase 1 by a proteasomal pathway that requires the KEN box, bromo-adjacent homology domain, and nuclear localization signal. Mol Cell Biol. 2005 Jun;25(11):4727–4741. .
   PubMed Web of Science ®Google Scholar
• Hollenbach PW, Nguyen AN, Brady H, et al. A comparison of azacitidine and decitabine activities in acute myeloid leukemia cell lines. PLoS One. 2010 Feb 2;5(2):e9001.
   PubMed Web of Science ®Google Scholar
• Jin S, Cojocari D, Purkal JJ, et al. 5-Azacitidine Induces NOXA to Prime AML Cells for Venetoclax-Mediated Apoptosis. Clin Cancer Res. 2020 Jul 1;26(13):3371–3383.
   PubMed Web of Science ®Google Scholar
• Stresemann C, Bokelmann I, Mahlknecht U, et al. Azacytidine causes complex DNA methylation responses in myeloid leukemia. Mol Cancer Ther. 2008 Sep;7(9):2998–3005. .
   PubMed Web of Science ®Google Scholar
• Hanekamp D, Cloos J, Schuurhuis GJ. Leukemic stem cells: identification and clinical application. International Journal of Hematology. 2017 May;105(5):549–557.
   PubMed Web of Science ®Google Scholar
• Lagadinou ED, Sach A, Callahan K, et al. BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell. 2013 Mar 7;12(3):329–341.
   PubMed Web of Science ®Google Scholar
• Suda T, Takubo K, Semenza GL. Metabolic regulation of hematopoietic stem cells in the hypoxic niche. Cell Stem Cell. 2011 Oct 4;9(4):298–310.
   PubMed Web of Science ®Google Scholar
• Konopleva M, Pollyea DA, Potluri J, et al. Efficacy and biological correlates of response in a phase 2 study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov. 2016 Oct;6(10):1106–1117. .
   PubMed Web of Science ®Google Scholar
• DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019 Jan 3;133(1):7–17.
   PubMed Web of Science ®Google Scholar
• Wei AH, Strickland SA, Jing-Zhou H, et al. Venetoclax combined with low-dose cytarabine for previously untreated patients with acute myeloid leukemia: results from a phase ib/ii study. J Clin Oncol. 2019 May 20;37(15):1277–1284.
   PubMed Web of Science ®Google Scholar
• DiNardo CD, Pratz KW, Letai A, et al. Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: A non-randomised, open-label, phase 1b study. Lancet Oncol. 2018 Feb;19(2):216–228. .
   PubMed Web of Science ®Google Scholar
• DiNardo CD, Maiti A, Rausch CR, et al. 10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial. Lancet Haematol. 2020 Oct;7(10):724–736. .
   PubMed Web of Science ®Google Scholar
• Chua CC, Roberts AW, Reynolds J, et al. Chemotherapy and venetoclax in elderly acute myeloid leukemia trial (caveat): a phase ib dose-escalation study of venetoclax combined with modified intensive chemotherapy. J Clin Oncol. 2020 Oct 20;38(30):3506–3517.
   PubMed Web of Science ®Google Scholar
• DiNardo CD, Jonas BA, Pullarkat MJ, et al. Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. N Engl J Med. 2020 Aug 13;383(7):617–629. .
   PubMed Web of Science ®Google Scholar
• Wei AH, Montesinos P, Ivanov V, et al. Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. Blood. 2020 Jun 11;135(24):2137–2145. .
   PubMed Web of Science ®Google Scholar
• Wei AH, Montesinos P, Ivanov V, et al. A phase III study of venetoclax plus low-dose cytarabine in previously untreated older patients with acute myeloid leukemia (VIALE-C): A six-month update. J Clin Oncol. 2020;38(15):7511. .
   Web of Science ®Google Scholar
• Winters AC, Gutman JA, Purev E, et al. Real-world experience of venetoclax with azacitidine for untreated patients with acute myeloid leukemia. Blood Adv. 2019 Oct 22;3(20):2911–2919.
   PubMed Web of Science ®Google Scholar
• Bewersdorf JP, Giri S, Wang R, et al. Venetoclax as monotherapy and in combination with hypomethylating agents or low dose cytarabine in relapsed and treatment refractory acute myeloid leukemia: a systematic review and meta-analysis. Haematologica. 2020 Jan 23;105(11):24282.
   Web of Science ®Google Scholar
• Ganzel C, Sun Z, Cripe LD, et al. Very poor long-term survival in past and more recent studies for relapsed AML patients: the ECOG-ACRIN experience. AM J Hematol. 2018 Jun 15;93(8):1074–1081. .
   PubMed Web of Science ®Google Scholar
• Ram R, Amit O, Zuckerman T, et al. Venetoclax in patients with acute myeloid leukemia refractory to hypomethylating agents-a multicenter historical prospective study. Ann Hematol. 2019 Aug;98(8):1927–1932. .
   PubMed Web of Science ®Google Scholar
• de Vos S, Swinnen LJ, Wang D, et al. Venetoclax, bendamustine, and rituximab in patients with relapsed or refractory NHL: a phase 1b dose-finding study. Ann Oncol. 2018 Sep 1;29(9):1932–1938.
   PubMed Web of Science ®Google Scholar
• Emami Riedmaier A, Lindley DJ, Hall JA, et al. Mechanistic physiologically based pharmacokinetic modeling of the dissolution and food effect of a biopharmaceutics classification system iv compound-the venetoclax story. J Pharm Sci. 2018 Jan;107(1):495–502. .
   PubMed Web of Science ®Google Scholar
• Salem AH, Agarwal SK, 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 Nov;56(11):1355–1361. .
   PubMed Web of Science ®Google Scholar
• Jones AK, Freise KJ, Agarwal SK, 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 Sep;18(5):1192–1202. .
   PubMed Web of Science ®Google Scholar
• Liu H, Michmerhuizen MJ, Lao Y, et al. Metabolism and disposition of a novel b-cell lymphoma-2 inhibitor venetoclax in humans and characterization of its unusual metabolites. Drug Metab Dispos. 2017 Mar;45(3):294–305. .
   PubMed Web of Science ®Google Scholar
• Salem AH, Dave N, Marbury T, et al. Pharmacokinetics of the BCL-2 Inhibitor Venetoclax in Subjects with Hepatic Impairment. Clin Pharmacokinet. 2019 Aug;58(8):1091–1100. .
   PubMed Web of Science ®Google Scholar
• Genentech Inc. Venclexta. [Package Insert]. South San Francisco, CA: Genentech USA: Inc; 2020.
   Google Scholar
• Davids MS, Roberts AW, Seymour JF, et al. Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma. J Clin Oncol. 2017 Mar 10;35(8):826–833.
   PubMed Web of Science ®Google Scholar
• Freise KJ, Shebley M, Salem AH. Quantitative prediction of the effect of cyp3a inhibitors and inducers on venetoclax pharmacokinetics using a physiologically based pharmacokinetic model. J Clin Pharmacol. 2017 Jan 4;57(6):796–804.
   PubMed Web of Science ®Google Scholar
• Weiss J, Gajek T, Köhler BC, et al. Venetoclax (ABT-199) Might Act as a Perpetrator in Pharmacokinetic Drug-Drug Interactions. Pharmaceutics. 2016;8(1):5. .
   Web of Science ®Google Scholar
• Agarwal SK, Salem AH, Danilov AV, et al. 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. 2017 Apr;83(4):846–854. .
   PubMed Web of Science ®Google Scholar
• Agarwal SK, DiNardo CD, Potluri J, et al. Management of venetoclax-posaconazole interaction in acute myeloid leukemia patients: evaluation of dose adjustments. Clin Ther. 2017 Feb;39(2):359–367. .
   PubMed Web of Science ®Google Scholar
• Agarwal SK, 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 Nov;56(11):1335–1343. .
   PubMed Web of Science ®Google Scholar
• Chiney MS, Menon RM, Bueno OF, et al. Clinical evaluation of P-glycoprotein inhibition by venetoclax: a drug interaction study with digoxin. Xenobiotica. 2018;48(9):904–910. .
   PubMed Web of Science ®Google Scholar
• Salem AH, Hu B, Freise KJ, et al. Evaluation of the pharmacokinetic interaction between venetoclax, a selective bcl-2 inhibitor, and warfarin in healthy volunteers. Clin Drug Investig. 2017;37(3):303–309. .
   PubMed Web of Science ®Google Scholar
• Pei S, Pollyea DA, Gustafson A, et al. Monocytic Subclones Confer Resistance to Venetoclax-Based Therapy in Patients with Acute Myeloid Leukemia. Cancer Discov. 2020 Apr;10(4):536–551. .
   PubMed Web of Science ®Google Scholar
• Richard-Carpentier G, DiNardo CD. Venetoclax for the treatment of newly diagnosed acute myeloid leukemia in patients who are ineligible for intensive chemotherapy. Ther Adv Hematol. 2019 Oct;23(10):1–14.
   Google Scholar
• Tahir SK, Smith ML, Hessler P, et al. Potential mechanisms of resistance to venetoclax and strategies to circumvent it. BMC Cancer. 2017 Jun 2;17(1):399.
   PubMed Web of Science ®Google Scholar
• Wei AH, Roberts AW, Spencer A, et al. Targeting MCL-1 in hematologic malignancies: rationale and progress. Blood Rev. 2020 Nov;44:100672.
   PubMed Web of Science ®Google Scholar
• Chyla B, Daver N, Doyle K, et al. Genetic biomarkers of sensitivity and resistance to venetoclax monotherapy in patients with relapsed acute myeloid leukemia. Am J Hematol. 2018 May 17;93(8):E202–E205.
   PubMed Web of Science ®Google Scholar
• Luedtke DA, Niu X, Pan Y, et al. Inhibition of Mcl-1 enhances cell death induced by the Bcl-2-selective inhibitor ABT-199 in acute myeloid leukemia cells. Signal Transduct Target Ther. 2017 Apr 7;2(1):17012.
   PubMedGoogle Scholar
• Thomas RL, Gustafsson AB. MCL1 is critical for mitochondrial function and autophagy in the heart. Autophagy. 2013 Nov 1;9(11):1902–1903.
   PubMed Web of Science ®Google Scholar
• Vick B, Weber A, Urbanik T, et al. Knockout of myeloid cell leukemia-1 induces liver damage and increases apoptosis susceptibility of murine hepatocytes. Hepatology. 2009 Feb;49(2):627–636. .
   PubMed Web of Science ®Google Scholar
• Luedtke DA, Su Y, Ma J, et al. Inhibition of CDK9 by voruciclib synergistically enhances cell death induced by the Bcl-2 selective inhibitor venetoclax in preclinical models of acute myeloid leukemia. Signal Transduct Target Ther. 2020 Feb 26;5(1):17.
   PubMed Web of Science ®Google Scholar
• Bogenberger J, Whatcott C, Hansen N, et al. Combined venetoclax and alvocidib in acute myeloid leukemia. Oncotarget. 2017 Dec 5;8(63):107206–107222.
   PubMedGoogle Scholar
• Han L, Zhang Q, Dail M, et al. Concomitant targeting of BCL2 with venetoclax and MAPK signaling with cobimetinib in acute myeloid leukemia models. Haematologica. 2020 Mar;105(3):697–707. .
   PubMed Web of Science ®Google Scholar
• Nechiporuk T, Kurtz SE, Nikolova O, et al. The TP53 Apoptotic Network Is a Primary Mediator of Resistance to BCL2 Inhibition in AML Cells. Cancer Discov. 2019 Jul;9(7):910–925. .
   PubMed Web of Science ®Google Scholar
• Bose P, Gandhi V, Konopleva M. Pathways and mechanisms of venetoclax resistance. Leuk Lymphoma. 2017 Sep;58(9):1–17.
   PubMed Web of Science ®Google Scholar
• Daver N, Pollyea DA, Yee KWL, et al. Preliminary results from a phase Ib study evaluating BCL-2 inhibitor venetoclax in combination with MEK inhibitor cobimetinib or MDM2 inhibitor idasanutlin in patients with relapsed or refractory (R/R) AML. Blood. 2017 Dec 7;130(1):813.
   Google Scholar
• Jones CL, Stevens BM, D’Alessandro A, et al. Inhibition of Amino Acid Metabolism Selectively Targets Human Leukemia Stem Cells. Cancer Cell. 2018 Nov 12;34(5):724–740.
   PubMed Web of Science ®Google Scholar
• Jones CL, Stevens BM, Pollyea DA, et al. Nicotinamide metabolism mediates resistance to venetoclax in relapsed acute myeloid leukemia stem cells. Cell Stem Cell. 2020 Nov 5;27(5):748–764.
   PubMed Web of Science ®Google Scholar
• Sharon D, Cathelin S, Mirali S, et al. Inhibition of mitochondrial translation overcomes venetoclax resistance in AML through activation of the integrated stress response. Sci Transl Med. 2019 Oct 30;11(516):eaax2863.
   PubMed Web of Science ®Google Scholar
• Lachowiez CA, Borthakur G, Loghavi S, et al. Phase Ib/II study of the IDH1-mutant inhibitor ivosidenib with the BCL2 inhibitor venetoclax ± azacitidine in IDH1-mutated hematologic malignancies. J Clin Oncol. 2020;38(15):7500. .
   Web of Science ®Google Scholar
• Kadia TM, Jain P, Ravandi F, et al. TP53 mutations in newly diagnosed acute myeloid leukemia: clinicomolecular characteristics, response to therapy, and outcomes. Cancer. 2016 Nov 15;122(22):3484–3491.
   PubMed Web of Science ®Google Scholar
• Welch JS, Petti AA, Miller CA et al. TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes. N Engl J Med. 2016 Nov 24;375(21):2023–2036
   PubMed Web of Science ®Google Scholar
• DiNardo CD, Tiong IS, Quaglieri A, et al. Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML. Blood. 2020 Mar 12;135(11):791–803.
   PubMed Web of Science ®Google Scholar
• Lal R, Lind K, Heitzer E, et al. Somatic TP53 mutations characterize preleukemic stem cells in acute myeloid leukemia. Blood. 2017 May 4;129(18):2587–2591.
   PubMed Web of Science ®Google Scholar
• Wong TN, Ramsingh G, Young AL, et al. Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia. Nature. 2015 Feb 26;518(7540):552–555.
   PubMed Web of Science ®Google Scholar
• Ball BJ, Famulare CA, Stein EM, et al. Venetoclax and hypomethylating agents (HMAs) induce high response rates in MDS, including patients after HMA therapy failure. Blood Adv. 2020 Jul 14;4(13):2866–2870.
   PubMed Web of Science ®Google Scholar
• Oran B, de Lima M, Garcia-Manero G, et al. A phase 3 randomized study of 5-azacitidine maintenance vs observation after transplant in high-risk AML and MDS patients. Blood Adv. 2020 Nov 10;4(21):5580–5588.
   PubMed Web of Science ®Google Scholar