Shutting Down Acute Myeloid Leukemia and Myelodysplastic Syndrome with BCL-2 Family Protein Inhibition
- 478 Downloads
Purpose of Review
Apoptosis results from the interaction between pro- and anti-apoptotic proteins, mediated by BCL-2 homology 3 (BH3) proteins. B cell lymphoma-2 (BCL-2) is an inhibitor of apoptosis which stabilizes the mitochondria, resulting in the prevention of activation of the pro-apoptotic proteins. In addition, BCL-2 is overexpressed in the leukemic stem cell (LSC) population, and its inhibition may lead to selective LSC eradication. Herein, we will discuss the mechanism and rationale of BCL-2 inhibition in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) with an overview of the selective BCL-2 inhibitor venetoclax.
Venetoclax has activity against AML and has displayed synergistic activity with hypomethylating agents in the preclinical setting. In the clinical setting, although it has only modest activity as a single agent in relapsed and refractory AML, in the older, treatment-naïve population, in combination with either a hypomethylator or low-dose cytarabine, it is well tolerated with impressive efficacy. In addition, BCL-2 inhibition may also have activity in MDS, and although clinical trials are in their early phases, this may be an effective strategy in both the up-front and relapsed setting.
BCL-2 inhibition with venetoclax is well tolerated and active in older patients with newly diagnosed AML and in the relapsed setting has activity that may be improved in combination with other therapies. It may prove to be effective in MDS and is an exciting treatment strategy for myeloid malignancies.
KeywordsBCL-2 Acute myeloid leukemia Myelodysplastic syndrome AML MDS Apoptosis Venetoclax
Compliance with Ethical Standards
Conflict of Interest
Daniel A Pollyea served as an advisory board member for Celyad, Agios, Celgene, Abbvie, Argenx, Pfizer, Curis, Takeda, and Servier, and received research funding from Agios and Pfizer. Prashant Sharma declares no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance•• Of major Importance
- 5.Schanz J, Tuchler H, Sole F, Mallo M, Luno E, Cervera J, et al. New comprehensive cytogenetic scoring system for primary myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia after MDS derived from an international database merge. J Clin Oncol. 2012;30(8):820–9.Google Scholar
- 6.SEER. Acute Myeloid Leukemia - Cancer Stat Facts 2017 [Available from: https://seer.cancer.gov/statfacts/html/amyl.html.
- 16.•• Lagadinou ED, Sach A, Callahan K, Rossi RM, Neering SJ, Minhajuddin M, et al. BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell. 2013;12(3):329–41. This study demonstrated that LSCs were characterized by low levels of reactive oxygen species (ROS-low), that ROS-low LSCs aberrantly overexpressed BCL-2, and that BCL-2 inhibition reduced oxidative phosphorylation and selectively eradicated LSCs.CrossRefPubMedCentralPubMedGoogle Scholar
- 34.Konopleva M, Tari AM, Estrov Z, Harris D, Xie Z, Zhao S, et al. Liposomal Bcl-2 antisense oligonucleotides enhance proliferation, sensitize acute myeloid leukemia to cytosine-arabinoside, and induce apoptosis independent of other antiapoptotic proteins. Blood. 2000;95(12):3929–38.PubMedGoogle Scholar
- 36.Marcucci G, Stock W, Dai G, Klisovic RB, Liu S, Klisovic MI, et al. Phase I study of oblimersen sodium, an antisense to Bcl-2, in untreated older patients with acute myeloid leukemia: pharmacokinetics, pharmacodynamics, and clinical activity. J Clin Oncol Off J Am Soc Clin Oncol. 2005;23(15):3404–11.CrossRefGoogle Scholar
- 38.Marcucci G, Moser W, Blum W, Stock M, Wetzler J, Kolitz JE, et al. A phase III randomized trial of intensive induction and consolidation chemotherapy ± oblimersen, a pro-apoptotic Bcl-2 antisense oligonucleotide in untreated acute myeloid leukemia patients > 60 years old. J Clin Oncol Off J Am Soc Clin Oncol. 2007;25:7012.CrossRefGoogle Scholar
- 40.Schimmer AD, Raza A, Carter TH, Claxton D, Erba H, DeAngelo DJ, et al. A multicenter phase I/II study of obatoclax mesylate administered as a 3- or 24-hour infusion in older patients with previously untreated acute myeloid leukemia. PLoS One. 2014;9(10):e108694.CrossRefPubMedCentralPubMedGoogle Scholar
- 44.Wilson WH, O'Connor OA, Czuczman MS, LaCasce AS, Gerecitano JF, Leonard JP, 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(12):1149–59.CrossRefPubMedCentralPubMedGoogle Scholar
- 49.• Ho TC, LaMere M, Stevens BM, Ashton JM, Myers JR, O'Dwyer KM, et al. Evolution of acute myelogenous leukemia stem cell properties after treatment and progression. Blood 2016;128(13):1671–8. This study showed the evolution of the LSCs showing increases in LSC frequency and heterogeneity at relapse. This study showed that LSC-directed therapies, like with venetoclax, would be more effective in up-front setting rather than after disease relapse.Google Scholar
- 53.• DiNardo CD, Pratz KW, Letai A, Jonas BA, Wei AH, Thirman M, 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;19(2):216–28. This ongoing study showed that venetoclax plus hypomethylating agent therapy is well-tolerated regimen with promising activity in elderly patient population in upfront setting.CrossRefPubMedGoogle Scholar
- 54.DiNardo CD, Pollyea DA, Jonas BA, Konopleva M, Pullarkat V, Wei A, et al. Updated Safety and Efficacy of Venetoclax with Decitabine or Azacitidine in Treatment-Naive, Elderly Patients with Acute Myeloid Leukemia. Blood. 2017;130(Suppl 1):2628.Google Scholar
- 56.Wei A, Strickland SA, Roboz GJ, Hou J-Z, Fiedler W, Lin TL, et al. Phase 1/2 Study of Venetoclax with Low-Dose Cytarabine in Treatment-Naive, Elderly Patients with Acute Myeloid Leukemia Unfit for Intensive Chemotherapy: 1-Year Outcomes. Blood. 2017;130(Suppl 1):890.Google Scholar
- 61.Daver N, Pollyea DA, Yee KWL, Fenaux P, Brandwein JM, Vey N, 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;130(Suppl 1):813.Google Scholar
- 67.Mali RS, Lasater EA, Doyle K, Malla R, Boghaert E, Souers A, et al. FLT3-ITD activation mediates resistance to the BCL-2 selective antagonist, venetoclax, in FLT3-ITD mutant AML models. 2017.Google Scholar
- 70.Tauchi T, Okabe S, Katagiri S, Tanaka Y, Ohyashiki K. Combining Effects of the SMO Inhibitor and BCL-2 Inhibitor in MDS-Derived Induced Potent Stem Cells (iPSC). Blood. 2017;130(Suppl 1):1249.Google Scholar
- 71.• Kurtz SE, Eide CA, Kaempf A, Khanna V, Savage SL, Rofelty A, et al. Molecularly targeted drug combinations demonstrate selective effectiveness for myeloid- and lymphoid-derived hematologic malignancies. Proc Natl Acad Sci U S A. 2017;114(36):E7554–e63. In this study, several combinations of kinase inhibitors with venetoclax were effective in inhibiting myeloid-derived cells showing that novel combination therapies with venetoclax could be avenues for future AML clinical trials.CrossRefPubMedCentralPubMedGoogle Scholar
- 72.Ebrahim AS, Kandouz M, Liddane A, Sabbagh H, Hou Y, Li C, et al. PNT2258, a novel deoxyribonucleic acid inhibitor, induces cell cycle arrest and apoptosis via a distinct mechanism of action: a new class of drug for non-Hodgkin’s lymphoma. Oncotarget. 2016;7(27):42374–84.CrossRefPubMedCentralPubMedGoogle Scholar