New Drugs for Acute Myeloid Leukemia Inspired by Genomics and when to Use Them

Overview

Journal Hematology Am Soc Hematol Educ Program

Specialty Hematology

Date 2018 Dec 4

PMID 30504290

Citations 15

Authors

Daniel A Pollyea

Affiliations

Soon will be listed here.

Abstract

We are several years into the "postdiscovery" era in acute myeloid leukemia (AML) thanks to extensive work involving the sequencing of genomes and exomes of countless patients, which has led to routine comprehensive targeted sequencing in clinical care. The ability to unlock the molecular underpinnings of each patient's disease was supposed to usher in a new treatment era in which each patient was assigned, based on her mutational profile, a personalized cocktail of targeted therapies that would snuff the disease into submission with minimal toxicity. Whether we have fully realized the promise of personalized therapy in AML is unclear. Here, I review those new drugs that have been inspired by genomics, discuss others that might be possible and their potential roles, and consider whether the ability to target genomic mutations in a personalized manner constitutes the future of AML therapeutics or is representative of an era that has already passed.

Citing Articles

MMP9-Associated Tumor Stem Cells, CCL1-Silenced Dendritic Cells, and Cytokine-Induced Killer Cells Have a Remarkable Therapeutic Efficacy for Acute Myeloid Leukemia by Activating T Cells.

Dong M, Zhang G, Meng J, Liu B, Jiang D, Liu F Stem Cells Int. 2023; 2023:2490943.

PMID: 37200633 PMC: 10188259. DOI: 10.1155/2023/2490943.

Targeting human mitochondrial NAD(P)-dependent malic enzyme (ME2) impairs energy metabolism and redox state and exhibits antileukemic activity in acute myeloid leukemia.

Chen K, Hsiao I, Huang Y, Chou Y, Lin Y, Hsieh J Cell Oncol (Dordr). 2023; 46(5):1301-1316.

PMID: 37079187 PMC: 10618384. DOI: 10.1007/s13402-023-00812-x.

Single-cell genomics in AML: extending the frontiers of AML research.

Ediriwickrema A, Gentles A, Majeti R Blood. 2022; 141(4):345-355.

PMID: 35926108 PMC: 10082362. DOI: 10.1182/blood.2021014670.

Reverse phase protein arrays in acute leukemia: investigative and methodological challenges.

Hoff F, Horton T, Kornblau S Expert Rev Proteomics. 2021; 18(12):1087-1097.

PMID: 34965151 PMC: 9148717. DOI: 10.1080/14789450.2021.2020655.

Deciphering the Role of Pyrvinium Pamoate in the Generation of Integrated Stress Response and Modulation of Mitochondrial Function in Myeloid Leukemia Cells through Transcriptome Analysis.

Fu Y, Tseng C, Lu J, Lu W, Lan P, Chen C Biomedicines. 2021; 9(12).

PMID: 34944685 PMC: 8698814. DOI: 10.3390/biomedicines9121869.

References

Pollyea D, Stevens B, Jones C, Winters A, Pei S, Minhajuddin M . Venetoclax with azacitidine disrupts energy metabolism and targets leukemia stem cells in patients with acute myeloid leukemia. Nat Med. 2018; 24(12):1859-1866. PMC: 7001730. DOI: 10.1038/s41591-018-0233-1. View

Antar A, Otrock Z, El-Cheikh J, Kharfan-Dabaja M, Battipaglia G, Mahfouz R . Inhibition of FLT3 in AML: a focus on sorafenib. Bone Marrow Transplant. 2016; 52(3):344-351. DOI: 10.1038/bmt.2016.251. View

Dohner K, Dohner H . Molecular characterization of acute myeloid leukemia. Haematologica. 2008; 93(7):976-82. DOI: 10.3324/haematol.13345. View

Stein E, DiNardo C, Pollyea D, Fathi A, Roboz G, Altman J . Enasidenib in mutant relapsed or refractory acute myeloid leukemia. Blood. 2017; 130(6):722-731. PMC: 5572791. DOI: 10.1182/blood-2017-04-779405. View

DiNardo C, Stein E, de Botton S, Roboz G, Altman J, Mims A . Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML. N Engl J Med. 2018; 378(25):2386-2398. DOI: 10.1056/NEJMoa1716984. View

Ward P, Patel J, Wise D, Abdel-Wahab O, Bennett B, Coller H . The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell. 2010; 17(3):225-34. PMC: 2849316. DOI: 10.1016/j.ccr.2010.01.020. View

Kurtz S, Eide C, Kaempf A, Khanna V, Savage S, Rofelty A . 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-E7563. PMC: 5594650. DOI: 10.1073/pnas.1703094114. View

Marcucci G, Haferlach T, Dohner H . Molecular genetics of adult acute myeloid leukemia: prognostic and therapeutic implications. J Clin Oncol. 2011; 29(5):475-86. DOI: 10.1200/JCO.2010.30.2554. View

Borthakur G, Popplewell L, Boyiadzis M, Foran J, Platzbecker U, Vey N . Activity of the oral mitogen-activated protein kinase kinase inhibitor trametinib in RAS-mutant relapsed or refractory myeloid malignancies. Cancer. 2016; 122(12):1871-9. PMC: 5779863. DOI: 10.1002/cncr.29986. View

10.

Pemmaraju N, Kantarjian H, Andreeff M, Cortes J, Ravandi F . Investigational FMS-like tyrosine kinase 3 inhibitors in treatment of acute myeloid leukemia. Expert Opin Investig Drugs. 2014; 23(7):943-54. PMC: 4109297. DOI: 10.1517/13543784.2014.911839. View

11.

Cortes J, Perl A, Dohner H, Kantarjian H, Martinelli G, Kovacsovics T . Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol. 2018; 19(7):889-903. PMC: 8152787. DOI: 10.1016/S1470-2045(18)30240-7. View

12.

Konopleva M, Pollyea D, Potluri J, Chyla B, Hogdal L, Busman T . Efficacy and Biological Correlates of Response in a Phase II Study of Venetoclax Monotherapy in Patients with Acute Myelogenous Leukemia. Cancer Discov. 2016; 6(10):1106-1117. PMC: 5436271. DOI: 10.1158/2159-8290.CD-16-0313. View

13.

Ravandi F, Alattar M, Grunwald M, Rudek M, Rajkhowa T, Richie M . Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Blood. 2013; 121(23):4655-62. PMC: 3674666. DOI: 10.1182/blood-2013-01-480228. View

14.

Seiler M, Yoshimi A, Darman R, Chan B, Keaney G, Thomas M . H3B-8800, an orally available small-molecule splicing modulator, induces lethality in spliceosome-mutant cancers. Nat Med. 2018; 24(4):497-504. PMC: 6730556. DOI: 10.1038/nm.4493. View

15.

DiNardo C, Pratz K, Letai A, Jonas B, Wei A, Thirman M . 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):216-228. DOI: 10.1016/S1470-2045(18)30010-X. View

16.

Vardiman J, Thiele J, Arber D, Brunning R, Borowitz M, Porwit A . The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009; 114(5):937-51. DOI: 10.1182/blood-2009-03-209262. View

17.

Yen K, Travins J, Wang F, David M, Artin E, Straley K . AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic Mutations. Cancer Discov. 2017; 7(5):478-493. DOI: 10.1158/2159-8290.CD-16-1034. View

18.

Arber D, Orazi A, Hasserjian R, Thiele J, Borowitz M, Le Beau M . The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016; 127(20):2391-405. DOI: 10.1182/blood-2016-03-643544. View

19.

Gokbuget N, Dombret H, Bonifacio M, Reichle A, Graux C, Faul C . Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood. 2018; 131(14):1522-1531. PMC: 6027091. DOI: 10.1182/blood-2017-08-798322. View

20.

Shah N, Talpaz M, Deininger M, Mauro M, Flinn I, Bixby D . Ponatinib in patients with refractory acute myeloid leukaemia: findings from a phase 1 study. Br J Haematol. 2013; 162(4):548-52. PMC: 3866040. DOI: 10.1111/bjh.12382. View