Acute myeloid leukemia

Disease ID:34
Name:Acute myeloid leukemia
Associated with:6 targets
3 immuno-relevant targets
5 immuno-relevant ligands
Synonyms
Acute myelogenous leukemia
Database Links
Disease Ontology: DOID:9119
OMIM: 601626
Orphanet: ORPHA519

Targets

FZD8
References:  15
KIT proto-oncogene receptor tyrosine kinase
Comments:  KIT mutations have been identified in founding clones from AML patients, which suggests that KIT mutations initiate development of AML.
Ligand interactions: 
Ligand Comments
crenolanib
Phase 3 clinical candidate for FLT3 mutation positive relapsed/refractory AML.
fms related tyrosine kinase 3
Role:  Internal tandem duplications and/or insertions in the FLT3 gene are implicated in 20-25% of all acute myeloid leukemias and rare cases of acute lymphoblastic leukemia (ALL). Such FLT3 length mutations (FLT3-LM, a.k.a. FLT3-ITD, FLT3 internal tandem duplication) correlate with poor prognosis and a high relapse rate.
Comments:  Somatic mutations in FLT3 have been found in cases of AML Idenification of FLT3 mutations in subclones of AML patient-derived cells, suggests that these may be cooperative mutations that drive established AML clones, rather than being disease initiating mutations.
References:  6
Ligand interactions: 
Ligand Comments
midostaurin
Approved drug for FLT3 mutation +ve AML.
crenolanib
Phase 3 clinical candidate for FLT3 mutation positive relapsed/refractory AML.
Janus kinase 2
KRAS
isocitrate dehydrogenase (NADP(+)) 1, cytosolic
Comments:  Mutant IDH1 isoforms are found in 6 to 10% of cases of AML and in a variety of solid tumours, and make these tumours susceptible to IDH1 inhibitor therapy.
Ligand interactions: 
Ligand Comments
ivosidenib
ivosidenib is an oral drug that is approved for the treatment of AML with isocitrate dehydrogenase 1 (IDH1) mutations.

Ligands

Key to terms and symbols Click ligand name to view ligand summary Click column headers to sort
Ligand References Clinical and Disease comments
midostaurin
Immuno Disease Comments: Approved drug for FLT3 mutation +ve AML.
Clinical Use: The FDA granted midostaurin accelerated approval in April 2017, and the EMA followed in September of the same year. These authorisations are for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) who are FLT3 mutation-positive (as detected by an FDA-approved test) to be used in combination with standard and induction and cytarabine consolidation. It was also approved for mastocytosis [4]. The EMA had previously granted midostaurin orphan drug designation for the treatment of AML and mastocytosis (effective via inhibition of KIT receptors on mast cells, which are involved in stimulating proliferation of mast cells in mastocytosis).
Click here to link to ClinicalTrials.gov's list of Phase II midostaurin trials. | View clinical data
Bioactivity Comments: Midostaurin inhibits proliferation of cells carrying FLT3 translocations or single amino acid changes, and inhibits autophosphorylation of mutant FLT3 receptors [16]. | View biological activity
gemtuzumab ozogamicin
Immuno Disease Comments: Approved in particular for CD33-positive AML. However, note that use in this indication has been withdrawn in some jurisdictions due to safety concerns and lack of significant efficacy.
Clinical Use: Used to treat CD33-positive acute myeloid leukemia (AML) in patients over 60 who are not candidates for other chemotherapy. Note that as requested by the US FDA, the drug was withdrawn from the US market in 2010, due to questions over its effectiveness and safety. Other international regulatory authorities still approve use of this drug.

In September 2017, after careful reveiw, the FDA approved gemtuzumab ozogamicin for two new uses:
1. Initial use in adults whose AML tumors express the CD33 antigen.
2. For patients aged ≥2 years with relapsed or refractory CD33-positive AML. | View clinical data
Bioactivity Comments: We have been unable to find publicly available affinity data for the interaction between gemtuzumab and CD33 to substantiate its primary molecular target. | View biological activity
crenolanib
Immuno Disease Comments: Phase 3 clinical candidate for FLT3 mutation positive relapsed/refractory AML.
Clinical Use: A Phase II clinical study for relapsed/refractory acute myeloid leukemia with FLT3 activating mutations (NCT01657682) has been completed. Phase 3 studies in FLT3 mutation positive AML (NCT02298166) and PDGFRA mutation positive gastrointestinal stromal tumours (NCT02847429) are underway (May 2017). Click here to link to ClinicalTrials.gov's complete listing of crenolanib trials. | View clinical data
vadastuximab talirine
Immuno Disease Comments: FDA and EMA orphan drug for AML.
Clinical Use: Both the US FDA and EMA have designated vadastuximab talirine as an orphan drug for acute myeloid leukemia (AML). In late 2016, the FDA put holds on phase 1 and 1/2 trials of vadastuximab talirine in AML following the deaths of several trial participants, whilst any link between hepatotoxicity and vadastuximab talirine is assessed. Click here to link to ClinicalTrials.gov's full list of vadastuximab talirine trials. | View clinical data
Bioactivity Comments: Preclinically SGN-CD33A proved more potent than the approved anti-CD33 mAb gemtuzumab ozogamicin, against a panel of AML cell lines and primary AML cells in vitro and in vivo, including efficacy against multidrug-resistant cells [7]. | View biological activity
ivosidenib 3
Immuno Disease Comments: ivosidenib is an oral drug that is approved for the treatment of AML with isocitrate dehydrogenase 1 (IDH1) mutations.
Clinical Use: Ivosidenib (AG-120) was initially granted orphan drug designation by the US FDA for the treatment of acute myeloid leukemia (AML) in patients carrying IDH1 gene mutations. Full approval was granted in July 2018 for the treatment of relapsed/refractory IDH1-mutated AML, with approval based on results from clinical trial NCT02074839 [3]. Differentaition syndrome [1], QT prolongation and Guillain-Barré syndrome are serious adverse reactions that are highlighted in the Medication Guide provided to patients who are given this drug.

Clinical trials in various other IDH1-mutant positive hematologic malignancies and solid tumours (e.g. cholangiocarcinoma, chondrosarcoma and glioma) are ongoing. Click here to link to ClinicalTrials.gov's full list of AG-120 trials. In Europe the EMA has granted ivosidenib orphan designation for the treatment of AML (2016) and biliary tract cancer (2018) with IDH1 mutations. | View clinical data
Bioactivity Comments: Ivosidenib inhibits both R132H and R132C IDH1 mutants with IC50s < 100nM [8]. | View biological activity

References

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1. Birendra KC, DiNardo CD. (2016) Evidence for Clinical Differentiation and Differentiation Syndrome in Patients With Acute Myeloid Leukemia and IDH1 Mutations Treated With the Targeted Mutant IDH1 Inhibitor, AG-120. Clin Lymphoma Myeloma Leuk, 16 (8): 460-5. [PMID:27245312]

2. Brewin J, Horne G, Chevassut T. (2013) Genomic landscapes and clonality of de novo AML. N. Engl. J. Med., 369 (15): 1472-3. [PMID:24106951]

3. DiNardo CD, Stein EM, de Botton S, Roboz GJ, Altman JK, Mims AS, Swords R, Collins RH, Mannis GN, Pollyea DA et al.. (2018) Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML. N. Engl. J. Med., 378 (25): 2386-2398. [PMID:29860938]

4. Gallogly MM, Lazarus HM, Cooper BW. (2017) Midostaurin: a novel therapeutic agent for patients with FLT3-mutated acute myeloid leukemia and systemic mastocytosis. Ther Adv Hematol, 8 (9): 245-261. [PMID:29051803]

5. Gou H, Zhou J, Ye Y, Hu X, Shang M, Zhang J, Zhao Z, Peng W, Zhou Y, Zhou Y et al.. (2016) The prevalence and clinical profiles of FLT3-ITD, FLT3-TKD, NPM1, C-KIT, DNMT3A, and CEBPA mutations in a cohort of patients with de novo acute myeloid leukemia from southwest China. Tumour Biol., 37 (6): 7357-70. [PMID:26676635]

6. Kiyoi H, Naoe T, Nakano Y, Yokota S, Minami S, Miyawaki S, Asou N, Kuriyama K, Jinnai I, Shimazaki C et al.. (1999) Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Blood, 93 (9): 3074-80. [PMID:10216104]

7. Kung Sutherland MS, Walter RB, Jeffrey SC, Burke PJ, Yu C, Kostner H, Stone I, Ryan MC, Sussman D, Lyon RP et al.. (2013) SGN-CD33A: a novel CD33-targeting antibody-drug conjugate using a pyrrolobenzodiazepine dimer is active in models of drug-resistant AML. Blood, 122 (8): 1455-63. [PMID:23770776]

8. Lemieux RM, Popovici-Muller J, Travins J, Cai Z, Cui D, Zhou D. (2013) Therapeutically active compounds and their methods of use. Patent number: WO2013107291. Assignee: Agios Pharmaceuticals, Inc.. Priority date: 19/01/2012. Publication date: 25/07/2013.

9. Linos K, Tafe LJ. (2018) Isocitrate Dehydrogenase 1 (IDH1) Mutations in Melanoma Frequently Co-Occur with NRAS Mutations. Histopathology, [Epub ahead of print]. [PMID:30003571]

10. Ma T, Zou F, Pusch S, Xu Y, von Deimling A, Zha X. (2018) Inhibitors of Mutant Isocitrate Dehydrogenases 1 and 2 (mIDH1/2): An Update and Perspective. J. Med. Chem., [Epub ahead of print]. [PMID:29847930]

11. Mead AJ, Linch DC, Hills RK, Wheatley K, Burnett AK, Gale RE. (2007) FLT3 tyrosine kinase domain mutations are biologically distinct from and have a significantly more favorable prognosis than FLT3 internal tandem duplications in patients with acute myeloid leukemia. Blood, 110 (4): 1262-70. [PMID:17456725]

12. Miller CA, Wilson RK, Ley TJ. (2013) Genomic landscapes and clonality of de novo AML. N. Engl. J. Med., 369 (15): 1473. [PMID:24106950]

13. Morizane C, Ueno M, Ikeda M, Okusaka T, Ishii H, Furuse J. (2018) New developments in systemic therapy for advanced biliary tract cancer. Jpn. J. Clin. Oncol., 48 (8): 703-711. [PMID:29893894]

14. Sidaway P. (2018) Ivosidenib effective in IDH1-mutant AML. Nat Rev Clin Oncol, 15 (8): 472. [PMID:29925981]

15. Sonnet M, Claus R, Becker N, Zucknick M, Petersen J, Lipka DB, Oakes CC, Andrulis M, Lier A, Milsom MD et al.. (2014) Early aberrant DNA methylation events in a mouse model of acute myeloid leukemia. Genome Med, 6 (4): 34. [PMID:24944583]

16. Weisberg E, Boulton C, Kelly LM, Manley P, Fabbro D, Meyer T, Gilliland DG, Griffin JD. (2002) Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. Cancer Cell, 1 (5): 433-43. [PMID:12124173]

17. Zhao Q, Manning JR, Sutton J, Costales A, Sendzik M, Shafer CM, Levell JR, Liu G, Caferro T, Cho YS et al.. (2018) Optimization of 3-Pyrimidin-4-yl-oxazolidin-2-ones as Orally Bioavailable and Brain Penetrant Mutant IDH1 Inhibitors. ACS Med Chem Lett, 9 (7): 746-751. [PMID:30034612]