Acute myeloid leukemia

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

Targets

FZD8
References:  7
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 Name Disease Association Comments Approved Primary Target Immuno
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:  4
Ligand interactions
Ligand Name Disease Association Comments Approved Primary Target Immuno
midostaurin
Approved drug for FLT3 mutation +ve AML.
 [  (Drugs.com) ]
crenolanib
Phase 3 clinical candidate for FLT3 mutation positive relapsed/refractory AML.

Ligands

Ligand Approved Immuno References Clinical comments
midostaurin  [  (Drugs.com) ]
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 [2]. 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.
Immuno Disease Comments: Approved drug for FLT3 mutation +ve AML.
gemtuzumab ozogamicin  [  (Drugs.com) ]
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.
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.
crenolanib
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.
Immuno Disease Comments: Phase 3 clinical candidate for FLT3 mutation positive relapsed/refractory AML.
vadastuximab talirine
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.
Immuno Disease Comments: FDA and EMA orphan drug for AML.

References

Show »

1. 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]

2. 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]

3. 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]

4. 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]

5. 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]

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

7. 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]