Mastocytosis

Disease ID:1194
Name:Mastocytosis
Associated with:1 targets
1 immuno-relevant targets
4 immuno-relevant ligands
Description
A disease caused by mast cell hyperplasia.
Database Links
Disease Ontology: DOID:350

Targets

KIT proto-oncogene receptor tyrosine kinase
Comments:  Constitutively active KIT D816V is associated with mast cell clonal disorders. KIT D816V detection in blood and bone marrow is important for diagnosing systemic mastocytosis.
Mutations:  KIT proto-oncogene receptor tyrosine kinase is associated with 1 mutation. Click here for details
Ligand interactions
Ligand Name Disease Association Comments Approved Primary Target Immuno
masitinib
EMA orphan drug for mastocytosis.

Ligands

Ligand Approved Immuno References Clinical comments
brentuximab vedotin  [  (Drugs.com) ]
Clinical Use: Brentuximab vedotin is an anti-neoplastic agent used in the treatment of Hodgkin's lymphoma [6] and systemic anaplastic large cell lymphoma. Several clinical trials are evaluating the combination of brentuximab vedotin with immune checkpoint inhibitors, to assess any synergistic effects as a result of dual targeting. Checkpoint inhibitors being investigated in this way include and (both anti-PD-1), and (anti-CTLA4). Brentuximab vedotin + pembrolizumab (NCT02684292) and brentuximab vedotin + nivolumab (NCT03138499) are both Phase 3 studies in patients with relapsed/refractory classical Hodgkin's lymphoma.

Expanded approvals:
In November 2017, the FDA approved brentuximab vedotin for the treatment of adult patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy, following review of results from the Phase 3 ALCANZA trial (NCT01578499) [3]. In March 2018, the FDA approved the use of brentuximab vedotin for the treatment of patients with previously untreated stage III or IV classical Hodgkin lymphoma (cHL) in combination with chemotherapy. This expansion was based on results from the ECHELON-1 clinical trial (NCT01712490) [2,11].
Immuno Disease Comments: Phase 2 clinical candidate for aggressive systemic mastocytosis, mast cell leukemia and systemic mastocytosis- see NCT01807598
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 [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.
Immuno Disease Comments: FDA approved drug for aggressive systemic mastocytosis and systemic mastocytosis with associated hematological neoplasm or mast cell leukemia. EMA orphan drug for mastocytosis.
masitinib
Clinical Use: The European Medicines Agency has granted this drug orphan status for treating pancreatic cancer, and it is in clinical trials for other human cancers. Under the synonym N-(methyl-diazacyclohexyl-methylbenzamide)-azaphenyl-aminothiopyrrole (a.k.a. Masican) the EMA has also granted orphan designation for the treatment of malignant gastrointestinal stromal tumours, mastocytosis and multiple myeloma. A Phase 3 trial of masitinib in combination with in amyotrophic lateral sclerosis (ALS, a.k.a. motor neurone disease, MND) is underway (NCT03127267). Click here to link to ClinicalTrials.gov's listing of masitinib trials. Fourteen Phase 3 trials are registered with ClinicalTrials.gov (as of Jan 2018), but many of these are not active.
Immuno Disease Comments: EMA orphan drug for mastocytosis.
cromoglicic acid  [  (Drugs.com) ]
Clinical Use: Cromoglicic acid is available in different formulations; nasal spray is used to treat allergic rhinitis, nebulizer solution to treat asthma, eye drops to treat allergic conjunctivitis and an oral form to treat mastocytosis,dermatographic urticaria and ulcerative colitis.
Recent reports suggest that cromolyn inhibits glycogen synthase kinase 3β and may therefore have potential to treat diabetes and obesity [7] and may prove effective in treating insulin-induced lipoatrophy [9].
Immuno Disease Comments: Mast cell stabiliser used to treat mastocytosis.

References

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1. Bibi S, Zhang Y, Hugonin C, Mangean MD, He L, Wedeh G, Launay JM, Van Rijn S, Würdinger T, Louache F et al.. (2016) A new humanized in vivo model of KIT D816V+ advanced systemic mastocytosis monitored using a secreted luciferase. Oncotarget, 7 (50): 82985-83000. [PMID:27783996]

2. Connors JM, Jurczak W, Straus DJ, Ansell SM, Kim WS, Gallamini A, Younes A, Alekseev S, Illés Á, Picardi M et al.. (2018) Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin's Lymphoma. N. Engl. J. Med., 378 (4): 331-344. [PMID:29224502]

3. FDA. FDA approves Brentuximab vedotin for the treatment of adult patients with primary cutaneous anaplastic large cell lymphoma. Accessed on 10/11/2017. Modified on 10/11/2017. fda.gov, https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm584543.htm?utm_campaign=Oncology%2011%2F9&utm_medium=email&utm_source=Eloqua&elqTrackId=06d11c937bec44c79cd3d453daecb608&elq=4d1b00c5aad64538a4ce8e687b3f3786&elqaid=1289&elqat=1&elqCampaignId=770

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. Greiner G, Gurbisz M, Ratzinger F, Witzeneder N, Simonitsch-Klupp I, Mitterbauer-Hohendanner G, Mayerhofer M, Müllauer L, Sperr WR, Valent P et al.. (2018) Digital PCR: A Sensitive and Precise Method forKITD816V Quantification in Mastocytosis. Clin. Chem., 64 (3): 547-555. [PMID:29237714]

6. Moskowitz CH, Nademanee A, Masszi T, Agura E, Holowiecki J, Abidi MH, Chen AI, Stiff P, Gianni AM, Carella A et al.. (2015) Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin's lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet, 385 (9980): 1853-62. [PMID:25796459]

7. Motawi TM, Bustanji Y, El-Maraghy SA, Taha MO, Al Ghussein MA. (2013) Naproxen and cromolyn as new glycogen synthase kinase 3β inhibitors for amelioration of diabetes and obesity: an investigation by docking simulation and subsequent in vitro/in vivo biochemical evaluation. J. Biochem. Mol. Toxicol., 27 (9): 425-36. [PMID:23784744]

8. Onnes MC, Tanno LK, Elberink JN. (2016) Mast Cell Clonal Disorders: Classification, Diagnosis and Management. Curr Treat Options Allergy, 3 (4): 453-464. [PMID:27942432]

9. Phua EJ, Lopez X, Ramus J, Goldfine AB. (2013) Cromolyn sodium for insulin-induced lipoatrophy: old drug, new use. Diabetes Care, 36 (12): e204-5. [PMID:24265375]

10. Taylor ML, Sehgal D, Raffeld M, Obiakor H, Akin C, Mage RG, Metcalfe DD. (2004) Demonstration that mast cells, T cells, and B cells bearing the activating kit mutation D816V occur in clusters within the marrow of patients with mastocytosis. J Mol Diagn, 6 (4): 335-42. [PMID:15507672]

11. Younes A, Connors JM, Park SI, Fanale M, O'Meara MM, Hunder NN, Huebner D, Ansell SM. (2013) Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin's lymphoma: a phase 1, open-label, dose-escalation study. Lancet Oncol., 14 (13): 1348-56. [PMID:24239220]