Midostaurin: A magic bullet that blocks mast cell expansion and activation

P. Valent; C. Akin; K. Hartmann; T. I. George; K. Sotlar; B. Peter; K. V. Gleixner; K. Blatt; W. R. Sperr; P. W. Manley; O. Hermine; H. C. Kluin-Nelemans; M. Arock; H. -P. Horny; A. Reiter; J. Gotlib

doi:10.1093/annonc/mdx290

Midostaurin: A magic bullet that blocks mast cell expansion and activation

P. Valent^*
, C. Akin
, K. Hartmann
, T. I. George
, K. Sotlar
, B. Peter
, K. V. Gleixner
, K. Blatt
, W. R. Sperr
, P. W. Manley
, O. Hermine
, H. C. Kluin-Nelemans
, M. Arock
, H. -P. Horny
, A. Reiter
, J. Gotlib

^*Corresponding author for this work

Research output: Contribution to journal › Review article › peer-review

68 Citations (Scopus)

252 Downloads (Pure)

Abstract

Clinically relevant features in patients with systemic mastocytosis (SM) include the cosmetic burden of lesional skin, mediator-related symptoms, and organ damage resulting from mast cell (MC) infiltration in advanced forms of SM. Regardless of the SM variant, expansion of neoplastic MC in the skin and other organs is triggered by mutant forms of KIT, the most prevalent being D816V. Activation of MC with subsequent release of chemical mediators is often caused by IgE-dependent mechanisms in these patients. Midostaurin, also known as PKC412, blocks the kinase activity of wild-type KIT and KIT D816V, counteracts KIT-dependent growth of neoplastic MC, and inhibits IgE-dependent mediator secretion. Based on this activity-profile, the drug has been used for treatment of patients with advanced SM. Indeed, encouraging results have been obtained with the drug in a recent multi-center phase II trial in patients with advanced SM, with an overall response rate of 60% and a substantial decrease in the burden of neoplastic MC in various organs. Moreover, midostaurin improved the overall survival and relapse-free survival in patients with advanced SM compared with historical controls. In addition, midostaurin was found to improve mediator-related symptoms and quality of life, suggesting that the drug may also be useful in patients with indolent SM suffering from mediator-related symptoms resistant to conventional therapies or those with MC activation syndromes. Ongoing and future studies will determine the actual value of midostaurin-induced MC depletion and MC deactivation in these additional indications.

Original language	English
Pages (from-to)	2367-2376
Number of pages	10
Journal	Annals of Oncology
Volume	28
Issue number	10
DOIs	https://doi.org/10.1093/annonc/mdx290
Publication status	Published - 1-Oct-2017

Keywords

mast cells
targeted drugs
IgE
mast cell activation
mast cell leukemia
ADVANCED SYSTEMIC MASTOCYTOSIS
TYROSINE KINASE INHIBITORS
PROTOONCOGENE C-KIT
OF-THE-ART
PROTEIN-KINASE
DEPENDENT ACTIVATION
RESPONSE CRITERIA
MYELOID-LEUKEMIA
BLOOD BASOPHILS
IN-VITRO

Access to Document

10.1093/annonc/mdx290

MidostaurinFinal publisher's version, 477 KBLicence: Taverne

Handle.net

Persistent link

Cite this

Valent, P., Akin, C., Hartmann, K., George, T. I., Sotlar, K., Peter, B., Gleixner, K. V., Blatt, K., Sperr, W. R., Manley, P. W., Hermine, O., Kluin-Nelemans, H. C., Arock, M., Horny, H. .-P., Reiter, A., & Gotlib, J. (2017). Midostaurin: A magic bullet that blocks mast cell expansion and activation. Annals of Oncology, 28(10), 2367-2376. https://doi.org/10.1093/annonc/mdx290

@article{024d0d0de5ed4aa3ba7c68c77e2490cf,

title = "Midostaurin: A magic bullet that blocks mast cell expansion and activation",

abstract = "Clinically relevant features in patients with systemic mastocytosis (SM) include the cosmetic burden of lesional skin, mediator-related symptoms, and organ damage resulting from mast cell (MC) infiltration in advanced forms of SM. Regardless of the SM variant, expansion of neoplastic MC in the skin and other organs is triggered by mutant forms of KIT, the most prevalent being D816V. Activation of MC with subsequent release of chemical mediators is often caused by IgE-dependent mechanisms in these patients. Midostaurin, also known as PKC412, blocks the kinase activity of wild-type KIT and KIT D816V, counteracts KIT-dependent growth of neoplastic MC, and inhibits IgE-dependent mediator secretion. Based on this activity-profile, the drug has been used for treatment of patients with advanced SM. Indeed, encouraging results have been obtained with the drug in a recent multi-center phase II trial in patients with advanced SM, with an overall response rate of 60\% and a substantial decrease in the burden of neoplastic MC in various organs. Moreover, midostaurin improved the overall survival and relapse-free survival in patients with advanced SM compared with historical controls. In addition, midostaurin was found to improve mediator-related symptoms and quality of life, suggesting that the drug may also be useful in patients with indolent SM suffering from mediator-related symptoms resistant to conventional therapies or those with MC activation syndromes. Ongoing and future studies will determine the actual value of midostaurin-induced MC depletion and MC deactivation in these additional indications.",

keywords = "mast cells, targeted drugs, IgE, mast cell activation, mast cell leukemia, ADVANCED SYSTEMIC MASTOCYTOSIS, TYROSINE KINASE INHIBITORS, PROTOONCOGENE C-KIT, OF-THE-ART, PROTEIN-KINASE, DEPENDENT ACTIVATION, RESPONSE CRITERIA, MYELOID-LEUKEMIA, BLOOD BASOPHILS, IN-VITRO",

author = "P. Valent and C. Akin and K. Hartmann and George, \{T. I.\} and K. Sotlar and B. Peter and Gleixner, \{K. V.\} and K. Blatt and Sperr, \{W. R.\} and Manley, \{P. W.\} and O. Hermine and Kluin-Nelemans, \{H. C.\} and M. Arock and Horny, \{H. -P.\} and A. Reiter and J. Gotlib",

year = "2017",

month = oct,

day = "1",

doi = "10.1093/annonc/mdx290",

language = "English",

volume = "28",

pages = "2367--2376",

journal = "Annals of Oncology",

issn = "0923-7534",

publisher = "Oxford University Press",

number = "10",

}

TY - JOUR

T1 - Midostaurin

T2 - A magic bullet that blocks mast cell expansion and activation

AU - Valent, P.

AU - Akin, C.

AU - Hartmann, K.

AU - George, T. I.

AU - Sotlar, K.

AU - Peter, B.

AU - Gleixner, K. V.

AU - Blatt, K.

AU - Sperr, W. R.

AU - Manley, P. W.

AU - Hermine, O.

AU - Kluin-Nelemans, H. C.

AU - Arock, M.

AU - Horny, H. -P.

AU - Reiter, A.

AU - Gotlib, J.

PY - 2017/10/1

Y1 - 2017/10/1

N2 - Clinically relevant features in patients with systemic mastocytosis (SM) include the cosmetic burden of lesional skin, mediator-related symptoms, and organ damage resulting from mast cell (MC) infiltration in advanced forms of SM. Regardless of the SM variant, expansion of neoplastic MC in the skin and other organs is triggered by mutant forms of KIT, the most prevalent being D816V. Activation of MC with subsequent release of chemical mediators is often caused by IgE-dependent mechanisms in these patients. Midostaurin, also known as PKC412, blocks the kinase activity of wild-type KIT and KIT D816V, counteracts KIT-dependent growth of neoplastic MC, and inhibits IgE-dependent mediator secretion. Based on this activity-profile, the drug has been used for treatment of patients with advanced SM. Indeed, encouraging results have been obtained with the drug in a recent multi-center phase II trial in patients with advanced SM, with an overall response rate of 60% and a substantial decrease in the burden of neoplastic MC in various organs. Moreover, midostaurin improved the overall survival and relapse-free survival in patients with advanced SM compared with historical controls. In addition, midostaurin was found to improve mediator-related symptoms and quality of life, suggesting that the drug may also be useful in patients with indolent SM suffering from mediator-related symptoms resistant to conventional therapies or those with MC activation syndromes. Ongoing and future studies will determine the actual value of midostaurin-induced MC depletion and MC deactivation in these additional indications.

AB - Clinically relevant features in patients with systemic mastocytosis (SM) include the cosmetic burden of lesional skin, mediator-related symptoms, and organ damage resulting from mast cell (MC) infiltration in advanced forms of SM. Regardless of the SM variant, expansion of neoplastic MC in the skin and other organs is triggered by mutant forms of KIT, the most prevalent being D816V. Activation of MC with subsequent release of chemical mediators is often caused by IgE-dependent mechanisms in these patients. Midostaurin, also known as PKC412, blocks the kinase activity of wild-type KIT and KIT D816V, counteracts KIT-dependent growth of neoplastic MC, and inhibits IgE-dependent mediator secretion. Based on this activity-profile, the drug has been used for treatment of patients with advanced SM. Indeed, encouraging results have been obtained with the drug in a recent multi-center phase II trial in patients with advanced SM, with an overall response rate of 60% and a substantial decrease in the burden of neoplastic MC in various organs. Moreover, midostaurin improved the overall survival and relapse-free survival in patients with advanced SM compared with historical controls. In addition, midostaurin was found to improve mediator-related symptoms and quality of life, suggesting that the drug may also be useful in patients with indolent SM suffering from mediator-related symptoms resistant to conventional therapies or those with MC activation syndromes. Ongoing and future studies will determine the actual value of midostaurin-induced MC depletion and MC deactivation in these additional indications.

KW - mast cells

KW - targeted drugs

KW - IgE

KW - mast cell activation

KW - mast cell leukemia

KW - ADVANCED SYSTEMIC MASTOCYTOSIS

KW - TYROSINE KINASE INHIBITORS

KW - PROTOONCOGENE C-KIT

KW - OF-THE-ART

KW - PROTEIN-KINASE

KW - DEPENDENT ACTIVATION

KW - RESPONSE CRITERIA

KW - MYELOID-LEUKEMIA

KW - BLOOD BASOPHILS

KW - IN-VITRO

U2 - 10.1093/annonc/mdx290

DO - 10.1093/annonc/mdx290

M3 - Review article

SN - 0923-7534

VL - 28

SP - 2367

EP - 2376

JO - Annals of Oncology

JF - Annals of Oncology

IS - 10

ER -

Midostaurin: A magic bullet that blocks mast cell expansion and activation

Abstract

Keywords

Access to Document

Handle.net

Fingerprint

Cite this