Frequency and prognostic impact of KIT and other genetic variants in indolent systemic mastocytosis

Muñoz‐González, Javier I.; Álvarez‐Twose, Iván; Jara‐Acevedo, María; Henriques, Ana; Viñas, Esther; Prieto, Carlos; Sánchez‐Muñoz, Laura; Caldas, Carolina; Mayado, Andrea; Matito, Almudena; Dasilva-Freire, Noelia; Órfão, Alberto; García‐Montero, Andrés C.

doi:10.1182/blood.2018886507

Cited by 49 publications

(68 citation statements)

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“…These results suggest nintedanib as a new drug candidate for targeted therapy in patients with advanced SM. Different prognostic scoring systems and genetic biomarkers have been reported [ 82 , 83 , 84 , 85 , 86 ]. These can be used to predict survival outcomes and guide therapy decisions.…”

Section: Discussionmentioning

confidence: 99%

New Insights into the Pathogenesis of Systemic Mastocytosis

2021

IJMS

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Mastocytosis is a type of myeloid neoplasm characterized by the clonal, neoplastic proliferation of morphologically and immunophenotypically abnormal mast cells that infiltrate one or more organ systems. Systemic mastocytosis (SM) is a more aggressive variant of mastocytosis with extracutaneous involvement, which might be associated with multi-organ dysfunction or failure and shortened survival. Over 80% of patients with SM carry the KIT D816V mutation. However, the KIT D816V mutation serves as a weak oncogene and appears to be a late event in the pathogenesis of mastocytosis. The management of SM is highly individualized and was largely palliative for patients without a targeted form of therapy in past decades. Targeted therapy with midostaurin, a multiple kinase inhibitor that inhibits KIT, has demonstrated efficacy in patients with advanced SM. This led to the recent approval of midostaurin by the United States Food and Drug Administration and European Medicines Agency. However, the overall survival of patients treated with midostaurin remains unsatisfactory. The identification of genetic and epigenetic alterations and understanding their interactions and the molecular mechanisms involved in mastocytosis is necessary to develop rationally targeted therapeutic strategies. This review briefly summarizes recent developments in the understanding of SM pathogenesis and potential treatment strategies for patients with SM.

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Section: Discussionmentioning

confidence: 99%

New Insights into the Pathogenesis of Systemic Mastocytosis

2021

IJMS

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“…However, in a subset of patients with SM, KIT D816V can be detected in MCs, as well as in other hematopoietic lineages 288 , 289 . Such multi-lineage involvement is typically found in smoldering SM and advanced SM and is of prognostic significance 290 .…”

Section: Neoplastic Disorders Of Mcs and Their Precursorsmentioning

confidence: 99%

Mast cells as a unique hematopoietic lineage and cell system: From Paul Ehrlich's visions to precision medicine concepts

et al. 2020

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The origin and functions of mast cells (MCs) have been debated since their description by Paul Ehrlich in 1879. MCs have long been considered 'reactive bystanders' and 'amplifiers' in inflammatory processes, allergic reactions, and host responses to infectious diseases. However, knowledge about the origin, phenotypes and functions of MCs has increased substantially over the past 50 years. MCs are now known to be derived from multipotent hematopoietic progenitors, which, through a process of differentiation and maturation, form a unique hematopoietic lineage residing in multiple organs. In particular, MCs are distinguishable from basophils and other hematopoietic cells by their unique phenotype, origin(s), and spectrum of functions, both in innate and adaptive immune responses and in other settings. The concept of a unique MC lineage is further supported by the development of a distinct group of neoplasms, collectively referred to as mastocytosis, in which MC precursors expand as clonal cells. The clinical consequences of the expansion and/or activation of MCs are best established in mastocytosis and in allergic inflammation. However, MCs have also been implicated as important participants in a number of additional pathologic conditions and physiological processes. In this article, we review concepts regarding MC development, factors controlling MC expansion and activation, and some of the fundamental roles MCs may play in both health and disease. We also discuss new concepts for suppressing MC expansion and/or activation using molecularly-targeted drugs.

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“…57 Alternative prognostic scoring systems that include information about S/A/R profiling and other molecular markers have been proposed, and others are still under investigation. [58][59][60][61] KIT as Therapeutic Target. The clinical spectrum of this disease is highly heterogeneous.…”

Section: Molecular Alterations Additional To Kit Mutationsmentioning

confidence: 99%

Systemic Mastocytosis: Molecular Landscape and Implications for Treatment

Monaldi

Santis²,

Mancini

et al. 2021

Mediterr J Hematol Infect Dis

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Over the past decade we have witnessed major advances in the molecular characterization of systemic mastocytosis (SM). This has provided important information for a better understanding of the pathogenesis of the disease but has also practically impacted on the way we diagnose and manage it. Advances in molecular testing has indeed run in parallel with advances in therapeutic targeting of constitutive active KIT, the major driver of the disease. Assessing the molecular landscape in each individual SM patient is nowadays important for diagnosis, prognosis, treatment and monitoring of therapeutic efficacy. This is facilitated by the routine availability of novel technologies like digital PCR and NGS. This review aims to summarize the pathogenesis of the disease, discuss the value of molecular diagnostic testing and how it should be performed, and provide an overview of present and future therapeutic concepts based on fine molecular characterization of SM patients.

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Frequency and prognostic impact of KIT and other genetic variants in indolent systemic mastocytosis

Cited by 49 publications

References 47 publications

New Insights into the Pathogenesis of Systemic Mastocytosis

New Insights into the Pathogenesis of Systemic Mastocytosis

Mast cells as a unique hematopoietic lineage and cell system: From Paul Ehrlich's visions to precision medicine concepts

Systemic Mastocytosis: Molecular Landscape and Implications for Treatment

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