Pathogenesis, classification and treatment of mastocytosis: state of the art in 2010 and future perspectives

Abstract

Mastocytosis is a myeloid neoplasm characterized by abnormal accumulation and frequent activation of mast cells (MCs) in various organs. Organ systems typically involved are the bone marrow, skin, liver and gastrointestinal tract. In most adult patients, the systemic form of mastocytosis (SM) is diagnosed, which includes an indolent subvariant, an aggressive subvariant and a leukemic subvariant, also termed MC leukemia. Whereas in pediatric mastocytosis, which is usually confined to the skin, a number of different KIT mutations and other defects may be detected, the KIT mutation D816V is detectable in most (adult) patients with SM. In a subset of these patients, additional oncogenic factors may lead to enhanced survival and growth of MCs and, thus, to advanced SM. Other factors may lead to MC activation, with consecutive anaphylactic reactions that can be severe or even fatal. Treatment of SM usually focuses on symptom relief by histamine receptor antagonists and other supportive therapy. However, in aggressive and leukemic variants, cytoreductive and targeted drugs must be applied. Unfortunately, the prognosis in these patients remains poor, even when treated with novel KIT-targeting agents, polychemotherapy or stem cell transplantation. This article provides a summary of our knowledge on the pathogenesis and on treatment options in SM.

Keywords::

• classification
• KIT
• mast cells
• mastocytosis
• mutations
• targeted therapy
• tyrosine kinase inhibitor

Financial & competing interests disclosure

This study was supported by the Fonds zur Förderung der Wissenschaftlichen Forschung in Österreich - FWF grants #P21173-B13 and #SFB-F01820, and by a grant from ANR (Agence Nationale de la Recherche Française) – ANR-06-MRAR-015 ‘Mastocytose’. In addition, Michel Arock received a research grant from BioAlliance Pharma and Peter Valent received research grants from Novartis and from Bristol-Myers Squibb. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Notes

^†If at least one major and one minor or at least three minor criteria are fulfilled, the diagnosis SM can be established.

^‡Activating mutations at codon 816, in most cases KIT D816V.

AHNMD: Associated clonal hematologic non-mast cell lineage disease; MC: Mast cell; SM: Systemic mastocytosis.

^†These defects are the same as found in the respective neoplasms when presenting without SM. Many of these defects are related to WHO criteria of myeloid neoplasms.

^‡Subclone formation by neoplastic stem cells may be an early process.

Therefore, transformation in SM can be associated with outgrowth of a KIT D816V-negative subclone, mostly as AHNMD, e.g., secondary acute leukemia.

AHNMD: Associated clonal hematologic non-mast cell lineage disease; SM: Systemic mastocytosis; SNP: Single nucleotide polymorphism.

^†If two or three B findings but no C findings are recorded, the diagnostic smouldering systemic mastocytosis should be established.

ANC: Absolute neutrophil count; B finding: Borderline-benign finding; C finding: Consider cytoreduction finding; CT: Computed tomography; MC: Mast cell; MDS: Myelodysplastic syndrome; MPN: Myeloproliferative neoplasm; US: Ultrasonography.