Hans-Peter Horny

Activation of tissue mast cells (MCs) and their abnormal growth and accumulation in various organs are typically found in primary MC disorders also referred to as mastocytosis. However, increasing numbers of patients are now being informed that their clinical findings are due to MC activation (MCA) that is neither associated with mastocytosis nor with a defined allergic or inflammatory reaction. In other patients with MCA, MCs appear to be clonal cells, but criteria for diagnosing mastocytosis are not met. A working conference was organized in 2010 with the aim to define criteria for diagnosing MCA and related disorders, and to propose a global unifying classification of all MC disorders and pathologic MC reactions. This classification includes three types of 'MCA syndromes' (MCASs), namely primary MCAS, secondary MCAS and idiopathic MCAS. MCA is now defined by robust and generally applicable criteria, including (1) typical clinical symptoms, (2) a substantial transient increase in serum total tryptase level or an increase in other MC-derived mediators, such as histamine or prostaglandin D(2), or their urinary metabolites, and (3) a response of clinical symptoms to agents that attenuate the production or activities of MC mediators. These criteria should assist in the identification and diagnosis of patients with MCAS, and in avoiding misdiagnoses or overinterpretation of clinical symptoms in daily practice. Moreover, the MCAS concept should stimulate research in order to identify and exploit new molecular mechanisms and therapeutic targets.

BACKGROUND: Advanced systemic mastocytosis comprises rare hematologic neoplasms that are associated with a poor prognosis and lack effective treatment options. The multikinase inhibitor midostaurin inhibits KIT D816V, a primary driver of disease pathogenesis. METHODS: We conducted an open-label study of oral midostaurin at a dose of 100 mg twice daily in 116 patients, of whom 89 with mastocytosis-related organ damage were eligible for inclusion in the primary efficacy population; 16 had aggressive systemic mastocytosis, 57 had systemic mastocytosis with an associated hematologic neoplasm, and 16 had mast-cell leukemia. The primary outcome was the best overall response. RESULTS: The overall response rate was 60% (95% confidence interval [CI], 49 to 70); 45% of the patients had a major response, which was defined as complete resolution of at least one type of mastocytosis-related organ damage. Response rates were similar regardless of the subtype of advanced systemic mastocytosis, KIT mutation status, or exposure to previous therapy. The median best percentage changes in bone marrow mast-cell burden and serum tryptase level were -59% and -58%, respectively. The median overall survival was 28.7 months, and the median progression-free survival was 14.1 months. Among the 16 patients with mast-cell leukemia, the median overall survival was 9.4 months (95% CI, 7.5 to not estimated). Dose reduction owing to toxic effects occurred in 56% of the patients; re-escalation to the starting dose was feasible in 32% of those patients. The most frequent adverse events were low-grade nausea, vomiting, and diarrhea. New or worsening grade 3 or 4 neutropenia, anemia, and thrombocytopenia occurred in 24%, 41%, and 29% of the patients, respectively, mostly in those with preexisting cytopenias. CONCLUSIONS: In this open-label study, midostaurin showed efficacy in patients with advanced systemic mastocytosis, including the highly fatal variant mast-cell leukemia. (Funded by Novartis Pharmaceuticals and others; ClinicalTrials.gov number, NCT00782067.).

Abstract Mastocytosis is a term used to denote a heterogeneous group of conditions defined by the expansion and accumulation of clonal (neoplastic) tissue mast cells in various organs. The classification of the World Health Organization (WHO) divides the disease into cutaneous mastocytosis, systemic mastocytosis, and localized mast cell tumors. On the basis of histomorphologic criteria, clinical parameters, and organ involvement, systemic mastocytosis is further divided into indolent systemic mastocytosis and advanced systemic mastocytosis variants, including aggressive systemic mastocytosis and mast cell leukemia. The clinical impact and prognostic value of this classification has been confirmed in numerous studies, and its basic concept remains valid. However, refinements have recently been proposed by the consensus group, the WHO, and the European Competence Network on Mastocytosis. In addition, new treatment options are available for patients with advanced systemic mastocytosis, including allogeneic hematopoietic stem cell transplantation and multikinase inhibitors directed against KIT D816V and other key signaling molecules. Our current article provides an overview of recent advances in the field of mastocytosis, with emphasis on classification, prognostication, and emerging new treatment options in advanced systemic mastocytosis. Cancer Res; 77(6); 1261–70. ©2017 AACR.

Mastocytosis is a neoplastic disease involving mast cells (MC) and their CD34+ progenitors. Symptoms in mastocytosis are caused by biological mediators released from MC and/or the infiltration of neoplastic MC in various organs, the skin and the bone marrow being predominantly involved. A WHO consensus classification for mastocytosis exists, which is widely accepted and includes three major categories: (1) Cutaneous mastocytosis (CM), a benign disease in which MC infiltration is confined to the skin, is preferentially seen in young children and exhibits a marked tendency to regress spontaneously. (2) Systemic mastocytosis (SM) which is commonly diagnosed in adults and includes four major subtypes: (i) indolent SM (ISM, the most common form involving mainly skin and bone marrow); (ii) a unique subcategory termed SM with an associated non-mast cell clonal hematological disease (SM-AHNMD); (iii) aggressive SM usually presenting without skin lesions, and (iv) MC leukemia, probably representing the rarest variant of human leukemias. (3) The extremely rare localized extracutaneous MC neoplasms, either presenting as malignancy (MC sarcoma) or as benign tumor termed extracutaneous mastocytoma. Diagnostic criteria for mastocytosis are available and are widely accepted. SM criteria include one major criterion (multifocal compact tissue infiltration by MC) and four minor criteria: (1) prominent spindling of MC; (2) atypical immunophenotype of MC with coexpression of CD2 and/or CD25 (antigens which have not been found to be expressed on normal/reactive MC); (3) activating (somatic) point mutations of the c-kit proto-oncogene usually involving exon 17, with the imatinib-resistant type D816V being most frequent, and (4) persistently elevated serum tryptase level (>20 ng/ml). To establish the diagnosis of SM, at least one major and one minor criterion, or at least three minor criteria, have to be fulfilled. The natural clinical course of mastocytosis is variable. Most patients, in particular those with CM and ISM, remain in an indolent stage over many years or even decades, while others, in particular those with aggressive SM, SM-AHNMD, or mast cell leukemia, show a progressive course, usually with a fatal outcome.