The Pathogenesis, Diagnosis, and Treatment of Systemic Mast Cell Disorders

National Institute Of Allergy And Infectious Diseases

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Linked publications & trials

Abstract

Patients with non-aggressive indolent systemic mastocytosis (ISM) are not in general candidates for cytoreductive therapy and are generally treated with symptomatic therapy that only partly decreases symptoms. There is, however, a documented association between severity of mastocytosis and elevated serum levels of interleukin IL-6. Furthermore, mast cells have been shown to double their rate of division and exhibit increased reactivity and release of mediators when cultured in the presence of IL-6. In addition, in an animal model of mastocytosis, anti-IL-6 has been shown to slow disease progression. In 2019, we initiated a clinical trial of adults with ISM that are randomized and treated with sarilumab which binds to the IL 6 receptor and inhibits IL 6 associated human mast cell signaling, proliferation and reactivity (decreased mediator release). In FY2022, several of our patients completed our clinical trial and others have been newly enrolled. So far based on over 12 subjects, the safety profile has been favorable and there seems to be a signal for improved quality of life in those subjects that have continued open label therapy after completing the blinded portion of the study. In addition to quality of life and symptom assessments, patients undergo measurement of serum tryptase levels and bone marrow examinations are performed at the onset and conclusion of the study. In addition to other debilitating manifestations involving multiple organs, patients with systemic mastocytosis suffer from osteoporosis and increased risk of fractures. In FY2022, utilizing several imaging modalities such as dual energy x-ray absorptiometry (DXA), and Trabecular Bone Scores, laboratory tests and a fracture questionnaire, we assessed fracture risk in a North American cohort of 50 patients with mastocytosis enrolled in this protocol. We published a report that describes a prediction model for fracture risk based on DXA spine T-scores, alkaline phosphatase, and designed a clinically relevant interactive calculator to evaluate fracture risk using these modalities. Children with mastocytosis may exhibit marked cutaneous symptoms which include flushing and blistering. In FY2022 two cases of infants with diffuse cutaneous mastocytosis (DCM) (characterized by a thickened skin with a peau d orange appearance and a reddish-brown discoloration) were assessed by measurement of serum tryptase. We reported that during a flare in the skin manifestations, while total serum tryptase did increase, there were not increases in mature trypase (stored in mast cell granules) which is usually associated with anaphylaxis and the patients remained hemodynamically stable. These findings suggest a more conservative approach to children with mastocytosis that experience acute cutaneous symptoms may be warranted by parents and caregivers. Patients with indolent ISM were examined as part of a cohort to determine a formula that may provide increased sensitivity for the determination of the clinical diagnosis of anaphylaxis in patients that exhibit and increase in serum tryptase during an event. In FY2022 a report determined a ratio of 1.685 comparing the acute elevation in tryptase over the basal level showed increased sensitivity over previous models for confirming the diagnosis of anaphylaxis in patients with hereditary -tryptasemia (HT) and ISM. In FY2022, we reported a rare case of spontaneous remission of ISM in a 62-year-old patient that was followed at the NIH Clinical center for 37 years. The absence of mast cell aggregates within the bone marrow, normalization of serum tryptase, and improvement in symptoms is consistent with disease remission. While ISM progression is rare this single case report highlights, that spontaneous disease remission without cytoreductive therapy can occur, and the need for a nuanced approach to targeted therapy. WHO-defined diagnostic criteria for classification of systemic mastocystosis (SM) variants including bone marrow mastocytosis (BMM), indolent SM (ISM), smoldering SM (SSM), aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN), or mast cell leukemia (MCL) have been updated in FY2022. Staff members from our group participated in these updated recommendations which were based on an international conference of the EU-US Cooperative Group regarding standards of pathology in the diagnosis of SM.