Laboratory Assessment of Patients with Systemic Mastocytosis

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Abstract

We prospectively studied in the past patients with over three idiopathic anaphylaxis episodes per year. The patients underwent a clinico-pathological evaluation that included bone marrow morphological, immunohistochemical and flow cytometric examination and molecular studies for KIT D816V mutation using sensitive allele-specific quantitative PCR (ASqPCR). Clonal mast cell disease (monoclonal mast cell activation syndrome (MMAS) or systemic mastocytosis (SM)) was diagnosed in 14% of patients referred with IA (7% ISM and 7% MMAS). The cohort of patients diagnosed with ISM and IA had no other clinical signs of systemic disease. Serum tryptase values alone did not predict diagnosis of systemic disease. However, peripheral blood ASqPCR KIT D816V mutational analysis was a useful adjunct in helping identify patients with systemic mastocytosis, since it was positive in all patients who fulfilled the major WHO criteria for diagnosis of systemic mastocytosis. Peripheral blood KIT D816V testing was negative in all patients with MMAS and in one patient with ISM who had no mast cell aggregates in the marrow biopsy and did not fulfil major WHO criteria for diagnosis of systemic disease. Thus, based on this test alone, the negative and positive predictive values of peripheral blood KIT D816V mutational analysis for diagnosis of ISM were 90.74% and 100%, respectively, in the population of patients with IA. There was no evidence of a hyperresponsive mast cell phenotype in patients with IA. Based on these findings, we developed a modified overall clonal prediction model using scoring system with increased specificity and sensitivity for identification of patients with recurrent IA who are candidates for a bone marrow biopsy, termed the NIH Idiopathic Clonal Anaphylaxis Score (NICAS). The NICAS prediction model was developed by combining clinical findings, serum tryptase determinations, and the results of KIT D816V mutation by peripheral blood ASqPCR. By utilizing peripheral blood ASqPCR, we increased the sensitivity and specificity of predicting a clonal disorder in patients with IA to 75% and 100%, respectively. Since idiopathic anaphylaxis is a diagnosis of exclusion, there is no option of therapeutic management focused on eliminating the inciting agent and there is no prophylactic therapy that reliably prevents anaphylaxis. To determine the efficacy of omalizumab (anti-IgE mAb) in the management of patients with frequent episodes of IA, a double-blind, placebo-controlled clinical trial was designed. 19 patients with frequent IA (6 episodes/y) were prospectively enrolled and underwent a medical evaluation that included a serum tryptase determination, mutational analysis for KIT D816V, and bone marrow evaluation to rule out a clonal mast cell disorder. The primary trial end point was the number of anaphylactic events in the 6 months after baseline. Data analysis showed a trend for efficacy in the treatment group, particularly after 60 days after baseline. However, no statistically significant difference was demonstrated between the placebo and treated groups at the six-month point. Overall safety profile was favorable without long-term side effects.