Long-Term Successful Treatment of Indolent Systemic Mastocytosis With Omalizumab

Despite maximal antihistamine and antileukotriene therapy with ranitidine (150 mg twice daily), cetirizine (10 mg twice daily), montelukast (10 mg daily), and cromolyn sodium (200 mg daily), the patient continued to experience recurrent episodes of anaphylaxis requiring subcutaneous epinephrine and systemic corticosteroids. In May 2016, the patient began a trial of off-label therapy with omalizumab injections (300 mg subcutaneous every 4 weeks). She has continued on therapy for more than 4 years and experienced only 1 anaphylactic episode. She also has had significant improvement in cutaneous symptoms.

Discussion

Mast cell overactivation and degranulation in mastocytosis is largely driven by the IgE antibody, which plays a significant role in atopic conditions, immediate hypersensitivity reactions, and anaphylaxis, as well as in the immunologic response to parasitic infections. The severity of atopic disease seems to be associated with serum IgE levels in many patients.⁷ IgE binding to surface receptors on mast cells and eosinophils prompts the release of toxic mediators, incites inflammation, and induces allergic symptoms.⁸ Activation of mast cells is classically elicited by IgE binding to the high-affinity Fcε RI receptor, the expression of which correlates with IgE levels.⁹

The anti-IgE, recombinant, humanized immunoglobulin G monoclonal antibody, omalizumab, decreases mastocytic and eosinophilic symptoms by binding and inhibiting IgE. This diminishes free IgE levels, inhibits IgE binding to the Fcε RI receptor, and affects downregulation of this high-affinity receptor on mast cells and basophils.⁶ Omalizumab is currently FDA approved only for the treatment of moderate-to-severe, persistent, allergic asthma that is not controlled by inhaled corticosteroids in patients aged ≥ 6 years, and for chronic idiopathic urticaria not controlled by H1 antihistamine therapy in patients aged ≥ 12 years.¹⁰ However, it stands to reason that this therapy also should be effective in the treatment of other poorly controlled atopic conditions, especially mastocytosis, the symptoms of which are driven by excessive mast cell degranulation and tissue infiltration.

As early as 2007, preliminary data showed that treatment with omalizumab could decrease the frequency of episodes of anaphylaxis.¹¹ A National Institutes of Health case report followed 2 patients, one for 5 months and the other for 24 months. Both patients experienced a decrease in frequency of anaphylaxis following initiation of omalizumab. In 2010, a second case report described the treatment of an Australian patient with recurrent idiopathic anaphylaxis also diagnosed with SM. After initiation of treatment with omalizumab, she, too, experienced decreased frequency of episodes of anaphylaxis over 14 months.¹² A review of patients treated at the Mastocytosis Centre Odense University Hospital in Denmark was published in 2017. Of 13 patients with SM treated with omalizumab, 5 experienced what was considered a complete response to the medication, with 3 each experiencing major and partial responses.⁵ The median treatment time in these patients was 27 months. Each of these cases showed significant promise in the use of omalizumab to treat SM, informing the decision to attempt this treatment in our patient.

The potential positive effects of omalizumab in reducing symptom severity in patients with SM was further supported by a 2017 meta-analysis. This review included several individual case reports noting that omalizumab could decrease frequency of pulmonary and gastrointestinal manifestations of SM.¹³ A small randomized control trial of omalizumab for treatment of mild symptoms of SM found improvement in disease severity, although neither primary nor secondary endpoints reached statistical significance.¹⁴

This case demonstrates a substantial, long-term, clinical benefit and quality of life improvement with omalizumab therapy in a patient with indolent SM that was not adequately controlled by conventional therapies. This is evidenced by an impressive decline in the frequency of mastocytic anaphylactic episodes as well as diminished patient-endorsed cutaneous symptoms.

This case provides further evidence of the efficacy of this therapy in diminishing disease burden for patients with SM who are otherwise limited to treatments aimed at transient symptomatic relief without significant alteration of the underlying cause of symptoms. At the time this article was written, our patient had now 52 months of continuous treatment without any adverse reactions noted, suggesting the treatment's long-term efficacy. It also adds to a small but growing body of literature that supports the use of anti-IgE therapy as a treatment option for improved management of this distressing, life-altering illness. Even in the time that our patient has been receiving omalizumab for SM, another small case series of 2 patients has been published showing sustained treatment effect at 12 years of therapy.¹⁵ This adds further insight that omalizumab can offer long-term, safe treatment for this limiting condition.

Omalizumab therapy is not without risk, but for patients afflicted by unrestrained mastocytic disease, the benefits may outweigh the risks. The most common significant risk with this medication is anaphylaxis, occurring in 1 to 2 per 1,000 patients, usually within 2 hours of an injection.¹⁶ This may correlate to the underlying degree of atopy in patients receiving omalizumab, and the risk of anaphylaxis is relatively low compared with that of many other biologic medications.¹⁷ Additionally, early data from initial phases of clinical trials indicated a potentially elevated malignancy risk with omalizumab. However, subsequent pooled analysis of larger numbers of patients has decreased suspicion that a causal relationship exists.¹⁸