Long-Term Successful Treatment of Indolent Systemic Mastocytosis With Omalizumab

Mastocytosis is a rare disease that causes allergic and anaphylactic symptoms due to chronic or episodic, excessive mast cell degranulation as well as mast cell infiltration of the skin or other organs.¹ Mast cells aid in innate immunity by generation of a vasodilatory and inflammatory response and are significant contributors to allergic reactions. Cutaneous mastocytosis is defined by isolated skin involvement. Systemic mastocytosis (SM) is characterized by mast cell infiltration of extracutaneous organs, most often bone marrow.²

Background

SM is divided into distinct subtypes (Table 1). Nonadvanced SM subtypes include indolent SM and smoldering SM. These are the most common forms and tend to have more slowly progressing courses without evidence of organ tissue dysfunction, a myelodysplastic syndrome, or of a myeloproliferative disorder.³ Advanced SM is less common and is associated with organ tissue dysfunction. It also may be associated with myeloproliferative, myelodysplastic, or lymphoproliferative hematologic neoplasms, and subtypes include aggressive SM, SM with an associated hematologic neoplasm, and mast cell leukemia (Table 2).⁴

Treatment options approved by the US Food and Drug Administration (FDA) for advanced SM include disease-altering medications, such as tyrosine kinase inhibitors (eg, imatinib), but the approved treatment options for nonadvanced SM are generally aimed at managing only symptoms (Table 3). Although not approved by the FDA for the treatment of SM, omalizumab may aid in the prevention of anaphylaxis, the reduction of disease burden, and the improvement in quality of life for patients with SM.⁵ Omalizumab is a humanized monoclonal antibody against the Fc portion of immunoglobulin E (IgE). It is approved by the FDA for treatment of asthma as well as chronic idiopathic urticaria.⁶

Case Presentation

A 32-year-old female initially presented to Womack Army Medical Center at Fort Bragg, North Carolina, for evaluation due to recurrent episodes of anaphylaxis occurring 1 to 2 times per month as well as chronic skin rashes that progressed over the previous 5 years (Figure). She initially was diagnosed with idiopathic anaphylaxis and subsequently had multiple emergency department (ED) and clinic visits for vasovagal syncope, unexplained allergic reactions, dizziness, giddiness, and shortness of breath. More recently, she was diagnosed with idiopathic urticaria.

The patient reported at least 12 episodes in the previous year involving facial flushing that proceeded inferiorly, chest tightness, shortness of breath, labored breathing, crampy abdominal pain, and nausea without urticaria or significant pruritus. These bouts often were accompanied by mild facial angioedema, acute sinus pressure, vomiting, tachycardia, and lightheadedness. She reported experiencing brief losses of consciousness with at least 4 of these episodes. Home and ED blood pressure measurements revealed hypotension on several occasions with systolic readings in the 80s. She also developed nonpruritic freckles on her upper chest initially with subsequent increase in number and spread to involve her entire trunk, proximal extremities, and eventually distal extremities.

The patient had received intramuscular epinephrine several times, which led to rapid resolution of her symptoms. Intensive care unit admission for observation overnight was deemed necessary following one of her first episodes, but she did not require intubation or vasopressor support. Eventually, she began treating most episodes at home with diphenhydramine, ranitidine, and occasionally an epinephrine auto-injector, only presenting to the ED for severe dyspnea or loss of consciousness. Some episodes awoke her from sleeping but no triggers were identified (eg, foods, alcohol, supplements, medications, insect stings, latex exposure, exercise, strong emotions, or menstrual cycle).

Examination revealed hyperpigmented macules and papules scattered on the trunk and extremities, with a positive Darier sign. Punch biopsy of one of the macules revealed focal basal cell hyperpigmentation and sheets of benign-appearing mast cells in the superficial dermis, highlighted by CD117 immunohistochemical stain. A serum tryptase level was obtained and found to be significantly elevated (134 mcg/L). The patient was diagnosed with maculopapular cutaneous mastocytosis (urticaria pigmentosa).

A bone marrow biopsy revealed multiple prominent infiltrates of monomorphic, spindled, CD117-positive, CD2-positive, and CD25-positive mast cells arranged interstitially and paratrabecularly, with associated reticulin fibrosis. Indolent SM was diagnosed according to the World Health Organization classification system with multifocal, dense aggregates of mast cells (> 25%) in the bone marrow and with persistently elevated serum tryptase levels (134, 134, 151, and 159 ng/mL) without laboratory evidence of an associated clonal myeloid disorder or findings consistent with infiltrating bone lesions on full body magnetic resonance imaging scan.⁴