A 8-year-old caucasian male was referred to our center after an episode of anaphylaxis of unknown origin (hypotension, tachycardia, general flushing, but no urticaria or angioedema) and persistent high tryptase value (27.5 ng/ml; n.v. < 11.4).

His past medical history was remarkable for the appearance of hyperpigmented skin lesions from the second month of age and the further diagnosis of CM (Urticaria Pigmentosa) at the age of 12 months, confirmed by skin biopsy. The skin lesions had started to regress when the child was 5 years old. The next medical history had been uneventful, except for rare occurrence of flushing, gastrointestinal discomfort and bronchospasm, with spontaneous resolution and without any effect on the quality of life.

When the child first came to our attention, his physical exam was normal; in particular, no skin lesions suggestive of CM could be observed. The working diagnosis was evolution of CM towards the systemic form of the disease, and the patient underwent an extensive diagnostic workup, including, among others, bone marrow biopsy, chest radiography, abdominal ultrasound and bone density scan. SM was verified by one major criterion and two minor WHO criteria: presence of dense aggregates of mast cells in bone biopsy (> 15), localized especially in the paratrabecular foci, confirmed by tryptase immunochemistry and expression of CD2, CD25 and CD117 (major criterion); persistently elevated serum tryptase plus evidence of D816V point mutation in the c-KIT gene in bone marrow biopsy (minor criteria). The c-KIT mutation was detected also in peripheral blood. Absence of B- and C-findings led to the diagnosis of indolent SM. Over time, our patient experienced frequent disease flares, characterized by recurrent (daily or almost daily) outbreaks of flushing, gastro-intestinal complaints (mainly diarrhea, abdominal pain), palpitations, musculoskeletal symptoms, fatigue. In the meanwhile, serum tryptase values kept on increasing up to 44 ng/ml.

The child was treated unsuccessfully with high doses of oral non-sedating antihistamines (cetirizine 10 mg up to 2 times daily, plus ketotifen 1 mg twice daily), cromolyn sodium (250 mg, 4 times daily) and topical steroids. Oral steroids (prednisone 1-2 mg/kg.day for average 2-5 consecutive days), firstly on demand and then on a daily basis, added only side effects without improving symptomatology. The child’s quality of life continued to deteriorate, with many lost school days, need to stop sporting activities and consequent social withdrawal.

One year after the SM diagnosis, the first line therapies failure was evident and we decided to treat our patient with Omalizumab (Xolair®; Genentech, San Francisco, CA, USA) on compassionate use, keeping unchanged the current therapy. Omalizumab was administered subcutaneously every 4 weeks and the dose of 300 mg was calculated according to the patient’s weight. Amazingly, the child became totally asymptomatic already after the second dose of Omalizumab.

To better objectivate the response to therapy, a modified Mastocytosis Symptom Assessment Form (MSAF) was carried out prior to each injection [35, 36]. In this score, every day in a week, each symptom was scored on a scale from 0 to 10. Before starting the Omalizumab therapy, the reported score ranged from 7/10 to 10/10 for all the symptoms. Already after the first dose of Omalizumab, the MSAF score decreased significantly, reached 0 after the third dose and remained unchanged for the subsequent months.

When, due to the COVID-19 quarantine, a dose of Omalizumab was missed, after 6 weeks after the last treatment, the patient returned to be symptomatic (flushing, headache, diarrhea) and steroid-dependent. Short after the reintroduction of Omalizumab therapy, the symptoms completely disappeared and, since then, steroids could be permanently discontinued. No other anaphylactic epysodes were observed.

Omalizumab has been well tolerated, without side effects, except for minimal local swelling. Cetirizine treatment was gradually reduced and permanently interrupted in  nine months.

The patient had been strictly monitored, but we did not notice any changes in routine blood analyses, including hemoglobin, leukocyte and differential count, platelets, liver and kidney function test or others metabolic parameters (data not shown).

Serum tryptase levels remained stable (median value 35,1 μg/L and 38,8 μg/L, before and during Omalizumab respectively).

Total IgE levels, normal at baseline (11 KU/l), increased by 10-fold after the first dose of Omalizumab and thereafter, despite a slight decrease, remained steadily increased (7.5-fold) (Fig. 1). The c-KIT D816V allele burden in peripheral blood decreased by about 40% (from 0.1598 to 0.097%).

Biological effects (total Ig-E, serum tryptase and c-Kit 816 allele burden in peripheral blood) of Omalizumab therapy. Legend: Try = tryptase

Twenty months later, Omalizumab therapy is still ongoing. The adjuvant treatment (ketotifen 1 mg/day, cromolyn sodium 250 mg × 3 daily), although much reduced, has been maintained, with the program to further reduce it over time. The patient is totally symptom-free, without disease flares; MSAF score is steadily 0. The child’s static-weight growth is adequate, the school attendance returned to be regular and a moderate sporting activity has been resumed.

In view of its extraordinary effectiveness, we did not plan if, when and how to discontinue Omalizumab. In alternative, we chose to prolong the treatment interval, which is currently 5 weeks. With the aim to contain the costs and to maintain the actual good compliance of the patients and his family, we are going to gradually increase the treatment interval, reaching the maximum interval length adequate to provide the symptoms control.