Allergen specific immunotherapy is safe and effective in patients with systemic mastocytosis and Hymenoptera allergy

Bonadonna, Patrizia; Zanotti, Roberta; Caruso, Beatrice; Castellani, Luca; Perbellini, Omar; Colarossi, Sabrina; Chilosi, Marco; Dama, Annarita; Schiappoli, Michele; Pizzolo, Giovanni; Senna, Gianenrico; Passalacqua, Giovanni

doi:10.1016/j.jaci.2007.10.014

« Previous Next »The Journal of Allergy and Clinical Immunology
Volume 121, Issue 1 , Pages 256-257, January 2008

Allergen specific immunotherapy is safe and effective in patients with systemic mastocytosis and Hymenoptera allergy

Patrizia Bonadonna, MD
- Allergy Unit, Verona General Hospital, Verona, Italy
Roberta Zanotti, MD
- Department of Clinical and Experimental Medicine, Section of Hematology, University of Verona, Verona, Italy
Beatrice Caruso, MD
- Allergy Unit, Verona General Hospital, Verona, Italy
Luca Castellani, MD
- Department of Dermatology, Santa Maria del Carmine Hospital, Rovereto, Rovereto, Italy
Omar Perbellini, MD
- Department of Clinical and Experimental Medicine, Section of Hematology, University of Verona, Verona, Italy
Sabrina Colarossi, MD
- Department of Hematology/Oncology, L. and A. Seragnoli, University of Bologna, Bologna, Italy
Marco Chilosi, MD
- Department of Pathology, University of Verona, Verona, Italy
Annarita Dama, MD
- Allergy Unit, Verona General Hospital, Verona, Italy
Michele Schiappoli, MD
- Allergy Unit, Verona General Hospital, Verona, Italy
Giovanni Pizzolo, MD
- Department of Clinical and Experimental Medicine, Section of Hematology, University of Verona, Verona, Italy
Gianenrico Senna, MD
- Allergy Unit, Verona General Hospital, Verona, Italy
Giovanni Passalacqua, MD
- Allergy and Respiratory Diseases, Dipartimento di Medicina Interna, University of Genoa, Genoa, Italy

To the Editor:

Systemic mastocytosis is a clonal disorder of the mast cell (MC) lineage, with an abnormal proliferation/maturation of this cell type. MCs are biological bombs which, if activated, release in a few seconds a large amount of mediators that are stored in their granules. In systemic mastocytosis (SM), the increased number of MCs provokes a wide variety of clinical pictures, ranging from the pauci-symptomatic form (indolent SM) to near-fatal anaphylaxis or aggressive mastocytosis. The skin is often involved, especially in children, with the typical lesions of urticaria pigmentosa. Diagnosis of SM requires the detection of 1 major and 1 minor criterion or at least 3 minor criteria, according to international guidelines.¹ The major criterion is the finding of multifocal dense MC infiltrates in bone marrow (BM) biopsy or in other extracutaneous organ. The minor criteria are an abnormal morphology of extracutaneous MC (including BM smears), the mutation in the KIT proto-oncogene at codon 816 (D816V mutation) in an extracutaneous organ, the expression of CD2 and/or CD25 on BM MCs, and an increased serum tryptase.

It is clear that in SM, any activation of MCs, either IgE-mediated or not, can have serious consequences. This is especially true in subjects with hymenoptera venom allergy (HVA) who are more at risk of severe events than subjects without SM.², ³ For this reason, although specific immunotherapy (SIT) is recognized as a life-saving treatment, its use in SM remains controversial. Looking at the literature, the general attitude in this regard is that SIT should be avoided in subjects with SM.⁴, ⁵ By contrast, our clinical observations and a report of a small cohorts of patients with mastocytosis and HVA, treated with SIT without adverse reactions,⁶ suggested that the risk-to-benefit ratio of SIT in patients with SM is overall low. To confirm this hypothesis, we systematically collected the clinical data of patients with HVA and SM referred to our unit. After a detailed clinical history and the standard diagnostic workup for HVA (ie, skin prick, intradermal testing, specific IgE CAP-RAST assay),⁷ serum tryptase level was measured (immunofluorimetric CAP assay, Unicap 100; Phadia, Uppsala, Sweden) in all patients with severe HVA. The measurement of tryptase was performed with the patient asymptomatic and no less than 2 weeks after the sting. Patients with serum tryptase level above 11.4 ng/mL (cut-off level in normal subjects) and severe reactions (grade III-IV), after informed consent, underwent BM examination. Those with suspect skin lesions had also skin biopsy. According to international consensus,¹ we evaluated the BM aspirate, stained by May-Grünwald-Giemsa, and BM biopsies stained with an antitryptase mAb. The presence of atypical MCs on BM aspirate was investigated by using a specific 5-color mAb combination (CD25/CD2/CD45/CD34/CD117). In addition, we assessed the presence of KIT-D816V mutation in BM mononuclear cells by RFLP analysis.

Once the diagnosis was established, the patients received SIT according to a regimen involving the weekly administration of the following increasing doses: 4.11, 5, 10, 20, 40, 70, and 100 μg. The maintenance dose, reached in 7 weeks, was then given monthly. All the injections were given by a physician at the clinic, with resuscitation facilities immediately available. The patients were prescribed autoinjectable epinephrine, regularly followed up, and instructed to contact the physicians immediately in the case of new stings. The diagnosis of SM in patients with a strong suspicion and the use of SIT (for which no clear recommendation exists) were considered part of the standard care, and no Institutional Review Board review was therefore required.

Between 2004 and 2007, 552 patients were seen. One hundred twenty-one have had a grade IV reaction, and 33 of them had raised tryptase. Sixteen of these patients (12 men; mean age, 49.3 years; range, 19-77 years) with HVA were diagnosed as having SM. In one of them, the clinical diagnosis of SM had been made before. Ten patients fulfilled both major and minor criteria, whereas in 6 patients, 3 minor criteria were found (Table I). SM was an indolent variant in all subjects, and in 2 cases, urticaria pigmentosa was confirmed by skin biopsies. All patients had a clinical history of grade IV reactions after sting, and all had to be treated in an emergency unit. The prescribed SITs were 6 Polistes dominulus (Anallergo, Florence, Italy), 8 Vespula germanica, 1 Polistes spp, and 1 Apis mellifera (Stallergenes, Antony, France).

Table I. Pathologic findings in 16 patients with HVA who fulfilled criteria for diagnosis of SM

No.	Age/sex	Serum tryptase (ng/mL)	>15 MCs/cluster (BM biopsy)	Atypical MC (BM smear)	MCs CD25/CD2⁺ (BM)	KIT D816V mutation (BM)	HVA
1∗	39/M	103.0	+	+	+	+	Apis m
2∗	33/M	56.2	+	+	+	+	Polistes d
3	62/M	31.6	–	+	–	+	Polistes d
4	19/M	20.0	–	–	+	+	Vespula g
5	45/M	13.7	+	+	+	–	Polistes d
6	74/M	21.2	+	–	+	–	Polistes spp
7	64/M	24.0	–	+	+	+	Polistes d
8	50/M	17.6	–	+	+	+	Polistes d
9	39/F	18.0	–	+	+	+	Vespula g
10	37/M	20.1	+	+	+	+	Vespula g
11	42/M	13.2	+	+	+	–	Vespula g
12	59/M	16.5	+	+	+	Not done	Vespula g
13	53/F	13.4	+	+	+	+	Polistes d
14	77/F	30.0	+	Not done	Not done	Not done	Vespula g
15	68/F	28.6	–	+	+	+	Vespula g
16	28/M	26.0	+	+	+	+	Vespula g

MC, Mast cell; BM, bone marrow; M, male; F, female; Apis m, Apis mellifera; Polistes d, Polistes dominulus; Vespula g, Vespula germanica.

∗Histologically confirmed cutaneous mastocytosis.

Two patients had reactions during the build-up phase of immunotherapy. One (patient 6) had generalized pruritus without skin lesions or other signs, and one (patient 9) had a grade I urticaria. In both cases, the dose escalation was temporarily stopped by repeating the last tolerated dose, and a premedication with cetirizine 10 mg was given. After 2 weeks, the patients could resume the build-up and reach the maintenance dose without further reactions. Thirteen patients received 1 or more Hymenoptera sting on-field during the maintenance phase, and only 2 of them (patient 3 and patient 14) had a grade IV reaction at the first resting. In these patients, the dose was safely increased to 200 μg, and at subsequent stings they had only a mild local reaction. In the remaining 11 patients, only mild local reactions were seen at re-sting.

On the basis of the current literature, SM is considered a high-risk situation for SIT in HVA, because severe events or fatalities can occur.³, ⁵ Nonetheless, these patients are also at very high risk when they are stung by the sensitizing Hymenoptera.², ³ and SIT can confer a satisfactory protection. On the basis of these considerations and previous clinical observations,⁶ we vaccinated several patients with SM without observing important side effects. Moreover, almost all of them achieved a relevant protection and decreased their grade of reaction from IV to I. The 2 patients who maintained a grade IV reaction on maintenance SIT could achieve a benefit by increasing the maintenance dose.⁸ We are aware that the population evaluated in our study is small, but if we take into account the rarity of SM and the low frequency of severe HVA, this study includes the largest cohorts of patients with HVA and SM treated with SIT. An accessory observation is that SM was indeed diagnosed in 16 of 121 patients with severe HVA. Thus it can be supposed that severe HVA could be a clinical manifestation of underlying SM, as reported with idiopathic anaphylaxis.⁹ This would support the usefulness of tryptase assay screening in patients with Hymenoptera-induced anaphylaxis. On the basis of the observed risk/benefit ratio, we suggest that patients with ascertained SM and HVA receive a specific vaccination with a very slow increase of the dose, carefully respecting the recommendations for a safe administration.

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