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Rapid oral desensitization in combination with omalizumab therapy in patients with cow’s milk allergy

2011; Elsevier BV; Volume: 127; Issue: 6 Linguagem: Inglês

10.1016/j.jaci.2011.04.009

1097-6825

Kari C. Nadeau, Lynda C. Schneider, Lisa Hoyte, I. Borras, Dale T. Umetsu,

Drug-Induced Adverse Reactions

To the Editor: We conducted a pilot phase I study in 11 children (age, 7-17 years) with cow’s milk allergy by using omalizumab (anti-IgE mAb; Xolair; Genentech, South San Francisco, Calif) in combination with relatively rapid oral milk desensitization. We hypothesized that oral desensitization might occur rapidly and with few side effects when performed with omalizumab. Our primary objectives were to examine the safety of this approach and to determine whether subjects could be dosed up to 2000 mg milk within 7 to 11 weeks of initiating the desensitization. Eleven patients with a history of IgE-mediated milk allergy were enrolled in the study at 2 sites—Children’s Hospital Boston and Stanford University—under institutional review board and US Food and Drug Administration approval. All subjects had histories of acute clinical reactions to milk, including immediate reactions (urticaria, vomiting, and/or anaphylaxis) after ingestion of milk, as well as elevated milk-specific IgE (median, 50 kilounits of antibody (kUA)/L; range, 41.6-342 kUA/L; Table I). At entry, the median wheal/flare skin prick test to milk was 20/50 mm (wheal/erythema diameter; range, 11-45/20-52 mm), and the median total serum IgE was 349 kU/L (range, 148-2593 kU/L). The median age was 8 years (range, 7-17 years). Seven subjects had a diagnosis of asthma and/or eczema. For children with IgE levels 700 kU/L, the dose was 225 to 300 mg (approximately 0.016 mg/kg/IgE [U/mL]) every 2 to 4 weeks. During the course of the study, subjects were asked to exclude all dairy products from their diets except what was given as the study milk dose.Table ICharacteristics of enrolled subjectsSubject no.Age (y)SexTotal IgE(kU/L)Milk-specificIgE(kUA/L)Milk skin testwheal (mm)/erythema (mm)Organ systems involved simultaneously in last historical reaction to milk (subjects had clinical reactivity to both cooked and uncooked milk products)∗None of the subjects had a diagnosis of eosinophilic esophagitis at screening and during the course of the study.Omalizumab dose and frequencyTotal doses of omalizumab111M5004225/50Urticaria, angioedema, vomiting225 mg every 2 wk928M3425045/50Wheezing, urticaria225 mg every 4 wk538M1487320/45Urticaria, wheezing150 mg every 4 wk5410F9004211/30Vomiting, congestion225 mg every 4 wk558M2395046/52Vomiting, generalized urticaria225 every 2 wk967F2974416/49Wheezing, vomiting, urticaria150 mg every 4 wk5712M1996815/50Wheezing, urticaria, allergic rhinitis150 mg every 4 wk4816M3495620/20Wheezing, urticaria, abdominal complaints225 mg every 2 wk12917M3644316/58Wheezing, urticaria, conjunctivitis300 mg every 2 wk9108F201626824/46Wheezing, vomiting, urticaria, conjunctivitis300 mg every 2 wk8117F259334216/22Wheezing, urticaria, conjunctivitis300mg every 2 wk9Median83495020/50Not applicableNot applicable8Entry criteria: children 4 to 18 years of age with cow’s milk–specific IgE >25 kUA/L, total IgE 25 kUA/L, total IgE 8000 mg/d, which included different types of milk products. In terms of overall safety, the mean frequency for total reactions reported by week 24 was 1.6% (32 reactions of 2199 doses total for all 11 subjects; Table II). All patients experienced some adverse events, though most reactions were defined as mild1Bock S.A. Sampson H.A. Atkins F.M. Zeiger R.S. Lehrer S. Sachs M. et al.Double-blind, placebo-controlled food challenge (DBPCFC) as an office procedure: a manual.J Allergy Clin Immunol. 1988; 82: 986-997Abstract Full Text PDF PubMed Scopus (12) Google Scholar (1%) and needed no treatment. There were moderate reactions (0.3%), and these included abdominal pain and vomiting, which responded within 1 hour to oral antihistamine dosing. Severe reactions (0.1%) included swelling of the tongue in 1 subject during the initial rush desensitization day, which responded to oral antihistamines. Another subject developed rhinitis and urticaria after the 1000-mg dose during the rush desensitization and responded to epinephrine. The most common types of reactions were local (mostly pruritus or urticaria) and/or gastrointestinal (eg, abdominal pain), occurring with a frequency of 1%. No reactions occurred that involved the cardiovascular system or that failed to respond rapidly to treatment. There were 2 other subjects who were given epinephrine at home by their guardians during the maintenance phase of dosing. One received epinephrine for a moderate reaction that was manifested by upper lip swelling and urticaria (7.5 cm × 5 cm) on the left upper leg; the second received epinephrine for urticaria (2.5 cm × 5 cm) on the right upper arm. In addition, this subject had wheezing, which began before the milk ingestion that day, and which most likely was a result of a viral infection. Overall, the reaction rate in our study was relatively low given the rapidity of the desensitization, although the rate of epinephrine use was similar to that in previous desensitization studies. All subjects tolerated omalizumab treatment with no signs of allergic reactions.Table IIOverall safety dataMilk doses per child, mean (range)209 (36-334)Total doses2301Symptom/treatmentNo. (%) of total dosesNo. of reactions per child, mean (range)Total reactions41 (1.8)3.7 (1-7)Grade 1 (mild) symptoms29 (1.3)2.6 (1-5)On rush desensitization day14During weekly dose escalation phase10During maintenance dosing5Grade 2 (moderate) symptoms8 (0.3)0.7 (0-2)On rush desensitization day5During weekly dose escalation phase1During maintenance dosing2Grade 3 (severe) symptoms4 (0.1)0.3 (0-1)On rush desensitization day2During weekly dose escalation phase1During maintenance dosing1Total number of subjects = 11.Grading of reactions was defined by Bock et al.1Bock S.A. Sampson H.A. Atkins F.M. Zeiger R.S. Lehrer S. Sachs M. et al.Double-blind, placebo-controlled food challenge (DBPCFC) as an office procedure: a manual.J Allergy Clin Immunol. 1988; 82: 986-997Abstract Full Text PDF PubMed Scopus (12) Google Scholar Grade 1 (mild) reactions did not require medications, whereas for any grade 2 (moderate) reaction, antihistamine was administered, and, in 2 cases, epinephrine was administered (by parent). Grade 3 (severe) reactions included 1 reaction during rush desensitization with severe rhinitis and moderate urticaria, treated with epinephrine (by physician); 1 reaction of generalized urticaria and severe rhinitis during the DBPCFC treated with antihistamines; 1 reaction of tongue swelling during the rush desensitization responding to oral antihistamines; and a reaction of severe abdominal pain during the home maintenance dosing, resolving with antihistamines. Reactions occurring at home were self-reported in diaries up to 24 to 28 weeks and were reported by phone or electronic mail throughout the study. Ten subjects have completed all 52 weeks of the study; reporting is complete for all subjects up to 36 weeks of the study. Open table in a new tab Total number of subjects = 11. Grading of reactions was defined by Bock et al.1Bock S.A. Sampson H.A. Atkins F.M. Zeiger R.S. Lehrer S. Sachs M. et al.Double-blind, placebo-controlled food challenge (DBPCFC) as an office procedure: a manual.J Allergy Clin Immunol. 1988; 82: 986-997Abstract Full Text PDF PubMed Scopus (12) Google Scholar Grade 1 (mild) reactions did not require medications, whereas for any grade 2 (moderate) reaction, antihistamine was administered, and, in 2 cases, epinephrine was administered (by parent). Grade 3 (severe) reactions included 1 reaction during rush desensitization with severe rhinitis and moderate urticaria, treated with epinephrine (by physician); 1 reaction of generalized urticaria and severe rhinitis during the DBPCFC treated with antihistamines; 1 reaction of tongue swelling during the rush desensitization responding to oral antihistamines; and a reaction of severe abdominal pain during the home maintenance dosing, resolving with antihistamines. Reactions occurring at home were self-reported in diaries up to 24 to 28 weeks and were reported by phone or electronic mail throughout the study. Ten subjects have completed all 52 weeks of the study; reporting is complete for all subjects up to 36 weeks of the study. Previous studies of slow, deliberate oral milk desensitization in patients with cow’s milk allergy showed that desensitization can increase the amount of milk tolerated by many of the treated subjects.2Skripak J.M. Nash S.D. Rowley H. Brereton N.H. Oh S. Hamilton R.G. et al.A randomized, double-blind, placebo-controlled study of milk oral immunotherapy for cow’s milk allergy.J Allergy Clin Immunol. 2008; 122: 1154-1160Abstract Full Text Full Text PDF PubMed Scopus (493) Google Scholar, 3Meglio P. Bartone E. Plantamura M. Arabito E. Giampietro P.G. A protocol for oral desensitization in children with IgE-mediated cow’s milk allergy.Allergy. 2004; 59: 980-987Crossref PubMed Scopus (320) Google Scholar, 4Longo G. Barbi E. Berti I. Meneghetti R. Pittalis A. Ronfani L. et al.Specific oral tolerance induction in children with very severe cow’s milk-induced reactions.J Allergy Clin Immunol. 2008; 121: 343-347Abstract Full Text Full Text PDF PubMed Scopus (412) Google Scholar, 5Staden U. Blumchen K. Blankenstein N. Dannenberg N. Ulbricht H. Dobberstein K. et al.Rush oral immunotherapy in children with persistent cow’s milk allergy.J Allergy Clin Immunol. 2008; 122: 418-419Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar, 6Pajno G.B. Caminiti L. Ruggeri P. De Luca R. Vita D. La Rosa M. et al.Oral immunotherapy for cow’s milk allergy with a weekly up-dosing regimen: a randomized single-blind controlled study.Ann Allergy Asthma Immunol. 2010; 105: 376-381Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar We now show that milk desensitization can be performed relatively rapidly with minimal hospitalization time when combined with omalizumab treatment. The limitations of our study include the small sample size, the lack of a placebo group, and lack of a baseline oral food challenge. In addition, it is possible that our desensitization protocol with omalizumab might be further optimized by limiting the number of milk doses during the rush phase; by extending the dose escalation phase over a longer period, beyond the 7 to 11 weeks used in our current protocol; and by performing the DBPCFC 12 or more weeks after discontinuation of omalizumab. In summary, we demonstrated that omalizumab treatment combined with oral milk desensitization in children with clinical reactions to cow’s milk permitted rapid milk dose escalation in the majority of subjects. This study is the first to use omalizumab in combination with oral desensitization and demonstrates a potential value of this approach for the treatment of food allergy, a major public health problem,7Boyce J.A. Assa’ad A. Burks A.W. Jones S.M. Sampson H.A. Wood R.A. et al.Guidelines for the diagnosis and management of food allergy in the United States: summary of the NIAID-sponsored Expert Panel report.J Allergy Clin Immunol. 2010; 126: 1105-1118Abstract Full Text Full Text PDF PubMed Scopus (1282) Google Scholar, 8Branum A.M. Lukacs S.L. Food allergy among children in the United States.Pediatrics. 2009; 124: 1549-1555Crossref PubMed Scopus (583) Google Scholar, 9Sicherer S.H. Sampson H.A. Food allergy.J Allergy Clin Immunol. 2010; 125: S116-S125Abstract Full Text Full Text PDF PubMed Scopus (911) Google Scholar although it must be first confirmed by future phase II and III trials. Nine of the 11 patients achieved the primary objective, tolerating desensitization to a dose of 2000 mg/d within a period of 7 to 11 weeks. Moreover, 9 of the 10 patients who completed the study passed a DBPCFC and an open challenge of milk without symptoms. Importantly, the 9 patients, after passing the DBPCFC, began tolerating almost normal amounts of milk in their diet (≥240 mL, equivalent to >8000 mg/d). The tenth patient is tolerating 4000 mg/d. We thank Genentech for generously providing omalizumab for this trial; Drs Hans Oettgen, Francisco Bonilla, and William Berquist, who are members of the Data and Safety Monitoring Board; Dr Lisa Bartnikas for reviewing this article critically; and our patients for participating in this study.