Could daratumumab be used to treat severe allergy?

Abstract

Allergic diseases, such as allergic asthma, rhinitis, and food allergy, affect millions of people worldwide and their prevalence seems to be increasing. Desensitization via allergy immunotherapy (AIT) is available for some allergens, such as pollen and insect venom, and there is a renewed interest in immunotherapy in food allergy. Although a strict and lengthy regimen of AIT is generally able to strongly decrease symptoms, no true curative treatment is available. Therefore, avoidance of the eliciting allergens is often necessary. Still, accidental exposure to culprit allergens occurs. In case of food allergy, this often leads to hospital admission and, in severe cases, treatment in an intensive care unit. A high need exists for curative treatment options. The specific immune response that defines allergy is characterized by the presence of IgE directed to an allergen (sensitization). After sensitization, exposure to an allergen induces crosslinking of IgE bound to mast cells and basophils, causing a wide release of vasoactive mediators, such as histamine. Therefore, therapy directed against IgE has been a research focus for several years. Therapy using mAbs against IgE (omalizumab) has proven to be effective in allergic asthma, with effectiveness also being researched in other (atopic) diseases, such as allergic rhinitis, and atopic dermatitis.1Baena-Cagnani C.E. Gómez R.M. Current status of therapy with omalizumab in children.Curr Opin Allergy Clin Immunol. 2014; 14: 149-154Crossref PubMed Scopus (22) Google Scholar In food allergy, omalizumab might be able to increase allergen tolerability in some patients and its role in (oral) AIT for food allergy is actively investigated. A different method of targeting IgE is by depleting plasma cells that produce (specific) IgE. The effect of B-cell depletion on IgE levels and clinical symptoms of atopic diseases has been studied before. For example, rituximab did not significantly decrease serum IgE levels compared with placebo at 3 or 6 months in patients with Idiopathic thrombocytopenic purpura.2Dasgupta A. Radford K. Arnold D.M. Thabane L. Nair P. The effects of rituximab on serum IgE and BAFF.Allergy Asthma Clin Immunol. 2013; 9: 39Crossref PubMed Scopus (7) Google Scholar Bortezomib, targeting (malignant) plasma cells via proteasome inhibition, is also being investigated as a treatment option in (auto)antibody-mediated diseases.3Rosenberg A.S. Pariser A.R. Diamond B. Yao L. Turka L.A. Lacana E. et al.A role for plasma cell targeting agents in immune tolerance induction in autoimmune disease and antibody responses to therapeutic proteins.Clin Immunol. 2016; 165: 55-59Crossref PubMed Scopus (16) Google Scholar In a mouse model for chronic asthma, bortezomib treatment reduced specific IgE (sIgE) levels.4Wegmann M. Lunding L. Orinska Z. Wong D.M. Manz R.A. Fehrenbach H. Long-term bortezomib treatment reduces allergen-specific IgE but fails to ameliorate chronic asthma in mice.Int Arch Allergy Immunol. 2012; 158: 43-53Crossref PubMed Scopus (12) Google Scholar The effect of plasma cell depletion on sIgE levels in humans remains unknown. Daratumumab is an mAb targeting CD38, which is highly expressed on malignant plasma cells. Because daratumumab has marked single agent activity in multiple myeloma (MM) and a favorable safety profile, it was recently approved by the Food and Drug Administration for the treatment of relapsed/refractory MM.5Lokhorst H.M. Plesner T. Laubach J.P. Nahi H. Gimsing P. Hansson M. et al.Targeting CD38 with daratumumab monotherapy in multiple myeloma.N Engl J Med. 2015; 373: 1207-1219Crossref PubMed Scopus (802) Google Scholar We wanted to test the hypothesis that treatment with daratumumab reduces the levels of total and specific IgE via depletion of IgE-producing plasma cells. To evaluate this, residual blood samples were collected from patients with relapsed or refractory MM treated with daratumumab monotherapy or daratumumab plus lenalidomide-dexamethasone in the University Medical Center Utrecht, Utrecht, The Netherlands, in the period April to August 2014.5Lokhorst H.M. Plesner T. Laubach J.P. Nahi H. Gimsing P. Hansson M. et al.Targeting CD38 with daratumumab monotherapy in multiple myeloma.N Engl J Med. 2015; 373: 1207-1219Crossref PubMed Scopus (802) Google Scholar, 6Plesner T. Arkenau H.-T. Gimsing P. Krejcik J. Lemech C. Minnema M.C. et al.Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma.Blood. 2016; 128 ([published online ahead of print August 16, 2016]): 1821-1828Crossref PubMed Scopus (85) Google Scholar Routine blood analysis was performed at baseline and after every 4 weeks of daratumumab treatment. In the baseline samples, total IgE level was determined and an ImmunoCAP Phadiatop (ThermoFisher, Uppsala, Sweden) was performed, according to manufacturer's instructions, to indicate sensitization to common inhalant allergens (eg, tree/grass pollen, animal dander, and house dust mite). If the Phadiatop was positive, sIgE levels against birch pollen, timothy grass pollen, and house dust mite were determined using ImmunoCAP (ThermoFisher). These are among the most frequently recognized inhalant allergens in the Netherlands. A total of 8 patients with MM were included, 5 treated with daratumumab monotherapy (16 mg/kg) and 3 with daratumumab (16 mg/kg) plus lenalidomide-dexamethasone (25 and 40 mg, respectively). Four patients had a detectable IgE level (≥2 kU/L) at baseline and are listed in Table I. All 4 subjects demonstrated a decrease in both benign and malignant plasma cells at 8 or 12 weeks of treatment (see Table E1 in this article's Online Repository at www.jacionline.org). Only for patient 1, total IgE levels were elevated above reference levels and a positive Phadiatop as well as sIgE against inhalant allergens were detected. Additional samples from patient 1 at week 4, 8, 12, 16, and 20 were analyzed, demonstrating a decrease of more than 80% in both total and specific IgE levels for timothy grass pollen and house dust mite after 20 weeks (Table II; see Fig E1 in this article's Online Repository at www.jacionline.org). Patient 1 achieved a complete response as determined by evaluation of plasma cell percentages in bone marrow aspirate and M-protein levels (see Tables E1 and E2 in this article's Online Repository at www.jacionline.org). The other 3 patients with detectable IgE levels also demonstrated a decrease in total IgE level after 8 weeks of treatment. For patient 2, total IgE levels decreased 88% (41 to 5 kU/L). For the other 2 patients, baseline IgE levels were very low and dropped below detection limit after 8 weeks.Table IMeasurements at baseline of patients with detectable IgEPatientTreatmentTotal IgE (kU/L)PhadiatopBirch pollen sIgE (kU/L)Timothy grass pollen sIgE (kU/L)HDM sIgE (kU/L)1D + LD356PositiveNegative9.833.232D + LD41NegativeNDNDND3D3NegativeNDNDND4D + LD7NegativeNDNDNDReference values: Total IgE, <100 kU/L; ImmunoCAP sIgE birch pollen/timothy grass pollen/HDM, <0.35 kU/L.D, Daratumumab monotherapy; D + LD, daratumumab plus lenalidomide-dexamethasone; HDM, house dust mite; ND, not determined. Open table in a new tab Table IIPatient 1 total and specific IgE levels at the investigated time pointsIgE levelsWeekWeek 0Week 4Week 8Week 12Week 16Week 20Total IgE (kU/L)3561971851459544Timothy grass pollen (kU/L)9.836.076.886.634.11.67HDM (kU/L)3.231.931.541.060.730.4Reference values: Total IgE, <100 kU/L; ImmunoCAP sIgE timothy grass pollen/HDM, <0.35 kU/L.HDM, House dust mite. Open table in a new tab Reference values: Total IgE, <100 kU/L; ImmunoCAP sIgE birch pollen/timothy grass pollen/HDM, <0.35 kU/L. D, Daratumumab monotherapy; D + LD, daratumumab plus lenalidomide-dexamethasone; HDM, house dust mite; ND, not determined. Reference values: Total IgE, <100 kU/L; ImmunoCAP sIgE timothy grass pollen/HDM, <0.35 kU/L. HDM, House dust mite. This proof of concept demonstrates that levels of total and specific IgE gradually decrease during daratumumab treatment in a single patient sensitized to 2 common inhalant allergens. This patient was cotreated with lenalidomide and dexamethasone. The effect of lenalidomide on IgE levels is unknown, although there are reports of increased immunoglobulin levels after lenalidomide treatment in chronic lymphocytic leukemia.7Lapalombella R. Andritsos L. Liu Q. May S.E. Browning R. Pham L.V. et al.Lenalidomide treatment promotes CD154 expression on CLL cells and enhances production of antibodies by normal B cells through a PI3-kinase-dependent pathway.Blood. 2010; 115: 2619-2629Crossref PubMed Scopus (106) Google Scholar, 8Strati P. Keating M.J. Wierda W.G. Badoux X.C. Calin S. Reuben J.M. et al.Lenalidomide induces long-lasting responses in elderly patients with chronic lymphocytic leukemia.Blood. 2013; 122: 734-737Crossref PubMed Scopus (63) Google Scholar Glucocorticoids are known to increase IgE synthesis.9Wu C.Y. Sarfati M. Heusser C. Fournier S. Rubio-Trujillo M. Peleman R. et al.Glucocorticoids increase the synthesis of immunoglobulin E by interleukin 4-stimulated human lymphocytes.J Clin Invest. 1991; 87: 870-877Crossref PubMed Scopus (147) Google Scholar Therefore, the drop in IgE levels observed in this study is unlikely to result from dexamethasone and lenalidomide cotreatment. Daratumumab is well tolerated both alone and in combination with other agents, with infusion-related reactions as the most frequent adverse reactions. These occur in approximately 50% of patients and mostly during the first infusion.5Lokhorst H.M. Plesner T. Laubach J.P. Nahi H. Gimsing P. Hansson M. et al.Targeting CD38 with daratumumab monotherapy in multiple myeloma.N Engl J Med. 2015; 373: 1207-1219Crossref PubMed Scopus (802) Google Scholar, 6Plesner T. Arkenau H.-T. Gimsing P. Krejcik J. Lemech C. Minnema M.C. et al.Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma.Blood. 2016; 128 ([published online ahead of print August 16, 2016]): 1821-1828Crossref PubMed Scopus (85) Google Scholar However, adverse reactions as well as long-term effects in a relatively healthy, allergic population could differ from those in patients with MM and require additional studies. In asthma, IgE depletion by omalizumab treatment resulted in clinical improvement, as well as an increased quality of life and reduced socioeconomic burden of disease, both in clinical trials and in daily practice studies. Although this proof of concept demonstrates the potential value of daratumumab in the management of severe IgE-mediated diseases, its effect on clinical parameters of allergy has yet to be investigated. Table E1Bone marrow plasma cell numbers for the 4 patients with detectable IgE as determined by flow cytometric analysis, as well as response to treatmentPatientResponse to treatment% Benign plasma cells% Malignant plasma cellsPretreatmentAt week 8/12PretreatmentAt week 8/121CR0.4200.2400.2260.0152CR0.1680.0332.4850.5393PD0.03202.5430.2834CR0.05506.2140.025CR, Complete response; PD, progressive disease. Open table in a new tab Table E2M-protein and free kappa light-chain levels for patient 1 at the investigated time pointsTime pointM-protein levels quantitative (g/L)Free kappa light-chains (mg/L)Week 01652.96Week 4514.52Week 8316.40Week 12014.28Week 16013.58Week 20012.69 Open table in a new tab CR, Complete response; PD, progressive disease.