David E. Sloane

Hypersensitivity reactions to chemotherapy: Outcomes and safety of rapid desensitization in 413 cases

BACKGROUND Hypersensitivity reactions (HSRs) to chemotherapeutic drugs, including mAbs, often require that the provoking medication be discontinued, thus raising a dilemma for the caregiver: further use could precipitate a severe, even fatal, allergic reaction on re-exposure, but alternative drugs might be poorly tolerated or much less effective compared with the preferred agent. OBJECTIVE We have developed a standardized rapid desensitization protocol for achieving temporary tolerization to drug allergens. In this study we evaluate the safety and efficacy of this protocol. METHODS Ninety-eight patients who had HSRs in response to treatment with carboplatin, cisplatin, oxaliplatin, paclitaxel, liposomal doxorubicin, doxorubicin, or rituximab received rapid desensitization to these agents. A standardized 12-step protocol was used, with treatment given intravenously or intraperitoneally. Initial desensitizations occurred in the medical intensive care unit, whereas most subsequent infusions took place in an outpatient setting. Safety and efficacy of the protocol were assessed by review of treatment records. RESULTS Of the 413 desensitizations performed, 94% induced mild or no reactions. No life-threatening HSRs or deaths occurred during the procedure, and all patients received their full target dose. Most reactions occurred during the first desensitization. Reactions were most commonly reported at the last step of the protocol. Desensitizations through the intravenous and intraperitoneal routes were equally effective. CONCLUSIONS Our standardized 12-step protocol for rapid drug desensitization is safe and effective and has been adopted as the standard of care at our institutions in treating patients with HSRs to chemotherapeutic drugs, including mAbs.

Hypersensitivity reactions to mAbs: 105 desensitizations in 23 patients, from evaluation to treatment

BACKGROUND Rapid desensitization, a procedure for graded drug administration, allows for the safe readministration of a medication after certain types of hypersensitivity reactions (HSRs) and is indicated in cases in which there are no reasonable therapeutic alternatives. The use of rapid desensitization for HSRs to mAbs has not been validated. OBJECTIVE We sought to describe our experience with rapid desensitization to mAbs, including rituximab, infliximab, and trastuzumab. METHODS One hundred five rapid desensitizations were performed in 23 patients with a standardized 12-step, 6-hour protocol. Our approach to patient evaluation before desensitization is described. The severity, characteristics, and timing of both initial HSRs and HSRs during desensitization were determined by means of retrospective review of medical records. After a reaction during desensitization, patient-specific protocol modifications were made before each subsequent desensitization. RESULTS 104 of 105 desensitizations undertaken were successfully completed. We observed HSRs during 29% of desensitizations, including 27 mild reactions, 1 moderate reaction, and 2 severe reactions. Overall, reactions during desensitization were markedly less severe than initial HSRs, but reactions did recur in a minority of successive desensitizations. CONCLUSIONS Rapid desensitization is a promising method for the delivery of monoclonal therapeutics after an HSR, but the possibility of a reaction remains with each desensitization.

Activation of human eosinophils through leukocyte immunoglobulin-like receptor 7

Eosinophils are implicated prominently in allergic diseases and the host response to parasitic infections. Eosinophils may be activated in vitro by diverse classes of agonists such as immunoglobulins, lipid mediators, and cytokines. The leukocyte Ig-like receptors (LIRs) comprise a family of inhibitory and activating cell-surface receptors. Inhibitory LIRs down-regulate cellular responses through cytoplasmic immunoreceptor tyrosine-based inhibitory motifs. There are limited data on the action of the activating LIRs, which are thought to signal through the Fc receptor γ chain, which contains an immunoreceptor tyrosine-based activation motif. We now demonstrate the expression of LIR1 (inhibitory), LIR2 (inhibitory), LIR3 (inhibitory), and LIR7 (activating) on eosinophils from 4, 4, 12, and 11, respectively, of 12 healthy donors. Cross-linking of LIR7 with plate-bound antibody elicited the dose- and time-dependent release of eosinophil-derived neurotoxin and leukotriene C4. Eosinophils activated with antibodies to LIR7 embedded in gel-phase EliCell preparations showed leukotriene C4 generation at the nuclear envelope and the release of IL-12 but not IL-4 by vesicular transport. Thus, LIR7 is an activating receptor for eosinophils that elicited the release of cytotoxic granule proteins, de novo lipid mediator generation, and cytokine release through vesicular transport.

Desensitization regimens for drug allergy: state of the art in the 21st century.

Adverse reactions to drugs are increasingly being recognized as important contributions to disease in their own right as well as impediments to the best treatment of various conditions, including infectious, autoimmune, and neoplastic maladies. Rapid drug desensitization (RDD) is an effective mechanism for safely administering important medications while minimizing or entirely circumventing such adverse reactions in sensitized patients. We reviewed the literature on RDD in the last 10 years, including our experience from the Brigham and Womens Hospital Desensitization Program with hundreds of patients desensitized to a broad variety of drugs. RDD in our programme has been uniformly successful in patients with hypersensitivity reactions to antibiotics, chemotherapeutics, and monoclonal antibodies. Any reactions that occur during desensitization are generally much less severe than the initial hypersensitivity reaction to the drug, and patients have received the full dose of the desired medication 99.9% of the time out of (796) desensitizations. To date, there have been no fatalities. RDD is a safe and highly effective method for treating sensitized patients with the optimal pharmacologic agents. Its use should be expanded, but because patient safety is paramount, protocols must be created, reviewed, and overseen by allergist–immunologists with special training and experience in modern techniques of desensitization.

Hereditary angioedema : a current state-of-the-art review, V: attenuated androgens for the treatment of hereditary angioedema

OBJECTIVE To provide a summary of the literature regarding the use of attenuated androgens during the past 40 to 50 years for the treatment of hereditary angioedema (HAE). DATA SOURCES MEDLINE and PubMed were searched to identify studies involving the treatment of HAE with androgens. STUDY SELECTION Studies were selected based on their relevance to the use of androgens for the treatment of HAE. RESULTS Attenuated androgens have proven successful for the short- and long-term treatment of HAE. Adverse effects are still concerning, and their use in children and pregnant women must be undertaken with great caution. Scheduled monitoring of liver function tests and lipid profiles in patients treated with these medications is critical. CONCLUSIONS Attenuated androgens have been successful in the short- and long-term treatment of HAE, and they are still the most frequently used medications in the United States for the treatment of this disease. There is a lack of readily available options for the treatment of acute HAE attacks apart from the administration of fresh frozen plasma or safe prophylactic therapies; however, several appropriate agents currently in clinical trials in the United States appear promising.

Purification from human milk of matriptase complexes with secreted serpins: mechanism for inhibition of matriptase other than HAI-1

Matriptase, a type 2 transmembrane serine protease, is predominately expressed by epithelial and carcinoma cells in which hepatocyte growth factor activator inhibitor 1 (HAI-1), a membrane-bound, Kunitz-type serine protease inhibitor, is also expressed. HAI-1 plays dual roles in the regulation of matriptase, as a conventional protease inhibitor and as a factor required for zymogen activation of matriptase. As a consequence, activation of matriptase is immediately followed by HAI-1-mediated inhibition, with the activated matriptase being sequestered into HAI-1 complexes. Matriptase is also expressed by peripheral blood leukocytes, such as monocytes and macrophages; however, in contrast to epithelial cells, monocytes and macrophages were reported not to express HAI-1, suggesting that these leukocytes possess alternate, HAI-1-independent mechanisms regulating the zymogen activation and protease inhibition of matriptase. In the present study, we characterized matriptase complexes of 110 kDa in human milk, which contained no HAI-1 and resisted dissociation in boiling SDS in the absence of reducing agents. These complexes were further purified and dissociated into 80-kDa and 45-kDa fragments by treatment with reducing agents. Proteomic and immunological methods identified the 45-kDa fragment as the noncatalytic domains of matriptase and the 80-kDa fragment as the matriptase serine protease domain covalently linked to one of three different secreted serpin inhibitors: antithrombin III, alpha1-antitrypsin, and alpha2-antiplasmin. Identification of matriptase-serpin inhibitor complexes provides evidence for the first time that the proteolytic activity of matriptase, from those cells that express no or low levels of HAI-1, may be controlled by secreted serpins.

Safety, Costs, and Efficacy of Rapid Drug Desensitizations to Chemotherapy and Monoclonal Antibodies

BACKGROUND Rapid drug desensitization (RDD) is used to address hypersensitivity reactions to chemotherapeutics and monoclonal antibodies, allowing patients to be treated with optimal pharmacological agents. RDD protocols are tailored to each individual patients reaction and needs, and protect against anaphylaxis, but overall risks, costs, and benefits have not been determined. OBJECTIVE We investigated the safety, efficacy, costs, and life expectancy of patients in a large population undergoing RDD. METHODS We analyzed 2177 RDD procedures performed in 370 patients with cancer, vasculitis, and hematological and connective tissue diseases who presented 402 reactions. A subgroup of carboplatin allergic patients with ovarian cancer treated with RDD was analyzed for costs and life expectancy and compared with a nonallergic control group. RESULTS RDD allowed all patients to receive safely the full dose of the medication to which they were reactive. A gradual increase in the fraction of outpatient desensitizations from 81% to 98% was achieved through risk stratification. Of the 2177 desensitizations, 93% had no or mild reactions whereas 7% had moderate to severe reactions, which did not preclude the completion of the treatment, and there were no deaths. Overall health costs in the carboplatin allergic group were not higher than those in the nonallergic group treated with standard of care. Administration of carboplatin through RDD was as effective as standard administration with a nonsignificant increase in life expectancy in desensitized patients as compared with nonallergic, nondesensitized controls. CONCLUSIONS RDD is cost effective and safe for allergic patients with cancer and chronic disease to remain on first line therapy.

Autoimmune progesterone dermatitis: clinical presentation and management with progesterone desensitization for successful in vitro fertilization

OBJECTIVE To report clinical cases of autoimmune progesterone (P) dermatitis, its relationship to IVF, and the potential for P desensitization to treat these cases to achieve viable pregnancies. DESIGN Clinical description. SETTING Institutional hospitalary practice. Allergy Division. PATIENT(S) Six patients from the Allergy Clinic consulting for cyclic rashes or anaphylaxis related to the luteal phase of the menstrual cycle. Three of the conditions were related to IVF. INTERVENTION(S) Skin tests were performed with P. For IVF, rapid 8- and 10-step P desensitization protocols were performed, with increasing doses administered every 20 minutes via intravaginal suppositories. A rapid oral desensitization protocol was performed in one patient who required an oral contraceptive for uterine bleeding. MAIN OUTCOME MEASURE(S) Progesterone skin test results. Tolerance to P desensitization. Achievement of viable pregnancies. RESULT(S) Skin tests were positive in all patients and negative in 10 controls. Desensitization was successful in four patients: three patients for IVF, resulting in viable pregnancies. Another patient achieved tolerance to oral contraceptives. CONCLUSION(S) Women with autoimmune P dermatitis can be desensitized successfully to P. We provide the first evidence of successful P desensitization in patients requiring IVF culminating in successful pregnancies.

Induced Loss of Syk in Human Basophils by Non-IgE-Dependent Stimuli

In the general population, Syk expression in human basophils is highly variable and correlates well with the IgE-mediated responsiveness of these cells. Previous studies established that IgE-mediated stimulation results in loss of Syk expression. The current studies investigated whether stimulation through other receptors results in loss of Syk. Two classes of stimulation were examined, those that operate through the kinase Syk and those that operate through a GTP-binding protein. These studies demonstrated that aggregation of leukocyte Ig-like receptor LILRA-2 resulted in phosphorylation of Syk and c-Cbl, was inhibited by a third generation Syk inhibitor with an expected IC50, and induced histamine release in strict proportion to release induced by anti-IgE Ab. Stimulation of LILRA-2 for 18 h resulted in modest loss of Syk that correlated with the more profound loss of Syk induced by anti-IgE Ab. Human recombinant histamine-releasing factor has also recently been shown to induce Syk phosphorylation and in the current studies has also been shown to induce loss of Syk in 18-h cultures. fMLP stimulation for 18 h was also found to induce modest loss of Syk. fMLP induced phosphorylation of c-Cbl that was sustained for at least 45 min. Phosphorylation of c-Cbl was inhibited by a Syk kinase inhibitor but with an IC50 that was not consistent with Syk activity, suggesting another kinase was responsible for Cbl phosphorylation following fMLP. These studies demonstrate that it is possible to induce the loss of Syk expression in human basophils by a non-IgE-dependent mechanism and even by a mechanism that does directly involve Syk in the reaction complex.

Desensitization for hypersensitivity reactions to medications.

Rapid drug desensitization (RDD) is a technique that induces temporary tolerance to a drug, allowing a medication-allergic patient to receive the optimal agent for his or her disease. Through RDD, patients with IgE and non-IgE hypersensitivity reactions (HSRs) including anaphylaxis can safely be administered important medications while minimizing or completely inhibiting adverse reactions. Adverse reactions to drugs are increasingly recognized as important contributors to disease as well as impediments to the best treatment of dermatological, infectious, autoimmune, and neoplastic disorders. With the development of novel pharmacologic agents and the evolution of personalized treatments based on pharmacogenetic profiling, clinicians must decide which agent is the best for a particular patient with a given disease. Biological agents have greatly improved the treatment of chronic inflammatory diseases and malignancies while limiting some medication-associated toxicities. Because of better outcomes, longer patient survival, and extended treatment courses, patients are exposed to drugs more frequently and for longer time periods, increasing the risk of sensitization and the potential for HSRs. The frequency of adverse drug reactions has therefore increased in the last 10 years. Because of the severity of some reactions and the fear of inducing a potentially lethal reaction in highly sensitized patients, first-line treatments are sometimes abandoned, relegating hypersensitive patients to secondary, less effective, therapy. Some of these reactions are mast cell-mediated HSRs, a subset of which occur through an IgE-dependent mechanism, and are thus true allergies. Others involve mast cells, but an IgE mechanism cannot be demonstrated. Both types of reactions are amenable to RDD, and our group has successfully performed several hundred desensitizations to chemotherapy, antibiotics and biological agents including monoclonal antibodies with a standardized 12-step protocol that can be universally applied to all desensitizations. The molecular basis of RDD has now been studied, and an in vitro mouse mast cell model has shown that RDD is an antigen-specific process that does not induce subclinical mast cell mediator release, and that blocks the release of acute and late mast cell mediators by preventing calcium influx and antigen/IgE/and IgE receptor internalization.