Matthieu Picard

Expanding Spectrum of Mast Cell Activation Disorders: Monoclonal and Idiopathic Mast Cell Activation Syndromes

BACKGROUND In recent years, 2 new syndromes of mast cell activation have been described in patients with episodes of mast cell mediator release that range from flushing and abdominal cramping to anaphylaxis: monoclonal mast cell activation syndrome (MMAS) and idiopathic mast cell activation syndrome (MCAS). OBJECTIVE This review will discuss these 2 new syndromes in the larger context of mast cell activation disorders as well as the diagnostic and treatment approaches for these conditions. METHODS PubMed was searched using the following terms: mast cell activation disorder, mast cell activation syndrome, and clonal mast cell. Only English-language articles published up until February 27, 2013, were considered. RESULTS MMAS has been diagnosed in patients with systemic reactions to hymenoptera stings and elevated baseline serum tryptase as well as in patients with unexplained episodes of anaphylaxis. A bone marrow biopsy establishes the diagnosis by revealing the presence of monoclonal mast cells that carry the D816V KIT mutation and/or express CD25 while the diagnostic requirements for systemic mastocytosis are not met. MCAS affects predominantly women in whom no mast cell abnormality or external triggers account for their episodes of mast cell activation. MCAS is a diagnosis of exclusion, and primary and secondary mast cell activation disorders as well as idiopathic anaphylaxis have to be ruled out before making the diagnosis. Patients with MCAS and MMAS are treated in a stepwise fashion with drugs that block the effects of mediators released by mast cells on activation. One third of MCAS patients experience complete resolution of symptoms with treatment, while one third have a major response and one third a minor response to treatment. A combination of drugs is usually necessary to achieve symptom control. No drug trial has been performed in patients with MMAS and MCAS. CONCLUSIONS MMAS and MCAS are 2 newly described, rare syndromes of mast cell activation. Further studies will be necessary to better understand the cause of these conditions and their natural evolution and to validate and improve the treatment approach. Research should also focus on developing drugs with the potential to cure these debilitating disorders. To achieve these goals, centers with expertise in mast cell activation disorders are essential as they allow for a critical mass of these patients to be enrolled in studies while providing those patients with the most up-to-date diagnostic procedures and treatment strategies.

Risk stratification and skin testing to guide re-exposure in taxane-induced hypersensitivity reactions

BACKGROUND The optimal approach to patients with hypersensitivity reactions (HSRs) to taxanes has not been established. OBJECTIVE We sought to assess the safety and efficacy of risk stratification based on the severity of the initial HSR and skin testing for guiding taxane reintroduction in patients with an HSR to these agents. METHODS Data on 164 patients treated for a taxane-related HSR from April 2011 to August 2014 at the Dana-Farber Cancer Institute and Brigham and Womens Hospital were collected retrospectively. Patients were re-exposed to taxanes either through desensitization, challenge, or regular infusion based on the severity of the initial HSR and skin test response. Depending on the initial risk stratification and tolerance to re-exposure, patients were then treated with shorter desensitization protocols, challenge, or both with the aim of resuming regular infusions, except in patients with a severe immediate initial HSR. RESULTS Of 138 patients desensitized, 29 (21%) had an immediate and 20 (14%) had a delayed HSR with the procedure. Of 49 patients challenged, 2 (4%) had a mild immediate and 1 (2%) had a delayed HSR with the procedure. No patients had a severe immediate HSR with desensitization or challenge. Thirty-six (22%) patients eventually resumed regular infusions. These patients were more likely to have negative skin test responses and to have experienced a delayed or mild immediate initial HSR. CONCLUSIONS Risk stratification based on the severity of the initial HSR and skin testing to guide taxane reintroduction is safe and allows a significant number of patients to resume regular infusions.

Re-visiting Hypersensitivity Reactions to Taxanes: A Comprehensive Review

Taxanes (a class of chemotherapeutic agents) are an important cause of hypersensitivity reactions (HSRs) in cancer patients. During the last decade, the development of rapid drug desensitization has been key to allow patients with HSRs to taxanes to be safely re-treated although the mechanisms of these HSRs are not fully understood. Earlier studies suggested that solvents, such as Cremophor EL used to solubilize paclitaxel, were responsible for HSRs through complement activation, but recent findings have raised the possibility that some of these HSRs are IgE-mediated. Taxane skin testing, which identifies patients with an IgE-mediated sensitivity, appears as a promising diagnostic and risk stratification tool in the management of patients with HSRs to taxanes. The management of patients following a HSR involves risk stratification and re-exposure could be performed either through rapid drug desensitization or graded challenge based on the severity of the initial HSR and the skin test result. Rapid drug desensitization has been shown to be an effective and safe method to re-introduce taxanes in hundreds of patients, including those with life-threatening HSRs. Patients with non-severe delayed skin HSRs may benefit from rapid drug desensitization since they may be at increased risk for an immediate HSR upon re-exposure. This review focuses on the clinical presentation, diagnosis, and novel mechanisms of immediate HSRs to taxanes. A new management strategy for HSRs to taxanes based on skin testing and rapid drug desensitization is proposed.

Drug Desensitization in the Management of Hypersensitivity Reactions to Monoclonal Antibodies and Chemotherapy

Hypersensitivity reactions to monoclonal antibodies and chemotherapy, which may vary in severity from mild to life-threatening, can lead to their discontinuation and replacement by alternative agents that are often less effective, more toxic, and/or more expensive. Drug desensitization has emerged as the best treatment modality capable of allowing re-introduction of the hypersensitivity reaction-inducing medication in highly sensitized patients in need of first line therapies. In recent years, the availability of new anti-neoplastic drugs and therapeutic monoclonal antibodies has increased, as has the potential for hypersensitivity reactions. Development of desensitization protocols for these new medications requires a careful assessment of the potential risks and benefits. The purposes of this review are to provide an overview of the presentation of hypersensitivity reactions amenable to desensitization and to increase awareness of the indications for and outcomes of desensitization protocols. Rapid drug desensitization has proven to be a safe and effective way of administering first line therapy to patients with hypersensitivity reactions, providing an extremely powerful treatment modality for patients for whom alternative drugs are deemed unacceptable. Rapid drug desensitization protocols should be administered only by highly trained allergists and nurses who have experience in determining which reactions are amenable to desensitization, and can identify high risk patients and provide them with appropriate care. Efforts should be made to increase awareness of the remarkable safety and efficacy of rapid drug desensitization among non-allergists, especially in the fields of oncology and rheumatology, so as to favor its universal application. Development of desensitization units to provide state-of-the-art care is possible only through coordinated teamwork.

Diagnostic Tools for Hypersensitivity to Platinum Drugs and Taxanes: Skin Testing, Specific IgE, and Mast Cell/Basophil Mediators

Hypersensitivity reactions (HSRs) to platinum drugs and taxanes are increasing in cancer patients, and rapid drug desensitization has emerged as a safe and effective method to reintroduce these drugs in reactive patients. Optimal management of patients presenting HSRs to chemotherapy depends on the use of various diagnostic tools, which include measurement of mast cell/basophil mediator release following a HSR and skin testing. Serum tryptase should be measured in patients presenting chemotherapy HSRs, and its elevation would support mast cell/basophil activation. Skin testing to platinum drugs has a high sensitivity and specificity and is critical to guide the management of platinum-reactive patients. Taxane skin testing is also emerging as a useful diagnostic and risk stratification tool in the evaluation of patients with HSRs to taxanes. Platinum sIgE assays have been recently developed and can be helpful in combination with skin testing or as an alternative when skin testing is not available.

Desensitization induces hyporesponsiveness and cell-surface phenotype changes on wild-type and humanized mouse mast cells

Background Rapid drug desensitization (DST) protocols have been developed based on clinical evidence, but in vitro studies are lacking. Understanding the mechanisms involved in the early stages of DST will allow improvements in patients’ treatment. The aim of this study is to demonstrate and characterize the induction of hyporesponsiveness in murine mast cells by desensitization. Methods We assessed the effect of rapid desensitization on murine bone marrow derived mast cells (BMMC). Experiments with three diferent types of murine BMMC were done: wild-type, LILRB4-/-, and transgenic expressing the human receptor FceRI. Wild-type and LILRB4-/- BMMC were sensitized with anti-DNP IgE and stimulated with DNP, while transgenic BMMC were sensitized with concentrated human serum of allergic subjects and stimulated with the respective allergen. BMMC were stimulated through desensitization or single activation, with optimal or suboptimal doses of antigen. Comparisions were made according to the percentage of b-Hexosaminidase (b-Hex) release by BMMC and the expression of LAMP-1 on the surface of these cells. Furthermore, expression of FceRI, PDL1 and LILRB4 on the surface of BMMC were also assessed. Results

Basophil activation test as a biomarker in allergic patients to platins undergoing rapid desensitization

Background Rapid Drug Desensitization (RDD) has become a cornerstone of the management of immediate hypersensitivity reactions (HSRs) to chemotherapeutic agents, including biologicals. It is the only effective procedure for overcoming HSRs to first-line therapy, thus representing an important advance in patients’ treatment and prognosis. Biomarkers to assess drug sensitization and monitor RDD safety and efficacy are lacking. Preliminary data suggested that in addition to skin testing, basophil activation test (BAT) could be used to assess patient’s IgE sensitization to platins and provide markers of activation to evaluate the response to RDD.

A new humanized in vitro model of IgE-mediated rapid desensitization

Background Rapid drug desensitization (RDD) is widely used to re-introduce medications that have caused an IgEmediated hypersensitivity in allergic patients. However, RDD protocols are largely based on empiric experience and few in vitro models have explored the rationale guiding the rate at which the dose should be increased, what the starting dose should be and how the time elapsed between doses affect the effectiveness of desensitization. This study addresses these issues in a new humanized in vitro model of rapid desensitization.

Desensitization induces hyporesponsiveness and cell-surface phenotype changes on mouse mast cells

Background Rapid drug desensitization (DST) protocols have been developed based on clinical evidence, but in vitro studies are lacking. Understanding the mechanisms involved in the early stages of DST will allow improvements in patients’ treatment, overcome unwanted adverse reactions, and identify markers for therapeutic efficacy. The aim of this study is to demonstrate and characterize the induction of hyporesponsiveness in murine mast cells by desensitization and activation, phenotyping the cell surface.

Basophil activation test in allergic patients to platins undergoing rapid desensitization

Background Desensitization (DST) has become a cornerstone in the management of immediate hypersensitivity reactions (HSRs) to chemotherapic agents. It is the only effective procedure for overcoming HSRs to first-line therapy, thus representing an important advance in patients’ treatment and prognosis. Nevertheless, there are still no good biomarkers to monitor DST safety and effectiveness. The basophil activation test (BAT) has greater applicability in difficult cases with inconclusive diagnosis and when other diagnostic tests (skin tests and serum specific IgE) have not been standardized, as in drug-induced reactions. The main goal of our study was to assess BAT as a test to monitor rapid DST in patients allergic to platins. Method We studied 7 oncologic patients who presented platin allergy and 4 healthy volunteers who had never been exposed to platins. We performed the BAT immediately before DST to platins, assessing CD 203c and CD63 expression on basophils. All patients were evaluated at least in 2 different DST. Results BAT was positive in 6 patients (85.7%), with increased expression of CD203c and CD63 in 6 and 3 patients, respectively. Subsequent BAT analysis in different DST procedures showed that the test remained positive with an even greater expression of CD203c and CD63 on basophils after platins exposure. Some patients with positive BAT reacted during DST, in spite of being premedicated, showing the correlation between BAT results and clinical outcomes. Further investigation is necessary to determine BAT predictive values and its clinical applicability. Conclusion We developed a BAT to platins that presented good sensitivity in our study. Short-term DST to platinum drugs does not induce persistent hyporresponsiveness on basophils, highlighting the need to maintain DST in allergic patients to platins.