Thanks to a generous corporate donation, The Australasian Mastocytosis Society’s Chair, David Mayne, traveled to Berlin for the European Competence Network on Mastocytosis (ECNM) annual meeting held in September 2024. It was an incredible opportunity to network with representatives from patient advocacy groups and hear the latest research and findings from the global medical community.
At this event, Professor Frank Siebenhaar hosted and participated in a highly anticipated roundtable discussion, where he and a distinguished panel of global experts in mastocytosis and mast cell activation disorders – including Professor Karin Hartmann, Dr Jens Panse, Professor Melody Carter, Professor Vito Sabato and Professor Mariana Castells – addressed questions submitted by patient advocacy bodies and patients from around the world.
Thanks to these specialists for their review and endorsement of the below roundtable wrap-up, which was written by TAMS Committee Member Jess Perlibachas.
Key highlights from the patient session are:
- A newly proposed classification and diagnostic criteria for mastocytosis: Aims to harmonise international standards and advance understanding and treatment pathways.
- c-kit positive patients and genetic risks: Familial mastocytosis is rare, with very few families reported. The KIT D816V mutation is usually somatic. Families should seek evaluation at specialised centres if a genetic link is suspected.
- Long-term use of anti-mediator therapy: Second-generation antihistamines are considered safe for long-term use, even at high doses, with no increased risk of secondary disease or significant adverse effects noted.
- Omalizumab benefits: Omalizumab reduces mast cell activation and is beneficial for spontaneous anaphylaxis and improving gastrointestinal symptoms. Monitoring for efficacy is essential.
- Proton pump inhibitors and H2 blockers: H2 blockers are preferred for gastrointestinal symptoms in mastocytosis, and, in select patients, a combination of proton pump inhibitors and H2 blockers is needed for a specific amount of time. Sodium cromoglicate is also effective, with leukotriene blockers as an alternative if symptoms persist.
- Role of the microbiota and diamine oxidase in histamine degranulation: Personalised dietary adjustments are emphasised over broad so-called low-histamine diets. It was noted that all humans can break down histamine, regardless of enzyme levels.
- Diagnostic standards for non-clonal MCADs: Adherence to World Health Organization (WHO) guidelines is crucial, with symptoms across two or more organ systems being key. Tryptase levels and urinary mediators are important for diagnosis, and strict criteria are required for accurate identification.
- Escalating treatment for MCADs: Treatment may involve increasing antihistamine dosages or introducing omalizumab for severe mast-cell mediator symptoms such as anaphylaxis, with careful consideration of alternative diagnoses.
- When to prescribe emergency epinephrine: Patients experiencing severe episodes, or anaphylaxis to a known trigger such as food, should be prescribed epinephrine. The decision for non-cardiovascular symptoms is personalised.
- Children with MCADs and emergency medication: The risk of anaphylaxis is lower in children, however personalised care is key, and children with medically confirmed risk or confirmed anaphylaxis carry emergency kits with epinephrine.
- Surgery and medication considerations: A one-week pause in medications such as avapritinib may be considered, particularly at higher doses (e.g., 100–200 mg), if there is a risk of bleeding. Short-term interruptions are generally regarded as safe and unlikely to affect treatment outcomes.
- Anaesthesia preparation for mastocytosis: Commonly used anaesthetics, with caution for neuromuscular blocking agents, are generally safe for mastocytosis patients, with peri/post-operative precautions to be determined on a case-by-case basis.
A full summary of the session is provided below:
Question: What recommendations or advice can be given to c-kit positive patients regarding the potential risk of mastocytosis to prospective children, particularly in families where a parent has the KIT D816V mutation and their children have inherited mastocytosis?
Response: Professor Melody Carter from the National Institute of Health in the United States explained that familial mastocytosis is extremely rare and she has only encountered 13 families in her career with offspring who developed mastocytosis, however, this was strictly cutaneous mastocytosis rather than systemic mastocytosis and none of the families have a KIT D816V mutation. She noted that in the majority of cases, the KIT D816V mutation is not inherited; rather, it is a somatic mutation.
Professor Karin Hartmann, Head of Division of Allergology and Deputy Head Department of Dermatology, University Hospital Basel, Switzerland, added that only about 50 families worldwide are known to have inheritable germline mutations. These mutations can be passed from generation to generation, but mastocytosis is typically sporadic and not inherited. If a family suspects a genetic link, they should seek evaluation at a mastocytosis centre, where the mutation can be identified, and possible treatment options like imatinib can be explored. Prof Carter further clarified that somatic mutations affect only tissues with the KIT molecule, while germline mutations are present in all tissues, which can be identified with tests such as buccal swabs.
Note: Families with a history of inherited mastocytosis confirmed by haematologists or immunologists in Australia and Aotearoa New Zealand, who need further help are encouraged to have their doctors contact TAMS if their specialist is seeking to connect them with a centre of excellence.
Question: What are the potential risks associated with the long-term use of anti-mediator therapy, specifically regarding the extended use of antihistamines and anti-anxiolytic drugs at high doses, and what advice can be provided to mitigate these risks?
Response: Professor Vito Sabato, Senior Allergology and Immunology expert at the University of Antwerp, Belgium, explained that second-generation antihistamines have a strong safety profile and rarely interact with other medications. He emphasised that even at high doses, toxicity risks such as sedation or cardiac issues are low, and any side effects tend to be patient-specific, often manageable by switching to a different antihistamine.
Dr Jens Panse, Deputy Director of the Department of Oncology, Hematology, Hemostaseology and Stem Cell Transplantation, University Hospital RWTH Aachen, further clarified that long-term antihistamine use does not increase the risk of developing other diseases, including cancer. Professor Frank Siebenhaar, MD, Head of Patient Care, University Medicine Berlin, Institute of Allergology, Hindenburgdamm, confirmed that lifelong antihistamine treatment is considered safe and has been extensively studied in other conditions other than mastocytosis over longer periods. He also noted that there is no evidence that these medications cause increased disease burden or progression, either in mastocytosis or more broadly. Collectively, the experts agreed that their substantial experience with patients on high doses of antihistamines consistently supports the absence of significant risks with long-term therapy.
Question: What effects does omalizumab have on the symptoms of mastocytosis beyond its role in inhibiting anaphylactic reactions?
Response: Professor Mariana Castells, Professor of Medicine, Allergy and Clinical Immunology, Harvard Medical School; and Director, Mastocytosis Center of Excellence, Brigham and Women’s Hospital, advised that omalizumab reduces mast cell activation by decreasing the availability of IgE receptors, noting it has proven effective in treating various conditions, including asthma, allergic rhinitis and chronic idiopathic urticaria, and has received approval in the United States protecting against food allergies, such as peanuts.
In the context of mastocytosis, Prof Castells noted that omalizumab is particularly beneficial for patients experiencing spontaneous anaphylaxis, as it significantly lessens both the severity and frequency of episodes. The panel agreed that additional improvements in gastrointestinal symptoms have also been observed among their patients on this medication.
The discussion then focused on the timeframe for evaluating omalizumab’s efficacy. It was mentioned that, based on asthma literature, it may take up to 90 days for omalizumab to demonstrate effectiveness, especially in cases of idiopathic anaphylaxis. While some patients experience a rapid response after the first dose, others may take longer. The consensus among the panel was that if no improvement is noted after four to six months of treatment, discontinuation of omalizumab should be considered, with alternative treatments explored.
Overall, the speakers affirmed that omalizumab is a promising treatment option for anaphylaxis and certain other symptoms of mastocytosis, necessitating individualised monitoring. They did not express concerns regarding its long-term safety or efficacy within this patient population.
Question: What is the comparative efficacy of proton pump inhibitors (PPIs) versus H2 blockers in managing gastrointestinal symptoms in patients with mastocytosis, and are there any alternative options if these do not provide relief?
Response: Prof Hartmann highlighted the existing treatment options for gastrointestinal symptoms, indicating that H2 blockers are generally seen to be more effective and appropriate for mastocytosis as compared to PPIs. She spoke about the use of PPIs for a limited duration, as prolonged use can alter the gastrointestinal microbiome. She suggested prioritising H2 blockers and mentioned that sodium cromoglicate is also a viable option, given it has a history of effectiveness with minimal side effects.
Omalizumab was also noted as a potential treatment, although the panel acknowledged that in the case these options do not provide relief, management becomes more challenging. Oral locally active corticosteroids were noted as potentially providing benefit, particularly if eosinophils are involved, but these patients often have access to more targeted treatments, including tyrosine kinase inhibitors.
The leukotriene blocker montelukast was mentioned as having had some positive effects on gastrointestinal symptoms in certain patients and was suggested on a case-by-case basis.
Question: How might specific microbiota contribute to gastrointestinal health in MCADs, and what is the significance of diamine oxidase in histamine degranulation for patients who may have deficiencies or reduced functionality of this enzyme?
Response: Prof Castells advised that in non-clonal MCADs, urine mediators such as methyl histamine, histamine, prostaglandins and leukotrienes are elevated during symptom flare-ups in the majority of patients. She clarified that histamine stored in mast cells and basophils significantly outweighs dietary sources, thus discouraging broad low-histamine diets and instead recommending personalised dietary adjustments based on individual intolerances to specific foods (e.g., strawberries, tomatoes).
Regarding microbiota, the panel spoke to its critical role, discussing the fact that many patients report inciting events, such as viral infections or surgeries, that may alter their immune system or microbiota. However, the exact causes of non-clonal MCADs remain unclear.
Prof Castells also addressed a common misunderstanding in new patients, clarifying that all humans, irrespective of diagnosis, have the ability to break down histamine, regardless of their levels of specific enzymes.
Everyone has the necessary enzymes (Diamine Oxidase (DAO) and Histamine N-Methyltransferase (HNMT)) for histamine metabolism, though their efficiency varies among individuals. Studies suggest that genetic variations and external influences, such as certain medications, gut dysbiosis, or chronic inflammation, may contribute to difficulties in effectively processing and breaking down histamine. Symptoms of histamine release, such as flushing, itching, gastrointestinal bloating and diarrhoea, can relate to tissue mast cells activation and release of histamine from granules and during scombroid poisoning due to the ingestion of spoiled fish, which contains high levels of histamine.
Enzyme level testing is not currently part of mainstream clinical practice due to insufficient quantitative research demonstrating its accuracy and clinical relevance. These tests are not included in the diagnostic criteria for any mast cell activation disorder (MCAD). For instance, plasma DAO levels do not always correlate with enzyme activity in the gut, and HNMT testing has not been widely implemented outside of research environments.
As such, these tests are not considered part of the diagnostic criteria for MCADs and should not be relied upon to assess an individual’s ability to tolerate considered histamine-rich foods or predict responsiveness to treatment. Instead, clinical responsiveness should guide decisions regarding the benefit of enzyme supplementation or prolonged exclusionary diets.
Question: What are the recommended diagnostic standards for non-clonal MCADs, considering the variability of specific tests available in different countries?
Response: Prof Castells explained that the accepted approach adheres to the WHO recommendations, which involve evaluating patients who present symptoms across two or more organ systems, such as flushing, abdominal pain, respiratory issues or brain fog. She highlighted the significance of measuring urinary mediators and tryptase levels while assessing the effectiveness of mast cell stabilisers, medications including H1 and H2 blockers, as well as sodium cromoglicate.
Prof Castells acknowledged some patients might not display elevated mediator levels at baseline. Therefore, it is common practice to allow for testing over a one-year period, enabling patients to experience sufficient symptomatic events to facilitate diagnosis. However, she noted that monitoring mediator levels can still be challenging, and physicians may choose to give patients the benefit of the doubt based on consistent symptoms and their responses to medications.
Additionally, the panel concurred that there is a necessity for strict diagnostic criteria to ensure accurate identification of non-clonal MCADs, given that its symptoms can overlap with various other conditions that must be ruled out prior to making a diagnosis. For patients presenting with severe symptoms or anaphylaxis, the panel indicated that testing tryptase levels, along with conducting a bone marrow biopsy and peripheral blood testing for KIT mutations, is appropriate.
Question: How do clinicians determine when to escalate treatment for patients suspected of having MCADs, especially when they have already been prescribed antihistamines by their general practitioners?
Answer: Prof Castells responded that the escalation of treatment can involve increasing the dosage or number of antihistamines, such as H1 and H2 blockers, and potentially adding medications like omalizumab to assess their impact. She noted that the effectiveness of antihistamines, including the dosage and whether patients are on multiple antihistamines, plays a critical role in this process.
Prof Sabato noted that the treatment approach varies based on diagnosis; for patients with known clonal MCADs, therapy escalation is straightforward. However, for those not meeting specific diagnostic criteria, he considers it crucial to explore alternative diagnoses, such as a Helicobacter pylori infection, before increasing treatment. He suggested that for patients new to anti-mediator medication, starting with one antihistamine tablet daily for two to four weeks is recommended, and if there is mild improvement, the dosage can be increased under physician advice.
Prof Castells emphasised delays in diagnosing conditions such as mastocytosis or non-clonal MCADs can extend up to nine years, which significantly affects patient well-being. She highlighted the crucial role of education in promoting awareness about the necessity of tryptase level testing and the potential for KIT mutations, noting that many practitioners may not be adequately informed about these important factors. The panel concurred that this information is vital and needs to be disseminated more broadly within the medical community.
Question: When should emergency epinephrine kits be prescribed to patients with mast cell-related conditions, especially for those who experience episodic symptoms?
Response: Prof Castells responded that patients who have had severe episodes, such as syncope, loss of consciousness or hypotension, should be provided with epinephrine and educated annually on its use. She stated in cases where episodes do not involve cardiovascular symptoms, the decision to prescribe epinephrine is more personalised. It was also noted that for patients with clonal MCADs, even non-cardiovascular symptoms may warrant an epinephrine kit. However, it was agreed this was to be assessed on a case-by-case basis.
Question: Which children with MCADs should be provided with emergency medication, specifically epinephrine?
Response: Prof Sabato explained that, while children typically have a lower risk of anaphylaxis compared to adults, it is essential to personalise care. Despite the low incidence of anaphylaxis in his patient population, he ensures all his young patients with confirmed or high risk of anaphylaxis are equipped with emergency epinephrine kits. Prof Carter confirmed that all children with known triggers for anaphylaxis should be provided epinephrine for an accidental exposure.
Dr Jens Panse and Prof Sabato noted that there is sometimes an overemphasis on avoiding potential triggers, which can cause unnecessary fear in patients and inexperienced practitioners, affecting their quality of life. The panel broadly echoed the importance of avoiding excessive restrictions, particularly in drug allergies, and emphasised a more personalised approach, often testing a patient’s tolerance in a controlled setting.
Prof Castells noted that only a small percentage of patients may have true reactions, indicating that in children, the percentage risks of intolerance for medications such as NSAIDs were as low as five per cent and that unnecessary avoidance can limit diagnostic and therapeutic options.
Question: Should patients scheduled for surgery discontinue avapritinib or other medications due to surgeons’ concerns about risks, including irregular bleeding?
Response: Prof Castells responded, noting that it depended on the medication. If avapritinib poses an increased bleeding risk, a one-week pause may be advised. These considerations would also apply to future medications, such as BTK inhibitors, especially regarding potential infection risks during surgery.
Prof Sabato added that a temporary pause of two to five days would not significantly impact the medication’s efficacy or disease control. He emphasised that if a patient’s physician recommends stopping the medication for a short period, it should be safe for that patient without compromising treatment outcomes.
Question: What are the current recommendations for giving anaesthesia to patients with mastocytosis, or how should they be prepared for surgery?
Prof Carter advised that in a study she undertook within the NIH on paediatric patients, no adverse effects were observed from commonly used anaesthetics such as propofol and sevoflurane. She highlighted that based on data from various studies adverse reactions to anaesthesia in mastocytosis patients are uncommon. She noted that while neuromuscular blocking agents (NMBAs) are not contraindicated in patients without prior adverse reactions, premedication and vigilant monitoring are strongly recommended due to their classification as high-risk medications. These agents are essential in many surgical settings but can activate MRGPRX2 receptors on mast cells, potentially triggering reactions in some patients. For mastocytosis patients with a history of reactions to NMBAs, alternatives like succinylcholine may offer a safer option. However, careful evaluation in consultation with a treating immunologist is essential to determine the most appropriate treatment protocol. Prof Carter also touched on vaccine safety, noting that reactions are rare but more common in patients with diffuse cutaneous mastocytosis.
Prof Sabato added that while local anaesthetics generally pose no issues, reactions can occasionally occur during general anaesthesia, often revealing a specific allergy. In such cases, the recommendation is to avoid the identified drug and use alternatives.
Prof Castells provided further guidance, noting that in the United States, antibiotics like vancomycin and quinolones are typically avoided due to increased reactions in mastocytosis patients. In closing, she emphasised that premedication is straightforward, using H1 and H2 blockers, and the addition of a leukotriene inhibitor, has proven effective in cases of presurgical management strategies and typically precludes the need for steroids.
Question: Can individuals with mastocytosis safely have children, and what precautions should be taken during pregnancy and delivery?
Response: Prof Castells confirmed individuals with mastocytosis can have children, and fertility is preserved. She clarified that mast cells don’t affect the ovaries, so people can get pregnant and have safe deliveries.
It was noted that while doctors often reach out to patient specialists for advice when handling a pregnant mastocytosis patient, generally, immunologist involvement is not required. It was also noted that H1 and H2 blockers, as well as any other mast cell disease management medications, such as sodium cromolyn or omalizumab, should be continued, as they and most other applicable medications can be safely administered during pregnancy. Additional information about medicine use during pregnancy and breastfeeding can be found on Drugs.com, and via The Royal Women’s Hospital website, and factsheets on pregnancy and breastfeeding.
Question: Why was Telangiectasia Macularis Eruptiva Perstans (TMEP) removed from the classification of cutaneous mastocytosis, and what should be recommended for patients previously diagnosed with TMEP?
Response: Prof Hartmann advised that TMEP was removed from the diagnostic classification because patients with these vascularised lesions usually also have classical maculopapular cutaneous mastocytosis (CM). She clarified that while there are variations, the disease course and clinical features are very similar to monomorphic maculopapular CM. It was therefore decided to no longer offer a separate category for TMEP.
The panel acknowledged that previously TMEP was occasionally diagnosed based on the presence of vascularised skin lesions and an increase in mast cells in histology, but noted that this wasn’t specific. Expanding upon this Prof Castells noted mast cells can appear in other skin conditions like inflammation or eczema. Now that there are more sensitive diagnostic tools, such as tryptase tests, and KIT allele burden testing in peripheral blood, reclassification with updated tools is recommended. Prof Hartmann noted that for patients with the previous TMEP diagnosis, it would be advisable for the treating physician to update and reclassify the diagnosis.
Question: Can the fatigue pattern of indolent systemic mastocytosis (ISM) mimic chronic fatigue syndrome, and what might be the cause of fatigue in mastocytosis patients?
Response: Prof Castells acknowledged that fatigue is a challenging yet common symptom for mastocytosis patients and may be linked to cytokines, such as TNF-alpha, which is known to cause fatigue in chronic illness and cancer patients. She explained that the release of mast cell mediators, like prostaglandins, could contribute to the fatigue in systemic mastocytosis patients. While chronic fatigue syndrome and systemic mastocytosis can appear similar in terms of fatigue, Prof Castells clarified that mastocytosis patients typically experience additional symptoms such as gastrointestinal issues, brain fog and other broader indicators of mast cell activation.
It was also noted that elevated cytokines, such as IL-6, have been found in patients with chronic conditions like long COVID, suggesting a commonality in immune cell behaviour. Although there is no definitive treatment for fatigue in mastocytosis, the panel agreed that reducing mast cell burden may help diminish fatigue and suggested that trials to this effect were needed in the future.
Question: What is the most recent update on the prognosis of indolent systemic mastocytosis (ISM) and the percentage of patients at risk of progression?
Response: Dr Panse responded, noting the prognosis for patients with ISM is generally good, with a very low risk of disease progression to a more aggressive form. He noted that studies indicate a progression rate of about 4 to 5 per cent. While Dr Panse noted some data indicating patients with ISM may have worse outcomes than the general population, he stated it to be complicated by the possibility that misdiagnoses may occur when patients are categorised solely based on medical records.
Dr Panse advised sequential bone marrow biopsies are usually unnecessary, as monitoring assessments can now be effectively undertaken using highly sensitive peripheral blood tests. He reassured patients that fluctuations in tryptase levels over time are normal and should not be a cause for concern, and he added that those with cutaneous mastocytosis have an even lower risk of progression.
Learn more from the expert with their recent insights on systemic mastocytosis and MCADs:
- Listen to Professor Sabato and other international experts as they discuss diagnosis, current and emerging treatments, and multidisciplinary care strategies.
- Listen to Professor Melody Carter discuss the diagnosis, prognosis and management of paediatric and adult mastocytosis.
- Listen to Professor Mariana Castells and TAMS Chair David Mayne discuss mastocytosis and MCAS at the 2019 ASCIA conference.
Disclaimer
The information in this summary reflects the views and discussions of the specialists participating in the 2024 ECNM Patient Roundtable.
Mast Cell Activation Disorders are complex and highly individualised, requiring personalised assessment and management by specialist healthcare professionals. This summary and the views expressed are for general informational purposes only and must not be used to replace, override or invalidate professional medical guidance, diagnosis or treatment tailored to a patient’s specific health circumstances.
