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Indolent and smoldering systemic mastocytosis: Management and prognosis

Indolent and smoldering systemic mastocytosis: Management and prognosis
Author:
Cem Akin, MD, PhD
Section Editor:
Sarbjit Saini, MD
Deputy Editors:
Anna M Feldweg, MD
Alan G Rosmarin, MD
Literature review current through: Jul 2022. | This topic last updated: Apr 14, 2021.

INTRODUCTION — Systemic mastocytosis (SM) consists of a group of disorders exhibiting excessive mast cell accumulation, typically in bone marrow and other extracutaneous tissues. Five variant forms have been delineated (table 1). The five variants may be broadly divided into two groups, which differ in clinical presentation, treatment, and prognosis:

Indolent systemic mastocytosis (ISM) and smoldering systemic mastocytosis (SSM) – ISM and SSM usually have a clinically indolent course, with median survival measured in decades. Previously, SSM was described as a subcategory of ISM, but the 2017 World Health Organization classification of hematolymphoid neoplasms redefined SSM as a distinct subtype of SM [1].

Advanced systemic mastocytosis, which has a more aggressive course with median survival measured in months to years and includes the following disease variants:

Aggressive systemic mastocytosis (ASM)

Systemic mastocytosis with an associated hematologic neoplasm (SM-AHN)

Mast cell leukemia (MCL)

The management and prognosis of ISM and SSM are similar and are discussed in this topic review. The management and prognosis of ASM, SM-AHN, and MCL are reviewed separately. (See "Advanced systemic mastocytosis: Management and prognosis".)

The clinical manifestations, evaluation, and diagnosis of SM are reviewed separately:

(See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)

(See "Systemic mastocytosis: Determining the subtype of disease".)

OVERVIEW — ISM accounts for more than 70 percent of all SM cases in the published literature, while SSM is rare. In both variants, patients may or may not have the characteristic skin lesions of maculopapular cutaneous mastocytosis (MPCM, formerly called urticaria pigmentosa) (picture 1). Patients may suffer a variety of episodic symptoms, including flushing, dyspepsia, and/or diarrhea, or they may experience recurrent anaphylaxis or persistent bone pain, neuropsychiatric symptoms, and fatigue. Morbidity in ISM and SSM is most commonly related to mast cell-mediator release and anaphylaxis. Therefore, treatment of the clinically indolent SM subtypes is focused on preventing mast cell activation and minimizing the resulting symptoms when it does occur [2]. In one study, severe anaphylaxis was seen more in patients with ISM compared with those with more aggressive forms of disease (ASM, SM-AHN, and MCL) [3]. (See 'Access to epinephrine' below.)

In addition to the morbidity associated with mast cell mediator release, there is some risk of progression to more severe forms of mastocytosis. ISM carries a low risk of progression, while the risk with SSM is intermediate. (See 'Monitoring for progression' below.)

GENERAL MEASURES — Patients with any form of SM may experience episodic symptoms of mast cell activation, including apparent allergic-like reactions triggered by a variety of exposures. Anaphylaxis is more common in ISM and SSM compared with advanced forms of the disease.

Elevated risk of anaphylaxis — Up to one-half of adult patients with mastocytosis experience anaphylaxis [4-7]. Symptoms of anaphylaxis in mastocytosis frequently involve hypotension, syncope or presyncope associated with flushing, tachycardia, and gastrointestinal cramping, while urticaria and angioedema are less common. One study found atopy, lack of skin lesions of MPCM, higher total immunoglobulin E (IgE), and lower baseline tryptase levels (27 versus 42 ng/mL) to be risk factors for anaphylaxis in mastocytosis [8]. Another study similarly found lack of MPCM, but in contrast, higher tryptase levels (60 versus 21 ng/mL) in patients who experience anaphylaxis [5]. All patients with SM should be educated about anaphylaxis and about triggers for mast cell degranulation and how to avoid them. They should consider wearing a medical identification bracelet, especially if they have already experienced anaphylaxis. In addition, patients can be equipped with an anaphylaxis emergency action plan or wallet card that identifies the condition and describes the proper treatment of anaphylaxis. Action plan forms are available in English and Spanish from Food Allergy Research and Education (Food Allergy & Anaphylaxis Emergency Care Plan) and the American Academy of Pediatrics (Allergy and Anaphylaxis Emergency Plan English, Spanish). These plans are appropriate for patients with anaphylaxis from any cause.

Access to epinephrine — Epinephrine is the primary medical treatment for anaphylaxis, and patients should have at least two doses of epinephrine in a self-injectable form available at all times, since a single dose may be inadequate to counteract the massive release of mediators that can occur [9]. They should also be taught to lie flat if they experience lightheadedness or presyncope during symptomatic episodes, because hypotension is a prominent feature of anaphylaxis in this population. Guidance in prescribing epinephrine autoinjectors is provided separately. (See "Prescribing epinephrine for anaphylaxis self-treatment".)

Obtaining tryptase measurements after episodes of symptoms — If patients experience episodes of symptoms that resemble anaphylaxis, serum tryptase should be obtained (ideally between 15 minutes and 3 hours after the onset of symptoms). A form requesting that tryptase be drawn can be given to patients to pass along to emergency care clinicians (form 1).

Elevations in serum tryptase can help determine, retrospectively, if the events were truly caused by mast cell-mediator release. However, because the results are not immediately available, the information is not useful in acute diagnosis. If serum tryptase increases ≥2 ng/mL + 1.2 x baseline in the hours following signs/symptoms, then those signs/symptoms can be attributed to mast cell activation.

Trigger avoidance — Patients with SM should be aware of the different triggers that can provoke mediator release from mast cells (eg, medications, medical procedures, and dietary factors). Of note, patients vary considerably in their sensitivity to specific triggers, so not all triggers are relevant to a given individual.

Possible triggers include:

Exposure to either heat and humidity or to cold

Acute emotional stress

Very strenuous exercise

Alcohol and spicy foods

Infections, fever

Anesthesia, surgery, and endoscopic procedures

Problematic medications — Medications that can trigger mast cell activation may include aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, antibiotics (most commonly vancomycin), radiocontrast agents, and certain muscle relaxers used during anesthesia. Alternative medications that are usually tolerated are discussed separately. (See "Cutaneous mastocytosis: Treatment, monitoring, and prognosis", section on 'Medications that are usually tolerated'.)

Insect stings — Stings from wasps, honey bees, fire ants, and other Hymenoptera can precipitate anaphylaxis in patients with mastocytosis, especially in those who have also developed IgE-mediated sensitization. Any patient with SM and systemic symptoms in response to a Hymenoptera sting should be tested for venom allergy, and those testing positive should be treated with venom immunotherapy (VIT) to reduce the risk of anaphylaxis upon subsequent stings. Patients with negative skin and in vitro venom-specific IgE should be retested in six months. (See "Advanced systemic mastocytosis: Management and prognosis", section on 'Information for patients' and "Hymenoptera venom immunotherapy: Efficacy, indications, and mechanism of action".)

Preparation for medical, surgical, and radiologic procedures — If patients have had procedures or surgery since developing a mast cell disorder, we attempt to retrieve the medical records of that procedure. If the patient had trouble tolerating the intervention, the medical records can help guide the selection of different perioperative drugs, and if the procedure was tolerated, the same medications could be used again.

We routinely administer premedications prior to surgery (especially those that require general anesthesia), minor medical procedures, or the administration of radiocontrast dyes. Retrospective data support this approach [10-13].

Local and regional anesthesia are safer alternatives than general anesthesia. Local anesthetics are generally well-tolerated. The optimal regimen for prevention of mast cell degranulation in mastocytosis patients has not been formally studied.

We administer the following one hour before the procedure, although the efficacy of this approach has not been studied (adult dosing):

Diphenhydramine, 25 to 50 mg orally or intravenously (IV) or equivalent doses of another oral antihistamine.

Famotidine 20 mg orally or IV (or another H2 antihistamine).

Montelukast (optional), 10 mg orally.

Prednisone (optional, preferred if the patient has frequent or hypotensive episodes of mast cell activation or has had problems tolerating anesthesia or surgery in the past), 25 to 50 mg orally, 12 hours and 1 to 2 hours prior to procedure.

The anesthesiologist and surgeon involved should be aware of the patient's susceptibility to anaphylaxis during and for several hours after the procedure and be prepared to treat it promptly and obtain a serum tryptase level. Physical triggers during procedures may include extremes of temperature, friction, and pressure. In addition, if the patient's tolerance of NSAIDs is unknown, these agents, especially in injectable forms (eg, ketorolac), should be avoided, as severe reactions can result.

After the procedure, the patient can resume normal daily medications. A few patients will have increased symptoms for several days, so we generally ensure that they are taking at least a combination of H1 and H2 antihistamines daily until fully recovered, if that was not part of their medication regimen.

Pregnancy and delivery — SM does not appear to reduce fertility, and women with ISM can have healthy pregnancies, although symptoms may worsen during gestation [14]. Mastocytosis is not genetically transmitted in the great majority of patients. Management during pregnancy and delivery is guided by the same general principles and management of ISM in general, with primary reliance on H1 and H2 antihistamines, glucocorticoids as needed to control exacerbations, oral cromolyn for gastrointestinal symptoms, antileukotriene agents, omalizumab if necessary, and sparing use of cytoreductive agents if symptoms cannot be controlled with other measures [15]. Avoidance of anaphylaxis is particularly critical during pregnancy, as hypotension can disproportionately impact the fetus, and anaphylaxis may induce uterine cramping. (See "Anaphylaxis in pregnant women", section on 'Consequences'.)

Very symptomatic patients should be managed by a multidisciplinary team, including high-risk obstetrics. Labor and delivery are approached similarly to other procedures, with avoidance of triggering medications when possible (see 'Problematic medications' above). Breastfeeding mothers should review medications with a clinician or lactation consultant to ensure that all agents are safe for infants (eg, sedating antihistamines should be avoided).

SPECIALIST INVOLVEMENT — Patients with well-controlled symptoms on antimediator therapy and stable complete blood count (CBC) with differential and tryptase levels can be followed by their primary care physician. Referral to a specialist with expertise in mast cell disorders should be pursued for patients who remain symptomatic despite antimediator therapy, have an increase in skin lesions, a change in labs (increased tryptase or abnormal CBC with differential), develop new clinical symptoms (eg, weight loss, bone fracture, anaphylaxis), or may be candidates for clinical trials.

Referral to an allergist is appropriate for patients with recurrent anaphylaxis or concurrent IgE-mediated allergies (such as Hymenoptera or food).

PHARMACOTHERAPY FOR SYMPTOMS RELATED TO MAST CELL MEDIATORS — Patients with ISM and SSM can be very symptomatic. Quality of life questionnaires have been developed and can be used to assess symptoms [16,17]. One study found that a majority reports some degree of functional limitation, with approximately one-sixth reporting extreme limitations [18]. A patient survey found more than two-thirds of the respondents were symptomatic with itching, flushing, fatigue, and stomach pain [19]. The following therapies may be needed for symptomatic patients with any subtype of SM. Symptoms arising from mediator release are most prominent in patients with ISM and SSM, but can occur in more advanced subtypes.

Antihistamines — Initial pharmacologic treatment includes the use of H1 and H2 antihistamines. H1 antihistamines are administered to prevent flushing and itching. H2 antihistamines are helpful in controlling abdominal pain, heartburn, cramping, and/or diarrhea.

H1 antihistamines (adult dosing) include oral cetirizine (10 to 40 mg daily), fexofenadine (180 to 360 mg daily), loratadine (10 to 40 mg daily), hydroxyzine (25 mg every six hours), or doxepin (10 to 100 mg per day) [2]. In some patients, a combination of two or more H1 antihistamines or increasing the standard dose of a nonsedating agent may provide better symptom control. Diphenhydramine (25 to 50 mg up to four times daily) may be added on an as-needed basis to manage breakthrough symptoms.

H2 antihistamines (adult dosing) include oral famotidine (20 mg twice daily) and cimetidine (300 mg twice daily) [2].

Ketotifen, which has been reported to have both mast cell-stabilizing and H1 antihistamine properties, may be administered where available (eg, Canada and Europe), although it can be quite sedating for some patients, and they should be cautioned about this side effect. This drug is not available in oral form in the United States, although it can be compounded. The adult dose is 1 to 4 mg orally every 12 hours [20].

Antileukotriene drugs — Antileukotriene agents (eg, montelukast 10 mg daily, zafirlukast 20 mg daily, or zileuton 1200 mg twice daily) may be added in patients with flushing, itching, or abdominal cramping unresponsive to H1 and H2 antihistamines [21]. The patient should be warned about psychiatric adverse effects.

Additional therapies for specific problems — Additional issues may arise that require specific interventions.

Recurrent anaphylaxis — For patients with SM who experience recurrent anaphylaxis or mast cell activation symptoms with hemodynamic instability despite trigger avoidance, maximized doses of antimediator agents (H1 and H2 antihistamines and antileukotriene drugs) should be prescribed. If episodes of anaphylaxis persist, the therapies below may be helpful, based on anecdotal clinical experience and indirect evidence.

Glucocorticoids — Glucocorticoids appear to reduce mast cell numbers through inhibition of stem cell factor synthesis [22]. For patients with recurrent anaphylaxis, the author's approach is to start with doses of oral prednisone no higher than 20 to 30 mg daily in adults, given for two to three weeks. Higher doses can be problematic and may cause flushing, tachycardia, and abdominal pain, side effects that can be difficult to differentiate from mast cell-mediator effects. This is followed by a slow taper (eg, by 5 to 10 mg per week). Some patients may require low-dose maintenance therapy, such as 5 to 10 mg daily in this setting.

Omalizumab — Omalizumab (anti-immunoglobulin E [IgE]), a humanized monoclonal antibody that inhibits the binding of IgE to mast cells, reduced the frequency of anaphylaxis in some patients with SM or monoclonal mast cell activation syndrome [23,24]. Omalizumab therapy was also reported to improve cutaneous and neurologic symptoms in a patient with urticaria pigmentosa (UP) who did not undergo bone marrow evaluation and so was not conclusively diagnosed with SM [25]. This use of omalizumab for these indications is not approved by the US Food and Drug Administration (FDA) but deserves further study. (See "Anti-IgE therapy".)

Cytoreductive agents — For patients with recurrent anaphylaxis whose symptoms cannot be controlled with other measures including omalizumab, there is a role for mast cell cytoreductive therapies. We generally prefer midostaurin, but interferon alfa and 2-chlorodeoxyadenosine (cladribine/2-CdA) are also helpful in certain settings [3,26]. Choice of agent should be based upon the underlying mutation and other clinical features, similar to the approach in advanced forms of SM, as discussed separately. (See "Advanced systemic mastocytosis: Management and prognosis", section on 'Aggressive SM (ASM) or mast cell leukemia (MCL)'.)

Midostaurin, which inhibits the protein product of KIT, including the common KIT D816V mutation, was shown to alleviate symptoms in an open-label study of 20 patients with ISM or SSM [27]. Midostaurin reduced the severity of symptoms (eg, fatigue, musculoskeletal pain) at 12 and 24 weeks, as measured by the Mastocytosis Symptom Assessment Form (MSAF). UP improved in 12 (80 percent) of the 15 patients with skin symptoms, resulting in a 40 percent reduction in median Scoring Mastocytosis Index score. Serum tryptase level declined in 19 patients and bone marrow mast cell burden declined in 8 of 16 patients. Most patients experienced a return of symptoms and an increase of tryptase levels when midostaurin was discontinued after 24 weeks, but 8 of 10 again experienced improvement of symptoms and reduction in serum tryptase levels after retreatment with midostaurin. Of note, the number of patients in the study was insufficient to assess the impact on anaphylaxis-like symptoms, although it would have anticipated efficacy by reducing mast cell numbers. The most common adverse effects of midostaurin are nausea and vomiting, which may limit its tolerability in patients with ISM. Bone marrow suppression may also occur.

Use of these agents is reviewed in more detail separately. (See "Advanced systemic mastocytosis: Management and prognosis", section on 'Other agents'.)

Flushing — In patients with prominent flushing not responsive to antihistamines, aspirin may be helpful, provided the patient is known to tolerate nonsteroidal anti-inflammatory drugs (NSAIDs) [2]. NSAIDs trigger mediator release in some patients, and these individuals should avoid them. Although aspirin can reduce flushing, high doses may be needed (up to 500 mg once or twice daily) and may not be tolerated by patients already predisposed to peptic ulcer disease [28].

If the patient's tolerance of NSAIDs is not known, the first dose of aspirin should be administered in a supervised setting. We typically give an initial dose of 81 mg, followed by 325 mg, allowing 90 minutes after each step to observe for symptoms. Emergency medications and equipment should be available. If symptoms develop or the patient has a history of NSAID allergy or intolerance, the patient is not a candidate for aspirin therapy, and we do not recommend attempting desensitization.

Gastrointestinal symptoms — Gastrointestinal symptoms in patients with SM may be treated with oral cromolyn sodium, H2 antihistamines, and proton pump inhibitors (PPIs).

Cromolyn sodium is available as an oral concentrate (100 mg per 5 mL vial) and may be administered by giving one to two vials in a glass of water, drunk four times daily prior to meals and bedtime [29]. Oral cromolyn should be initiated at the lower end of the dose range and gradually increased, as it is minimally absorbed through the intestine and can cause osmotic diarrhea in some patients if introduced at high doses.

H2 antihistamines are helpful in patients with symptoms of hyperacidity and abdominal pain.

PPIs may be added to H2 antihistamines in patients with peptic ulcer disease or those with abdominal complaints unresponsive to antihistamines alone. If this is needed, the H2 antihistamine and PPI should be administered at different times. As an example, the PPI can be given in the morning before the first meal of the day, and an H2 antagonist can be given several hours later and before bed or vice versa. (See "Proton pump inhibitors: Overview of use and adverse effects in the treatment of acid related disorders".)

Intractable diarrhea may be treated with oral or topical steroids. There are no studies examining optimal dosing. We typically start with prednisone 0.5 mg/kg daily dose and attempt to taper it over the following two to three weeks. Efficacy of oral budesonide has been suggested but not studied.

Osteoporosis and fractures — Patients with all forms of SM should be monitored for osteopenia and osteoporosis and treated appropriately [30-34]. Management in patients with SM is essentially the same as that in patients without SM. In patients with normal bone density, we repeat densitometry in three years. Appropriate daily intake of calcium and vitamin D should be maintained. For patients with osteoporosis-related fractures, treatment with the combination of bisphosphonate and low-dose interferon alfa has been reported to be helpful [35]. (See "Screening for osteoporosis in postmenopausal women and men" and "Treatment of osteoporosis in men" and "Overview of the management of osteoporosis in postmenopausal women".)

Cutaneous pruritus refractory to antihistamines — Topical cromolyn ointment, topical corticosteroids, and narrowband UVB phototherapy have been used with variable success for patients whose symptoms were not controlled with oral antihistamines and antileukotriene agents. These therapies are reviewed in more detail separately. (See "Cutaneous mastocytosis: Treatment, monitoring, and prognosis", section on 'Treatment of refractory symptoms'.)

TREATMENT OF COEXISTENT ALLERGIC DISEASE — Patients with SM develop allergic diseases at a rate similar to that of the general population and may experience anaphylaxis to Hymenoptera venom (honey bee, wasp, hornet, yellow jacket, or fire ant stings), as well as allergic rhinitis, asthma, and food and drug allergies [4,36-38]. The treatment of allergic disorders in SM patients may need to be modified in individuals who are prone to episodes of mast cell activation.

Hymenoptera venom allergy — Patients with mastocytosis can suffer severe anaphylaxis in response to an insect sting [39-42]. Fatalities have been reported in patients with SM who were stung by Hymenoptera, despite self-treatment with epinephrine [43]. Thus, patients with anaphylaxis following a known or possible Hymenoptera sting should be evaluated with skin tests or in vitro tests for venom-specific immunoglobulin E (IgE), and if found to be sensitized, they should be offered venom immunotherapy (VIT). (See "Hymenoptera venom immunotherapy: Efficacy, indications, and mechanism of action" and "Hymenoptera venom immunotherapy: Technical issues, protocols, adverse effects, and monitoring" and "Diagnosis of Hymenoptera venom allergy".)

The benefits of VIT in patients with SM appear to outweigh the risks of systemic allergic reactions to the therapy itself, which can be increased in patients with SM compared to those without SM. Patients should be counseled about this when giving consent to receive VIT. Most experts agree that the duration of VIT should be lifelong [40]. Safety measures during administration of VIT include starting with a less concentrated venom preparation (ie, 0.01 to 0.1 micrograms/mL) and premedicating with an H1 antihistamine on the day of each injection. Epinephrine should be available to treat potential systemic reactions. (See "Hymenoptera venom immunotherapy: Technical issues, protocols, adverse effects, and monitoring".)

Safety and efficacy were evaluated in retrospective series:

In a series of 21 subjects with mastocytosis who underwent VIT, 12 patients were re-stung during treatment, and nine of these developed only local reactions, suggesting protection against repeat anaphylaxis [39]. However, 30 percent experienced adverse reactions during the build-up phase of immunotherapy, most of which involved hypotension in combination with other symptoms.

VIT was also evaluated in a retrospective study of 46 patients: 22 with SM, 10 with monoclonal mast cell activation syndrome, and 14 controls without mast cell disorders [44]. Approximately 34 percent of patients with mast cell disorders experienced adverse reactions to VIT, compared with 7 percent of controls, although only one SM patient suffered anaphylaxis. Patient-based protection from anaphylaxis was 76 percent and 100 percent in patients with mast cell disorders and controls, respectively. Venom-specific IgG4 levels correlated with protection from anaphylaxis, as has been noted before with VIT. (See "Allergen immunotherapy for allergic disease: Therapeutic mechanisms", section on '"Blocking" IgG4'.)

Omalizumab has been administered before initiating VIT to reduce the risk of systemic reactions to the treatment injections. A case report described a patient with SM who suffered near-fatal anaphylaxis to a Hymenoptera sting and was begun on VIT, but then experienced repeated systemic reactions to the injections and was unable to reach maintenance doses [45]. Omalizumab was administered one week prior to his subsequent venom injection at a dose of twice what is generally indicated for the treatment of asthma. Using this approach before each monthly injection, he was able to advance immunotherapy to the effective dose. Subsequent attempts to lower the dose of omalizumab or to extend the time between maintenance injections beyond 30 days resulted in recurrent systemic reactions [46]. The patient sustained later Hymenoptera stings without reacting. However, another case report described a patient in whom omalizumab was administered to prevent systemic reactions to VIT, but the patient was not able to tolerate VIT once omalizumab was discontinued [47]. In the United States, omalizumab is not approved for this use, although the drug can sometimes be obtained on a compassionate-use basis in individual cases.

Allergic rhinitis and asthma — Patients with SM and allergic rhinitis, conjunctivitis, and/or asthma are managed with the same medications as patients without SM, although dosing requirements may be higher. We generally avoid the use of subcutaneous immunotherapy (SCIT) for respiratory allergy, as patients with SM are at greater risk for systemic reactions and anaphylaxis as a consequence of the therapy itself, and the benefit conferred by immunotherapy for respiratory disease is not as great as that for venom allergy. The safety of SCIT with inhalant allergens in patients with SM has not been formally studied. (See "Allergen avoidance in the treatment of asthma and allergic rhinitis" and "Pharmacotherapy of allergic rhinitis" and "An overview of asthma management".)

MONITORING FOR PROGRESSION

Indolent systemic mastocytosis — Yearly monitoring is appropriate for uncomplicated patients with ISM, a normal physical examination (other than skin lesions), and stable weight, although the frequency of evaluation should be increased if symptoms worsen or new signs/symptoms appear:

Serum tryptase levels, which reflect mast cell burden.

Complete blood count (CBC) with differential to monitor for changes in leukocytes, platelets, and eosinophils, as well as abnormal forms, since advanced forms of SM can be associated with other hematologic malignancies. New abnormalities of the CBC should prompt repeat evaluation for a more advanced form of disease.

Serum chemistry panel to monitor for liver involvement and electrolyte imbalances. Elevation of the serum alkaline phosphatase level is the most common presentation of liver involvement by mast cell disease.

Changes in any of these tests, weight loss, or the development of splenomegaly should prompt evaluation for advanced forms of the disease. Serum levels of beta-2 microglobulin have been identified as an independent predictor of progression but need further validation. (See "Systemic mastocytosis: Determining the subtype of disease".)

Changes in the appearance of skin lesions in patients with maculopapular cutaneous mastocytosis (MPCM) do not necessarily correlate with changes in the underlying disease. About 10 to 15 percent of patients with ISM and MPCM may experience a regression of skin lesions, which may correspond to either improvement or worsening in the systemic disease [48]. Similarly, increases in MPCM lesions, even dramatic increases, do not necessitate additional evaluation if the patient is feeling well.

Smoldering systemic mastocytosis — Patients with SSM are generally seen and monitored every six months using the same approach as that for patients with ISM or more frequently if there are signs/symptoms of progression. The development of unexplained hematologic abnormalities (eg, increased white blood count, immature forms, monocytosis, increased or decreased platelets), hepatosplenomegaly, unexplained weight loss, coagulopathy, ascites, or gastrointestinal bleeding should alert the clinician to the possibility of disease progression.

PROGNOSIS

Morbidity from anaphylaxis — A primary concern in the management of ISM is anaphylaxis, as severe disability and death have been reported [3]. Risk factors and triggers are reviewed above. (See 'Elevated risk of anaphylaxis' above.)

Risk of progression — The category of SM is the single most important prognostic factor. Other prognostic factors include molecular abnormalities, beta-2 microglobulin levels, allelic frequency and presence of KIT D816V mutation in multiple cell lineages [49].

By disease category — Most patients with ISM have a normal life expectancy [49,50]. Approximately 3 percent of patients with an initial diagnosis of ISM will progress to a more severe form of SM, including systemic mastocytosis with an associated hematologic neoplasm (SM-AHN), aggressive systemic mastocytosis (ASM), or mast cell leukemia (MCL) [49].

Among patients with SSM, 18 percent progressed to ASM or MCL in a large study [50]. Of note, these data are from a single institution retrospective analysis of 342 patients with all types of SM followed for a median of 21 months (range 0 to 35 years), and there may have been referral bias for more severe disease in this study [50-52]. In addition, the shorter life expectancy observed in patients with SSM may be due to older age at diagnosis [53].

Molecular abnormalities — Next-generation sequencing myeloid mutation panels performed at the time of diagnosis can provide prognostic information. In a series of 200 patients from two referral centers with ISM, who were followed for a median of nine years, 7 percent progressed to more advanced forms of SM, including five who developed SSM. All who progressed exhibited KIT mutation of bone marrow (BM) cells with variant allele frequency (VAF) ≥1 percent, pathogenic mutations of ASXL1, RUNX1, and/or DNMT3A (A/R/D) with VAF ≥30 percent, and/or elevated baseline tryptase levels [54]. Reduced progression-free survival was independently associated with KIT D816V VAF ≥1 percent in the BM (hazard ratio [HR] 12; 95% CI 1.3-108), serum beta-2 microglobulin ≥2.5 mcg/mL (HR 9.8; 95% CI 2.6-3.6), and A/R/D VAF ≥30 percent (HR 4; 95% CI 1.2-10) in multivariate analysis. Lower overall survival was independently associated only with A/R/D VAF ≥30 percent (HR 52; 95% CI 4-647). Findings were validated in a separate cohort of 122 patients. (See "Systemic mastocytosis: Determining the subtype of disease", section on 'Advanced testing'.)

Other poor prognostic factors — Certain clinical features are associated with an increased risk of death due to disease progression, independent of the category of SM present, including the following [50,55,56]:

Older age at onset of systemic symptoms

Elevated lactate dehydrogenase (LDH)

Elevated alkaline phosphatase

Hepatosplenomegaly

Understanding of the significance of skin lesions is evolving. Historically, the absence of maculopapular cutaneous mastocytosis (MPCM) (formerly called urticaria pigmentosa) was believed to be a poor prognostic indicator in patients who fulfilled World Health Organization criteria for SM. However, now that more patients without cutaneous involvement are being diagnosed with ISM, absent skin lesions do not appear to reflect a poor prognosis. For example, less than 50 percent of patients with SM presenting with Hymenoptera sting anaphylaxis have MPCM or other forms of cutaneous mastocytosis, yet this subset of patients does not appear to have a worse prognosis or to be at increased risk for disease progression [39]. In addition, one study indicated that some patients with ISM who initially presented with MPCM lesions may lose the lesions over time and have an excellent prognosis, even those who demonstrate the D816V mutation [48,57].

Increased risk for other disorders — In a Danish registry of 687 adults with SM diagnosed between 1997 and 2012, patients were found to have an increased risk for several other disorders, compared with those without SM [58]. In addition to anaphylaxis, osteoporosis, and fractures, hazard ratios in the patient cohort were dramatically increased for melanoma and nonmelanoma skin cancers. This may have been in part due to previous phototherapy, but further study is required.

INVESTIGATIONAL AGENTS — Information and instructions for referring a patient to an appropriate research center can be obtained from www.clinicaltrials.gov. Investigational agents include masitinib, avapritinib, and monoclonal antibodies [59-61].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Mast cell disorders".)

INFORMATION FOR PATIENTS — Information for patients, including lists of triggers for mast cell degranulation, is available online on the Mastocytosis Society website and the National Institute of Allergy and Infectious Diseases website. Additional information is available on the National Institutes of Health Genetic and Rare Diseases (GARD) website.

SUMMARY AND RECOMMENDATIONS

Systemic mastocytosis (SM) is a heterogeneous disorder in which patients are classified into one of five subtypes, which are managed with distinct approaches (table 1). Indolent systemic mastocytosis (ISM) accounts for more than 50 percent of all SM cases in the published literature, while smoldering systemic mastocytosis (SSM) is rare. (See 'Overview' above.)

Although patients with any form of SM may experience episodic symptoms of mast cell activation and anaphylaxis, these symptoms are more common in ISM and SSM, with up to one-half of patients experiencing anaphylaxis. Anaphylaxis represents the primary threat to patients with these variants of disease. A variety of exposures may trigger symptoms, including physical factors, alcohol, medications, emotional stress, insect stings, and allergens. All patients should be equipped with epinephrine autoinjectors and carry at least two doses at all times. (See 'General measures' above.)  

Pharmacotherapy for most patients includes H1 and H2 antihistamines, antileukotriene drugs, and cromolyn sodium, with additional treatments as needed for specific disorders, such as flushing, osteoporosis, or depression. (See 'Pharmacotherapy for symptoms related to mast cell mediators' above.)

For patients with recurrent anaphylaxis or episodes of mast cell activation symptoms with hemodynamic instability despite trigger avoidance and maximized doses of H1 and H2 antihistamines and antileukotriene drugs, we suggest a course of oral glucocorticoids (Grade 2C). In adults, we give 20 to 30 mg daily for two to three weeks, followed by a slow taper. Higher doses can be problematic and may cause flushing, tachycardia, and abdominal pain, side effects that can be difficult to differentiate from mast cell-mediator effects. (See 'Recurrent anaphylaxis' above.)

For patients with Hymenoptera venom-induced anaphylaxis and positive skin tests or in vitro tests to venom, we suggest lifelong venom immunotherapy (VIT), despite the higher risk of allergic reactions induced by the injections (Grade 2C). In contrast, we typically do not administer subcutaneous immunotherapy for allergic rhinitis or asthma, as these conditions can be managed with medications and the risk of systemic reactions to the injections usually outweighs the additional benefit of the immunotherapy. (See 'Treatment of coexistent allergic disease' above.)

Patients with ISM and SSM should be followed regularly with a review of systems and laboratory testing to detect signs and symptoms of disease progression. Osteopenia and osteoporosis are common complications, and screening, prevention, and treatment are important. (See 'Monitoring for progression' above.)

Patients with ISM have a near-normal life expectancy, with less than 3 percent of patients progressing to a more severe form of systemic mastocytosis. In these patients, disability or death from anaphylaxis often represents the greater threat. Patients with SSM are at higher risk for progression, although data are limited. (See 'Prognosis' above.)

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