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Systemic mastocytosis: Management and prognosis
Authors:
Cem Akin, MD, PhD
Jason Gotlib, MD, MS
Section Editor:
Sarbjit Saini, MD
Deputy Editors:
Anna M Feldweg, MD
Alan G Rosmarin, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2018. | This topic last updated: Aug 28, 2017.

INTRODUCTION — Systemic mastocytosis (SM) consists of a group of disorders exhibiting excessive mast cell accumulation, typically in bone marrow and other extracutaneous tissues (table 1). The general management and pharmacologic treatment of SM will be discussed in this topic review. The clinical manifestations, classification, pathogenesis, evaluation, and diagnosis of SM are reviewed separately:

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

(See "Mastocytosis (cutaneous and systemic): Evaluation and diagnosis in adults".)

(See "Mastocytosis (cutaneous and systemic): Evaluation and diagnosis in children".)

OVERVIEW — Systemic mastocytosis (SM) is a heterogenous disorder. Patients are classified into one of five clinical subtypes (also called variants), which differ in clinical presentation, treatment, and prognosis (table 1):

Indolent systemic mastocytosis (ISM)

Smoldering systemic mastocytosis (SSM)

Aggressive systemic mastocytosis (ASM)

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

Mast cell leukemia (MCL)

ISM and SSM usually have a clinically indolent course, with median survival measured in decades. In contrast, the other three subtypes have a more aggressive course, with median survival measured in months to years. As such, the term "advanced mastocytosis" is used to collectively refer to ASM, SM-AHN, and MCL. Patients with advanced forms of SM should be referred to centers with expertise in these disorders, when possible.

The evaluation to determine the category of SM is reviewed in detail elsewhere. (See "Systemic mastocytosis: Determining the subtype of disease".)

Indolent and smoldering subtypes — Indolent systemic mastocytosis (ISM) and smoldering systemic mastocytosis (SSM) account for approximately one-half of the cases of SM in published series. ISM carries a low-risk of progression to more severe forms of disease, while the risk with SSM is intermediate. (See 'Indolent systemic mastocytosis' below and 'Smoldering systemic mastocytosis' below.)

Morbidity in ISM and SSM is most commonly related to mast cell-mediator release, such as flushing, gastrointestinal disorders, neuropsychiatric symptoms, 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 [1]. In one study, severe anaphylaxis was unexpectedly seen more in patients with ISM compared with those with more aggressive forms of disease [2].

Additional therapies to reduce mast cell numbers can be associated with significant toxicity and are generally not indicated, except in rare cases when mast cell activation cannot be controlled by other means.

Advanced subtypes — Patients with ASM, SM-AHN, and MCL have an aggressive clinical course with end-organ damage (eg, cytopenias, liver dysfunction, malabsorption, ascites, large osteolyses with or without pathologic fractures) and significantly shortened survival. Collectively, they are referred to as "advanced systemic mastocytosis." Patients with advanced forms of SM should be referred to centers with expertise in these disorders (when possible) and often require cytoreductive therapy. However, they may also experience symptoms related to mast cell-mediator release.

There have been no randomized trials evaluating the treatment of patients with advanced SM. Data regarding treatment comes from case series or single-arm prospective trials. Cytoreductive therapies have demonstrated improvements in organ function, but impact on survival rates has been harder to estimate. Allogeneic hematopoietic cell transplantation (allogeneic HCT) offers the potential for cure in patients responding to therapy, although at a substantial risk of transplant-related mortality. Early referral for transplant evaluation is suggested to provide a risk-benefit assessment and allow for the early identification of a donor.

GENERAL MEASURES — Patients with any form of systemic mastocytosis (SM) may experience episodic symptoms of mast cell activation, including apparent allergic reactions triggered by a variety of exposures. Up to one-half of adult patients with mastocytosis experience anaphylaxis [3-6]. All patients with SM should be educated about anaphylaxis and about how to avoid triggers for mast cell degranulation.

Preparation for treating anaphylaxis — All patients with SM should be educated about the management of anaphylaxis. Anaphylaxis is more common in indolent systemic mastocytosis (ISM) and smoldering systemic mastocytosis (SSM) compared with advanced forms of the disease. Patients should be taught to lie flat if they experience lightheadedness or presyncope during symptomatic episodes. Epinephrine is the primary medical treatment for anaphylaxis. 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 when patients with SM develop anaphylaxis [7]. The treatment of anaphylaxis is discussed elsewhere. (See "Anaphylaxis: Emergency treatment".)

Mastocytosis patients should consider wearing a medical identification bracelet, especially if they have a history of 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 (Anaphylaxis Emergency Action Plan - English) (Anaphylaxis Emergency Action Plan - Spanish) (Anaphylaxis Emergency Action Plan - Wallet card).

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). This can help determine, retrospectively, if the events were truly caused by mast cell-mediator release. If serum tryptase increases ≥2 + 1.2 x baseline in the hours following signs/symptoms, then those signs/symptoms can be attributed to mast cell activation. In rare instances, patients with SM can also suffer from panic attacks, and it is important to distinguish the two disorders so that effective treatment can be instituted for the panic disorder and overuse of epinephrine can be avoided. However, it is important to realize the serum tryptase results will not be available immediately, and the emergency evaluations still rely on clinical judgment.

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 that may precipitate symptoms). 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 heat or cold

Acute emotional stress

Very strenuous exercise

Alcohol and spicy foods

Medications (eg, aspirin, nonsteroidal anti-inflammatory drugs [NSAIDs], antibiotics)

Infections

Anesthesia, surgery, and endoscopic procedures

Insect stings (wasp, honey bee, and other Hymenoptera) can precipitate anaphylaxis in patients with mastocytosis, especially in those who have also developed immunoglobulin E (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 blood tests should be retested in six months. (See 'Information for patients' below and 'Treatment of coexistent allergic disease' below and "Hymenoptera venom immunotherapy: Efficacy, indications, and mechanism of action".)

Problematic medications — There are various medications that may cause mast cell activation in patients with either systemic or cutaneous mastocytosis. As a precaution, these medications should be avoided when possible, unless the patient's tolerance for a specific agent is already known. Problematic medications, as well as medications that are usually tolerated, are discussed separately. (See "Treatment and prognosis of cutaneous mastocytosis", section on 'Problematic medications' and "Treatment and prognosis of cutaneous mastocytosis", section on 'Medications that are usually tolerated'.)

Preparation for medical and surgical 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 usually 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 [8-10]. 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:

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

Ranitidine, 150 mg orally or 50 mg 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 2 hours prior to procedure.

The anesthesiologist and/or surgeon involved should be aware of the patient's susceptibility to anaphylaxis and be prepared to treat it promptly. 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 his/her 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.

PHARMACOTHERAPY FOR SYMPTOMS RELATED TO MAST CELL MEDIATORS — The following therapies may be needed for symptomatic patients with any subtype of systemic mastocytosis (SM). Symptoms arising from mediator release are most prominent in patients with indolent and smoldering systemic mastocytosis, 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), hydroxyzine (25 mg every six hours), or doxepin (10 to 100 mg per day) [1]. Each of these agents may be used in children, at age/weight-appropriate doses. 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 ranitidine (150 mg every 12 hours), famotidine (10 to 20 mg every 12 hours), and cimetidine (300 mg twice daily) [1]. Ranitidine and famotidine may be used in children at age/weight-appropriate doses.

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 [11]. Ketotifen may be used in children at age/weight-appropriate doses.

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 [12].

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) may provide benefit. (See 'Antihistamines' above and 'Antileukotriene drugs' above.)

Omalizumab — Omalizumab (anti-IgE), a humanized monoclonal antibody that inhibits the binding of immunoglobulin E (IgE) to mast cells, reduced the frequency of anaphylaxis in a few patients with SM or monoclonal mast cell activation syndrome [13,14]. 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 [15]. This use of omalizumab for these indications is not approved by the US Food and Drug Administration (FDA) and deserves further study. (See "Anti-IgE therapy".)

Other therapies — In patients who are unresponsive to antimediator therapies and omalizumab, low-dose maintenance glucocorticoids or cytoreductive measures (such as interferon-alfa, cladribine, or a tyrosine kinase inhibitor [TKI] depending on KIT mutational status) can be considered as second-line approaches. (See 'Cytoreductive therapies for advanced disease' below.)

Glucocorticoids appear to reduce mast cell numbers through inhibition of stem cell factor synthesis [16]. We start with doses or 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.

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) [1]. NSAIDs trigger mediator release in some patients, and these individuals should avoid NSAIDs. Although aspirin can reduce flushing, high doses are typically needed and may not be tolerated by patients already predisposed to peptic ulcer disease.

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 a full dose, allowing 90 minutes after each step to observe for symptoms. If symptoms develop, 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). Orally administered glucocorticoids are helpful for patients with aggressive systemic mastocytosis (ASM) and severe malabsorption or ascites [17].

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 [18]. 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. (See "Proton pump inhibitors: Overview of use and adverse effects in the treatment of acid related disorders".)

Glucocorticoids may be helpful for malabsorption and can be dosed as previously described. (See 'Other therapies' above.)

Osteoporosis and fractures — Patients with all forms of SM should be monitored for osteoporosis and treated appropriately [19-23]. Appropriate daily intake of calcium and vitamin D should be maintained. For patients with osteoporosis-related fractures, treatment with the combination of pamidronate and low-dose interferon-alfa has been reported to be helpful [24]. (See "Screening for osteoporosis" and "Treatment of osteoporosis in men" and "Overview of the management of osteoporosis in postmenopausal women".)

Depression — One study found that patients with SM and depression experienced relief of their psychiatric symptoms following treatment with TKI therapy [25]. (See 'Choice of therapy' below.)

Other reports have suggested that oral cromolyn sodium [26] or antidepressant medications may be helpful. Referral to a mental health clinician may be warranted [27].

CYTOREDUCTIVE THERAPIES FOR ADVANCED DISEASE — Patients with advanced forms of systemic mastocytosis (SM; ie, aggressive systemic mastocytosis [ASM], SM with an associated hematologic neoplasm [SM-AHN], or mast cell leukemia [MCL]) are collectively referred to as "advanced SM," because these disorders have an aggressive clinical course with end-organ damage (eg, cytopenias, liver dysfunction, malabsorption, ascites) leading to shortened survival. In addition to therapies aimed at preventing mast cell-mediator release, patients may benefit from cytoreductive therapies to reduce the tumor burden and improve organ function.

Patients with advanced forms of SM should be evaluated at centers with expertise in these disorders, although treatment can generally be carried out locally if not participating in a clinical trial.

Indications — Treatment of advanced SM is indicated to mitigate organ dysfunction and improve quality of life. For those patients eligible for hematopoietic cell transplantation (HCT), the goal is to control symptoms and prevent progression until a donor can be found. Treatment modifications may be necessary based on serial assessments of disease tempo and status. (See 'Hematopoietic cell transplantation' below.)

Treatment with cytoreductive therapy is also appropriate for select patients with indolent systemic mastocytosis (ISM) or smoldering systemic mastocytosis (SSM) who suffer from recurrent anaphylaxis that cannot be controlled with antimediator treatments, although this is only appropriate when all other options have been exhausted [28].

Choice of therapy — We suggest midostaurin for initial systemic treatment of advanced SM, regardless of KIT mutational status (ie, wild type, mutant, or KIT status unknown).

Exceptions to the suggested use of midostaurin as initial cytoreductive therapy are generally limited to the following clinical scenarios:

FIP1L1-PDGFRA (Fip1-like1-platelet-derived growth factor receptor alpha)-positive myeloid neoplasm with eosinophilia that may be characterized by increased numbers of atypical, CD25+ bone marrow mast cells. Although this disease entity can phenotypically mimic SM-CEL (systemic mastocytosis with chronic eosinophilic leukemia), it is not considered a subtype of SM.

Well-differentiated advanced SM, which may have wild-type KIT or KIT mutations outside of exon 17 (eg, KIT F522C or other mutations of the juxtamembrane/transmembrane region) that are sensitive to imatinib. In this entity, mast cells are typically round rather than spindled in morphology and are CD25 low or negative.

For such patients, acceptable therapeutic alternatives include imatinib, other agents (eg, cladribine, fludarabine, multiagent chemotherapy, such as cytarabine with an anthracycline), and investigational therapies, as described below.

Midostaurin — Midostaurin is a multikinase/KIT inhibitor that has demonstrated activity in patients with advanced SM. Midostaurin inhibits the protein product of KIT, including the KIT D816V mutation, which is the most common driver mutation in SM. It is approved by the US Food and Drug Administration (FDA) for treatment of ASM, SM-AHN, and MCL.

Midostaurin treatment achieves responses in approximately two-thirds of patients with advanced SM (including ASM, SM-AHN, and MCL), with major responses in one-half. Responses are generally sustained for 18 to 24 months, but longer-term responses (>5 years) have been observed in some patients. In addition to reducing organ damage (eg, cytopenias, liver dysfunction) and providing symptomatic relief, treatment with midostaurin reduces bone marrow mast cell burden, KIT mutant allele burden, and serum tryptase levels. Toxicities include moderate (grade 1 to 2) nausea/vomiting and mild cytopenias. Midostaurin has not been directly compared with other cytoreductive therapies or placebo controls in advanced SM.

Studies that examined this role in SM include:

In a multicenter phase II study of midostaurin (100 mg twice daily) that included 89 patients with ASM and associated organ damage, the overall response rate (ORR) was 60 percent (45 percent major response, 15 percent partial response, none complete) with the following additional findings [29]:

Responses in organ damage (eg, normalization of cytopenias/red blood cell or platelet transfusion dependence, liver function abnormalities, hypoalbuminemia) were observed regardless of KIT D816V status, prior therapy, or the presence of an associated hematologic neoplasm.

Bone marrow mast cell burden and serum tryptase levels decreased by a median of 59 and 58 percent, respectively, and 57 percent of patients had a >50 percent reduction in bone marrow mast cells.

After a median follow-up of 26 months, the median duration of response and median overall survival (OS) were 24 and 29 months, respectively. Median OS was higher in responders (44 versus 15 months).

The drug was generally well-tolerated with a manageable toxicity profile consisting mostly of gastrointestinal side effects, including nausea and vomiting, primarily grade 1 to 2 in nature. High-grade myelosuppression more commonly occurred in patients with pre-existing cytopenias.

A multicenter study of midostaurin in 26 patients (3 ASM, 17 SM-AHN, 6 MCL) reported 69 percent ORR (50 percent major response, 19 percent partial response) with clinical benefit in all variants of advanced SM [30]. Median survival for the entire cohort was 40 months and 19 months for patients with MCL. With median follow-up of 10 years, no unexpected toxicities emerged.

In a retrospective analysis of midostaurin in 28 patients with advanced mastocytosis, ORR was 71 percent (57 percent major, 14 percent partial, none complete) with a median duration of response of 17 months [31]. At a median follow-up of 19 months, OS was 43 percent. The risk of death was approximately one-half of that seen in a control group matched for age at diagnosis and subtype of mastocytosis.

A study of 38 patients with advanced SM reported that the nature of additional mutations beyond KIT D816V and the depth of reduction of KIT D816V allele burden reflect the nature of response to midostaurin, disease progression, and prognosis [32]. Among the reported findings were:

Compared with patients who did not have mutations in SRSF2, ASXL1, and/or RUNX1, those patients with mutations in at least one of those genes had lower ORR (39 versus 75 percent, respectively).

Patients who responded to midostaurin with ≥25 percent reduction in KIT D816V expressed allele burden had improved OS compared with those patients with lesser responses (hazard ratio [HR] 6.8; 95% CI, 1.8-25.3).

Acquisition of additional mutations or increasing variant allele frequency in K/NRAS, RUNX1, IDH2, or NPM1 was associated with disease progression.

Other tyrosine kinase inhibitors — For patients with advanced SM, regardless of KIT mutational status (ie, wild type, mutant, or KIT status unknown), we generally offer treatment with midostaurin, but other tyrosine kinase inhibitors (TKIs; eg, imatinib) may be effective in certain patients. (See 'Choice of therapy' above.)

Other TKIs that have been administered to patients with SM include:

Imatinib is approved by the FDA for patients with ASM who do not have a KIT D816V mutation or for those with unknown mutational status. Most patients with SM are not candidates for imatinib, because they have the D816V KIT mutation, which confers resistance to imatinib [33]. Imatinib has activity against mast cells with wild-type KIT [34], and some patients without KIT D816V may respond to imatinib [33,35-38]. However, we generally suggest treatment with midostaurin rather than imatinib in this setting. Case reports have demonstrated clinical responses to imatinib in cases of mastocytosis with the following mutations in exons 8 to 10 of KIT: F522C transmembrane KIT mutation [36], germline KIT K509I mutation [39], deletion of codon 419 in exon 8 of KIT [40], and p.A502_Y503dup exon 9 mutation [41].

Most reported responses to imatinib among patients with "mastocytosis" likely represent misdiagnoses or systemic mastocytosis associated with another hematologic disorder with a molecular lesion sensitive to imatinib. As an example, patients with hypereosinophilic syndrome or CEL that are associated with imatinib-responsive fusion proteins (eg, FIP1L1-PDGFRA) typically have an associated increase in bone marrow mast cell numbers and an elevated serum tryptase level. Diagnosis of these disorders is described separately. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Systemic mastocytosis with eosinophilia'.)

An open-label phase 2 trial of nilotinib in 61 patients with SM showed efficacy in some patients [42]. In 37 patients with ASM, the overall response rate was 22 percent, although there were no complete responses.

Clinical trials with dasatinib have been generally disappointing [43,44].

Clinical trials that are evaluating other TKIs in the treatment of SM are discussed below. (See 'Clinical trials' below.)

Cladribine — Cladribine may be appropriate for patients with rapidly progressive advanced SM that failed to respond adequately to midostaurin (or other TKIs), as therapy reduces the total burden of mast cells [45-47]. Patients with more rapidly progressing advanced SM may receive several cycles of cladribine as a bridge to allogeneic HCT. Cladribine may also be used in patients who do not respond to TKIs or interferon-alfa (IFN-alfa). Cladribine is not warranted for ISM, except in patients with severe and refractory symptoms that significantly impair quality of life, because responses are transient.

Dose ranges that have been used include 0.10 to 0.14 mg/kg/day or 5 mg/m2 daily, infused over two hours for five days at four- to eight-week intervals [48,49]. Up to six cycles may be given.

Patients can experience transient responses, although nearly all relapse eventually [43,50]. Side effects are mainly related to bone marrow suppression [46,49]. Prophylaxis to prevent Pneumocystis jirovecii pneumonia is suggested for at least three months after therapy is complete and until the CD4 count is >200/mcL [51]. Patients should use contraception, because cladribine is a teratogen. (See "Treatment and prevention of Pneumocystis pneumonia in HIV-uninfected patients", section on 'Prophylaxis'.)

In one series, patients with indolent (36 patients) or advanced (32 patients) SM were treated with a median of 3.7 courses of cladribine (range 1 to 9) and followed long-term [28]. In most circumstances, cladribine is only appropriate for those with advanced forms of SM. In this series, cladribine was administered as an infusion or subcutaneously at a dose of 0.14 mg/kg, for 1 to 5 days, every 4 to 12 weeks [28]. The overall response rate was 72 percent (ie, 92 percent and 50 percent for indolent and advanced disease, respectively). Among patients with advanced SM, major and partial responses were seen in 38 and 13 percent, respectively. There were no complete responses. Significant decreases in serum tryptase levels were only observed in ISM patients. Median durations of response were 3.71 (0.1 to 8) and 2.47 (0.5 to 8.6) years for indolent and advanced SM, respectively. The most common severe (grade 3/4) adverse events were lymphopenia (82 percent), neutropenia (47 percent), and opportunistic infections (13 percent).

Interferon-alfa — Interferon-alfa (IFN-alfa) has been used for decades to treat SM [52]. It is usually reserved for patients with slowly progressive symptomatic disease who are not candidates for other therapies (eg, older adults), given the slow time to response and frequent toxicities [17]. IFN-alfa increases bone density and so may be particularly useful in patients with severe bone disease and multiple fractures. It is also an option for patients with organ involvement limited to the liver with ascites [53].

Case series have described the use of IFN-alfa as a single agent or in combination with prednisone [45,52,54-57]. Indirect studies evaluating whether prednisone improves response rates are inconclusive. There have been rare reports of anaphylactic symptoms when IFN-alfa is initiated without glucocorticoids [58]. As such, some clinicians advocate hospitalization for the first few days of administration and pretreatment with prednisone. One published approach is to administer prednisone (1 mg/kg body weight daily) for three to seven days prior to initiating IFN-alfa [17]. IFN-alfa is then begun at 3 million units three times weekly. The dose of prednisone is then gradually reduced as the dose of IFN-alfa is increased to a maximum of 5 million units daily, if tolerated. In patients with severe mediator-related symptoms or ascites, a small maintenance dose of prednisone (≤5 to 10 mg/day) should be continued. Otherwise, prednisone is discontinued, if possible, to minimize the risk of osteoporosis [23].

Up to 20 percent of patients may experience partial remission of bone pain and lesions, although complete remissions are rare [45,52,54-56]. Adverse effects include flu-like symptoms, thrombocytopenia, cardiac toxicity, and depression. Elevated serum aminotransferases are the most common laboratory abnormality other than myelosuppression. If there is clinical improvement, interferon therapy can be continued as long as tolerated.

Pegylated interferon-alfa-2a is a formulation with a longer half-life that has been used in other myeloproliferative neoplasms and generally exhibits a more favorable toxicity profile. The starting dose is typically 45 micrograms/week subcutaneously and is incrementally escalated according to tolerability and efficacy. Its role in advanced SM merits further investigation.

Hydroxyurea — Hydroxyurea is rarely used, although it has been administered to patients with ASM and SM-AHN, mainly for the treatment of leukocytosis and/or splenomegaly-associated myeloproliferative neoplasms. There is little published data on efficacy [45]. Hydroxyurea has relatively few side effects compared with other chemotherapy agents, although hematologic toxicity and gastrointestinal side effects may be problematic at higher doses. The initial dose is 500 mg daily for the first four to six weeks. Complete blood counts (CBC) and liver function tests should be monitored regularly. If tolerated, the dose can be increased to 1000 to 1500 mg daily. Patients should use contraception because hydroxyurea is a teratogen.

HEMATOPOIETIC CELL TRANSPLANTATION — Allogeneic hematopoietic cell transplantation (HCT) offers the potential for cure in patients with advanced systemic mastocytosis (SM) responding to therapy, although at a substantial risk of transplant-related mortality. Early referral for transplant evaluation is suggested to provide a risk-benefit assessment and allow for the early identification of a donor. Further details regarding the selection of patients for allogeneic HCT have been presented in a consensus opinion document [53]. Allogeneic HCT is not appropriate for indolent or cutaneous forms of mastocytosis.

Allogeneic HCT for any condition has traditionally been limited to patients less than 60 years of age and to those who have a human-leukocyte antigen (HLA)-identical sibling donor, although there has been increasing use of both matched-unrelated and mismatched-related donors and transplantation of older adults. Eligibility for allogeneic HCT is discussed separately. (See "Determining eligibility for allogeneic hematopoietic cell transplantation".)

Data regarding the use of allogeneic HCT in advanced SM comes from retrospective case series [59-62]. The largest retrospective series included 57 patients with systemic mastocytosis with an associated hematologic neoplasm (SM-AHN; 38 patients), mast cell leukemia (MCL; 12 patients), or aggressive systemic mastocytosis (ASM; 7 patients) [62]. Different types of donors and conditioning regimens were used. Overall, 70 percent of patients responded, as evidenced by improvements in the percentage of bone marrow mast cells, serum tryptase levels, or organ involvement. Nearly one-third demonstrated complete remission. Survival at three years was 74, 17, and 43 percent for SM-AHN, MCL, and ASM, respectively, which was significantly greater than historical controls, particularly for patients with SM-AHN. Myeloablative conditioning regimens were superior to reduced-intensity regimens.

Further studies are needed to better define the role of allogeneic HCT in SM, including the selection of patients, optimal timing in relation to other therapies, preferred debulking strategy prior to allogeneic HCT, and ideal conditioning regimen.

TREATMENT OF COEXISTENT ALLERGIC DISEASE — Patients with systemic mastocytosis (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, food and drug allergies [63-65]. The treatment of allergic disorders in SM patients may need to be modified in individuals who are prone to episodes of mast cell activation.

Venom immunotherapy — Patients with mastocytosis can suffer severe anaphylaxis in response to an insect sting [66-68]. Fatalities have been reported in patients with SM who were stung by Hymenoptera, despite self-treatment with epinephrine [69]. 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. The safety and utility of VIT in mastocytosis patients was evaluated in a retrospective series of 21 subjects who underwent VIT [66]. Twelve patients were re-stung during treatment, and nine of these developed only local reactions, suggesting protection against repeat anaphylaxis. However, adverse reactions during the build-up phase of immunotherapy were experienced by a large proportion of patients (30 percent). Patients should be counseled about this when giving consent to receive VIT. Most experts agree that the duration of VIT should be lifelong [67]. 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. (See "Hymenoptera venom immunotherapy: Technical issues, protocols, adverse effects, and monitoring".)

Pretreatment with omalizumab may reduce the risk of systemic reactions to VIT. 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 [70]. 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 [71]. 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 [72]. 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".)

TREATMENT, MONITORING, AND PROGNOSIS OF SPECIFIC SUBTYPES

Indolent systemic mastocytosis — Indolent systemic mastocytosis (ISM) progresses slowly or not at all, and most patients have a normal life expectancy [73,74]. Less than 3 percent of patients with an initial diagnosis of ISM will progress to a more severe form of systemic mastocytosis (SM), including systemic mastocytosis with an associated hematologic neoplasm (SM-AHN), aggressive systemic mastocytosis (ASM), or mast cell leukemia (MCL) [74].

Women with ISM may have healthy pregnancies and give birth to unaffected infants, as mastocytosis is not genetically transmitted in the great majority of patients [75].

A primary concern in the management of ISM is anaphylaxis, as severe disability and death have been reported [2]. (See 'Recurrent anaphylaxis' above.)

Yearly monitoring is appropriate for uncomplicated patients with ISM, although the frequency of evaluation should be increased if symptoms worsen or new signs/symptoms appear. Patients with smoldering systemic mastocytosis (SSM) are generally seen every six months or more frequently if there are signs/symptoms of progression. In patients whose physical exam is unremarkable and weight is stable, the following yearly assessment is suggested:

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.

Serum chemistry panel to monitor for liver involvement and electrolyte imbalances.

Yearly bone densitometry for patients with documented osteopenia or osteoporosis. We repeat densitometry every three years in patients with normal bone density. (See 'Osteoporosis and fractures' above.)

About 10 to 15 percent of patients with ISM and urticaria pigmentosa (UP) may experience a regression of UP lesions, which may correspond to either improvement or worsening in the systemic disease [76]. Increases in UP lesions, even dramatic increases, do not necessitate additional evaluation if the patient is feeling well. New abnormalities on the CBC or the development of splenomegaly should prompt repeat evaluation for a more advanced form of disease.

Studies evaluating negative prognostic indicators in ISM have found the following:

The identification of KIT D816V in highly purified bone marrow mesenchymal stem cells (MSC) from patients with ISM was associated with more advanced disease features and shorter progression-free survival [77]. The finding of KIT D816V-mutated MSC is consistent with the development of the mutation in a pluripotent progenitor, which gives rise to both MSC and hematopoietic cells. However, detection of KIT mutations in different hematopoietic cells or MSC is limited to research laboratories.

A large prospective study of 145 consecutive patients with ISM followed for a median of nine years found that increased serum levels of beta-2-microglobulin combined with the presence of KIT D816V mutation in all hematopoietic cell lines identified patients at higher risk for progression [74]. This observation is preliminary and needs to be reproduced in other studies.

Smoldering systemic mastocytosis — Among patients with smoldering systemic mastocytosis (SSM), 18 percent progressed to ASM or MCL in one large study [73,78]. Progression may occur within months to years from the initial diagnosis. Development of unexplained hematologic abnormalities (eg, increased white blood count [WBC], 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.

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.

Aggressive systemic mastocytosis — Aggressive systemic mastocytosis (ASM) is associated with end-organ damage (eg, cytopenias, liver dysfunction, malabsorption, ascites) and shortened estimated survival. In addition to therapies aimed at preventing mast cell-mediator release and minimizing symptoms of mast cell degranulation, these patients are offered therapies to reduce the tumor burden and improve organ function. Cytoreductive therapies (eg, cladribine, tyrosine kinase inhibitors [TKIs]) are usually administered with the goal of achieving a response and proceeding with allogeneic hematopoietic cell transplantation (HCT) in eligible patients.

The clinical course of patients with ASM is variable, with some experiencing a rapidly declining course over 12 to 24 months, while others follow a slower course with several years of survival [54,79-81].

We see these patients in clinic every one to six months, depending upon the patient's clinical status. At these visits, we evaluate the following laboratory studies:

Serum tryptase levels, which reflect mast cell burden.

CBC with differential.

Serum chemistry panel to monitor for liver involvement and electrolyte imbalances.

A bone marrow biopsy is performed periodically (eg, every 6 to 12 months) to monitor disease and if there are signs/symptoms of progressive SM.

Systemic mastocytosis with an associated hematologic neoplasm — Treatment of patients with systemic mastocytosis with an associated hematologic neoplasm (SM-AHN) depends upon the associated hematologic neoplasm (AHN) [45,82,83]. The approach is to treat the AHN as if SM were not present and to treat the mastocytosis as if the AHN were not present, although patients should be monitored closely for mast cell activation symptoms during therapy [35]. Prioritization of treatment of the SM versus AHN component requires evaluation of the clinicopathologic burden of disease and determination of which disease component is producing clinical sequelae/organ damage. As an example, in a patient with liver function abnormalities and ascites, a liver biopsy may be useful in determining whether the hepatic dysfunction is due to liver involvement by SM or chronic myelomonocytic leukemia (CMML) (or both).

A retrospective study found better-than-expected average survival rates in patients with SM-AHN undergoing allogeneic hematopoietic cell transplantation (HCT) as compared with historic controls [62]. We agree with a consensus opinion statement which suggests allogeneic HCT in the following two populations [53]:

Patients with SM-AHN who would be candidates for allogeneic HCT based on their AHN alone (eg, acute myeloid leukemia).

Patients with SM-AHN who would be candidates for allogeneic HCT based on their SM alone (eg, ASM or MCL).

Most patients with SM-AHN have the KIT D816V (or another codon 816 mutation), but for the few who do not, treatment with imatinib is an option. It should be noted that false-negative results can occur when peripheral blood is analyzed. Therefore, samples of bone marrow or lesional tissue are preferred for mutational analysis. Bone marrow evaluation is reviewed elsewhere. KIT D816V can be identified at a variable rate in microdissected cells from the AHN component (eg, most commonly from monocytes in CMML) [84]. (See "Mastocytosis (cutaneous and systemic): Evaluation and diagnosis in adults", section on 'Bone marrow analysis'.)

If a cytopenia is considered related to a form of advanced SM, therapies such as cladribine, pegylated interferon-alfa-2a, or TKIs, which have demonstrated hematologic responses in selected patients, may be helpful. Splenectomy is generally considered a palliative maneuver for hypersplenism in association with severe anemia and thrombocytopenia, after consideration of other treatment options [85].

The prognosis of patients with SM-AHN is usually that of the AHN present. SM-AHN has been reported in patients with CMML, chronic myeloid leukemia (CML), myelodysplastic syndromes (MDS), unclassifiable myeloproliferative neoplasms (MPN-U), hypereosinophilic syndrome (HES), chronic eosinophilic leukemia (CEL), acute myeloid leukemia, multiple myeloma, hairy cell leukemia, polycythemia vera, Hodgkin and non-Hodgkin lymphomas, essential thrombocythemia, and myelofibrosis. (See related topic reviews).

Mast cell leukemia — There is no standard approach to treatment of patients with mast cell leukemia (MCL), and substantial heterogeneity exists in this variant:

Aleukemic versus leukemic MCL In the leukemia MCL subtype, >10 percent of the circulating cells are mast cells. These patients generally exhibit a worse prognosis than patients with aleukemic MCL.

Acute versus chronic MCL – Although this division of MCL is not formally recognized by the World Health Organization (WHO), the term "chronic MCL" has been used to designate those patients without evidence of organ damage ("C" findings), despite meeting the histopathologic criterion of >20 percent mast cells on a bone marrow aspirate. Although these patients typically have a less rapidly progressive course, differences in survival between these two subtypes require further investigation [86-88].

Primary versus secondary MCL – MCL can arise de novo (primary MCL) or progress from pre-existing ISM, SSM, or ASM. There are no substantive data regarding prognostic differences between these subgroups.

MCL with or without an AHN – Similar to other subtypes of SM, an AHN may partner with MCL. It is not known whether the coexistence of an AHN (and the type of AHN) may influence the already poor prognosis of MCL.

The frequency of KIT D816V mutation in MCL (approximately 50 to 70 percent) is less than other SM subtypes. Infrequently, patients with MCL may exhibit mast cells with well-differentiated mast cell morphology (eg, mature, round mast cells rather than atypical, spindled forms; usually low or absent CD25 expression). The histopathology in these cases is often referred to as well-differentiated systemic mastocytosis (WDSM). Such patients may exhibit wild-type KIT, or extracellular or transmembrane KIT mutations, which have shown responsiveness to imatinib [89-91]. WDSM is not restricted to MCL, but can be observed across the spectrum of SM subtypes.

In patients with typical mast cell morphology with or without the KIT D816V mutation, we offer treatment with cladribine or midostaurin (available on a compassionate-use basis and under regulatory review). In patients with rapidly progressive disease, we offer combination chemotherapy regimens, similar to those used for acute myeloid leukemia, or referral for participation in clinical trials of investigational agents. Because patients with MCL without organ damage (eg, chronic MCL) still exhibit compromised survival, we offer treatment with either cladribine or midostaurin or consideration of upfront allogeneic HCT. (See 'Hematopoietic cell transplantation' above.)

Allogeneic HCT may be considered, as it offers the only curative option, although response rates are low [35]. The added value of cytoreductive agents such as cladribine or midostaurin as bridging therapies to allogeneic HCT has not been formally studied, but is considered a rational approach in these poor prognosis patients. (See "Induction therapy for acute myeloid leukemia in younger adults" and "Acute myeloid leukemia: Treatment and outcomes in older adults".)

Patients with MCL are particularly prone to gastrointestinal bleeding due to heparin release from the high number of mast cells present and also possibly due to associated coagulopathies. These individuals should be maintained on a proton pump inhibitor (PPI).

Patients with MCL have an overall poor prognosis. Progression to multiple organ failure with weight loss, bone pain, and organomegaly develops over weeks to months, with death usually occurring within 12 months of diagnosis. There appears to be a chronic form of disease (generally without significant mast cells in peripheral circulation) in which patients meet the pathologic criteria for aleukemic MCL without anemia, thrombocytopenia, or organopathy and demonstrate longer survival [86-88].

Prognosis — Disease subtype is one of the strongest prognostic predictors in SM (table 1). This was illustrated in a single institution retrospective analysis of 342 patients with SM followed for a median of 21 months (range 0 to 35 years), which reported an estimated median overall survival (OS) of five years in the group as a whole, although there may have been referral bias for more severe disease in this study [73,78,92]. Specific details about treatment, including transplantation, were not reported. Survival rates and progression to leukemia varied dramatically by disease subtype, as follows:

Indolent systemic mastocytosis (ISM) – 137 cases; median OS 301 months; 3 percent progressed to ASM or leukemia. Studies of other investigational negative prognostic indicators are reviewed above.

Smoldering systemic mastocytosis (SSM) – 22 cases; median OS 120 months; 18 percent progressed to ASM or leukemia.

Aggressive systemic mastocytosis (ASM) – 41 cases; median OS 41 months; 5 percent transformed to leukemia.

Systemic mastocytosis with an associated hematologic neoplasm (SM-AHN) – 138 cases; median OS 24 months; 13 percent transformed to leukemia. The prognosis of patients with SM-AHN is usually that of the AHN present.

Mast cell leukemia (MCL) – 4 cases; median OS 2 months.

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 [73,93,94]. These features include the following:

Older age at onset of systemic symptoms

Weight loss

Low platelet count

Low serum albumin

Low hemoglobin levels

Elevated lactate dehydrogenase (LDH)

High alkaline phosphatase

Hepatosplenomegaly

Ascites

Excess bone marrow blasts

Historically, absence of cutaneous lesions was believed to be a poor prognostic indicator in patients who fulfilled World Health Organization (WHO) 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 UP 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 [66]. In addition, one study indicated that some patients with ISM who initially presented with UP lesions may lose the UP lesions over time and have an excellent prognosis, even those who demonstrate the D816V mutation [76,95].

The presence of high-grade mast cell morphologic features, such as bilobed nuclei and significant hypogranulation, is usually associated with more serious forms of SM, such as ASM or MCL [96].

Experimental evidence suggests that higher numbers of mast cell precursors in peripheral blood reflect aggressive disease [97,98]. One study found that peripheral blood CD34-CD117+ cells, cells capable of becoming mast cells in vitro, were more prevalent in patients with aggressive forms of SM, compared with those with indolent forms and cutaneous mastocytosis [97]. Further study is warranted.

Mutations in the TET2 (ten-eleven translocation 2) gene may be a marker of poor prognosis, as these mutations have been detected in advanced forms of mastocytosis, including SM-AHN and ASM [99-102]. Additional mutations in epigenetic transcriptional regulation genes DNA methyltransferase genes (DNMT3A), additional sex comb-like 1 (ASXL1), and in the proto-oncogene CBL have also been detected in patients with advanced disease and may indicate increased genomic instability and poorer prognosis. In patients with advanced SM, OS was significantly shorter in patients with additional molecular abnormalities besides KIT D816V [103]. In particular, mutation of SRSF2, ASXL1, or RUNX1 was associated with an adverse prognosis in patients with advanced SM, and overall survival (OS) was influenced by the number of mutated genes in this panel [104].

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 [105]. 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.

CLINICAL TRIALS — Often, there is no better therapy to offer a patient than enrollment in a well-designed, scientifically-valid, peer-reviewed clinical trial. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health. Consensus response criteria for advanced systemic mastocytosis (SM) have been published in order to harmonize adjudication of clinically relevant responses across clinical trials [106].

The following is a sampling of agents that are under investigation:

Brentuximab vedotin – CD30 (Ki-1) is a cytoplasmic and membrane-bound antigen expressed by neoplastic mast cells in Hodgkin lymphoma and anaplastic large cell lymphoma. CD30 is also expressed by neoplastic mast cells in SM, including advanced and indolent forms of disease [107-109]. In a small case series, two of four patients demonstrated a response to the anti-CD30 antibody-drug conjugate brentuximab vedotin [110]. Pre-clinical data indicate that this agent can induce apoptosis in CD30+ mast cell lines and primary neoplastic CD30+ mast cells from SM patients [111]. A phase II trial of brentuximab vedotin is in progress (clinicaltrials.gov identifier: NCT01807598).

Other antibody drug conjugates – Based on the expression of CD123 (interleukin-3 [IL-3] receptor-alpha) on neoplastic mast cells [112], an anti-CD123 antibody linked to diphtheria toxin, SL-401, has also commenced trial evaluation in advanced SM (clinicaltrials.gov identifier: NCT02268253).

Tyrosine kinase inhibitors – Masitinib is a multikinase inhibitor with activity against at least three mast cell signaling molecules. In a multicenter randomized trial of 135 severely symptomatic patients with indolent SM or smoldering SM, oral masitinib reduced symptoms, tryptase levels, and urticaria pigmentosa lesions compared with placebo [113]. Importantly, 24 percent of patients receiving masitinib had side effects (eg, diarrhea, rash, and asthenia) that required discontinuation of the medication. The drug is under regulatory review, and further data about its safety and efficacy are needed before its use can be recommended.

Inhibition of Bruton tyrosine kinase (BTK) with the agent ibrutinib is being studied in advanced SM (clinicaltrials.gov identifier: NCT02415608), and specific tyrosine kinase inhibitors (TKIs) of KIT D816V, such as BLU-285, have entered trials (clinicaltrials.gov identifier: NCT02561988).

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 heterogenous disorder in which patients are classified into one of five subtypes, which are managed with distinct approaches. The subtypes are indolent systemic mastocytosis (ISM), smoldering systemic mastocytosis (SSM), aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL) (table 1). The clinical course of the different subtypes ranges from clinically indolent disorders with survival approaching that of the general population to aggressive diseases with survival measured in months to a year. (See 'Overview' above.)

Patients with any form of SM may experience episodic symptoms of mast cell activation, including apparent allergic reactions triggered by a variety of exposures (eg, physical factors, alcohol, medications, emotional stress, and allergens). All patients should be equipped with epinephrine autoinjectors, because up to half of individuals with SM experience anaphylaxis. (See 'General measures' above.)

Patients with ISM have a near-normal life expectancy, although a small number will evolve into more aggressive forms of SM. Patients with SSM are at higher risk for progression, although data are limited. Patients with these clinically indolent subtypes are particularly prone to anaphylaxis. Treatment should focus on preventing mast cell-mediator release and minimizing the resulting symptoms (eg, flushing, gastrointestinal symptoms, and neuropsychiatric symptoms).

Treatments include antihistamines, antileukotriene agents, cromolyn sodium, and other therapies for specific allergic conditions. (See 'Pharmacotherapy for symptoms related to mast cell mediators' above.)

For patients with Hymenoptera venom-induced anaphylaxis and positive skin tests or in vitro tests to venom, we suggest lifelong venom immunotherapy (VIT) (Grade 2C). (See 'Venom immunotherapy' 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 'Indolent systemic mastocytosis' above and 'Smoldering systemic mastocytosis' above.)

ASM, SM-AHN, and MCL are collectively referred to as "advanced SM" because these disorders have an aggressive clinical course with end-organ damage (eg, cytopenias, liver dysfunction, malabsorption, ascites), leading to shortened survival. In addition to therapies aimed at preventing mast cell-mediator release, patients may benefit from cytoreductive therapies to reduce the tumor burden and improve organ function. (See 'Cytoreductive therapies for advanced disease' above.)

Treatment of advanced SM has the goal of achieving a response and proceeding to allogeneic hematopoietic cell transplantation (HCT) in transplant-eligible patients, as this approach offers the potential for cure (albeit with a substantial risk of transplant-related mortality). (See 'Hematopoietic cell transplantation' above.)

For most patients with advanced SM, we suggest initial treatment with midostaurin, rather than other tyrosine kinase inhibitors (TKIs), interferon-alfa (IFN-alfa), or other agents (Grade 2B). This suggestion applies to patients with advanced SM, regardless of KIT mutational status (ie, wild type, mutant, or KIT status unknown). (See 'Choice of therapy' above.)

The only exceptions to the suggestion of midostaurin as initial cytoreductive therapy in advanced SM are those patients with SM associated with chronic eosinophilic leukemia (CEL) or with well-differentiated advanced SM, for whom imatinib or other cytoreductive treatments may be acceptable alternatives.

The choice of initial cytoreductive therapy may also be influenced by toxicity profile and/or tempo of disease.

Patients with SM-AHN should be treated for the disease component that is felt to be contributing to the major current clinical concerns. Prognosis often relates to the associated hematologic neoplasm.

Allogeneic HCT should be considered in selected patients whose associated hematologic disorder constitutes an indication for this procedure and for those with rapidly progressive SM. (See 'Systemic mastocytosis with an associated hematologic neoplasm' above.)

Patients with MCL have poor long-term prognosis. Allogeneic HCT may offer the only curative option, although response rates are low. (See 'Mast cell leukemia' above.)

Treatment options as a bridge to allogeneic HCT include midostaurin, cladribine, or combination chemotherapy regimens, similar to those with acute myeloid leukemia. Less aggressive variants of MCL may respond to treatment with TKIs or cladribine.

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Mariana C Castells, MD, PhD, who contributed to an earlier version of this topic review.

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