Mastocytosis is a group of heterogeneous disorders resulting from the clonal proliferation of abnormal mast cells and their accumulation in the skin and/or in various extracutaneous organs. Systemic mastocytosis is the most common form of mastocytosis diagnosed in adults, characterized by mast cell infiltration of one or more extracutaneous organs (with or without skin involvement). The identification of KIT D816V mutation and the emergence of novel targeted therapies have significantly improved the diagnosis and treatment of systemic mastocytosis. However, certain aspects of clinical care, particularly the diagnosis, assessment, and management of mediator-related symptoms continue to present challenges. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with systemic mastocytosis.

Abstract

Mastocytosis is a group of heterogeneous disorders resulting from the clonal proliferation of abnormal mast cells and their accumulation in the skin and/or in various extracutaneous organs. Systemic mastocytosis is the most common form of mastocytosis diagnosed in adults, characterized by mast cell infiltration of one or more extracutaneous organs (with or without skin involvement). The identification of KIT D816V mutation and the emergence of novel targeted therapies have significantly improved the diagnosis and treatment of systemic mastocytosis. However, certain aspects of clinical care, particularly the diagnosis, assessment, and management of mediator-related symptoms continue to present challenges. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with systemic mastocytosis.

NCCN Categories of Evidence and Consensus

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise noted.

Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

Overview

Mastocytosis is a group of heterogeneous disorders resulting from the clonal proliferation of abnormal mast cells and their accumulation in the skin and/or in various extracutaneous organs.1 In the revised 2017 WHO classification, mastocytosis was removed as one of the subtypes of myeloproliferative neoplasms (MPN) and listed as a separate major disease entity with distinctive clinical and pathologic features.2 Mastocytosis is divided into 3 broad subtypes, depending on pathology, distribution of disease, and clinical manifestations. Cutaneous mastocytosis (CM) is limited to the skin and is most commonly diagnosed in children. Systemic mastocytosis (SM) is the most common form of mastocytosis diagnosed in adults, characterized by mast cell infiltration of one or more extracutaneous organs (with or without skin involvement). Mast cell sarcoma, defined as a malignant mast cell neoplasm presenting as a solitary destructive mass, is extremely rare in humans.3

The management of patients with mastocytosis requires a multidisciplinary team approach (involving dermatologists, hematologists, gastroenterologists, pathologists, and allergists/immunologists) preferably in specialized medical centers with expertise in the treatment of patients with mast cell disorders.4,5 The identification of KIT D816V mutation and the emergence of novel targeted therapies have significantly improved the diagnosis and treatment of SM.6,7 However, certain aspects of clinical care, particularly the diagnosis, assessment, and management of mediator-related symptoms, continue to present challenges.

These NCCN Guidelines provide recommendations for the diagnosis and management of patients with SM. Management of CM is not included in these guidelines. Referral to centers with expertise in CM is strongly recommended.

Diagnostic Classification

Cutaneous Mastocytosis

The diagnosis of CM requires the presence of clinical and histopathologic findings of abnormal mast cell infiltration of the dermis with no evidence of systemic mast cell infiltration either in the bone marrow or other

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NCCN Clinical Practice Guidelines in Oncology: Systemic Mastocytosis, Version 2.2019

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extracutaneous organs.2 CM is further subdivided into 3 different subvariants: urticaria pigmentosa/maculopapular cutaneous mastocytosis (MPCM), diffuse CM, and mastocytoma of the skin.8

Systemic Mastocytosis

WHO diagnostic criteria include 1 major diagnostic criterion (multifocal, dense infiltrates of mast cells [≥15 mast cells in aggregates] detected in the biopsy sections of bone marrow and/or other extracutaneous organs) and 4 minor diagnostic criteria (the presence of atypical mast cells in lesional tissues; the presence of KIT D816V mutation; the aberrant expression of CD25 with or without CD2 on neoplastic mast cells, and a persistently elevated serum tryptase level [> 20 ng/mL]).2

The diagnosis of SM is established when 1 major criterion and at least 1 minor criterion are present, or when at least 3 minor criteria are present. SM is further divided into 5 different subvariants (based on the mast cell burden, organ involvement, and SM-related organ damage):

  • Indolent SM (ISM)

  • Smoldering SM (SSM)

  • Aggressive SM (ASM)

  • SM with an associated hematologic neoplasm (SM-AHN)

  • Mast cell leukemia (MCL)

This subclassification has been validated in a number of studies.911 The diagnostic criteria for variants of systemic mastocytosis are outlined in the algorithm (SM-5; page 1506).

Well-differentiated SM (WDSM) is a rare variant characterized by bone marrow infiltration of round rather than spindle-shaped mast cells, often lacking KIT D816V mutation and low or absent CD25 expression.12 WDSM is not a WHO-defined variant but rather is a morphologic variant that exists across the spectrum of WHO-defined subtypes of both ISM and advanced SM.

Mast Cell Activation Syndrome

Mast cell activation syndrome (MCAS) refers to a group of disorders associated with episodic symptoms related to mast cell mediator release. MCAS is not considered a subtype of SM. MCAS is not associated with an overproliferation of cells and is not considered a prediagnostic condition that ultimately progresses to SM. MCAS can be divided into primary, secondary, and idiopathic. Basic defining criteria of MCAS include (1) episodic symptoms consistent with mast cell mediator release affecting ≥2 organ systems; (2) a decrease in the frequency or severity of symptoms, or resolution of symptoms with anti-mediator drug therapy; and (3) elevation of a validated urinary or serum marker of mast cell activation, such as the serum tryptase level (which is the marker of choice).1315

In patients with mast cell activation symptoms but with normal mast cell morphology/immunophenotype without the KIT D816V mutation, other causes of mast cell activation should be considered (eg, secondary causes such as allergies, chronic inflammatory or neoplastic disorders, urticaria). In patients with mast cell activation symptoms for whom no cause is identified, a diagnosis of idiopathic MCAS is rendered on a provisional basis until a specific cause of mast cell activation is found.

More recently, some patients with MCAS and/or other systemic symptoms have been diagnosed with hereditary alpha-tryptasemia, a multisystem disorder characterized by duplications and triplications in the TPSAB1 gene encoding a-tryptase. Elevation of the basal serum tryptase level is found in 4%–6% of the general population. This condition is associated with elevation of the basal serum tryptase level and symptoms including cutaneous flushing and pruritus, dysautonomia, functional gastrointestinal symptoms, chronic pain, and connective tissue abnormalities, including joint hypermobility.16 Although it is currently unclear how this symptom complex relates to increased copy number of the TPSAB1 gene, testing for this genetic variant may be considered.

Clinical Presentation

Mastocytosis is associated with a variety of symptoms related to the release of mast cell mediators1719 The most common clinical symptoms and potential triggers for mast cell activation are summarized in “Signs and Symptoms of Mast Cell Activiation” (see page 1513 [SM-H]). Although some patients present with isolated symptoms, others develop a constellation of symptoms related to mast cell activation. Anaphylaxis can be a life-threatening manifestation of mast cell activation that requires immediate medical attention, the use of epinephrine, and other supportive care measures. The mastocytosis quality-of-life questionnaire (MQLQ) and the mastocytosis symptom assessment form (MSAF) can be used for the assessment of symptoms at baseline and for monitoring symptom status during the course of treatment in patients with ISM and SSM.19

In the WHO diagnostic criteria, clinical signs of disease related to SM are classified as B-findings or C-findings depending on the presence or absence of organ involvement and/or organ damage.2 Evaluation of B-findings and C-findings is key to establishing the diagnosis of subtype of SM.

B-Findings

B-findings indicate a higher burden of SM and include: (1) high mast cell burden on bone marrow biopsy (>30% infiltration of cellularity by focal, dense aggregates of mast cells, and serum tryptase level >200 ng/mL); (2) hepatomegaly without impairment of liver function, palpable splenomegaly without hypersplenism, and/or lymphadenopathy on palpation or imaging; and (3) signs of dysplasia or myeloproliferation in non-mast cell lineage(s), but criteria are not met for the definitive diagnosis of an AHN, with normal or only slightly abnormal blood counts.

C-Findings

C-findings are defined by one or more signs of organ damage due to infiltration by neoplastic mast cells, and are common in patients with advanced SM.2 Examples of organ damage include cytopenias (eg, absolute neutrophil count <1 x 109/L; hemoglobin <10 g/dL, and/or platelet count <100 x 109/L) due to bone marrow dysfunction by neoplastic mast cell infiltration; palpable hepatomegaly with impairment of liver function, ascites, and/or portal hypertension; skeletal involvement, with large osteolyses with or without pathologic fractures; palpable splenomegaly with hypersplenism; and malabsorption (eg, hypoalbuminemia) with weight loss due to gastrointestinal mast cell infiltrates.20

Diagnostic Criteria for Variants of Systemic Mastocytosis

Indolent Systemic Mastocytosis

ISM is characterized by low mast cell burden, no evidence of C-findings, or an AHN. Patients exhibit a relatively younger age at presentation, lower incidence of constitutional symptoms (15%), and a higher prevalence of skin lesions (85%) and cutaneous symptoms (78%).11 Patients with ISM exhibit a life expectancy similar to that in the age-matched general population, with a median survival of 301 months.

Bone marrow mastocytosis (BMM) is a subvariant of ISM in which mast cell infiltration is confined to the bone marrow with no skin or multiorgan visceral lesions.11,21 The incidence of symptoms associated with mast cell mediator release is higher in BMM (86% compared with 67% for ISM and 50% for SSM), but the median survival is superior for patients with BMM (not reached compared with 301 months for ISM).11

Smoldering Systemic Mastocytosis

SSM is defined by ≥2 B-findings and no evidence of C-findings or an AHN.11 SSM is characterized by a relatively high mast cell burden, older age at presentation, and higher frequency of constitutional symptoms (45%). SSM is associated with inferior median survival (120 months compared with 301 months for ISM) and a significantly higher risk of transformation to acute myeloid leukemia (AML) or ASM (18% compared with <1% for ISM).11 However, patients with SSM were significantly older, and in a multivariate analysis, advanced age was the primary determinant of inferior overall survival (OS), and SSM was not independently associated with inferior OS. Owing to these clinical and prognostic differences (age distribution and risk of disease transformation), SSM was removed as a subcategory of ISM and listed as its own subvariant in the 2017 revised WHO classification.2

Aggressive Systemic Mastocytosis

The diagnosis of ASM requires the presence of one or more C-findings, but does not meet the criteria for MCL.2 The diagnosis of ASM indicates that only morphologic evidence for mast cell disease is found; conversely, the concomitant presence of an AHN indicates a diagnosis SM-AHN, even if C-findings are believed to be related to the mast cell component. Skin lesions are less common in ASM compared with ISM. The median survival of patients with ASM was 41 months in one study.10

Systemic Mastocytosis With An Associated Hematologic Neoplasm

SM-AHN fulfills the diagnostic criteria for SM as well as the diagnostic criteria for the AHN.2 SM-AHN is detected in about 40% of patients with SM. AHNs are of myeloid lineage in the overwhelming majority of patients, and lymphoid neoplasms (eg, chronic lymphocytic leukemia, lymphomas, multiple myeloma) are rarely observed. C-findings may or may not be present. AHNs include AML, MPN, myelodysplastic syndromes (MDS), MDS/MPN (eg, chronic myelomonocytic leukemia [CMML]) or MDS/MPN-unclassifiable (MDS/MPN-U), and chronic eosinophilic leukemia, not otherwise specified (CEL, NOS).10,22

SM-AHN is characterized by older age at presentation, higher incidences of constitutional symptoms and hematologic abnormalities, and an inferior OS compared with other subtypes of SM without AHN.23 The outcome of patients with SM-AHN varies with the type of AHN. SM-MPN is associated with a significantly longer median survival (31 months; P=.003) compared with SM-CMML (15 months), SM-MDS (13 months), and SM-AML (11 months). The rate of leukemic transformation is more frequent in SM-MDS (29%) than in SM-MPN (11%) or SM-CMML (6%).22

Mast Cell Leukemia

MCL is defined histopathologically by the presence of ≥20% neoplastic mast cells on a bone marrow aspirate.2 The aleukemic variant (<10% circulating mast cells in peripheral blood) is more common than the leukemic variant (≥10% circulating mast cells in peripheral blood). Acute MCL, characterized by the presence of C-findings/organ damage, is present in most patients.2 Chronic MCL is defined as MCL without C-findings/organ damage and may display a more indolent course over time, but its natural history requires more study.2426 Immunostaining with Ki-67 has been shown to differentiate between the acute and chronic variants, since most mast cells in chronic MCL stain negative for Ki-67 whereas mast cells in acute MCL frequently display Ki-67.24 These findings require validation in additional studies.

MCL can either present as a de novo disorder or it can transform from advanced forms of SM such as ASM, SM-AHN, or very rarely, ISM.10,27,28 MCL is associated with a poor prognosis regardless of the subtype or the presence of signs/symptoms of organ damage. In a study that evaluated the clinical and molecular characteristics of 28 patients with MCL, de novo MCL and secondary MCL resulting from leukemic transformation of SM-AHN or ASM were diagnosed in 57% and 43% of patients, respectively, with no differences in clinical, morphologic, or molecular characteristics between the 2 variants.28 AHNs (CMML, MDS/MPN unclassifiable, MDS, and CEL) were diagnosed in 71% (20 of 28) of patients. KIT D816V mutation was identified in 68% of patients and additional prognostically relevant mutations in SRSF2, ASXL1, or RUNX1 genes were identified in 52% of patients.

Workup

Evaluation for SM is recommended in patients with suspected clinical symptoms associated with the release of mast cell mediators or anaphylaxis, and/or increased serum tryptase level or adult onset mastocytosis of the skin (MIS), as outlined in the algorithm (pages 1502 and 1503 [SM-1 and SM-2]).

Serum Tryptase Level

Serum tryptase is elevated in the vast majority of patients with SM across all subtypes.29 Persistently elevated serum total tryptase (>20 ng/mL) is one of the minor criteria.2 However, it is important to interpret elevated serum tryptase levels in the appropriate context because serum tryptase may also be transiently elevated during anaphylaxis or a severe allergic reaction.30 Elevated levels of serum tryptase have also been documented in patients with other myeloid malignancies and hereditary alpha-tryptasemia.16,31,32 A minority of patients with SM have normal tryptase levels, possibly related to the lack of alpha tryptase genes described in Caucasian populations.33

Bone marrow evaluation should be done to confirm the diagnosis of SM in symptomatic patients with persistently elevated levels of serum tryptase.32 Although measurement of serum tryptase level is useful to estimate mast cell burden in patients with mastocytosis, such correlations may be confounded by the presence of an AHN, which may also contribute to elevation of the serum tryptase level.16,31,32

Bone Marrow Evaluation

The detection of multifocal, dense infiltrates of mast cells (≥15 mast cells in aggregates) in the biopsy sections of the bone marrow and/or other extracutaneous organs is a major criterion for the diagnosis of SM. The presence of spindle-shaped or atypical mast cells in the trephine biopsy sections of bone marrow or bone marrow aspirate smears or other extracutaneous organs is one of the minor criteria.2

Bone marrow aspiration and biopsy with mast cell immunophenotyping is almost always necessary to establish the diagnosis of SM.34 Bone marrow evaluation also helps in the detection of AHN, if present. Although bilateral bone marrow biopsies might be useful for the early diagnosis of SM or for the detection of minimal bone marrow involvement, a unilateral bone marrow biopsy is generally recommended.35

Mast Cell Immunophenotyping

Immunohistochemical (IHC) evaluation is necessary to confirm the diagnosis of SM in patients with low mast cell burden or if bone marrow involvement is not morphologically conspicuous on the bone marrow aspirate or core biopsy by hematoxylin and eosin staining.36,37 The expression of CD25, with or without CD2, in addition to normal mast cell markers, is a minor diagnostic criterion.2

Tryptase and CD117 are co-expressed on normal mast cells. Tryptase is considered the most sensitive marker because it allows for the detection of small and/or immature mast cell infiltrates. However, immunostaining with neither of these markers is able to distinguish between normal and neoplastic mast cells.3840 Aberrant expression of CD2 and CD25 has been reported to be useful to differentiate mast cells in SM from normal/reactive mast cells in the bone marrow.4042 Further studies have shown that CD25 is a more sensitive marker than CD2, because the latter is not expressed in mast cells of advanced SM and is only expressed in about 50% to 60% of mast cells in cases of indolent SM.39,43,44 The use of immunostaining for CD45 in combination with CD25 has been shown to specifically identify abnormal mast cells in patients with SM, a finding that has to be confirmed in further studies.45

Cytoplasmic and/or surface expression of CD30 has also been reported in neoplastic mast cells in patients with SM.12,4649 Earlier reports suggested that CD30 is preferentially expressed in the neoplastic mast cells of advanced SM compared with ISM.46,47 However, more recent reports confirm that CD30 is also frequently expressed in CM as well as in all subtypes of SM, suggesting that CD30 expression does not contribute to the differential diagnosis and prognostic stratification of different subtypes of SM.48,49 However, increased expression of CD30 along with the absence of CD25 may be useful in the diagnosis of WDSM and its distinction from other subtypes of SM.12

IHC with markers for mast cell tryptase, CD117, and CD25 should be performed for the quantification of mast cell burden in bone marrow.3842 CD30 is considered optional; it can be useful in cases where CD25 is negative.12 CD34 staining may also be obtained to quantify whether the proportion of myeloblasts are increased, especially in SM-AHN.50 Flow cytometry is a complementary tool for the diagnosis or monitoring of SM. CD117, CD25, and CD2 are the standard markers; CD30 can also be considered.51,52

Molecular Testing

KIT D816V mutation occurs in most patients (>90%) with SM.6,7,22,53,54 In SM-AHN, the KIT D816V mutation can also be found in cells comprising the AHN. However, the frequency of KIT D816V mutation in these cells is variable depending on subtype of AHN, being most common in patients with SM-CMML (89%) and less frequent in patients with SM-MPN (20%) and SM-AML (30%).55

In addition to KIT D816V mutation, prognostically relevant mutations in several other genes (TET2, SRSF2, CBL, ASXL1, RUNX1, JAK2, and/or RAS) have also been identified in advanced SM (ASM, SM-AHN, and MCL).7,5662 The presence of ≥1 mutations beyond KIT D816V has been associated with worse OS.7 In addition, mutation(s) in SRSF2, ASXL1, and/or RUNX1 (S/A/Rpos) have been associated with significantly inferior OS.59,60,62 A mutation-augmented prognostic scoring system incorporating clinical and laboratory variables and the ASXL1 mutation has been developed to stratify patients with advanced SM into low-, intermediate- and high-risk groups with significantly different median survival (86, 21, and 5 months, respectively).62 More refined prognostic scoring systems that include the results of S/A/R profiling are currently being developed. Myeloid mutation panel testing should be performed on the bone marrow but can be performed on the peripheral blood in the presence of an AHN and/or circulating mast cells.

The FIP1L1-PDGFRA fusion oncogene resulting from the deletion of the CHIC2 locus at chromosome 4q12 usually presents as a chronic myeloid neoplasm with eosinophilia. Atypical or spindle-shaped mast cells that also express CD25 may be found in the bone marrows of such patients, usually in a loosely scattered or interstitial pattern without forming multifocal aggregates. Although patients with the FIP1L1-PDGFRA fusion oncogene are not considered to have a subtype of SM, and KIT D816V is rarely found in these individuals, identifying the fusion in patients with eosinophilia is critical because it is a predictor of excellent response to imatinib.6365 The FIP1L1-PDGFRA fusion oncogene should be tested in patients with eosinophilia in peripheral blood who do not have the KIT D816V mutation.

KIT D816V Mutational Analysis: Detection of the KIT D816V mutation in the bone marrow, blood, or another extracutaneous organ is included as a minor criterion.2 Myeloid mutation panels are not recommended for the detection of KIT D816V because such next generation sequencing (NGS) assays exhibit low sensitivity.

Mutation analysis for KIT D816V is preferably performed using the bone marrow sample because the yield from the peripheral blood may be lower. Several different sensitive assays have been used for the detection of KIT D816V mutation, including reverse transcriptase polymerase chain reaction (PCR) plus restriction fragment length polymorphism, nested reverse transcriptase PCR followed by denaturing high-performance liquid chromatography, peptide nucleic acid–mediated PCR and allele-specific oligonucleotide quantitative reverse transcriptase PCR (ASO-qPCR).66

ASO-qPCR is a highly sensitive method for the detection of KIT D816V mutation in various tissues.67 Recent studies have reported the possibility of detecting the KIT D816V in peripheral blood using a highly sensitive ASO-qPCR.6870 However, ASO-qPCR may not be useful for patients with low mast cell burden since KIT D816V mutation may not be detectable in the peripheral blood. In addition, ASO-qPCR also does not detect KIT mutations other than D816V (very rare, occurring in <3% of patients). Therefore, if a diagnosis of SM is suspected, molecular testing with a highly sensitive ASO-qPCR assay can be first performed on peripheral blood in combination with measurement of the serum tryptase level and evaluation of clinical signs and/or symptoms suggestive of SM-related organ involvement. If positive, this should be followed by a detailed KIT mutation analysis on the bone marrow aspirate. KIT D816V mutational analysis on the bone marrow aspirate is particularly useful to establish the diagnosis of SM in patients with low mast cell burden, those with limited systemic disease who may have serum tryptase levels <20 ng/mL and lack multifocal mast cell clusters in a bone marrow biopsy.36,37

In patients with low mast cell burden who are otherwise negative for KIT D816V mutation, evaluation for KIT D816V mutation in the skin or an extracutaneous organ besides the bone marrow could be considered.66 In patients with a high mast cell burden who are otherwise negative for KIT D816V mutation, molecular testing should be confirmed with ASO-qPCR, if not originally obtained with this technique. If KIT D816V mutation is still negative, molecular testing for KIT mutations other than D816V should be done, preferably using peptide nucleic acid–mediated PCR.71 Sequencing of the whole KIT by NGS may be undertaken.

Evaluation of B-Findings and C-Findings and Organ Involvement

B-findings and C-findings are used for the diagnosis of the WHO subtype of SM. The International Working Group-Myeloproliferative Neoplasms Research and Treatment-European Competency Network on Mastocytosis (IWG-MRT-ECNM) established eligible organ damage findings for enrollment of patients with advanced SM into clinical trials and to allow more stringent adjudication of organ damage responses to therapy. Although WHO definitions of C-findings and IWG-MRT-ECNM–defined organ damage partially overlap, the latter criteria quantify the thresholds of SM-related organ damage that are eligible for response assessment on a clinical trial basis. This should permit harmonization of the types and severity of organ damage that are evaluable across studies of patients with advanced SM who are being treated with novel therapies (See “Response Criteria,” page 1531).2,72

Imaging studies (CT/MRI or ultrasound of the abdomen/pelvis) are useful to document organomegaly, lymphadenopathy, and ascites in patients with advanced SM. Chest radiographs and/or CT of the thorax may be needed in selected circumstances to further assess whether pleural effusions are present in patients with advanced SM presenting with relevant pulmonary symptoms. C-findings (organ damage caused by mast cell infiltration) should be confirmed with appropriate organ-directed biopsy as needed with IHC (eg, CD117, CD25, tryptase).

Osteoporosis and osteopenia are the most common bone complications in patients with SM.20 The risk of osteoporotic fracture is high in patients with ISM, and higher urinary N-methylhistamine levels are also associated with a higher risk of osteoporosis.7375 Skeletal involvement with large osteolytic lesions with or without pathologic fractures is considered a C-finding. However, the presence of one or more small lytic lesions in the absence of other C-findings is insufficient to make a diagnosis of advanced SM and should not alone be considered an indication for cytoreductive therapy. Dual-energy x-ray absorptiometry (DEXA) scan to evaluate for osteopenia or osteoporosis and metastatic skeletal survey to evaluate for osteolytic lesions are recommended as part of the initial work up.

24-hour Urine Studies

The measurement of urinary metabolites of histamine and prostaglandin in a 24-hour urine sample has been shown to correlate with mast cell burden and activation.76 N-methylhistamine, prostaglandin D2, and 2,3-dinor-11 beta-prostaglandin F2 alfa are the most commonly measured metabolites.7782 Any elevation above normal is considered significant; however, cut-off levels for significant elevation of these metabolites has not been established.

Although 24-hour urine studies do not have much utility in patients with markedly elevated serum tryptase, the measurement of urinary metabolites may be useful in the diagnosis and initiation of appropriate targeted therapy for some of the mast cell activation symptoms (eg, higher urinary N-methylhistamine levels are associated with a higher risk of osteoporosis; certain symptoms associated with elevated urinary prostaglandin levels can be targeted with aspirin).75,83

Treatment Considerations

Referral to specialized centers with expertise in the management of mastocytosis is strongly recommended.4,5 Multidisciplinary collaboration with subspecialists (eg, anesthesia for invasive procedures/surgery; high-risk obstetrician for pregnancy) is recommended.

Patients should be counseled about the signs and symptoms of mast cell activation and the importance of avoiding known triggers of mast cell activation. Anaphylactic reactions are significantly more frequent in patients with ISM and should be managed with the use of epinephrine injection. All patients should carry 2 auto injectors of epinephrine to manage anaphylaxis. Premedications are recommended for most procedures in patients with SM, because surgery, endoscopy, and other invasive and radiologic procedures can induce mast cell activation and anaphylaxis.

Anti-mediator drug therapy for mast cell activation symptoms (as described in next section) is recommended for all patients with SM. Assessment of symptoms at baseline and monitoring symptom status during the course of treatment with MQLQ and MSAF is recommended for patients with ISM and SSM (see “Treatment for ISM and SSM,” pages 1504 and 1505 [SM-3 and SM-4]).19 Patient-reported outcome instruments are currently under development for patients with advanced SM.

Cytoreductive therapy (discussed in next section) is recommended for patients with advanced SM (ASM, SM-AHN, and MCL) because of the frequent presence of organ damage and shortened survival of this patient population (see algorithm, pages 1506–1509 [SM-5–SM-8]). In patients with SM-AHN, an initial assessment is undertaken to determine whether the SM component or the AHN component requires more immediate treatment (see “Treatment for SM-AHN,” page 1507 [SM-6]). This determination can be challenging and reflects a comprehensive evaluation of several factors, including the relative burden and/or stage of the SM and AHN disease components in the bone marrow and/or other extracutaneous organs. In some cases, organ-directed biopsy may be useful to determine whether organ damage is related to the SM or AHN or both (eg, liver biopsy in a patient with liver function abnormalities). Although chronic MCL may follow a more indolent disease course compared with acute MCL with organ damage,2426 cytoreductive therapy should still be considered for such patients given the poor prognosis of both MCL subtypes (see “Treatment for MCL,” page 1509, [SM-8]).

Enrollment in well-designed clinical trials investigating novel therapeutic strategies (eg, selective KIT D816 inhibitors) is encouraged to enable further advances.

Anti-mediator Drug Therapy

Management of Chronic Symptoms Related To Mast Cell Mediator Release: A stepwise treatment approach for specific symptoms should be considered for all patients who present with symptoms related to mast cell mediator release, as outlined in “Diagnostic Algorithm for the Patient Presenting with Signs or Symptoms of Mastocytosis” (page 1502 [SM-I]). The treatment plan may vary according to specific patient scenarios. Standard doses need to be titrated. Higher doses may be necessary for symptoms refractory to standard dose treatment.

Histamine receptor type 1 (H1) and histamine receptor type 2 (H2) blockers have been shown to control skin symptoms (eg, pruritus, flushing, urticaria, angioedema dermatographism), gastrointestinal symptoms (eg, diarrhea, abdominal cramping, nausea, vomiting), neurologic (eg, headache, poor concentration and memory, brain fog), cardiovascular (eg, presyncope, syncope, tachycardia), pulmonary (eg, wheezing, throat swelling), and naso-ocular symptoms (nasal stuffiness or pruritus, conjunctival injection).84

Cromolyn sodium is effective for the management of cutaneous, gastrointestinal, and neurologic symptoms.85,86 In one double-blind cross-over study, cromolyn sodium resulted in marked amelioration of skin pruritus, whealing, flushing, diarrhea, abdominal pain, and disorders of cognitive function compared with placebo.85 In another double-blind cross-over study, although cromolyn sodium was significantly beneficial for the treatment of gastrointestinal symptoms (diarrhea, abdominal pain, nausea, vomiting) compared with placebo, the benefit for nongastrointestinal symptoms was not statistically significant.86 Cromolyn sodium in the form of ointment or cream can be used to decrease flare-ups of cutaneous symptoms in response to triggers.

Aspirin, corticosteroids, and leukotriene receptor antagonists are useful for the management of symptoms that are refractory to other treatment options.84 In particular, leukotriene receptor antagonists have been used for the management of skin and gastrointestinal symptoms that have not responded to other therapies.87,88 Aspirin has been shown to be effective for the management of symptoms associated with elevated urinary prostaglandin levels.89 However, the risks and benefits of aspirin need to be weighed carefully because aspirin can trigger mast cell activation in some patients.

Omalizumab, an anti-immunoglobulin E (IgE) monoclonal antibody, can be used for the management of mast cell activation symptoms insufficiently controlled by conventional therapy.90 Omalizumab was particularly effective for recurrent anaphylaxis and skin symptoms, more so than for gastrointestinal, musculoskeletal, and neuropsychiatric symptoms.90

Management of Anaphylaxis: The prevalence of anaphylaxis has been reported in 24%–49% of patients with SM.18,91,92 Increased serum tryptase levels have been identified as a risk factor for anaphylaxis in some studies,18,93 whereas other studies have identified absence of MIS, atopic SM, low baseline tryptase levels, and higher total IgE levels as risk factors for severe anaphylaxis.9395

Hymenoptera venom allergy is an IgE-mediated hypersensitivity to the allergens in insect venom and accounts for 2%–34% of all cases of anaphylaxis.96,97 Hymenoptera venom allergy remains the only established risk factor for severe recurrent anaphylaxis in patients with SM.98 Hymenoptera venom anaphylaxis is more prevalent in patients with ISM and it seems to be absent in patients with advanced SM with high mast cell burden.99 Hymenoptera anaphylaxis may be the presenting symptom of mastocytosis in an otherwise healthy individual. Therefore, mastocytosis should be suspected in patients who present with anaphylactic reactions after Hymenoptera sting.

Elevated baseline serum tryptase levels and mastocytosis are considered risk factors for severe Hymenoptera venom anaphylaxis.100103 In addition, vespid venom allergy, older age, male sex, angiotensin-converting enzyme inhibitor therapy, and previous insect stings with a less severe systemic reaction have also been identified as predictors of systemic anaphylactic reactions in patients with Hymenoptera venom allergy.102 KIT D816V mutation has been implicated in the hyperactivity of mast cells by amplifying the IgE-dependent mast cell mediator release.104 However, the exact mechanism of increased susceptibility to Hymenoptera venom anaphylaxis has not been elucidated in patients with SM.

Anaphylactic symptoms should be treated with epinephrine as first-line therapy. Antihistamines (H1 and H2 blockers) and steroids can be added as required. Systemic hives with no organ involvement can be managed with the use of antihistamines. Epinephrine injection is the preferred treatment for systemic hives with organ involvement (upper/lower airway, gastrointestinal, neurologic, cardiovascular) or an acute onset of anaphylaxis with the following symptoms: hypotension, laryngeal edema, vasomotor collapse, oxygen desaturation, and/or seizures.97

Venom immunotherapy (VIT) is effective for the treatment of IgE-mediated Hymenoptera venom anaphylaxis in patients with SM and it has also been shown to significantly reduce the risk of anaphylaxis after a re-sting.105108 VIT is recommended for all patients with a positive skin test or a positive test for Hymenoptera specific IgE antibodies as well as for those with a history of Hymenoptera venom anaphylaxis after an insect sting.97

Omalizumab is an effective treatment option for unprovoked anaphylaxis, Hymenoptera venom– or food-induced anaphylaxis in patients with a negative skin test or those with a negative test for specific IgE antibodies.109,110 Omalizumab also can improve tolerance while on VIT.

Management of Osteoporosis: The use of bisphosphonates (with continued use of antihistamines) is recommended to resolve bone pain and improve vertebral bone mineral density (BMD).111 Pamidronate and zoledronic acid have demonstrated efficacy, resulting in significant increases in spine and hip BMD and decreases of bone turnover markers in a small series of patients with SM.112,113 Interferon-alfa or pegylated interferon alfa may be considered for patients with refractory bone pain and/or worsening bone mineral density on bisphosphonate therapy.114116

Denosumab, an anti-RANKL monoclonal antibody, has also been associated with significant increases in BMD at lumbar and femoral sites, decreases in bone turnover markers in serum (mainly C-terminal telopeptide of collagen type I and bone alkaline phosphatase to a lesser extent).117 Denosumab can be used as an alternative treatment option for patients with bone pain not responding to bisphosphonates or for patients who are not candidates for bisphosphonates because of renal insufficiency. Vertebroplasty or kyphoplasty could also be used in selected patients for refractory pain associated with vertebral compression fractures.118

Cytoreductive Therapy

Midostaurin: Midostaurin, an oral multikinase inhibitor, has shown activity for the treatment of advanced SM (ASM, SM-AHN, and MCL).119121 In an open-label study of 116 patients with advanced SM, 89 patients had evaluable mastocytosis-related organ damage: 16 patients with ASM, 57 patients with SM-AHN, and 16 patients with MCL. Treatment with midostaurin (100 mg twice daily) resulted in an overall response rate (ORR) of 60% (45% of the patients had a major response, defined as complete resolution of at least one type of mastocytosis-related organ damage).119 Response rates were similar across all subtypes of advanced SM, KIT mutation status (63% for patients who were KIT D816V mutation-positive and 44% for those who were KIT D816V mutation-negative or unknown mutation status), or exposure to previous therapy. The median OS and progression-free survival (PFS) were 29 months and 14 months, respectively. The median OS and PFS were longer for patients with ASM (not reached and 29 months, respectively) than for patients with SM-AHN (21 months and 11 months, respectively) and MCL (9 months and 11 months, respectively). In a multivariate analysis, a subtype of advanced SM other than MCL and ≥50% reduction of bone marrow mast cell burden were identified as independent predictors of longer OS. Low-grade nausea, vomiting, and diarrhea were the most frequent adverse events. New or worsening grade 3 or 4 neutropenia, anemia, and thrombocytopenia occurred in 24%, 41%, and 29% of the patients respectively, and were more common in patients with pre-existing cytopenias. Midostaurin was approved by the FDA in 2017 for patients with a diagnosis of ASM, SM-AHN, or MCL.

A recent study that evaluated the impact of KIT D816V mutation and other molecular markers on the clinical outcome of 38 patients with advanced SM treated with midostaurin found that the ORR, median duration of midostaurin treatment, and OS were significantly higher in patients with a S/A/Rneg (vs S/A/Rpos) mutation profile and in patients with a ≥25% (vs <25%) reduction in the KIT D816V allele burden using ASO-qPCR. The acquisition of additional mutations in KRAS, NRAS, RUNX1, IDH2, or NPM1 genes was identified in patients with disease progression.122

Cladribine: Cladribine (2-chlorodexyadnosine) is not approved by the FDA for SM but is used on an off-label basis because of its activity across a spectrum of SM subtypes, including MCL refractory to prior cytoreductive therapy.123125 In an analysis including 108 patients with SM treated with cytoreductive therapy, cladribine resulted in an ORR of 56%, 50%, and 55% respectively, in patients with ISM, ASM, and SM-AHN.124 The presence of circulating immature myeloid cells was a predictor of inferior response. In a more recent study that reported the long-term safety and efficacy of cladribine in 68 patients with SM, the ORR was 72%, split between 92% for patients with ISM (major/partial, 56%/36%) and 50% for those with advanced SM (major/partial, 38%/13%). The median duration of response was 4 years and 3 years for ISM and ASM, respectively.125 In a multivariate analysis, only mastocytosis subtypes (SM-AHN vs ISM, P=.02; ASM vs ISM, P=.006) and age >50 years at diagnosis were independently associated with mortality. Lymphopenia (82%), neutropenia (47%), and opportunistic infections (13%) were the most frequent grade 3 or 4 toxicities. Because of its toxicity profile, for patients with advanced SM, cladribine may be particularly useful when rapid debulking of disease is required. However, cladribine may also be useful in selected patients with ISM or SSM with severe, refractory symptoms related to mast cell mediator release or bone disease not responsive to anti-mediator drug therapy or bisphosphonates.

Interferons: Standard and pegylated formulations of interferon alfa (with or without prednisone) also elicit responses across all subtypes of SM, but because of its cytostatic mechanism of action, responses may take longer to emerge and may be more suitable for patients with slowly progressive disease without the need for rapid cytoreduction. Interferon alfa can induce marked reduction in serum and urine metabolites of mast cell activation, reduce symptoms related to mast cell mediator release, resolve cutaneous lesions, improve skeletal disease, and improve both bone marrow mast cell burden and C-findings.124,126129 In a retrospective study evaluating the efficacy of different cytoreductive therapies in SM, the ORR was 47% and 57%, respectively, among patients treated with interferon alfa with or without prednisone.124 The ORR in patients with ISM, ASM, and SM-AHN were 60%, 60%, and 45%, respectively. Absence of systemic mediator-related symptoms was significantly associated with inferior response rates. Fatigue, depression, and thrombocytopenia were the most common toxicities.

Imatinib: Imatinib is approved by the FDA for the treatment of adult patients with ASM without the KIT D816V mutation (including wild-type) or with unknown mutational status. For example, it has shown activity against the KIT F522C transmembrane mutation, V560G juxtamembrane mutation, germline K509I mutation, deletion of codon 419 in exon 8, and p.A502_Y503dup mutation in exon 9.130137 As previously noted, imatinib is very effective in the treatment of patients with eosinophilia-associated myeloid neoplasms characterized by the FIP1L1-PDGFRA fusion tyrosine kinase.63 In a study that evaluated the efficacy of imatinib in 10 patients with SM lacking the KIT D816V mutation and meeting criteria for WDSM (including 3 patients with ISM and 3 patients with MCL), imatinib resulted in an ORR of 50%, including early and sustained complete response in 4 patients and partial response in one patient with wild-type KIT.137

Allogeneic Hematopoietic Cell Transplant

Allogeneic hematopoietic cell transplant (HCT) has been evaluated in patients with advanced SM, and the outcomes are significantly affected by the subtype of SM and the type of conditioning regimen used.138140 In the largest retrospective analysis, which included 57 patients with advanced SM (median age, 46 years; SM-AHN, n=38; MCL, n=12; ASM, n=7), allogeneic HCT was associated with 70% response rate (28% complete response [CR]; 21% stable disease), and the 3-year OS rate was 57% for all patients (74% for patients with SM-AHN; 43% and 17% respectively, for patients with ASM and MCL).140 MCL subtype was the strongest risk factor for poor OS. Reduced intensity conditioning regimens were associated with lower survival than myeloablative conditioning regimens. The role of allogeneic HCT needs to be determined in a prospective trial. However, given the rarity of SM, no larger prospective trials of HCT have been initiated to confirm the role of allogeneic HCT.

In 2016, a consensus opinion was published on indication for allogeneic HCT in patients with advanced SM.141 Allogeneic HCT can be considered as an initial treatment option for patients with ASM and acute MCL. Among patients with SM-AHN, allogeneic HCT should be considered as part of initial treatment when the AHN component requires HCT and it should also be considered if the SM component presents as advanced SM or progresses to advanced SM during treatment. Prophylactic anti-mediator drug therapy (corticosteroids, antihistamines, and epinephrine) should be used with the conditioning regimen in all patients.141

Response Criteria

Response criteria for advanced SM were first published in 2003 and were subsequently modified in 2013 by the IWG-MRT and ECNM with the addition of more specific and quantifiable criteria to establish eligible organ damage findings for clinical trial enrollment and facilitate response evaluation to targeted therapies.72,142 These response criteria were developed mainly for use in clinical trials. In addition to the IWG-MRT-ECNM response criteria, treatment response criteria have also been published to adjudicate responses in the AHN component.

The revised 2013 IWG-MRT-ECNM response criteria delineate definitions for nonhematologic and hematologic organ damage eligible for response evaluation and adjudication of response.72 Absolute neutrophil count, transfusion-dependent and independent anemia and thrombocytopenia are used for the assessment of hematologic organ damage. Nonhematologic organ damage is assessed based on the presence of symptomatic ascites or pleural effusion, liver function abnormalities, hypoalbuminemia and symptomatic marked splenomegaly. The development of ascites usually reflects aggressive liver disease and may be accompanied by hepatomegaly, abnormal liver function test results, and/or portal hypertension. Hypoalbuminemia is indicative of worsening synthetic function of the liver and/or worsening nutritional status due to gastrointestinal tract infiltration by neoplastic mast cells.

Clinical improvement is defined as the resolution of ≥1 findings of nonhematologic or hematologic organ damage without concomitant worsening of other eligible organ damage.72 CR and partial response (PR) are defined based on the percent reduction in bone marrow mast cells and the reduction of serum tryptase levels.72 In addition, the achievement of CR or PR also requires the resolution of all or at least one clinical improvement finding, respectively. Responses (resolution of findings of organ damage as well as reduction in bone marrow mast cell burden and serum tryptase level) should be maintained or confirmed for a period of at least 12 weeks to fulfill the criteria for clinical improvement, CR, and PR. Additional criteria are also included for progressive disease, stable disease, and loss of response.

Monitoring Response and Additional Therapy

ISM or SSM

History and physical examination, laboratory evaluation (annually for patients with ISM and every 6–12 months for patients with SSM), DEXA scan (every 1–3 years for patients with osteopenia or osteoporosis) and assessment of symptom burden and quality of life using MSAF and MQLQ is recommended for patients with ISM and SSM.

Although increased serum beta-2-microglobulin has been identified in one study as an independent predictor of disease progression in patients with ISM, this is not routinely performed in clinical practice.9 Progressively increasing serum tryptase levels have been associated with disease progression to SSM or ASM and shorter PFS in patients with ISM.143 Patients with ISM and SSM should also be monitored for the development of signs of disease progression to advanced SM (eg, development of B-findings and/or C-findings/organ damage).

Advanced SM

Bone marrow aspirate and biopsy with cytogenetics, serum tryptase level and additional staging studies to document organ damage are recommended for patients with ASM, SM with AHN and MCL, if supported by increased symptoms and signs of progression (return or progression of hematologic or nonhematologic organ damage; symptomatic or progressive hepatomegaly or splenomegaly).72 Repeat NGS panel testing may be considered to determine whether signs of disease progression are associated with the development of new mutations compared with baseline.

Biopsy of involved extramedullary organ may be considered to evaluate the grade and extent of SM-related organ damage.72 Evaluation of organ damage in SM with an AHN might require a tissue biopsy to ascertain the relationship between organ damage and burden of mast cell infiltration and/or AHN involvement.72 Additional staging studies include complete blood count for the evaluation of hematologic organ damage, liver functions tests (measurement of total bilirubin, alanine aminotransferase, aspartate aminotransferase, and serum alkaline phosphatase [the most common SM-associated sign of hepatic damage]) for the evaluation of nonhematologic organ damage and imaging studies (CT or MRI) to verify physical examinations findings of organ involvement or organ damage.

KIT D816V allele burden has been shown to correlate with serum tryptase levels and response to cytoreductive therapy. However, the role of KIT D816V allele burden in monitoring response is not yet well established.144,145

Additional Therapy

The panel acknowledges that the 2013 IWG-MRT-ECNM response criteria were developed mainly for use in clinical trials and that clinical benefit may not reach the threshold of these response criteria.72 Response assessment should be based on the improvement of mast cell activation symptoms and SM-related organ damage at the discretion of the clinician.

Continuation of prior treatment is recommended for patients experiencing adequate response to anti-mediator drug therapy (ISM or SSM) or cytoreductive therapy (advanced CM). Evaluation of allogeneic HCT should be considered for patients with advanced SM (ASM, SM-AHN, or MCL) with adequate response to cytoreductive therapy and with suitable donor(s) identified.140,141

Patients with ISM or SSM with inadequate response or loss of response or progression to advanced SM should be managed with cytoreductive therapy. Patients with advanced SM with inadequate response or loss of response should be treated with alternate cytoreductive therapy not previously received. Restaging studies (as described previously) are recommended before start of additional therapy.

Special Considerations

Surgery

Mast cell activation can occur in patients with mastocytosis undergoing surgical procedures, and the risk may persist for several hours after surgery because of delayed mast cell mediator release.146,147 The primary goal is to prevent mast cell activation during and in the immediate aftermath of the surgical procedure. Multidisciplinary management is recommended with the involvement of surgical, anesthesia, and perioperative medical teams (see “Special Considerations for the Management of Patients With Systemic Mastocytosis,” page 1518 [SM-J, page 1]).

The efficacy and safety of perioperative drugs in patients with SM has not been fully established, although anecdotal reports suggest that certain perioperative drugs are considered safer in patients with SM.148 Nevertheless, the use of perioperative drugs is not contraindicated in patients with SM.147,149 Although it is important that analgesics should not be withheld from patients with SM (since pain can be a trigger for mast cell activation), caution should be exercised with the use of opioids (eg, codeine or morphine).

Management of mast cell activation symptoms depends on the severity of the symptoms. The use of benzodiazepines, antihistamines (H1 and H2 blockers), and corticosteroids is probably helpful in reducing the frequency and/or severity of mast cell activation symptoms.147,148 Other options include fluid resuscitation, intravenous epinephrine, and discontinuation of the suspected drug or anesthetic agent.147 The risk of anaphylaxis in the perioperative period is estimated to be higher patients with SM relative to the general population.149 In the event of anaphylaxis or other mast cell activation event, a full allergic workup should be initiated.149,150 The workup should include skin tests or detection of specific IgE antibodies for the identification of IgE-mediated hypersensitivity to drugs and measurement of serum tryptase level within 30 to 120 minutes of onset of symptoms and also after full recovery.147,148

Pregnancy

Although mast cells have been associated with beneficial effects in early stages of pregnancy (in terms of implantation, placentation, and fetal growth), in later stages of pregnancy, excessive release of mast cell mediators is associated with preterm delivery.151 The diagnosis of SM does not appear to have any effect on fertility. There is limited evidence regarding the impact of mastocytosis on pregnancy compared with the general population. Spontaneous miscarriages and worsening of symptoms related to mast cell activation have been reported in 20% to 30% of pregnant women with mastocytosis.152154 Symptoms related to mast cell mediator release have been observed in 11% of patients without any fatal outcome.154

SM is not a contraindication to a successful pregnancy. Pregnant women with SM should be managed by a multidisciplinary team, including a high-risk obstetrician and anesthesiologist during preconception, pregnancy, and the peripartum period (see “Special Considerations for the Management of Patients With Systemic Mastocytosis,” page 1518 [SM-J, page 2]). Management of SM during pregnancy involves alleviation of symptoms related to mast cell activation with the use of acceptable medications to minimize potential harm to the fetus. Breast-feeding by patients with SM should be done in consultation with a pediatrician and international board certified lactation consultant.

Avoidance of known triggers and prophylactic anti-mediator drug therapy (corticosteroids, antihistamines, and epinephrine) are standard approaches during pregnancy and early postpartum period.155,156 Cytoreductive therapy with interferon-alfa can be considered for pregnant women with severe symptoms that are refractory to conventional therapy. However, the use of cladribine, imatinib, and midostaurin is not recommended. Medications used to treat SM and their potential risks during both pregnancy and lactation are summarized in “Special Considerations for the Management of Patients With Systemic Mastocytosis” (pages 1519 and 1520 [SM-J, pages 3 and 4]).

Individual Disclosures for Systemic Mastocytosis Panel

T1

References

  • 1.

    ValentPHornyHPEscribanoL. Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res2001;25:603625.

  • 2.

    SwerdlowSHCampoEHarrisNL. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (Revised 4th edition). International Agency for Research on Cancer; Lyon, France; 2017.

    • Search Google Scholar
    • Export Citation
  • 3.

    RyanRJAkinCCastellsM. Mast cell sarcoma: a rare and potentially under-recognized diagnostic entity with specific therapeutic implications. Mod Pathol2013;26:533543.

    • Search Google Scholar
    • Export Citation
  • 4.

    JawharMSchwaabJHornyHP. Impact of centralized evaluation of bone marrow histology in systemic mastocytosis. Eur J Clin Invest2016;46:392397.

    • Search Google Scholar
    • Export Citation
  • 5.

    Sanchez-MunozLMorgadoJMAlvarez-TwoseI. Diagnosis and classification of mastocytosis in non-specialized versus reference centres: a Spanish Network on Mastocytosis (REMA) study on 122 patients. Br J Haematol2016;172:5663.

    • Search Google Scholar
    • Export Citation
  • 6.

    NagataHWorobecASOhCK. Identification of a point mutation in the catalytic domain of the protooncogene c-kit in peripheral blood mononuclear cells of patients who have mastocytosis with an associated hematologic disorder. Proc Natl Acad Sci U S A1995;92:1056010564.

    • Search Google Scholar
    • Export Citation
  • 7.

    SchwaabJSchnittgerSSotlarK. Comprehensive mutational profiling in advanced systemic mastocytosis. Blood2013;122:24602466.

  • 8.

    HartmannKEscribanoLGrattanC. Cutaneous manifestations in patients with mastocytosis: Consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology. J Allergy Clin Immunol2016;137:3545.

    • Search Google Scholar
    • Export Citation
  • 9.

    EscribanoLAlvarez-TwoseISanchez-MunozL. Prognosis in adult indolent systemic mastocytosis: a long-term study of the Spanish Network on Mastocytosis in a series of 145 patients. J Allergy Clin Immunol2009;124:514521.

    • Search Google Scholar
    • Export Citation
  • 10.

    LimKHTefferiALashoTL. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood2009;113:57275736.

    • Search Google Scholar
    • Export Citation
  • 11.

    PardananiALimKHLashoTL. WHO subvariants of indolent mastocytosis: clinical details and prognostic evaluation in 159 consecutive adults. Blood2010;115:150151.

    • Search Google Scholar
    • Export Citation
  • 12.

    Alvarez-TwoseIJara-AcevedoMMorgadoJM. Clinical, immunophenotypic, and molecular characteristics of well-differentiated systemic mastocytosis. J Allergy Clin Immunol2016;137:168178e161.

    • Search Google Scholar
    • Export Citation
  • 13.

    AkinCScottLMKocabasCN. Demonstration of an aberrant mast-cell population with clonal markers in a subset of patients with “idiopathic” anaphylaxis. Blood2007;110:23312333.

    • Search Google Scholar
    • Export Citation
  • 14.

    PardananiAChenDAbdelrahmanRA. Clonal mast cell disease not meeting WHO criteria for diagnosis of mastocytosis: clinicopathologic features and comparison with indolent mastocytosis. Leukemia2013;27:20912094.

    • Search Google Scholar
    • Export Citation
  • 15.

    AkinC. Mast cell activation syndromes. J Allergy Clin Immunol2017;140:349355.

  • 16.

    LyonsJJYuXHughesJD. Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number. Nat Genet2016;48:15641569.

    • Search Google Scholar
    • Export Citation
  • 17.

    CastellsMAustenKF. Mastocytosis: mediator-related signs and symptoms. Int Arch Allergy Immunol2002;127:147152.

  • 18.

    BrockowKJoferCBehrendtHRingJ. Anaphylaxis in patients with mastocytosis: a study on history, clinical features and risk factors in 120 patients. Allergy2008;63:226232.

    • Search Google Scholar
    • Export Citation
  • 19.

    van AnrooijBKluin-NelemansJCSafyM. Patient-reported disease-specific quality-of-life and symptom severity in systemic mastocytosis. Allergy2016;71:15851593.

    • Search Google Scholar
    • Export Citation
  • 20.

    GulenTHagglundHDahlenBNilssonG. Mastocytosis: the puzzling clinical spectrum and challenging diagnostic aspects of an enigmatic disease. J Intern Med2016;279:211228.

    • Search Google Scholar
    • Export Citation
  • 21.

    ZanottiRBonadonnaPBonifacioM. Isolated bone marrow mastocytosis: an underestimated subvariant of indolent systemic mastocytosis. Haematologica2011;96:482484.

    • Search Google Scholar
    • Export Citation
  • 22.

    PardananiALimKHLashoTL. Prognostically relevant breakdown of 123 patients with systemic mastocytosis associated with other myeloid malignancies. Blood2009;114:37693772.

    • Search Google Scholar
    • Export Citation
  • 23.

    WangSAHutchinsonLTangG. Systemic mastocytosis with associated clonal hematological non-mast cell lineage disease: clinical significance and comparison of chomosomal abnormalities in SM and AHNMD components. Am J Hematol2013;88:219224.

    • Search Google Scholar
    • Export Citation
  • 24.

    ValentPSotlarKSperrWR. Refined diagnostic criteria and classification of mast cell leukemia (MCL) and myelomastocytic leukemia (MML): a consensus proposal. Ann Oncol2014;25:16911700.

    • Search Google Scholar
    • Export Citation
  • 25.

    ValentPBergerJCerny-ReitererS. Chronic mast cell leukemia (MCL) with KIT S476I: a rare entity defined by leukemic expansion of mature mast cells and absence of organ damage. Ann Hematol2015;94:223231.

    • Search Google Scholar
    • Export Citation
  • 26.

    ValentPSotlarKSperrWR. Chronic mast cell leukemia: a novel leukemia-variant with distinct morphological and clinical features. Leuk Res2015;39:15.

    • Search Google Scholar
    • Export Citation
  • 27.

    Georgin-LavialleSLhermitteLDubreuilP. Mast cell leukemia. Blood2013;121:12851295.

  • 28.

    JawharMSchwaabJMeggendorferM. The clinical and molecular diversity of mast cell leukemia with or without associated hematologic neoplasm. Haematologica2017;102:10351043.

    • Search Google Scholar
    • Export Citation
  • 29.

    SperrWRJordanJHFieglM. Serum tryptase levels in patients with mastocytosis: correlation with mast cell burden and implication for defining the category of disease. Int Arch Allergy Immunol2002;128:136141.

    • Search Google Scholar
    • Export Citation
  • 30.

    SchwartzLBMetcalfeDDMillerJS. Tryptase levels as an indicator of mast-cell activation in systemic anaphylaxis and mastocytosis. N Engl J Med1987;316:16221626.

    • Search Google Scholar
    • Export Citation
  • 31.

    SperrWREl-SamahiAKundiM. Elevated tryptase levels selectively cluster in myeloid neoplasms: a novel diagnostic approach and screen marker in clinical haematology. Eur J Clin Invest2009;39:914923.

    • Search Google Scholar
    • Export Citation
  • 32.

    AbererESavicSBretterklieberA. Disease spectrum in patients with elevated serum tryptase levels. Australas J Dermatol2015;56:713.

  • 33.

    CaugheyGH. Tryptase genetics and anaphylaxis. J Allergy Clin Immunol2006;117:14111414.

  • 34.

    HornyHPSotlarKValentP. Differential diagnoses of systemic mastocytosis in routinely processed bone marrow biopsy specimens: a review. Pathobiology2010;77:169180.

    • Search Google Scholar
    • Export Citation
  • 35.

    ButterfieldJHLiCY. Bone marrow biopsies for the diagnosis of systemic mastocytosis: is one biopsy sufficient?Am J Clin Pathol2004;121:264267.

    • Search Google Scholar
    • Export Citation
  • 36.

    Sanchez-MunozLAlvarez-TwoseIGarcia-MonteroAC. Evaluation of the WHO criteria for the classification of patients with mastocytosis. Mod Pathol2011;24:11571168.

    • Search Google Scholar
    • Export Citation
  • 37.

    ReichardKKChenDPardananiA. Morphologically occult systemic mastocytosis in bone marrow: clinicopathologic features and an algorithmic approach to diagnosis. Am J Clin Pathol2015;144:493502.

    • Search Google Scholar
    • Export Citation
  • 38.

    JordanJHWalchshoferSJureckaW. Immunohistochemical properties of bone marrow mast cells in systemic mastocytosis: evidence for expression of CD2, CD117/Kit, and bcl-x(L). Hum Pathol2001;32:545552.

    • Search Google Scholar
    • Export Citation
  • 39.

    HornyHPSotlarKValentP. Mastocytosis: immunophenotypical features of the transformed mast cells are unique among hematopoietic cells. Immunol Allergy Clin North Am2014;34:315321.

    • Search Google Scholar
    • Export Citation
  • 40.

    TeodosioCMayadoASanchez-MunozL. The immunophenotype of mast cells and its utility in the diagnostic work-up of systemic mastocytosis. J Leukoc Biol2015;97:4959.

    • Search Google Scholar
    • Export Citation
  • 41.

    EscribanoLDiaz AgustinBBravoP. Immunophenotype of bone marrow mast cells in indolent systemic mast cell disease in adults. Leuk Lymphoma1999;35:227235.

    • Search Google Scholar
    • Export Citation
  • 42.

    SotlarKHornyHPSimonitschI. CD25 indicates the neoplastic phenotype of mast cells: a novel immunohistochemical marker for the diagnosis of systemic mastocytosis (SM) in routinely processed bone marrow biopsy specimens. Am J Surg Pathol2004;28:13191325.

    • Search Google Scholar
    • Export Citation
  • 43.

    PardananiAKimlingerTReederT. Bone marrow mast cell immunophenotyping in adults with mast cell disease: a prospective study of 33 patients. Leuk Res2004;28:777783.

    • Search Google Scholar
    • Export Citation
  • 44.

    MorgadoJMSanchez-MunozLTeodosioCG. Immunophenotyping in systemic mastocytosis diagnosis: ‘CD25 positive’ alone is more informative than the ‘CD25 and/or CD2’ WHO criterion. Mod Pathol2012;25:516521.

    • Search Google Scholar
    • Export Citation
  • 45.

    ChisholmKMMerkerJDGotlibJR. Mast cells in systemic mastocytosis have distinctly brighter CD45 expression by flow cytometry. Am J Clin Pathol2015;143:527534.

    • Search Google Scholar
    • Export Citation
  • 46.

    SotlarKCerny-ReitererSPetat-DutterK. Aberrant expression of CD30 in neoplastic mast cells in high-grade mastocytosis. Mod Pathol2011;24:585595.

    • Search Google Scholar
    • Export Citation
  • 47.

    ValentPSotlarKHornyHP. Aberrant expression of CD30 in aggressive systemic mastocytosis and mast cell leukemia: a differential diagnosis to consider in aggressive hematopoietic CD30-positive neoplasms. Leuk Lymphoma2011;52:740744.

    • Search Google Scholar
    • Export Citation
  • 48.

    MorgadoJMPerbelliniOJohnsonRC. CD30 expression by bone marrow mast cells from different diagnostic variants of systemic mastocytosis. Histopathology2013;63:780787.

    • Search Google Scholar
    • Export Citation
  • 49.

    Russano de Paiva SilvaGTournierESarianLO. Prevalence of CD30 immunostaining in neoplastic mast cells: a retrospective immunohistochemical study. Medicine (Baltimore)2018;97:e10642.

    • Search Google Scholar
    • Export Citation
  • 50.

    MayadoATeodosioCDasilva-FreireN. Characterization of CD34(+) hematopoietic cells in systemic mastocytosis: potential role in disease dissemination. Allergy2018;73:12941304.

    • Search Google Scholar
    • Export Citation
  • 51.

    EscribanoLGarcia MonteroACNunezR. Flow cytometric analysis of normal and neoplastic mast cells: role in diagnosis and follow-up of mast cell disease. Immunol Allergy Clin North Am2006;26:535547.

    • Search Google Scholar
    • Export Citation
  • 52.

    Sanchez-MunozLTeodosioCMorgadoJM. Flow cytometry in mastocytosis: utility as a diagnostic and prognostic tool. Immunol Allergy Clin North Am2014;34:297313.

    • Search Google Scholar
    • Export Citation
  • 53.

    LongleyBJTyrrellLLuSZ. Somatic c-KIT activating mutation in urticaria pigmentosa and aggressive mastocytosis: establishment of clonality in a human mast cell neoplasm. Nat Genet1996;12:312314.

    • Search Google Scholar
    • Export Citation
  • 54.

    Garcia-MonteroACJara-AcevedoMTeodosioC. KIT mutation in mast cells and other bone marrow hematopoietic cell lineages in systemic mast cell disorders: a prospective study of the Spanish Network on Mastocytosis (REMA) in a series of 113 patients. Blood2006;108:23662372.

    • Search Google Scholar
    • Export Citation
  • 55.

    SotlarKColakSBacheA. Variable presence of KITD816V in clonal haematological non-mast cell lineage diseases associated with systemic mastocytosis (SM-AHNMD). J Pathol2010;220:586595.

    • Search Google Scholar
    • Export Citation
  • 56.

    TefferiALevineRLLimKH. Frequent TET2 mutations in systemic mastocytosis: clinical, KITD816V and FIP1L1-PDGFRA correlates. Leukemia2009;23:900904.

    • Search Google Scholar
    • Export Citation
  • 57.

    TrainaFVisconteVJankowskaAM. Single nucleotide polymorphism array lesions, TET2, DNMT3A, ASXL1 and CBL mutations are present in systemic mastocytosis. PLoS One2012;7:e43090.

    • Search Google Scholar
    • Export Citation
  • 58.

    DamajGJorisMChandesrisO. ASXL1 but not TET2 mutations adversely impact overall survival of patients suffering systemic mastocytosis with associated clonal hematologic non-mast-cell diseases. PLoS One2014;9:e85362.

    • Search Google Scholar
    • Export Citation
  • 59.

    JawharMSchwaabJHausmannD. Splenomegaly, elevated alkaline phosphatase and mutations in the SRSF2/ASXL1/RUNX1 gene panel are strong adverse prognostic markers in patients with systemic mastocytosis. Leukemia2016;30:23422350.

    • Search Google Scholar
    • Export Citation
  • 60.

    JawharMSchwaabJSchnittgerS. Additional mutations in SRSF2, ASXL1 and/or RUNX1 identify a high-risk group of patients with KIT D816V(+) advanced systemic mastocytosis. Leukemia2016;30:136143.

    • Search Google Scholar
    • Export Citation
  • 61.

    PardananiADLashoTLFinkeC. ASXL1 and CBL mutations are independently predictive of inferior survival in advanced systemic mastocytosis. Br J Haematol2016;175:534536.

    • Search Google Scholar
    • Export Citation
  • 62.

    PardananiALashoTElalaY. Next-generation sequencing in systemic mastocytosis: derivation of a mutation-augmented clinical prognostic model for survival. Am J Hematol2016;91:888893.

    • Search Google Scholar
    • Export Citation
  • 63.

    PardananiAKetterlingRPBrockmanSR. CHIC2 deletion, a surrogate for FIP1L1-PDGFRA fusion, occurs in systemic mastocytosis associated with eosinophilia and predicts response to imatinib mesylate therapy. Blood2003;102:30933096.

    • Search Google Scholar
    • Export Citation
  • 64.

    PardananiABrockmanSRPaternosterSF. FIP1L1-PDGFRA fusion: prevalence and clinicopathologic correlates in 89 consecutive patients with moderate to severe eosinophilia. Blood2004;104:30383045.

    • Search Google Scholar
    • Export Citation
  • 65.

    BohmAFodingerMWimazalF. Eosinophilia in systemic mastocytosis: clinical and molecular correlates and prognostic significance. J Allergy Clin Immunol2007;120:192199.

    • Search Google Scholar
    • Export Citation
  • 66.

    ArockMSotlarKAkinC. KIT mutation analysis in mast cell neoplasms: recommendations of the European Competence Network on Mastocytosis. Leukemia2015;29:12231232.

    • Search Google Scholar
    • Export Citation
  • 67.

    KristensenTVestergaardHMollerMB. Improved detection of the KIT D816V mutation in patients with systemic mastocytosis using a quantitative and highly sensitive real-time qPCR assay. J Mol Diagn2011;13:180188.

    • Search Google Scholar
    • Export Citation
  • 68.

    KristensenTVestergaardHBindslev-JensenC. Sensitive KIT D816V mutation analysis of blood as a diagnostic test in mastocytosis. Am J Hematol2014;89:493498.

    • Search Google Scholar
    • Export Citation
  • 69.

    Jara-AcevedoMTeodosioCSanchez-MunozL. Detection of the KIT D816V mutation in peripheral blood of systemic mastocytosis: diagnostic implications. Mod Pathol2015;28:11381149.

    • Search Google Scholar
    • Export Citation
  • 70.

    KristensenTVestergaardHBindslev-JensenC. Prospective evaluation of the diagnostic value of sensitive KIT D816V mutation analysis of blood in adults with suspected systemic mastocytosis. Allergy2017;72:17371743.

    • Search Google Scholar
    • Export Citation
  • 71.

    SotlarKEscribanoLLandtO. One-step detection of c-kit point mutations using peptide nucleic acid-mediated polymerase chain reaction clamping and hybridization probes. Am J Pathol2003;162:737746.

    • Search Google Scholar
    • Export Citation
  • 72.

    GotlibJPardananiAAkinC. International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) & European Competence Network on Mastocytosis (ECNM) consensus response criteria in advanced systemic mastocytosis. Blood2013;121:23932401.

    • Search Google Scholar
    • Export Citation
  • 73.

    BareteSAssousNde GennesC. Systemic mastocytosis and bone involvement in a cohort of 75 patients. Ann Rheum Dis2010;69:18381841.

  • 74.

    RossiniMZanottiRBonadonnaP. Bone mineral density, bone turnover markers and fractures in patients with indolent systemic mastocytosis. Bone2011;49:880885.

    • Search Google Scholar
    • Export Citation
  • 75.

    van der VeerEvan der GootWde MonchyJG. High prevalence of fractures and osteoporosis in patients with indolent systemic mastocytosis. Allergy2012;67:431438.

    • Search Google Scholar
    • Export Citation
  • 76.

    MetcalfeDDPawankarRAckermanSJ. Biomarkers of the involvement of mast cells, basophils and eosinophils in asthma and allergic diseases. World Allergy Organ J2016;9:7.

    • Search Google Scholar
    • Export Citation
  • 77.

    MorrowJDGuzzoCLazarusG. Improved diagnosis of mastocytosis by measurement of the major urinary metabolite of prostaglandin D2. J Invest Dermatol1995;104:937940.

    • Search Google Scholar
    • Export Citation
  • 78.

    OranjeAPMulderPGHeideR. Urinary N-methylhistamine as an indicator of bone marrow involvement in mastocytosis. Clin Exp Dermatol2002;27:502506.

    • Search Google Scholar
    • Export Citation
  • 79.

    ButterfieldJH. Increased leukotriene E4 excretion in systemic mastocytosis. Prostaglandins Other Lipid Mediat2010;92:7376.

  • 80.

    van DoormaalJJvan der VeerEvan Voorst VaderPC. Tryptase and histamine metabolites as diagnostic indicators of indolent systemic mastocytosis without skin lesions. Allergy2012;67:683690.

    • Search Google Scholar
    • Export Citation
  • 81.

    DivekarRButterfieldJ. Urinary 11beta-PGF2alpha and N-methyl histamine correlate with bone marrow biopsy findings in mast cell disorders. Allergy2015;70:12301238.

    • Search Google Scholar
    • Export Citation
  • 82.

    ChoCNguyenABryantKJ. Prostaglandin D2 metabolites as a biomarker of in vivo mast cell activation in systemic mastocytosis and rheumatoid arthritis. Immun Inflamm Dis2016;4:6469.

    • Search Google Scholar
    • Export Citation
  • 83.

    RaviAButterfieldJWeilerCR. Mast cell activation syndrome: improved identification by combined determinations of serum tryptase and 24-hour urine 11beta-prostaglandin2alpha. J Allergy Clin Immunol Pract2014;2:775778.

    • Search Google Scholar
    • Export Citation
  • 84.

    CardetJCAkinCLeeMJ. Mastocytosis: update on pharmacotherapy and future directions. Expert Opin Pharmacother2013;14:20332045.

  • 85.

    SoterNAAustenKFWassermanSI. Oral disodium cromoglycate in the treatment of systemic mastocytosis. N Engl J Med1979;301:465469.

  • 86.

    HoranRFShefferALAustenKF. Cromolyn sodium in the management of systemic mastocytosis. J Allergy Clin Immunol1990;85:852855.

  • 87.

    TolarJTopeWDNegliaJP. Leukotriene-receptor inhibition for the treatment of systemic mastocytosis. N Engl J Med2004;350:735736.

  • 88.

    TurnerPJKempASRogersMMehrS. Refractory symptoms successfully treated with leukotriene inhibition in a child with systemic mastocytosis. Pediatr Dermatol2012;29:222223.

    • Search Google Scholar
    • Export Citation
  • 89.

    ButterfieldJH. Survey of aspirin administration in systemic mastocytosis. Prostaglandins Other Lipid Mediat2009;88:122124.

  • 90.

    Broesby-OlsenSVestergaardHMortzCG. Omalizumab prevents anaphylaxis and improves symptoms in systemic mastocytosis: efficacy and safety observations. Allergy2018;73:230238.

    • Search Google Scholar
    • Export Citation
  • 91.

    Gonzalez de OlanoDde la Hoz CaballerBNunez LopezR. Prevalence of allergy and anaphylactic symptoms in 210 adult and pediatric patients with mastocytosis in Spain: a study of the Spanish network on mastocytosis (REMA). Clin Exp Allergy2007;37:15471555.

    • Search Google Scholar
    • Export Citation
  • 92.

    GulenTHagglundHDahlenBNilssonG. High prevalence of anaphylaxis in patients with systemic mastocytosis—a single-centre experience. Clin Exp Allergy2014;44:121129.

    • Search Google Scholar
    • Export Citation
  • 93.

    GorskaANiedoszytkoMLangeM. Risk factors for anaphylaxis in patients with mastocytosis. Pol Arch Med Wewn2015;125:4653.

  • 94.

    Alvarez-TwoseIZanottiRGonzalez-de-OlanoD. Nonaggressive systemic mastocytosis (SM) without skin lesions associated with insect-induced anaphylaxis shows unique features versus other indolent SM. J Allergy Clin Immunol2014;133:520528.

    • Search Google Scholar
    • Export Citation
  • 95.

    GulenTLjungCNilssonGAkinC. Risk factor analysis of anaphylactic reactions in patients with systemic mastocytosis. J Allergy Clin Immunol Pract2017;5:12481255.

    • Search Google Scholar
    • Export Citation
  • 96.

    NiedoszytkoMBonadonnaPOude ElberinkJNGoldenDB. Epidemiology, diagnosis, and treatment of Hymenoptera venom allergy in mastocytosis patients. Immunol Allergy Clin North Am2014;34:365381.

    • Search Google Scholar
    • Export Citation
  • 97.

    Jimenez-RodriguezTWGarcia-NeuerMAlenazyLACastellsM. Anaphylaxis in the 21st century: phenotypes, endotypes, and biomarkers. J Asthma Allergy2018;11:121142.

    • Search Google Scholar
    • Export Citation
  • 98.

    ValentP. Risk factors and management of severe life-threatening anaphylaxis in patients with clonal mast cell disorders. Clin Exp Allergy2014;44:914920.

    • Search Google Scholar
    • Export Citation
  • 99.

    van AnrooijBvan der VeerEde MonchyJG. Higher mast cell load decreases the risk of Hymenoptera venom-induced anaphylaxis in patients with mastocytosis. J Allergy Clin Immunol2013;132:125130.

    • Search Google Scholar
    • Export Citation
  • 100.

    HaeberliGBronnimannMHunzikerTMullerU. Elevated basal serum tryptase and Hymenoptera venom allergy: relation to severity of sting reactions and to safety and efficacy of venom immunotherapy. Clin Exp Allergy2003;33:12161220.

    • Search Google Scholar
    • Export Citation
  • 101.

    BonadonnaPPerbelliniOPassalacquaG. Clonal mast cell disorders in patients with systemic reactions to Hymenoptera stings and increased serum tryptase levels. J Allergy Clin Immunol2009;123:680686.

    • Search Google Scholar
    • Export Citation
  • 102.

    RueffFPrzybillaBBiloMB. Predictors of severe systemic anaphylactic reactions in patients with Hymenoptera venom allergy: importance of baseline serum tryptase-a study of the European Academy of Allergology and Clinical Immunology Interest Group on Insect Venom Hypersensitivity. J Allergy Clin Immunol2009;124:10471054.

    • Search Google Scholar
    • Export Citation
  • 103.

    Alvarez-TwoseIBonadonnaPMatitoA. Systemic mastocytosis as a risk factor for severe Hymenoptera sting-induced anaphylaxis. J Allergy Clin Immunol2013;131:614615.

    • Search Google Scholar
    • Export Citation
  • 104.

    CastellsMCHornickJLAkinC. Anaphylaxis after hymenoptera sting: is it venom allergy, a clonal disorder, or both?J Allergy Clin Immunol Pract2015;3:350355.

    • Search Google Scholar
    • Export Citation
  • 105.

    Gonzalez de OlanoDAlvarez-TwoseIEsteban-LopezMI. Safety and effectiveness of immunotherapy in patients with indolent systemic mastocytosis presenting with Hymenoptera venom anaphylaxis. J Allergy Clin Immunol2008;121:519526.

    • Search Google Scholar
    • Export Citation
  • 106.

    BonadonnaPGonzalez-de-OlanoDZanottiR. Venom immunotherapy in patients with clonal mast cell disorders: efficacy, safety, and practical considerations. J Allergy Clin Immunol Pract2013;1:474478.

    • Search Google Scholar
    • Export Citation
  • 107.

    VerburgMOldhoffJMKlemansRJ. Rush immunotherapy for wasp venom allergy seems safe and effective in patients with mastocytosis. Eur Ann Allergy Clin Immunol2015;47:192196.

    • Search Google Scholar
    • Export Citation
  • 108.

    RueffFWenderothAPrzybillaB. Patients still reacting to a sting challenge while receiving conventional Hymenoptera venom immunotherapy are protected by increased venom doses. J Allergy Clin Immunol2001;108:10271032.

    • Search Google Scholar
    • Export Citation
  • 109.

    CarterMCRobynJABresslerPB. Omalizumab for the treatment of unprovoked anaphylaxis in patients with systemic mastocytosis. J Allergy Clin Immunol2007;119:15501551.

    • Search Google Scholar
    • Export Citation
  • 110.

    WarrierPCasaleTB. Omalizumab in idiopathic anaphylaxis. Ann Allergy Asthma Immunol2009;102:257258.

  • 111.

    RossiniMZanottiROrsoliniG. Prevalence, pathogenesis, and treatment options for mastocytosis-related osteoporosis. Osteoporos Int2016;27:24112421.

    • Search Google Scholar
    • Export Citation
  • 112.

    MarshallAKavanaghRTCrispAJ. The effect of pamidronate on lumbar spine bone density and pain in osteoporosis secondary to systemic mastocytosis. Br J Rheumatol1997;36:393396.

    • Search Google Scholar
    • Export Citation
  • 113.

    RossiniMZanottiRViapianaO. Zoledronic acid in osteoporosis secondary to mastocytosis. Am J Med2014;127:1127e11211124.

  • 114.

    LehmannTBeyelerCLammleB. Severe osteoporosis due to systemic mast cell disease: successful treatment with interferon alpha-2B. Br J Rheumatol1996;35:898900.

    • Search Google Scholar
    • Export Citation
  • 115.

    WeideREhlenzKLorenzW. Successful treatment of osteoporosis in systemic mastocytosis with interferon alpha-2b. Ann Hematol1996;72:4143.

    • Search Google Scholar
    • Export Citation
  • 116.

    LarocheMLivideanuCPaulCCantagrelA. Interferon alpha and pamidronate in osteoporosis with fracture secondary to mastocytosis. Am J Med2011;124:776778.

    • Search Google Scholar
    • Export Citation
  • 117.

    OrsoliniGGavioliITripiG. Denosumab for the treatment of mastocytosis-related osteoporosis: a case series. Calcif Tissue Int2017;100:595598.

    • Search Google Scholar
    • Export Citation
  • 118.

    KrugerAHamannCBrendelC. Multimodal therapy for vertebral involvement of systemic mastocytosis. Spine (Phila Pa 1976)2009;34:E626628.

    • Search Google Scholar
    • Export Citation
  • 119.

    GotlibJKluin-NelemansHCGeorgeTI. Efficacy and safety of midostaurin in advanced systemic mastocytosis. N Engl J Med2016;374:25302541.

    • Search Google Scholar
    • Export Citation
  • 120.

    ChandesrisMODamajGCanioniD. Midostaurin in advanced systemic mastocytosis. N Engl J Med2016;374:26052607.

  • 121.

    DeAngeloDJGeorgeTILinderA. Efficacy and safety of midostaurin in patients with advanced systemic mastocytosis: 10-year median follow-up of a phase II trial. Leukemia2018;32:470478.

    • Search Google Scholar
    • Export Citation
  • 122.

    JawharMSchwaabJNaumannN. Response and progression on midostaurin in advanced systemic mastocytosis: KIT D816V and other molecular markers. Blood2017;130:137145.

    • Search Google Scholar
    • Export Citation
  • 123.

    Kluin-NelemansHCOldhoffJMVan DoormaalJJ. Cladribine therapy for systemic mastocytosis. Blood2003;102:42704276.

  • 124.

    LimKHPardananiAButterfieldJH. Cytoreductive therapy in 108 adults with systemic mastocytosis: outcome analysis and response prediction during treatment with interferon-alpha, hydroxyurea, imatinib mesylate or 2-chlorodeoxyadenosine. Am J Hematol2009;84:790794.

    • Search Google Scholar
    • Export Citation
  • 125.

    BareteSLortholaryODamajG. Long-term efficacy and safety of cladribine (2-CdA) in adult patients with mastocytosis. Blood2015;126:10091016.

    • Search Google Scholar
    • Export Citation
  • 126.

    DelaporteEPierardEWolthersBG. Interferon-alpha in combination with corticosteroids improves systemic mast cell disease. Br J Dermatol1995;132:479482.

    • Search Google Scholar
    • Export Citation
  • 127.

    CasassusPCaillat-VigneronNMartinA. Treatment of adult systemic mastocytosis with interferon-alpha: results of a multicentre phase II trial on 20 patients. Br J Haematol2002;119:10901097.

    • Search Google Scholar
    • Export Citation
  • 128.

    HauswirthAWSimonitsch-KluppIUffmannM. Response to therapy with interferon alpha-2b and prednisolone in aggressive systemic mastocytosis: report of five cases and review of the literature. Leuk Res2004;28:249257.

    • Search Google Scholar
    • Export Citation
  • 129.

    SimonJLortholaryOCaillat-VigneronN. Interest of interferon alpha in systemic mastocytosis. The French experience and review of the literature. Pathol Biol (Paris)2004;52:294299.

    • Search Google Scholar
    • Export Citation
  • 130.

    FrostMJFerraoPTHughesTPAshmanLK. Juxtamembrane mutant V560GKit is more sensitive to imatinib (STI571) compared with wild-type c-kit whereas the kinase domain mutant D816VKit is resistant. Mol Cancer Ther2002;1:11151124.

    • Search Google Scholar
    • Export Citation
  • 131.

    AkinCBrockowKD'AmbrosioC. Effects of tyrosine kinase inhibitor STI571 on human mast cells bearing wild-type or mutated c-kit. Exp Hematol2003;31:686692.

    • Search Google Scholar
    • Export Citation
  • 132.

    AkinCFumoGYavuzAS. A novel form of mastocytosis associated with a transmembrane c-kit mutation and response to imatinib. Blood2004;103:32223225.

    • Search Google Scholar
    • Export Citation
  • 133.

    ZhangLYSmithMLSchultheisB. A novel K509I mutation of KIT identified in familial mastocytosis-in vitro and in vivo responsiveness to imatinib therapy. Leuk Res2006;30:373378.

    • Search Google Scholar
    • Export Citation
  • 134.

    HeinrichMCJoensuuHDemetriGD. Phase II, open-label study evaluating the activity of imatinib in treating life-threatening malignancies known to be associated with imatinib-sensitive tyrosine kinases. Clin Cancer Res2008;14:27172725.

    • Search Google Scholar
    • Export Citation
  • 135.

    Vega-RuizACortesJESeverM. Phase II study of imatinib mesylate as therapy for patients with systemic mastocytosis. Leuk Res2009;33:14811484.

    • Search Google Scholar
    • Export Citation
  • 136.

    MitalAPiskorzALewandowskiK. A case of mast cell leukaemia with exon 9 KIT mutation and good response to imatinib. Eur J Haematol2011;86:531535.

    • Search Google Scholar
    • Export Citation
  • 137.

    Alvarez-TwoseIMatitoAMorgadoJM. Imatinib in systemic mastocytosis: a phase IV clinical trial in patients lacking exon 17 KIT mutations and review of the literature. Oncotarget2017;8:6895068963.

    • Search Google Scholar
    • Export Citation
  • 138.

    PrzepiorkaDGiraltSKhouriI. Allogeneic marrow transplantation for myeloproliferative disorders other than chronic myelogenous leukemia: review of forty cases. Am J Hematol1998;57:2428.

    • Search Google Scholar
    • Export Citation
  • 139.

    NakamuraRChakrabartiSAkinC. A pilot study of nonmyeloablative allogeneic hematopoietic stem cell transplant for advanced systemic mastocytosis. Bone Marrow Transplant2006;37:353358.

    • Search Google Scholar
    • Export Citation
  • 140.

    UstunCReiterAScottBL. Hematopoietic stem-cell transplantation for advanced systemic mastocytosis. J Clin Oncol2014;32:32643274.

  • 141.

    UstunCGotlibJPopatU. Consensus opinion on allogeneic hematopoietic cell transplantation in advanced systemic mastocytosis. Biol Blood Marrow Transplant2016;22:13481356.

    • Search Google Scholar
    • Export Citation
  • 142.

    ValentPAkinCSperrWR. Aggressive systemic mastocytosis and related mast cell disorders: current treatment options and proposed response criteria. Leuk Res2003;27:635641.

    • Search Google Scholar
    • Export Citation
  • 143.

    MatitoAMorgadoJMAlvarez-TwoseI. Serum tryptase monitoring in indolent systemic mastocytosis: association with disease features and patient outcome. PLoS One2013;8:e76116.

    • Search Google Scholar
    • Export Citation
  • 144.

    ErbenPSchwaabJMetzgerothG. The KIT D816V expressed allele burden for diagnosis and disease monitoring of systemic mastocytosis. Ann Hematol2014;93:8188.

    • Search Google Scholar
    • Export Citation
  • 145.

    HoermannGGleixnerKVDinuGE. The KIT D816V allele burden predicts survival in patients with mastocytosis and correlates with the WHO type of the disease. Allergy2014;69:810813.

    • Search Google Scholar
    • Export Citation
  • 146.

    PardananiA. How I treat patients with indolent and smoldering mastocytosis (rare conditions but difficult to manage). Blood2013;121:30853094.

    • Search Google Scholar
    • Export Citation
  • 147.

    DewachterPCastellsMCHepnerDLMouton-FaivreC. Perioperative management of patients with mastocytosis. Anesthesiology2014;120:753759.

  • 148.

    HermansMAWArendsNJTGerth van WijkR. Management around invasive procedures in mastocytosis: an update. Ann Allergy Asthma Immunol2017;119:304309.

    • Search Google Scholar
    • Export Citation
  • 149.

    MatitoAMorgadoJMSanchez-LopezP. Management of anesthesia in adult and pediatric mastocytosis: a study of the Spanish Network on Mastocytosis (REMA) based on 726 anesthetic procedures. Int Arch Allergy Immunol2015;167:4756.

    • Search Google Scholar
    • Export Citation
  • 150.

    GuyerACSaffRRConroyM. Comprehensive allergy evaluation is useful in the subsequent care of patients with drug hypersensitivity reactions during anesthesia. J Allergy Clin Immunol Pract2015;3:94100.

    • Search Google Scholar
    • Export Citation
  • 151.

    WoidackiKZenclussenACSiebenhaarF. Mast cell-mediated and associated disorders in pregnancy: a risky game with an uncertain outcome?Front Immunol2014;5:231.

    • Search Google Scholar
    • Export Citation
  • 152.

    WorobecASAkinCScottLMMetcalfeDD. Mastocytosis complicating pregnancy. Obstet Gynecol2000;95:391395.

  • 153.

    CiachKNiedoszytkoMAbacjew-ChmylkoA. Pregnancy and delivery in patients with mastocytosis treated at the Polish Center of the European Competence Network on Mastocytosis (ECNM). PLoS One2016;11:e0146924.

    • Search Google Scholar
    • Export Citation
  • 154.

    MatitoAAlvarez-TwoseIMorgadoJM. Clinical impact of pregnancy in mastocytosis: a study of the Spanish Network on Mastocytosis (REMA) in 45 cases. Int Arch Allergy Immunol2011;156:104111.

    • Search Google Scholar
    • Export Citation
  • 155.

    UlbrichFEngelstadterHWittauNSteinmannD. Anaesthetic management of emergency caesarean section in a parturient with systemic mastocytosis. Int J Obstet Anesth2013;22:243246.

    • Search Google Scholar
    • Export Citation
  • 156.

    LeiDAkinCKovalszkiA. Management of mastocytosis in pregnancy: a review. J Allergy Clin Immunol Pract2017;5:12171223.

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    NCCN Clinical Practice Guidelines in Oncology: Systemic Mastocytosis, Version 2.2019

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    NCCN Clinical Practice Guidelines in Oncology: Systemic Mastocytosis, Version 2.2019

    Version 2.2019, 09-29-18 ©2018 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

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    NCCN Clinical Practice Guidelines in Oncology: Systemic Mastocytosis, Version 2.2019

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    NCCN Clinical Practice Guidelines in Oncology: Systemic Mastocytosis, Version 2.2019

    Version 2.2019, 09-29-18 ©2018 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

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    NCCN Clinical Practice Guidelines in Oncology: Systemic Mastocytosis, Version 2.2019

    Version 2.2019, 09-29-18 ©2018 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

  • View in gallery

    NCCN Clinical Practice Guidelines in Oncology: Systemic Mastocytosis, Version 2.2019

    Version 2.2019, 09-29-18 ©2018 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

  • View in gallery

    NCCN Clinical Practice Guidelines in Oncology: Systemic Mastocytosis, Version 2.2019

    Version 2.2019, 09-29-18 ©2018 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

References

  • 1.

    ValentPHornyHPEscribanoL. Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res2001;25:603625.

  • 2.

    SwerdlowSHCampoEHarrisNL. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (Revised 4th edition). International Agency for Research on Cancer; Lyon, France; 2017.

    • Search Google Scholar
    • Export Citation
  • 3.

    RyanRJAkinCCastellsM. Mast cell sarcoma: a rare and potentially under-recognized diagnostic entity with specific therapeutic implications. Mod Pathol2013;26:533543.

    • Search Google Scholar
    • Export Citation
  • 4.

    JawharMSchwaabJHornyHP. Impact of centralized evaluation of bone marrow histology in systemic mastocytosis. Eur J Clin Invest2016;46:392397.

    • Search Google Scholar
    • Export Citation
  • 5.

    Sanchez-MunozLMorgadoJMAlvarez-TwoseI. Diagnosis and classification of mastocytosis in non-specialized versus reference centres: a Spanish Network on Mastocytosis (REMA) study on 122 patients. Br J Haematol2016;172:5663.

    • Search Google Scholar
    • Export Citation
  • 6.

    NagataHWorobecASOhCK. Identification of a point mutation in the catalytic domain of the protooncogene c-kit in peripheral blood mononuclear cells of patients who have mastocytosis with an associated hematologic disorder. Proc Natl Acad Sci U S A1995;92:1056010564.

    • Search Google Scholar
    • Export Citation
  • 7.

    SchwaabJSchnittgerSSotlarK. Comprehensive mutational profiling in advanced systemic mastocytosis. Blood2013;122:24602466.

  • 8.

    HartmannKEscribanoLGrattanC. Cutaneous manifestations in patients with mastocytosis: Consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology. J Allergy Clin Immunol2016;137:3545.

    • Search Google Scholar
    • Export Citation
  • 9.

    EscribanoLAlvarez-TwoseISanchez-MunozL. Prognosis in adult indolent systemic mastocytosis: a long-term study of the Spanish Network on Mastocytosis in a series of 145 patients. J Allergy Clin Immunol2009;124:514521.

    • Search Google Scholar
    • Export Citation
  • 10.

    LimKHTefferiALashoTL. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood2009;113:57275736.

    • Search Google Scholar
    • Export Citation
  • 11.

    PardananiALimKHLashoTL. WHO subvariants of indolent mastocytosis: clinical details and prognostic evaluation in 159 consecutive adults. Blood2010;115:150151.

    • Search Google Scholar
    • Export Citation
  • 12.

    Alvarez-TwoseIJara-AcevedoMMorgadoJM. Clinical, immunophenotypic, and molecular characteristics of well-differentiated systemic mastocytosis. J Allergy Clin Immunol2016;137:168178e161.

    • Search Google Scholar
    • Export Citation
  • 13.

    AkinCScottLMKocabasCN. Demonstration of an aberrant mast-cell population with clonal markers in a subset of patients with “idiopathic” anaphylaxis. Blood2007;110:23312333.

    • Search Google Scholar
    • Export Citation
  • 14.

    PardananiAChenDAbdelrahmanRA. Clonal mast cell disease not meeting WHO criteria for diagnosis of mastocytosis: clinicopathologic features and comparison with indolent mastocytosis. Leukemia2013;27:20912094.

    • Search Google Scholar
    • Export Citation
  • 15.

    AkinC. Mast cell activation syndromes. J Allergy Clin Immunol2017;140:349355.

  • 16.

    LyonsJJYuXHughesJD. Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number. Nat Genet2016;48:15641569.

    • Search Google Scholar
    • Export Citation
  • 17.

    CastellsMAustenKF. Mastocytosis: mediator-related signs and symptoms. Int Arch Allergy Immunol2002;127:147152.

  • 18.

    BrockowKJoferCBehrendtHRingJ. Anaphylaxis in patients with mastocytosis: a study on history, clinical features and risk factors in 120 patients. Allergy2008;63:226232.

    • Search Google Scholar
    • Export Citation
  • 19.

    van AnrooijBKluin-NelemansJCSafyM. Patient-reported disease-specific quality-of-life and symptom severity in systemic mastocytosis. Allergy2016;71:15851593.

    • Search Google Scholar
    • Export Citation
  • 20.

    GulenTHagglundHDahlenBNilssonG. Mastocytosis: the puzzling clinical spectrum and challenging diagnostic aspects of an enigmatic disease. J Intern Med2016;279:211228.

    • Search Google Scholar
    • Export Citation
  • 21.

    ZanottiRBonadonnaPBonifacioM. Isolated bone marrow mastocytosis: an underestimated subvariant of indolent systemic mastocytosis. Haematologica2011;96:482484.

    • Search Google Scholar
    • Export Citation
  • 22.

    PardananiALimKHLashoTL. Prognostically relevant breakdown of 123 patients with systemic mastocytosis associated with other myeloid malignancies. Blood2009;114:37693772.

    • Search Google Scholar
    • Export Citation
  • 23.

    WangSAHutchinsonLTangG. Systemic mastocytosis with associated clonal hematological non-mast cell lineage disease: clinical significance and comparison of chomosomal abnormalities in SM and AHNMD components. Am J Hematol2013;88:219224.

    • Search Google Scholar
    • Export Citation
  • 24.

    ValentPSotlarKSperrWR. Refined diagnostic criteria and classification of mast cell leukemia (MCL) and myelomastocytic leukemia (MML): a consensus proposal. Ann Oncol2014;25:16911700.

    • Search Google Scholar
    • Export Citation
  • 25.

    ValentPBergerJCerny-ReitererS. Chronic mast cell leukemia (MCL) with KIT S476I: a rare entity defined by leukemic expansion of mature mast cells and absence of organ damage. Ann Hematol2015;94:223231.

    • Search Google Scholar
    • Export Citation
  • 26.

    ValentPSotlarKSperrWR. Chronic mast cell leukemia: a novel leukemia-variant with distinct morphological and clinical features. Leuk Res2015;39:15.

    • Search Google Scholar
    • Export Citation
  • 27.

    Georgin-LavialleSLhermitteLDubreuilP. Mast cell leukemia. Blood2013;121:12851295.

  • 28.

    JawharMSchwaabJMeggendorferM. The clinical and molecular diversity of mast cell leukemia with or without associated hematologic neoplasm. Haematologica2017;102:10351043.

    • Search Google Scholar
    • Export Citation
  • 29.

    SperrWRJordanJHFieglM. Serum tryptase levels in patients with mastocytosis: correlation with mast cell burden and implication for defining the category of disease. Int Arch Allergy Immunol2002;128:136141.

    • Search Google Scholar
    • Export Citation
  • 30.

    SchwartzLBMetcalfeDDMillerJS. Tryptase levels as an indicator of mast-cell activation in systemic anaphylaxis and mastocytosis. N Engl J Med1987;316:16221626.

    • Search Google Scholar
    • Export Citation
  • 31.

    SperrWREl-SamahiAKundiM. Elevated tryptase levels selectively cluster in myeloid neoplasms: a novel diagnostic approach and screen marker in clinical haematology. Eur J Clin Invest2009;39:914923.

    • Search Google Scholar
    • Export Citation
  • 32.

    AbererESavicSBretterklieberA. Disease spectrum in patients with elevated serum tryptase levels. Australas J Dermatol2015;56:713.

  • 33.

    CaugheyGH. Tryptase genetics and anaphylaxis. J Allergy Clin Immunol2006;117:14111414.

  • 34.

    HornyHPSotlarKValentP. Differential diagnoses of systemic mastocytosis in routinely processed bone marrow biopsy specimens: a review. Pathobiology2010;77:169180.

    • Search Google Scholar
    • Export Citation
  • 35.

    ButterfieldJHLiCY. Bone marrow biopsies for the diagnosis of systemic mastocytosis: is one biopsy sufficient?Am J Clin Pathol2004;121:264267.

    • Search Google Scholar
    • Export Citation
  • 36.

    Sanchez-MunozLAlvarez-TwoseIGarcia-MonteroAC. Evaluation of the WHO criteria for the classification of patients with mastocytosis. Mod Pathol2011;24:11571168.

    • Search Google Scholar
    • Export Citation
  • 37.

    ReichardKKChenDPardananiA. Morphologically occult systemic mastocytosis in bone marrow: clinicopathologic features and an algorithmic approach to diagnosis. Am J Clin Pathol2015;144:493502.

    • Search Google Scholar
    • Export Citation
  • 38.

    JordanJHWalchshoferSJureckaW. Immunohistochemical properties of bone marrow mast cells in systemic mastocytosis: evidence for expression of CD2, CD117/Kit, and bcl-x(L). Hum Pathol2001;32:545552.

    • Search Google Scholar
    • Export Citation
  • 39.

    HornyHPSotlarKValentP. Mastocytosis: immunophenotypical features of the transformed mast cells are unique among hematopoietic cells. Immunol Allergy Clin North Am2014;34:315321.

    • Search Google Scholar
    • Export Citation
  • 40.

    TeodosioCMayadoASanchez-MunozL. The immunophenotype of mast cells and its utility in the diagnostic work-up of systemic mastocytosis. J Leukoc Biol2015;97:4959.

    • Search Google Scholar
    • Export Citation
  • 41.

    EscribanoLDiaz AgustinBBravoP. Immunophenotype of bone marrow mast cells in indolent systemic mast cell disease in adults. Leuk Lymphoma1999;35:227235.

    • Search Google Scholar
    • Export Citation
  • 42.

    SotlarKHornyHPSimonitschI. CD25 indicates the neoplastic phenotype of mast cells: a novel immunohistochemical marker for the diagnosis of systemic mastocytosis (SM) in routinely processed bone marrow biopsy specimens. Am J Surg Pathol2004;28:13191325.

    • Search Google Scholar
    • Export Citation
  • 43.

    PardananiAKimlingerTReederT. Bone marrow mast cell immunophenotyping in adults with mast cell disease: a prospective study of 33 patients. Leuk Res2004;28:777783.

    • Search Google Scholar
    • Export Citation
  • 44.

    MorgadoJMSanchez-MunozLTeodosioCG. Immunophenotyping in systemic mastocytosis diagnosis: ‘CD25 positive’ alone is more informative than the ‘CD25 and/or CD2’ WHO criterion. Mod Pathol2012;25:516521.

    • Search Google Scholar
    • Export Citation
  • 45.

    ChisholmKMMerkerJDGotlibJR. Mast cells in systemic mastocytosis have distinctly brighter CD45 expression by flow cytometry. Am J Clin Pathol2015;143:527534.

    • Search Google Scholar
    • Export Citation
  • 46.

    SotlarKCerny-ReitererSPetat-DutterK. Aberrant expression of CD30 in neoplastic mast cells in high-grade mastocytosis. Mod Pathol2011;24:585595.

    • Search Google Scholar
    • Export Citation
  • 47.

    ValentPSotlarKHornyHP. Aberrant expression of CD30 in aggressive systemic mastocytosis and mast cell leukemia: a differential diagnosis to consider in aggressive hematopoietic CD30-positive neoplasms. Leuk Lymphoma2011;52:740744.

    • Search Google Scholar
    • Export Citation
  • 48.

    MorgadoJMPerbelliniOJohnsonRC. CD30 expression by bone marrow mast cells from different diagnostic variants of systemic mastocytosis. Histopathology2013;63:780787.

    • Search Google Scholar
    • Export Citation
  • 49.

    Russano de Paiva SilvaGTournierESarianLO. Prevalence of CD30 immunostaining in neoplastic mast cells: a retrospective immunohistochemical study. Medicine (Baltimore)2018;97:e10642.

    • Search Google Scholar
    • Export Citation
  • 50.

    MayadoATeodosioCDasilva-FreireN. Characterization of CD34(+) hematopoietic cells in systemic mastocytosis: potential role in disease dissemination. Allergy2018;73:12941304.

    • Search Google Scholar
    • Export Citation
  • 51.

    EscribanoLGarcia MonteroACNunezR. Flow cytometric analysis of normal and neoplastic mast cells: role in diagnosis and follow-up of mast cell disease. Immunol Allergy Clin North Am2006;26:535547.

    • Search Google Scholar
    • Export Citation
  • 52.

    Sanchez-MunozLTeodosioCMorgadoJM. Flow cytometry in mastocytosis: utility as a diagnostic and prognostic tool. Immunol Allergy Clin North Am2014;34:297313.

    • Search Google Scholar
    • Export Citation
  • 53.

    LongleyBJTyrrellLLuSZ. Somatic c-KIT activating mutation in urticaria pigmentosa and aggressive mastocytosis: establishment of clonality in a human mast cell neoplasm. Nat Genet1996;12:312314.

    • Search Google Scholar
    • Export Citation
  • 54.

    Garcia-MonteroACJara-AcevedoMTeodosioC. KIT mutation in mast cells and other bone marrow hematopoietic cell lineages in systemic mast cell disorders: a prospective study of the Spanish Network on Mastocytosis (REMA) in a series of 113 patients. Blood2006;108:23662372.

    • Search Google Scholar
    • Export Citation
  • 55.

    SotlarKColakSBacheA. Variable presence of KITD816V in clonal haematological non-mast cell lineage diseases associated with systemic mastocytosis (SM-AHNMD). J Pathol2010;220:586595.

    • Search Google Scholar
    • Export Citation
  • 56.

    TefferiALevineRLLimKH. Frequent TET2 mutations in systemic mastocytosis: clinical, KITD816V and FIP1L1-PDGFRA correlates. Leukemia2009;23:900904.

    • Search Google Scholar
    • Export Citation
  • 57.

    TrainaFVisconteVJankowskaAM. Single nucleotide polymorphism array lesions, TET2, DNMT3A, ASXL1 and CBL mutations are present in systemic mastocytosis. PLoS One2012;7:e43090.

    • Search Google Scholar
    • Export Citation
  • 58.

    DamajGJorisMChandesrisO. ASXL1 but not TET2 mutations adversely impact overall survival of patients suffering systemic mastocytosis with associated clonal hematologic non-mast-cell diseases. PLoS One2014;9:e85362.

    • Search Google Scholar
    • Export Citation
  • 59.

    JawharMSchwaabJHausmannD. Splenomegaly, elevated alkaline phosphatase and mutations in the SRSF2/ASXL1/RUNX1 gene panel are strong adverse prognostic markers in patients with systemic mastocytosis. Leukemia2016;30:23422350.

    • Search Google Scholar
    • Export Citation
  • 60.

    JawharMSchwaabJSchnittgerS. Additional mutations in SRSF2, ASXL1 and/or RUNX1 identify a high-risk group of patients with KIT D816V(+) advanced systemic mastocytosis. Leukemia2016;30:136143.

    • Search Google Scholar
    • Export Citation
  • 61.

    PardananiADLashoTLFinkeC. ASXL1 and CBL mutations are independently predictive of inferior survival in advanced systemic mastocytosis. Br J Haematol2016;175:534536.

    • Search Google Scholar
    • Export Citation
  • 62.

    PardananiALashoTElalaY. Next-generation sequencing in systemic mastocytosis: derivation of a mutation-augmented clinical prognostic model for survival. Am J Hematol2016;91:888893.

    • Search Google Scholar
    • Export Citation
  • 63.

    PardananiAKetterlingRPBrockmanSR. CHIC2 deletion, a surrogate for FIP1L1-PDGFRA fusion, occurs in systemic mastocytosis associated with eosinophilia and predicts response to imatinib mesylate therapy. Blood2003;102:30933096.

    • Search Google Scholar
    • Export Citation
  • 64.

    PardananiABrockmanSRPaternosterSF. FIP1L1-PDGFRA fusion: prevalence and clinicopathologic correlates in 89 consecutive patients with moderate to severe eosinophilia. Blood2004;104:30383045.

    • Search Google Scholar
    • Export Citation
  • 65.

    BohmAFodingerMWimazalF. Eosinophilia in systemic mastocytosis: clinical and molecular correlates and prognostic significance. J Allergy Clin Immunol2007;120:192199.

    • Search Google Scholar
    • Export Citation
  • 66.

    ArockMSotlarKAkinC. KIT mutation analysis in mast cell neoplasms: recommendations of the European Competence Network on Mastocytosis. Leukemia2015;29:12231232.

    • Search Google Scholar
    • Export Citation
  • 67.

    KristensenTVestergaardHMollerMB. Improved detection of the KIT D816V mutation in patients with systemic mastocytosis using a quantitative and highly sensitive real-time qPCR assay. J Mol Diagn2011;13:180188.

    • Search Google Scholar
    • Export Citation
  • 68.

    KristensenTVestergaardHBindslev-JensenC. Sensitive KIT D816V mutation analysis of blood as a diagnostic test in mastocytosis. Am J Hematol2014;89:493498.

    • Search Google Scholar
    • Export Citation
  • 69.

    Jara-AcevedoMTeodosioCSanchez-MunozL. Detection of the KIT D816V mutation in peripheral blood of systemic mastocytosis: diagnostic implications. Mod Pathol2015;28:11381149.

    • Search Google Scholar
    • Export Citation
  • 70.

    KristensenTVestergaardHBindslev-JensenC. Prospective evaluation of the diagnostic value of sensitive KIT D816V mutation analysis of blood in adults with suspected systemic mastocytosis. Allergy2017;72:17371743.

    • Search Google Scholar
    • Export Citation
  • 71.

    SotlarKEscribanoLLandtO. One-step detection of c-kit point mutations using peptide nucleic acid-mediated polymerase chain reaction clamping and hybridization probes. Am J Pathol2003;162:737746.

    • Search Google Scholar
    • Export Citation
  • 72.

    GotlibJPardananiAAkinC. International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) & European Competence Network on Mastocytosis (ECNM) consensus response criteria in advanced systemic mastocytosis. Blood2013;121:23932401.

    • Search Google Scholar
    • Export Citation
  • 73.

    BareteSAssousNde GennesC. Systemic mastocytosis and bone involvement in a cohort of 75 patients. Ann Rheum Dis2010;69:18381841.

  • 74.

    RossiniMZanottiRBonadonnaP. Bone mineral density, bone turnover markers and fractures in patients with indolent systemic mastocytosis. Bone2011;49:880885.

    • Search Google Scholar
    • Export Citation
  • 75.

    van der VeerEvan der GootWde MonchyJG. High prevalence of fractures and osteoporosis in patients with indolent systemic mastocytosis. Allergy2012;67:431438.

    • Search Google Scholar
    • Export Citation
  • 76.

    MetcalfeDDPawankarRAckermanSJ. Biomarkers of the involvement of mast cells, basophils and eosinophils in asthma and allergic diseases. World Allergy Organ J2016;9:7.

    • Search Google Scholar
    • Export Citation
  • 77.

    MorrowJDGuzzoCLazarusG. Improved diagnosis of mastocytosis by measurement of the major urinary metabolite of prostaglandin D2. J Invest Dermatol1995;104:937940.

    • Search Google Scholar
    • Export Citation
  • 78.

    OranjeAPMulderPGHeideR. Urinary N-methylhistamine as an indicator of bone marrow involvement in mastocytosis. Clin Exp Dermatol2002;27:502506.

    • Search Google Scholar
    • Export Citation
  • 79.

    ButterfieldJH. Increased leukotriene E4 excretion in systemic mastocytosis. Prostaglandins Other Lipid Mediat2010;92:7376.

  • 80.

    van DoormaalJJvan der VeerEvan Voorst VaderPC. Tryptase and histamine metabolites as diagnostic indicators of indolent systemic mastocytosis without skin lesions. Allergy2012;67:683690.

    • Search Google Scholar
    • Export Citation
  • 81.

    DivekarRButterfieldJ. Urinary 11beta-PGF2alpha and N-methyl histamine correlate with bone marrow biopsy findings in mast cell disorders. Allergy2015;70:12301238.

    • Search Google Scholar
    • Export Citation
  • 82.

    ChoCNguyenABryantKJ. Prostaglandin D2 metabolites as a biomarker of in vivo mast cell activation in systemic mastocytosis and rheumatoid arthritis. Immun Inflamm Dis2016;4:6469.

    • Search Google Scholar
    • Export Citation
  • 83.

    RaviAButterfieldJWeilerCR. Mast cell activation syndrome: improved identification by combined determinations of serum tryptase and 24-hour urine 11beta-prostaglandin2alpha. J Allergy Clin Immunol Pract2014;2:775778.

    • Search Google Scholar
    • Export Citation
  • 84.

    CardetJCAkinCLeeMJ. Mastocytosis: update on pharmacotherapy and future directions. Expert Opin Pharmacother2013;14:20332045.

  • 85.

    SoterNAAustenKFWassermanSI. Oral disodium cromoglycate in the treatment of systemic mastocytosis. N Engl J Med1979;301:465469.

  • 86.

    HoranRFShefferALAustenKF. Cromolyn sodium in the management of systemic mastocytosis. J Allergy Clin Immunol1990;85:852855.

  • 87.

    TolarJTopeWDNegliaJP. Leukotriene-receptor inhibition for the treatment of systemic mastocytosis. N Engl J Med2004;350:735736.

  • 88.

    TurnerPJKempASRogersMMehrS. Refractory symptoms successfully treated with leukotriene inhibition in a child with systemic mastocytosis. Pediatr Dermatol2012;29:222223.

    • Search Google Scholar
    • Export Citation
  • 89.

    ButterfieldJH. Survey of aspirin administration in systemic mastocytosis. Prostaglandins Other Lipid Mediat2009;88:122124.

  • 90.

    Broesby-OlsenSVestergaardHMortzCG. Omalizumab prevents anaphylaxis and improves symptoms in systemic mastocytosis: efficacy and safety observations. Allergy2018;73:230238.

    • Search Google Scholar
    • Export Citation
  • 91.

    Gonzalez de OlanoDde la Hoz CaballerBNunez LopezR. Prevalence of allergy and anaphylactic symptoms in 210 adult and pediatric patients with mastocytosis in Spain: a study of the Spanish network on mastocytosis (REMA). Clin Exp Allergy2007;37:15471555.

    • Search Google Scholar
    • Export Citation
  • 92.

    GulenTHagglundHDahlenBNilssonG. High prevalence of anaphylaxis in patients with systemic mastocytosis—a single-centre experience. Clin Exp Allergy2014;44:121129.

    • Search Google Scholar
    • Export Citation
  • 93.

    GorskaANiedoszytkoMLangeM. Risk factors for anaphylaxis in patients with mastocytosis. Pol Arch Med Wewn2015;125:4653.

  • 94.

    Alvarez-TwoseIZanottiRGonzalez-de-OlanoD. Nonaggressive systemic mastocytosis (SM) without skin lesions associated with insect-induced anaphylaxis shows unique features versus other indolent SM. J Allergy Clin Immunol2014;133:520528.

    • Search Google Scholar
    • Export Citation
  • 95.

    GulenTLjungCNilssonGAkinC. Risk factor analysis of anaphylactic reactions in patients with systemic mastocytosis. J Allergy Clin Immunol Pract2017;5:12481255.

    • Search Google Scholar
    • Export Citation
  • 96.

    NiedoszytkoMBonadonnaPOude ElberinkJNGoldenDB. Epidemiology, diagnosis, and treatment of Hymenoptera venom allergy in mastocytosis patients. Immunol Allergy Clin North Am2014;34:365381.

    • Search Google Scholar
    • Export Citation
  • 97.

    Jimenez-RodriguezTWGarcia-NeuerMAlenazyLACastellsM. Anaphylaxis in the 21st century: phenotypes, endotypes, and biomarkers. J Asthma Allergy2018;11:121142.

    • Search Google Scholar
    • Export Citation
  • 98.

    ValentP. Risk factors and management of severe life-threatening anaphylaxis in patients with clonal mast cell disorders. Clin Exp Allergy2014;44:914920.

    • Search Google Scholar
    • Export Citation
  • 99.

    van AnrooijBvan der VeerEde MonchyJG. Higher mast cell load decreases the risk of Hymenoptera venom-induced anaphylaxis in patients with mastocytosis. J Allergy Clin Immunol2013;132:125130.

    • Search Google Scholar
    • Export Citation
  • 100.

    HaeberliGBronnimannMHunzikerTMullerU. Elevated basal serum tryptase and Hymenoptera venom allergy: relation to severity of sting reactions and to safety and efficacy of venom immunotherapy. Clin Exp Allergy2003;33:12161220.

    • Search Google Scholar
    • Export Citation
  • 101.

    BonadonnaPPerbelliniOPassalacquaG. Clonal mast cell disorders in patients with systemic reactions to Hymenoptera stings and increased serum tryptase levels. J Allergy Clin Immunol2009;123:680686.

    • Search Google Scholar
    • Export Citation
  • 102.

    RueffFPrzybillaBBiloMB. Predictors of severe systemic anaphylactic reactions in patients with Hymenoptera venom allergy: importance of baseline serum tryptase-a study of the European Academy of Allergology and Clinical Immunology Interest Group on Insect Venom Hypersensitivity. J Allergy Clin Immunol2009;124:10471054.

    • Search Google Scholar
    • Export Citation
  • 103.

    Alvarez-TwoseIBonadonnaPMatitoA. Systemic mastocytosis as a risk factor for severe Hymenoptera sting-induced anaphylaxis. J Allergy Clin Immunol2013;131:614615.

    • Search Google Scholar
    • Export Citation
  • 104.

    CastellsMCHornickJLAkinC. Anaphylaxis after hymenoptera sting: is it venom allergy, a clonal disorder, or both?J Allergy Clin Immunol Pract2015;3:350355.

    • Search Google Scholar
    • Export Citation
  • 105.

    Gonzalez de OlanoDAlvarez-TwoseIEsteban-LopezMI. Safety and effectiveness of immunotherapy in patients with indolent systemic mastocytosis presenting with Hymenoptera venom anaphylaxis. J Allergy Clin Immunol2008;121:519526.

    • Search Google Scholar
    • Export Citation
  • 106.

    BonadonnaPGonzalez-de-OlanoDZanottiR. Venom immunotherapy in patients with clonal mast cell disorders: efficacy, safety, and practical considerations. J Allergy Clin Immunol Pract2013;1:474478.

    • Search Google Scholar
    • Export Citation
  • 107.

    VerburgMOldhoffJMKlemansRJ. Rush immunotherapy for wasp venom allergy seems safe and effective in patients with mastocytosis. Eur Ann Allergy Clin Immunol2015;47:192196.

    • Search Google Scholar
    • Export Citation
  • 108.

    RueffFWenderothAPrzybillaB. Patients still reacting to a sting challenge while receiving conventional Hymenoptera venom immunotherapy are protected by increased venom doses. J Allergy Clin Immunol2001;108:10271032.

    • Search Google Scholar
    • Export Citation
  • 109.

    CarterMCRobynJABresslerPB. Omalizumab for the treatment of unprovoked anaphylaxis in patients with systemic mastocytosis. J Allergy Clin Immunol2007;119:15501551.

    • Search Google Scholar
    • Export Citation
  • 110.

    WarrierPCasaleTB. Omalizumab in idiopathic anaphylaxis. Ann Allergy Asthma Immunol2009;102:257258.

  • 111.

    RossiniMZanottiROrsoliniG. Prevalence, pathogenesis, and treatment options for mastocytosis-related osteoporosis. Osteoporos Int2016;27:24112421.

    • Search Google Scholar
    • Export Citation
  • 112.

    MarshallAKavanaghRTCrispAJ. The effect of pamidronate on lumbar spine bone density and pain in osteoporosis secondary to systemic mastocytosis. Br J Rheumatol1997;36:393396.

    • Search Google Scholar
    • Export Citation
  • 113.

    RossiniMZanottiRViapianaO. Zoledronic acid in osteoporosis secondary to mastocytosis. Am J Med2014;127:1127e11211124.

  • 114.

    LehmannTBeyelerCLammleB. Severe osteoporosis due to systemic mast cell disease: successful treatment with interferon alpha-2B. Br J Rheumatol1996;35:898900.

    • Search Google Scholar
    • Export Citation
  • 115.

    WeideREhlenzKLorenzW. Successful treatment of osteoporosis in systemic mastocytosis with interferon alpha-2b. Ann Hematol1996;72:4143.

    • Search Google Scholar
    • Export Citation
  • 116.

    LarocheMLivideanuCPaulCCantagrelA. Interferon alpha and pamidronate in osteoporosis with fracture secondary to mastocytosis. Am J Med2011;124:776778.

    • Search Google Scholar
    • Export Citation
  • 117.

    OrsoliniGGavioliITripiG. Denosumab for the treatment of mastocytosis-related osteoporosis: a case series. Calcif Tissue Int2017;100:595598.

    • Search Google Scholar
    • Export Citation
  • 118.

    KrugerAHamannCBrendelC. Multimodal therapy for vertebral involvement of systemic mastocytosis. Spine (Phila Pa 1976)2009;34:E626628.

    • Search Google Scholar
    • Export Citation
  • 119.

    GotlibJKluin-NelemansHCGeorgeTI. Efficacy and safety of midostaurin in advanced systemic mastocytosis. N Engl J Med2016;374:25302541.

    • Search Google Scholar
    • Export Citation
  • 120.

    ChandesrisMODamajGCanioniD. Midostaurin in advanced systemic mastocytosis. N Engl J Med2016;374:26052607.

  • 121.

    DeAngeloDJGeorgeTILinderA. Efficacy and safety of midostaurin in patients with advanced systemic mastocytosis: 10-year median follow-up of a phase II trial. Leukemia2018;32:470478.

    • Search Google Scholar
    • Export Citation
  • 122.

    JawharMSchwaabJNaumannN. Response and progression on midostaurin in advanced systemic mastocytosis: KIT D816V and other molecular markers. Blood2017;130:137145.

    • Search Google Scholar
    • Export Citation
  • 123.

    Kluin-NelemansHCOldhoffJMVan DoormaalJJ. Cladribine therapy for systemic mastocytosis. Blood2003;102:42704276.

  • 124.

    LimKHPardananiAButterfieldJH. Cytoreductive therapy in 108 adults with systemic mastocytosis: outcome analysis and response prediction during treatment with interferon-alpha, hydroxyurea, imatinib mesylate or 2-chlorodeoxyadenosine. Am J Hematol2009;84:790794.

    • Search Google Scholar
    • Export Citation
  • 125.

    BareteSLortholaryODamajG. Long-term efficacy and safety of cladribine (2-CdA) in adult patients with mastocytosis. Blood2015;126:10091016.

    • Search Google Scholar
    • Export Citation
  • 126.

    DelaporteEPierardEWolthersBG. Interferon-alpha in combination with corticosteroids improves systemic mast cell disease. Br J Dermatol1995;132:479482.

    • Search Google Scholar
    • Export Citation
  • 127.

    CasassusPCaillat-VigneronNMartinA. Treatment of adult systemic mastocytosis with interferon-alpha: results of a multicentre phase II trial on 20 patients. Br J Haematol2002;119:10901097.

    • Search Google Scholar
    • Export Citation
  • 128.

    HauswirthAWSimonitsch-KluppIUffmannM. Response to therapy with interferon alpha-2b and prednisolone in aggressive systemic mastocytosis: report of five cases and review of the literature. Leuk Res2004;28:249257.

    • Search Google Scholar
    • Export Citation
  • 129.

    SimonJLortholaryOCaillat-VigneronN. Interest of interferon alpha in systemic mastocytosis. The French experience and review of the literature. Pathol Biol (Paris)2004;52:294299.

    • Search Google Scholar
    • Export Citation
  • 130.

    FrostMJFerraoPTHughesTPAshmanLK. Juxtamembrane mutant V560GKit is more sensitive to imatinib (STI571) compared with wild-type c-kit whereas the kinase domain mutant D816VKit is resistant. Mol Cancer Ther2002;1:11151124.

    • Search Google Scholar
    • Export Citation
  • 131.

    AkinCBrockowKD'AmbrosioC. Effects of tyrosine kinase inhibitor STI571 on human mast cells bearing wild-type or mutated c-kit. Exp Hematol2003;31:686692.