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Sandra Kurtin, PhD, ANP-C, FAPO University of Arizona Cancer Center, Tucson, Arizona
Cem Akin, MD, PhD University of Michigan, Ann Arbor, Michigan
Tracey I. George, MD ARUP Laboratories, Salt Lake City, Utah University of Utah, Salt Lake City, Utah
Edward Pearson, MD Texas Oncology, Dallas, Texas
Introduction
The scope of practice for advanced practitioners (APs) in hematology and oncology varies widely across practice types, size of the organization, and regions. Many community-based APs see a broad range of diagnoses. In larger academic
centers, APs may be aligned with specific subspecialties within solid tumor or hematologic malignancy umbrellas. Unfortunately, classical hematology and rare diseases continue to be underserved across practice settings with
limited training for fellows and APs (Panwar et al., 2023; West et al., 2024).
Limited exposure to patients with rare diseases may deter effective differential diagnosis and clinical management of these diseases.
Recognizing the challenge most APs face in managing a broad range of diagnoses, the Advanced Practitioner Society for Hematology and Oncology (APSHO) convened an AP-led multidisciplinary
steering committee to evaluate the role of APs in the diagnosis, management, and support of patients living with systemic mastocytosis (SM) and their caregivers.
Systemic mastocytosis is a rare clonal mast cell neoplasm with heterogeneous presentation. It is characterized by chronic, debilitating, and at times life threatening (anaphylaxis) symptom burden. It is estimated
to occur in 1 per 10,000 to 20,000 individuals worldwide (Jennings et al., 2018). Most patients with SM see multiple providers across many subspecialties
and care sites, including urgent care and emergency services, and go undiagnosed for years with their disease (median 3 years, range 1–9 years; Jennings et al., 2018).
The Toolkit for SM represents the work of the steering committee that included a review of the literature and current guidelines for practice, and input from a multidisciplinary AP focus group and an APSHO member
forum. It is intended to provide APs and other health-care professionals with the tools to:
Recognize signs and symptoms that may indicate a possible diagnosis of SM
Order the appropriate tests to confirm the diagnosis of SM
Guide the AP in clinical management and support of patients living with SM.
This toolkit contains concise summaries of key elements for differential diagnosis and multidisciplinary management of SM as well as strategies for supporting patients and caregivers. The authors encourage readers to view the links
to online resources included throughout the toolkit.
Overview of Systemic Mastocytosis
Systemic mastocytosis is a clonal mast cell neoplasm associated with the uncontrolled proliferation and activation of abnormal mast cells throughout the body (Valent et al., 2023).
Mast cells are white blood cells that originate in the bone marrow and are subsequently localized in mucosal and epithelial tissues throughout the body such as the gastrointestinal tract, the lining of the airway, and the skin
(
Valent et al., 2023). Mast cell infiltration of organs can cause organ damage, which is a hallmark of advanced SM (Gotlib et al., 2024; Valent et al., 2024).
Mast cells are part of the immune system and involved in mounting allergic reactions. They are among the first cells to interact with environmental antigens, invading pathogens, or microorganisms. Antigens bind to immunoglobulin
E (IgE) on the surface of mast cells in response to antigens, activating mast cells (Figure 1). Activated mast cells release granules filled with mediators that produce the symptoms common in allergic reactions (Sapkota, 2022; Theoharides et al., 2015). Clinically relevant mediators, associated symptoms, and available treatments are described
later in this toolkit.
Figure 1. IgE Cross-linking Induces Mast Cell Activation and Degranulation
Image reproduced from Sapkota (2022).
Mast cells originate from CD34+/CD117+ pluripotent progenitor cells in the bone marrow (Kirschenbaum & Metcalfe, 2006). Maturation of these cells depends
on KIT activation. Most patients with SM (approximately 95%) harbor a driver mutation, KIT D816V (Valent et al., 2023). Additional gene
mutations may be present in some patients. Systemic mastocytosis is associated with a significant symptom burden largely due to mediators released when mast cells are activated (Figure 2).
Cutaneous manifestations in patients with mastocytosis (European Competence Network on Mastocytosis; the American Academy of Allergy,
Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology)
Differential Diagnosis, Staging, and Classification
Given the heterogenous nature of presenting signs and symptoms for SM, vigilance across multiple specialties is required to detect hallmark manifestations of SM. Although skin manifestations are required for the diagnosis of cutaneous
mastocytosis, not all patients with more advanced disease have dermatologic findings. Mast cells are present in most soft tissue, however, and when mutated may infiltrate organs causing tissue damage. Therefore, screening for
organ damage is a component of the diagnostic workup of SM and requires a multidisciplinary approach to diagnosis.
The diagnostic criteria for SM have been modified as understanding of driver mutations and the heterogeneity of the disease have evolved. The World Health Organization (WHO) 5th Edition (Khoury et al., 2022; Li et al., 2023; Valent et al., 2023) and
the International Consensus Classification (ICC) (Leguit et al., 2023; Wang et al., 2023)
are the two primary sources for characterization of systemic mastocytosis (Table 1). Harmonized diagnostic criteria have been developed to simplify the process for diagnosis globally where more advanced diagnostic tools may
not be readily available (Valent et al., 2024). Additional publications are included in the references section of the toolkit.
Table 1. WHO and ICC Diagnostic Criteria for Systemic Mastocytosis
WHO 5th Edition
1 major + 1 minor criteria OR ≥ 3 minor criteria
ICC
1 major criteria OR ≥ 3 minor criteria
Major Criterion
Multifocal dense aggregates of mast cells
≥ 15 mast cells/aggregate detected in bone marrow and/or extracutaneous organs
Minor Criterion
> 25% mast cells with atypical morphology
KIT D816V or other activating KIT mutation
CD2, CD25, and/or CD30 expression on mast cells
Serum total tryptase > 20 ng/mL
B Findings
(indicative of disease burden but not full organ damage)
WHO
≥ 30% mast cells on bone marrow biopsy and/or serum total tryptase ≥ 200 ng/mL and/or KIT D816V variant allele frequency ≥ 10%
Signs of myeloproliferation and/or myelodysplasia not fulfilling criteria for an associated hematologic neoplasm
Hepatomegaly without impaired liver function and/or palpable splenomegaly without hypersplenism and/or lymphadenopathy (palpation or imaging)
ICC
> 30% mast cells on bone marrow biopsy and serum total tryptase > 200 ng/mL
Cytopenia does not meet criteria for C findings or -cytosis. Reactive causes are excluded and criteria for myeloid neoplasms are not met.
Hepatomegaly without impaired liver function, palpable splenomegaly without hypersplenism and/or lymphadenopathy > 1 cm (palpation or imaging)
C Findings
(indicative of organ damage due to mast cell infiltration)
Bone marrow dysfunction caused by neoplastic mast cell infiltration, manifested by ≥ 1 cytopenia
Skeletal involvement, with large osteolytic lesions (if the size of the lesion is ≥ 2 cm, it is considered large) with or without pathologic fractures (pathologic fractures caused by osteoporosis do not qualify
as a C finding). Small osteolytic and/or sclerotic lesions do not define advanced SM.
Hepatopathy: Ascites and elevated liver enzymes +/- hepatomegaly or cirrhotic liver +/- portal hypertension
Malabsorption with hypoalbuminemia +/- weight loss due to gastrointestinal mast cell infiltrates
Note. WHO = World Health Organization; ICC = International Consensus Classification; ANC = absolute neutrophil count; Hbg = hemoglobin. Information from Gotlib et al. (2024); Khoury et al. (2022); Valent et
al. (2024); Wang et al. (2023).
Diagnostic criteria are categorized as major (hallmark findings) or minor (associated findings). Although serum tryptase levels are included in the diagnostic criteria, it is recommended that basal serum tryptase levels be collected
during a symptom-free interval and be corrected for any patients with concurrent hereditary α-tryptasemia (HαT; Valent et al, 2021). A serum tryptase level < 20 ng/mL does not exclude a diagnosis of SM. High-sensitivity testing for the KIT D816V mutation is recommended for patients with other findings
suspicious for SM (Valent et al., 2021). In addition, B (burden of disease) and
C (cytoreductive requiring) findings are added to further stratify disease categories based on the extent of organ involvement and favorable vs. unfavorable prognostic variables. B findings suggest more extensive mast cell
involvement or tumor burden (Valent et al., 2021). C findings imply organ damage caused by mast cells and are associated with more advanced forms of
SM (Valent et al., 2021). Patients meeting criteria for cutaneous mastocytosis (CM), although they may have extensive skin involvement, are not considered
to have SM.
The algorithm for classifying the subtype of SM requires comprehensive assessment and diagnostic testing to fully characterize the disease (Figure 3; Table 2). In addition to classification, risk stratification has evolved with
categorization of SM into either non-advanced or advanced and favorable and unfavorable risk factors (Tables 3 and 4).
Figure 3. Algorithm for the Diagnosis of Subtypes of Systemic Mastocytosis (Interactive)
Yes → systemic mastocytosis with associated hematologic neoplasm
Yes → mast cell leukemia
Yes → advanced systemic mastocytosis
Yes → smoldering systemic mastocytosis
No → indolent systemic mastocytosis/bone marrow mastocytosis
Adapted from Pardanani (2019).
Table 2. Classification/Subtypes of Systemic Mastocytosis
All subtypes must meet criteria for SM and are subdivided by additional findings
Systemic mastocytosis with associated hematologic neoplasm (SM-AHN)
Meets the criteria for an AHN
Classified as a distinct entity by WHO
Mast cell leukemia (MCL)
≥ 20% mast cells in bone marrow. In classic cases, mast cells account for ≥ 10% of the peripheral WBCs.
Mast cell variants include: Acute MCL (≥ 1 C finding[s]) vs. chronic MCL (no C findings); MCL with an AHN vs. MCL without an AHN; primary (de novo) vs. secondary MCL (arising from another SM variant)
Skin lesions are usually absent.
Aggressive systemic mastocytosis (ASM)
≥ 1 C finding
Does not meet the criteria for MCL
Skin lesions are usually absent
Smoldering systemic mastocytosis (SSM)
≥ 2 B findings
No C findings
No evidence of an AHN
High mast cell burden
Does not meet the criteria for MCL
Indolent systemic mastocytosis (ISM)
No C findings
No evidence of an AHN
Low mast cell burden
Skin lesions are frequently present
Bone marrow mastocytosis (BMM)
Same as for ISM but with bone marrow involvement only and no skin lesions
Note. AHN = associated hematologic neoplasm; WBC = white blood cells. Information from Gotlib et al. (2024).
Table 3. Adverse Prognostic Variables
Demographic variables
Male gender
Clinical/laboratory variables
WHO subclassification of SM
Advanced age, history of weight loss, anemia, thrombocytopenia, hypoalbuminemia, and excess bone marrow blasts (> 5%)
Eosinophilia
Splenomegaly
Increased alkaline phosphatase
Cytogenetic/molecular variable
Poor-risk karyotype (monosomy 7 or complex karyotype)
Multilineage involvement of KIT D816V mutation
Number of non-KIT D816V mutations
KIT D816V VAF > 10%
SRSF2/ASXL1/RUNX1 (S/A/R), and/or EZH2 or ASXL1/CBL mutation profile
Note. WHO = World Health Organization; VAF = variant allele frequency. Information from Valent et al. (2021)
Table 4. Non-Advanced vs. Advanced Systemic Mastocytosis
Classification
Life expectancy
Goals of care
Approach to therapy
Non-Advanced SM
Bone marrow mastocytosis, smoldering systemic mastocytosis, and indolent systemic mastocytosis
Normal or near normal
Reduce mediator symptoms and improve QOL
Mediator inhibitors, KIT D816V–directed therapies
Advanced SM
Aggresive systemic mastocytosis, mast cell leukemia, and systemic mastocytosis with associated hematologic neoplasm
< 6 months to ~4 years
Reverse organ damage, improve QOL, and extend survival/cure
Note. QOL = quality of life. Information from Gotlib et al. (2024).
Due to its heterogeneous and nonspecific symptoms, SM is often mistaken for other disorders (Table 5). Multiple medical specialties may be involved in the diagnostic workup (Table 6). Patients living with rare diseases see an average
of 7.3 providers across multiple specialties before receiving an accurate diagnosis. Receiving an accurate diagnosis of ISM can take on average 3 to 6 years from symptom onset (median 3 years, range 1-9 years; Jennings et al., 2018).
Patients living with rare diseases see an average of 7.3 providers across multiple specialties before receiving an accurate diagnosis.
Table 5. Conditions That Mimic Mast Cell Disorders
Cardiac conditions
Coronary hypersensitivity (the Kounis syndrome)a
Postural orthostatic tachycardia syndrome
Endocrine conditions
Fibromyalgia
Parathyroid tumor
Pheochromocytoma
Carcinoid syndrome
Digestive conditions
Adverse reaction to fooda
Eosinophilic esophagitisa
Eosinophilic gastroenteritisa
Gastroesophageal reflux disease
Gluten enteropathy
Irritable bowel syndrome
Vasoactive intestinal peptide–secreting tumor
Immunologic conditions
Autoinflammatory disorders such as deficiency of interleukin-1–receptor antagonista
Familial hyper-IgE syndrome
Vasculitisa
Neurologic and psychiatric conditions
Anxiety
Chronic fatigue syndrome
Depression
Headaches
Mixed organic brain syndrome
Somatization disorder
Autonomic dysfunction
Multiple sclerosis
Skin conditions
Angioedemaa
Atopic dermatitisa
Chronic urticariaa
Sclerodermaa
Note. Information from Theoharides et al. (2015).aLocalized mast cell activation can occur.
Table 6. Multidisciplinary Diagnosis of Systemic Mastocytosis
Allergy and Immunology
General approach to diagnosis
History, including symptom assessment and trigger analysis
Symptom presentation drives testing. SM patients frequently present with flushing, tachycardia, and low blood pressure
Focused physical exam including skin exam
Referral to hematology/oncology for further testing
Procedures/laboratory and pathology testing
Referral for procedures based on evaluation and testing
Serum tryptase level (level > 8 ng/mL should trigger testing for KIT D816V if patient has other findings). Elevated tryptase level alone is not enough to make a diagnosis and does not always indicate
a mast cell disease.
KIT D816V testing: Consider with anaphylaxis and venom reactions
Consider testing for hereditary alpha tryptasemia in the setting of tryptase levels >20 ng/mL.
Dermatology
General approach to diagnosis
History including symptom assessment and trigger analysis
Physical exam and review of symptoms including full body skin exam
Referral to other specialties including mast cell disease specialist or hematology/oncology for further workup for possible SM
Procedures/laboratory and pathology testing
Biopsy for suspicious lesions in adults
H&E stain and CD117 staining
High-sensitivity qPCR for KIT D816V mutation analysis may be obtained on fresh tissue sample if indicated in adults
Gastroenterology
General approach to diagnosis
History including symptom assessment and trigger analysis
Physical exam and review of symptoms
Workup for IBS-like symptoms
Co-management of GI symptoms
Referral to mast cell disease specialist or hematology/oncology for further workup for possible SM
Procedures/laboratory and pathology testing
Endoscopy/colonoscopy with biopsy (can sometimes be the first finding)
Note: In GI biopsies, tryptase staining can be dim to negative in SM. It is helpful to get a panel of stains with CD117, tryptase, and if mast cells are increased, then CD25. The pattern of bright CD117, dim/negative
tryptase is helpful in separating neoplastic mast cells from normal mast cells. CD2 is not indicated in staining GI samples for SM workup as can be confused with T lymphocytes
Morphology: H&E stain
High-sensitivity qPCR for KIT D816V mutation analysis may be obtained on fresh tissue sample if indicated
Hematology/Oncology
General approach to diagnosis
History including symptom assessment including trigger analysis
Prior history of mast cell activation symptoms; history of anaphylaxis; chronic diarrhea, weight loss, rashes, osteopenia, or osteoporosis
Examination for mast cell infiltration; skin, spleen, and liver size by palpation
Contacting the hematopathologist prior to collecting or submitting samples is recommended
to ensure appropriate samples are sent and correct tests are ordered.
Peripheral blood
Complete blood count (CBC) with differential
Hematopathology examination of blood smear (e.g., monocytosis, eosinophilia, dysplasia)
Comprehensive metabolic panel with uric acid, lactate dehydrogenase (LDH), and liver function tests (including AST, ALT, and ALP)
Serum tryptase level
KIT D816V (VAF) using high-sensitivity testing
Bone marrow biopsy and aspirate
Hematopathology: Immunohistochemistry to confirm mast cell %
Flow cytometry: CD34, CD117, CD25, CD30, CD2
IHC: CD117, CD25, CD30, tryptase
Metaphase cytogenetics
Critical for smoldering or advanced SM and AHN-related abnormalities.
FISH as needed for AHN
Molecular testing for KIT D816V using an assay with high sensitivity (~0.01% VAF):
If negative for KIT D816V mutation and eosinophilia is present, then hematopathologist flex to screen for FIP1L1-PDGFRA gene fusion
Multigene NGS panel that includes genes such as SRSF2, ASXL1, and RUNX1
Hepatology
General approach to diagnosis
History includes symptom assessment and risk factors for hepatic disease
Physical exam including evaluation of hepatosplenomegaly
Procedures/laboratory and pathology testing
Liver biopsy: may refer to interventional radiology of hepatic surgery
CT/MRI of the liver
IHC (CD117, CD25, tryptase, and CD3 as a control T-cell marker)
General testing for B or C findings
CT/MRI or ultrasound of the abdomen/pelvis to evaluate organomegaly
DEXA scan to evaluate osteopenia/osteoporosis
Metastatic skeletal survey to evaluate osteolytic, osteosclerotic lesions
Organ-directed biopsy IHC (CD117, CD25, tryptase, and CD3 as a control T-cell marker)
Note. CBC = complete blood count; H&E = hematoxylin and eosin; IHC = immunohistochemistry; qPCR = quantitative polymerase chain reaction; ddPCR = digital droplet polymerase chain reaction; ASO-qPCR = allele-specific
oligonucleotide quantitative reverse transcriptase polymerase chain reaction; FISH = fluorescence in situ hybridization; NGS = next-generation sequencing; VAF = variant allele frequency; GI = gastrointestinal; SM
= systemic mastocytosis; IBS = irritable bowel syndrome; ALT = alanine aminotransferase; AST = aspartate aminotransferase; ALP = alkaline phosphatase; LDH = lactate dehydrogenase; AHN = associated hematologic neoplasm;
DEXA = dual x-ray absorptiometry. Information from Hartmann et al. (2016); Li et al. (2023); Ungerstedt et al. (2022); Valent et al. (2021, 2023).
Careful attention to triggers for mast cell–driven symptoms is essential to helping the patient manage their disease
Symptom burden is the leading driver for patients to seek medical care (Figure 4). Patients with moderate-to-severe indolent systemic mastocytosis (ISM) report more skin, gastrointestinal, neurocognitive, fatigue, and pain signs
and symptoms compared with patients with mild ISM (Zeiger et al., 2025). Careful attention to triggers for mast cell–driven symptoms is essential
to helping the patient manage their disease (Table 7). Understanding the role of mediators in driving various symptoms will guide prevention and treatment strategies. Systemic mastocytosis should be considered in the differential
diagnosis of patients experiencing severe symptoms such as recurrent anaphylaxis or an osteoporotic fracture. Familiarity with the diagnostic criteria and common or rare presenting signs and symptoms of SM will assist the AP
in the differential diagnosis, ordering of appropriate tests, and referrals to other specialties.
Figure 4. Patients With ISM Can Have Severe and Unpredictable Symptoms
Organopathy due to mast cell infiltration can also occur, causing lymphadenopathy, splenomegaly/hypersplenism, hepatomegaly/ascites, cytopenias, malabsorption, or protein-losing enteropathy with weight loss5,6
Information from Theoharides et al. (2015); Gilreath et al. (2019); Jennings et al. (2018); Amin (2012); Gulen et al. (2015); Mickys et al. (2007). PAF = platelet-activating factor.
Table 7. Trigger Analysis for Mast Cell Activation
General characteristics of triggers
Variable for each patient (heterogenous)
May change over time
Interviewing patients to elicit triggers and strategies to manage them is a critical component of the diagnosis and management
of SM
Common triggers
Heat, cold, or sudden temperature changes
Sun/sunlight
Natural and chemical odors
Food or beverages, including alcohol
Insect stings
Venoms (e.g., hymenoptera, spiders, fire ants, jellyfish, snakes)
Infections (viral, bacterial, or fungal)
Stress: emotional; physical, including pain; or environmental (e.g., weather changes, pollution, pollen, pet dander)
Lack of sleep/sleep deprivation
Exercise
Drugs (e.g., opioids, nonsteroidal anti-inflammatory drugs, some antibiotics [e.g., vancomycin, quinolones, some local/general anesthetics]) and contrast dyes
Vaccines
Mechanical irritation, friction, or vibration
Surgery
Procedures (e.g., endoscopy, colonoscopy)
Measuring SM Symptom Burden
Strategies to elicit patient perceptions of the severity and frequency of SM symptoms are at the core of preventing and treating those symptoms. Consistent approaches over time will facilitate patient involvement in the process.It
is also important to take into account that patient perceptions of well-controlled vs. poorly controlled symptoms is subjective and may be skewed by the longevity of the symptom burden common to patients with SM. Setting expectations
for the patient and their caregivers between visits will encourage improved tracking of symptoms.
Using a validated tool may improve the consistent measurement of SM-related symptoms over time and better characterize improvement with treatment or progression symptoms when the disease is not well-controlled. There are several
online resources to assist with measuring SM-related symptoms (Table 8). Importantly, it is critical to consider symptoms that may be related to comorbidities or to treatments for SM. Newer tools are under investigation to
facilitate measures of symptom burden.
Table 8. Tools for Measuring Systemic Mastocytosis–Related Symptoms
The ISM Symptom Assessment Form (Table 9) and Advanced SM (AdvSM) Symptom Assessment Form were developed to measure relevant and important symptoms of ISM and AdvSM from the patient perspective. Designed with input from disease
experts, patients and regulatory authorities, it was used in clinical trials to measure symptom improvement over time, as the primary endpoint for most SM clinical trials is > 30% reduction in symptom burden/severity (
Akin et al., n.d).
Table 9. Indolent Systemic Mastocytosis Symptom Assessment Form
Score
Scored 0–10 daily (24-hour recall) on a handheld device
0 is no symptoms and 10 is worst imaginable
Total Symptom Score (0–110)
Domain
GI (0-30)
Symptoms
Abdominal pain
Diarrhea
Nausea
Domain
Skin (0–30)
Symptoms
Spots
Itching
Flushing
Domain
Neurocognitive (0–30)
Symptoms
Brain fog
Headache
Dizziness
Domain
Other (0–30)
Symptoms
Bone pain
Fatigue
Note. Information from Padilla et al. (2021); Shields et al. (2023); Taylor et al. (2021).
Multidisciplinary Management of SM
The prevention and effective treatment of SM requires a multidisciplinary approach (Figure 5). Coordinating care among the members of the multidisciplinary team can be an arduous task, often landing with the patient and their caregiver.
Communication via the electronic health record, phone, fax, or other messaging applications will build a consistent understanding of the patient’s disease, symptom burden, and effectiveness of interventions. Encouraging
the patient and their caregiver team to engage via the patient portal or other disease-specific advocacy organization will provide additional resources for tracking and reporting symptoms and response to treatment.
Figure 5. A Multispecialty Approach is Needed to Manage Systemic Mastocytosis
Hematology/oncology
Allergy/immunology
Dermatology
Gastroenterology
Primary care, internal medicine, family medicine
Psychiatry, social work, mental health specialty
Pathology
Other specialties as needed:
Anesthesiology and dentistry
Emergency medicine
Endocrinology
Neurology
Obstetrics/gynecology
Adapted from Ungerstedt et al. (2022).
General Principles of Treatment for Systemic Mastocytosis
The primary goals of treatment for SM are to reduce symptom burden, improve quality of life, and prolong life (Table 10). The heterogeneity of the disease requires an approach to treatment tailored to the individual patient’s
disease and symptom profile.
Table 10. General Strategies for the Management of Systemic Mastocytosis
Educate patients to avoid triggers and be prepared for potential reactions
Engage patients and caregivers to track triggers and the severity of reactions
Agents to be avoided include the muscle relaxants atracurium and mivacurium (rocuronium and vecuronium may be safer) and succinylcholine. While caution should be exercised with opioids (e.g., codeine
or morphine), it is important, however, that analgesics are not withheld from patients with SM since pain can be a trigger for mast cell activation.
Consider venom therapy for select patients with hymenoptera venom allergies.
Patients should carry two epinephrine auto-injectors. It is recommended to use an H1 blocker 1 hour before receiving a vaccine. Following vaccination, patients should be observed for 60 minutes.
Patients of childbearing age should be counseled on the risks of certain treatments during pregnancy and unknown risks of certain triggers associated with SM during pregnancy. Patients who become pregnant
should be followed by high-risk obstetrics, allergy/immunology, and other subspecialties as indicated concurrently.
Educate patients on using moisturizers regularly and minimizing friction to prevent irritation
Pill case for patient/online medication management tools for patients
Treat for osteoporosis and disease-related bone pain
Supplemental calcium and vitamin D
Bisphosphonates (with continued use of antihistamines)
Peginterferon alfa-2a
Anti-RANKL monoclonal antibody (e.g., denosumab)
Vertebroplasty/kyphoplasty for refractory pain associated with vertebral compression fractures in selected patients
Symptom reduction is aimed at mediating mast cell mediators. Emerging targeted therapies may alter the natural history of the disease by directly targeting the KIT D816V mutation, a known driver of systemic mastocytosis
(Table 11; Gotlib et al., 2024; Li et al., 2023; Valent et al., 2021).
Table 11. FDA-Approved Cytoreductive Therapy for Systemic Mastocytosis
Avapritinib (Ayvakit)
Class
Selective inhibitor of KIT D816V
FDA-approved indication
Adv-SM: The treatment of adult patients with AdvSM. AdvSM includes patients with ASM, SM-AHN, and MCL. Avapritinib is not recommended for the treatment of patients
with AdvSM with platelet counts less than 50 x 109/L.
ISM: The treatment of adult patients with ISM. Avapritinib is not recommended for the treatment of patients with ISM with platelet counts of less than 50 x 109/L.
Dosing
AdvSM: The recommended dosage is 200 mg orally once daily.
ISM: The recommended dosage is 25 mg orally once daily.
Patients with severe hepatic impairment (Child-Pugh Class C): reduce dose.
Most common AEs
AdvSM (≥ 20% incidence): edema, diarrhea, nausea, and fatigue/asthenia.
ISM (≥ 10% incidence): eye edema, dizziness, peripheral edema, and flushing.
Midostaurin (Rydapt)
Class
Multikinase inhibitor with activity against D816V-mutated KIT
FDA-approved indication
ASM, SM-AHN, or MCL
Dosing
ASM, SM-AHN, and MCL: The recommended dosage is 25 mg orally once daily.
100 mg orally twice daily with food.
Most common AEs
The most common adverse reactions (≥ 20%) were nausea, vomiting, diarrhea, edema, musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, constipation, pyrexia, headache, and
dyspnea.
Cladribine (2-chlorodeoxyadenosine; Leustatin)
Class
Purine analog
FDA-approved indication
Not FDA approved but is used on an off-label basis because of its activity across all subtypes of SM, including MCL refractory to prior cytoreductive therapy.
Cladribine may be particularly useful for patients with advanced SM when rapid debulking of disease is required.
Peginterferon alfa-2a (Pegasys) With or Without Prednisone
Class
Biological response modifier
Interferon
Not FDA approved. Interferon alfa (with or without prednisone) carries the potential to induce a 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 across all subtypes of SM.
Imatinib (Gleevec)
Class
Tyrosine kinase inhibitor
FDA-approved indication
FDA-approved for the treatment of adult patients with ASM without the KIT D816V mutation or with unknown KIT mutational status. Very effective in the treatment of patients with eosinophilia-associated
myeloid neoplasms characterized by the FIP1L1-PDGFRA gene fusion.
Note. AdvSM = advanced systemic mastocytosis; AE = adverse event; ASM = aggressive systemic mastocytosis; SM-AHN = systemic mastocytosis with an associated hematologic neoplasm; MCL = mast cell leukemia;
ISM = indolent systemic mastocytosis; FDA = US Food and Drug Administration. Information from Gotlib et al. (2022, 2023, 2024).
Clinical trials should always be considered for patients who require active treatment of their disease (Table 12). All FDA-approved therapies are available because patients participated in clinical trials. Clinical trials offer
treatment options that may not otherwise be available to the patient. Referral to specialty centers may be required. The treatment landscape is rapidly changing. Regularly checking updates to the National Comprehensive Cancer
Network (NCCN) Guidelines, ClinicalTrials.gov, publications, and continuing education activities is recommended.
Table 12. Investigational Agents and Clinical Trials
Evaluation of the DALY on a Cohort of Patients with Indolent Systemic Mastocytosis
Status
Recruiting
Condition
Indolent systemic mastocytosis
Note. SM-AHN = systemic mastocytosis with an associated hematologic neoplasm; SSM = smoldering systemic mastocytosis; SM = systemic mastocytosis; ISM = indolent systemic mastocytosis; BMM = bone marrow
mastocytosis. Information from clinicaltrials.gov. Last updated 2/17/2025.
All patients with SM should carry an epinephrine auto-injector.
Mast cells typically proliferate in certain areas of the body, including the upper and lower respiratory tract, the skin, and the gastrointestinal tract. These are the systems with the greatest symptom burden (Table 13). Most patients
will require medications from multiple classes to achieve optimal control (Table 14). The mix of drugs may vary from day to day or over time based on triggers and resulting symptoms.
Regular medication reconciliation is essential to avoid drug-drug interactions. Second-generation antihistamines are preferred over first-generation antihistamines due to the lower potential for sedation. All patients with SM should
carry an epinephrine auto-injector.
Table 13. Medications Used to Manage Mast Cell Mediator–Related Symptoms by Organ System
Note. Information from Gotlib et al. (2024); Li et al. (2023); Theoharides et al. (2015).
Strategies for Improving Quality of Life and Health Self-Management
Living with a rare cancer demands every ounce of courage and unrelenting self-advocacy an individual can muster. The unpredictable and at times life-threatening constellation of symptoms characteristic of SM, the difficulty in
reaching a diagnosis, limited treatment options, and a paucity of clinical expertise create additional challenges for patients and caregivers.
Patients take an average of 3 to 11 OTC medications and as many as 5 prescription medications to manage their SM.
Systemic mastocytosis is a lifelong disease for most patients. Although there has been progress in understanding the pathobiology of SM and drivers of symptoms associated with SM, most patients continue to report a significant
symptom burden that interferes with their quality of life despite taking multiple symptom-directed therapies (Table 15; Jennings et al., 2018). Patients describe a sense of not being heard and not being seen. They focus on
minimizing the impact of symptoms to achieve a level of symptom control that reduces the disruption of daily activities (Jennings et al., 2018). Patients
take an average of 3 to 11 OTC medications and as many as 5 prescription medications to manage their SM (Pulfer et al., 2021). Over-the-counter medications
are not covered by insurance, adding to the cost of managing symptoms.
Table 15. Factors Reported to Interfere With Daily Activities and Quality Of Life
Unpredictability of the disease (e.g., anaphylaxis and allergic reactions, fear or anxiety, effect on mental health)
Stigma around symptoms
Social isolation
Brain fog
Flushing, diarrhea, fatigue, and fear of anaphylaxis were reported to be among the most frequent causes of impairment to quality of life
A third of patients experience anxiety, and about 10% to 15% report being depressed or express low satisfaction with life
Impairment of health-related quality of life is more common in:
Impairment of health-related quality of life is more common in:
Patients with ISM report that the disease and its symptoms affect both their personal and work lives (Jennings et al., 2018). Living with SM is associated
with substantial financial burden. Up to 52% of patients with SM report disability related to performance status. Up to 30% of patients are not able to work because of their symptoms. Most patients are at their peak employment
age (53 years and younger; Jennings et al., 2018).
Deploying a multidisciplinary approach to the care of patients with SM, including referrals to support groups, social work, financial counselors, and advocacy organizations, provides the patient and their caregivers with the tools
to engage in self-management and self-advocacy. Adding patient-reported outcomes to clinical trials brings the patient voice to the lived experience of SM. Quality of life is frequently impaired in patients with SM and should
be assessed in all patients by using validated disease-specific tools (e.g., Mastocytosis Quality of Life Questionnaire [MC-QoL], mastocytosis quality-of-life questionnaire [MQLQ], or Quality of Life in Mastocytosis Scale [QLMS]).
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