Answering the Call in Nonadvanced Systemic Mastocytosis

Learning Objectives • Describe key pathophysiologic processes in systemic mastocytosis, with a focus on potential clinical manifestations and the rationale for new targeted therapies • Evaluate patients with suspected nonadvanced systemic mastocytosis to characterize symptoms, disease burden, and results from appropriate ancillary testing • Discuss clinical trial evidence and appropriate use of targeted treatment options for nonadvanced systemic mastocytosis • Individualize treatment regimens for nonadvanced systemic mastocytosis to reflect clinical evidence for efficacy and safety, patient-reported outcomes, and shared clinical decision-making

PATHOPHYSIOLOGIC PROCESSES IN NONADVANCED SYSTEMIC MASTOCYTOSIS Matthew Giannetti, MD

SM Is a Rare Clonal MC Disorder • Systemic mastocytosis (SM) is characterized by the abnormal expansion and accumulation of MCs in 1 or more organ systems1 • SM affects approximately 1 in 10,000 people1 Nonadvanced SM (~88%-95%)2-4 • Bone marrow mastocytosis (BMM) • Indolent SM (ISM; 88% of cases)3 • Smoldering SM (SSM)

Advanced SM (~5%-12%)2-4 • SM with associated hematologic neoplasm (SM-AHN) • Aggressive SM (ASM) • Mast cell leukemia (MCL)

• No apparent gender or ethnic bias • Average 6- to 9-year diagnostic delay from symptom onset to diagnosis MC, mast cell.

1. Brockow K. Immunol Allergy Clin North Am. 2014;34(2):283-295; 2. Cohen SS, et al. Br J Haematol. 2014;166(4):521-528; 3. Ungerstedt J, et al. Cancers (Basel). 2022;14(16):3942.

Exploring KIT Mutations in SM Normal signaling

Normal KIT

MCs

KIT with D816V SCF

Outside cell

Ras-ERK JAK/STAT PI3K-mTOR

Inside cell

Abnormal signaling KITD 816V causes constitutive activation of the KIT receptor and downstream signaling

Infiltration of multiple organ systems

SCF binds KIT and activates signaling pathways that control MC differentiation, maturation, migration, proliferation, survival, and cytokine production.

~95% of patients with nonadvanced SM have a KIT D816V mutation.

Ras-ERK, Ras-extracellular signal-regulated kinase; JAK-STAT, Janus kinase-signal transducer and activator of transcription; PI3K-mTOR, phosphatidylinositol 3-kinase-mammalian target of rapamycin; SCR, stem cell factor.

Adapted from Gilreath JA, et al. Clin Pharmacol. 2019;11:77-92; Dr. Tracy George, MD, personal communication.

MC Mediators

Environmental stimuli

Preformed mediators (found in granules): Histamine Tryptase Heparin MC activation MRGPRX2

Lipid mediators (synthesized from arachidonic acid): Leukotrienes Prostaglandins Chemokines/cytokines: IL-4, IL-6, TNF, etc

FcεR1, high-affinity IgE receptor 1; GPCR, G protein-coupled receptor; IgE, immunoglobulin E; IL, interleukin; MRGPRX2, mas-related G protein-coupled receptor X2; TNF, tumor necrosis factor.

Giannetti MP. Ann Allergy Asthma Immunol. 2021;127(4):412-419.

IgE FcεRI GPCR

Known Triggers for MC Activation Events Triggers

Examples

Venoms

Bee, wasp, mixed vespids, fire ants

Food Drugs Infection Temperature Stress Environment

Spicy foods, alcohol Opioids, NSAIDs, some antibiotics (eg, vancomycin), some local anesthetics, contrast dyes Viral, bacterial, or fungal Heat, cold, sudden changes in temperature Emotional, physical, pain Weather changes, pollution, natural and chemical odors, perfumes, chemicals, sun/sunlight

Allergens Fatigue Physical triggers Vaccinations Surgery Procedures

Pollen, pet dander, dust mites Lack of sleep/sleep deprivation Mechanical irritation, friction, vibration, exercise Anesthesia Colonoscopy, endoscopy, interventional radiology

NSAID, nonsteroidal anti-inflammatory drug.

Adapted from National Comprehensive Cancer Network (NCCN®) Guidelines. https://www.nccn.org/professionals/physician_gls/pdf/mastocytosis.pdf.

BEST PRACTICES IN SM DIAGNOSIS Matthew Giannetti, MD

Clinical Consequences of MC Mediator Release Cardiovascular • Hypotension • Syncope or near syncope

• Lightheadedness • Tachycardia

• Urticaria • Angioedema

CRH, histamine, IL-6, IL-8, IL-33, PAF, PGD2, TNF, tryptase Histamine, IL-6, CysLTs, PAF, PGD2

Respiratory • Nasal congestion • Nasal pruritus • Shortness of • Throat swelling breath • Wheezing

Neurologic

Allergens, bacteria, cytokines, drugs, fungi, peptides, toxins, viruses CRH, chymase, histamine, IL-6, PAF, renin, TNF, tryptase

Cutaneous • Flushing • Pruritus

MC Activators

CRH, histamine, IL-6, neurotensin, PAF, PGD2, TNF

MCs

IL-6, PGD2, RANKL, TNF, tryptase

CRH, histamine, IL-6, TNF CRH, histamine, IL-6, neurotensin, PAF, PGD2, serotonin, TNF, tryptase, VIP

Digestive • Abdominal cramps • Diarrhea

• Esophageal reflux • Nausea and vomiting

• Anxiety • Decreased concentration and memory

• Depression • Insomnia • Migraines

Musculoskeletal • Aches • Osteopenia • Bone pain • Osteoporosis • Pathologic fractures

Systemic • Fatigue • Weight loss

• Generalized malaise

CRH, corticotropin-releasing hormone; CysLT, cysteinyl leukotriene; PAF, platelet-activating factor; PGD2, prostaglandin D2, RANKL, receptor activator of nuclear factor-κB ligand; VIP, vasoactive intestinal peptide.

Theoharides TC, et al. N Engl J Med. 2015;373(2):163-172.

SM Testing Standard of Care • CBC/Diff • Serum tryptase • CMP

• High-sensitivity mutation analysis (ddPCR, ASO-qPCR) or qPCR for KIT D816V • Optional: • Myeloid gene panel (NGS) • HαT

• Blood smear • BM aspirate smear • BM biopsy

Laboratory

Morphology

Genetics

Phenotype

• Flow cytometry (CD2, CD25, CD34, CD117, CD30 [optional]) • Immunohistochemistry (tryptase, CD25, CD117, CD30 [optional])

ASO-qPCR, allele-specific oligonucleotide-quantitative PCR; BM, bone marrow; CBC/Diff, complete blood count with differential; CMP, comprehensive metabolic panel; ddPCR, droplet digital PCR; FISH, fluorescence in situ hybridization; NGS, next-generation sequencing; PCR, polymerase chain reaction; qPCR, quantitative PCR. Adapted from NCCN Guidelines®. https://www.nccn.org/professionals/physician_gls/pdf/mastocytosis.pdf.

Benefits of High-Sensitivity Assays • Sensitivity and specificity affect detection of KIT D816V1,2 – NGS and Sanger sequencing lacked sensitivity compared with highsensitivity PCR – International Consensus Classification of Myeloid Neoplasms and Acute Leukemias revised SM criteria recommend high-sensitivity PCR testing to avoid false-negative results – qPCR methods should be assessed in PB and BM samples if initial measurement is negative and there is a high test probability of disease

• ddPCR detected KIT D816V mutations in 95% of PB samples vs 28% by NGS vs 80% by local detection3 PB, peripheral blood.

1. Boggs NA, et al. Blood Adv. 2023;7(13):3150-3154; 2. Arber DA, et al. Blood. 2022;140(11):1200-1228; 3. George T, et al. Blood. 2020;136(suppl 1):7-8.

Decision to Perform BM Biopsy in an Adult With Suspected SM YES

Does the patient have skin lesions consistent with MPCM/UP?

Perform • Serum tryptase • CBC/Diff • High-sensitivity assay for KIT D816V mutational analysis on PB (if available)

NO

Does the patient experience presyncope, syncope, signs of recurrent mediatorrelated symptoms, anaphylaxis, unexplained osteoporosis?

YES NO

NO YES

Is tryptase >20 ng/mL?

Perform BM biopsy Perform high-sensitivity assay for KIT D816V mutational analysis on PB (if available) Mutation not detected or not available BM biopsy may be needed in the future; continue to monitor patient MPCM/UP, maculopapular cutaneous mastocytosis/urticaria pigmentosa.

Figure adapted from Zanotti R, et al. J Clin Med. 2021;10(7):1420.

Mutation detected Perform BM biopsy

SM not likely

Differential Diagnoses • HαT – Due to extra-allelic copies of α tryptase at the TPSAB1 locus, which increases basal serum tryptase levels (>8 ng/mL)1,2 – Symptoms consistent with MC activation3 – KIT D816V–negative, no evidence of MC aggregates or markers of MC activation in BM biopsy3 – Patients often do not have elevated MC urinary metabolites as seen with SM3

• MMAS4 – KIT D816V present – Symptoms consistent with MC activation and evidence of clonal population aLocalized MC activation can occur.

• Other conditions to consider5-7 – Cardiovascular: coronary hypersensitivity,a labile hypertension, orthostatic hypotension, paroxysmal arrhythmias – Digestive: adverse food reaction,a celiac disease, gastroesophageal reflux disease, gluten enteropathy, IBS – Endocrinological: fibromyalgia, carcinoid syndrome, insulinoma, parathyroid/thyroid carcinoma, pheochromocytoma, thyrotoxicosis – Immunological: autoinflammatory disorders,a familial hyper-IgE syndrome, vasculitisa – Neurological: anxiety, chronic fatigue syndrome, depression, headaches/migraines, hyperventilation, multiple sclerosis, panic attacks, postural orthostatic tachycardia syndrome, seizure disorder, somatization disorder, stroke – Skina: angioedema, atopic dermatitis, chronic urticaria, scleroderma

HαT, hereditary α tryptasemia; IBS, irritable bowel syndrome; MMAS, monoclonal mast cell activation syndrome.

1. Lyons JJ, et al. Nat Genet. 2016;48(12):1564-1569; 2. Lyons JJ. Immunol Allergy Clin North Am. 2018;38(3):483-495; 3. Giannetti MP, et al. J Allergy Clin Immunol. 2022;150(5):12251227; 4. Picard M, et al. Clin Ther. 2013;35(5):548-562; 5. Scherber RM, Borate U. Br J Haematol. 2018;180(1):11-23; 6. Theoharides TC, et al. N Engl J Med. 2015;373(2):163-172; 7. Castells M, Butterfield J. J Allergy Clin Immunol Pract. 2019;7(4):1097-1106.

Minor Criteria

Multifocal infiltrates of MC (≥15 MC/aggregate) in BM biopsy and/or ECO)

Serum tryptase level >20 ng/mL (in the case of known HαT, tryptase levels should be adjusted)

KIT D816V point mutation (or any other mutation causing ligandindependent activation of KIT)

Diagnosis

Major Criterion

WHO Diagnostic Criteria for SM 1 major criterion + 1 minor criterion

OR ≥3 minor criteria

In biopsy of BM or ECO, >25% of MC in infiltrate are spindle shaped or atypical or >25% of all MC in BM aspirate smears are immature or atypical

CD2/CD25/CD30 detected on MC in BM, blood, or other ECO

ECO, extracutaneous organ; WHO, World Health Organization.

Khoury JD, et al. Leukemia. 2022;36(7):1703-1719; NCCN Guidelines®. https://www.nccn.org/professionals/physician_gls/pdf/mastocytosis.pdf. Images courtesy of Dr. Tracy George.

Pitfalls in SM WHO Criteria • BST variability and HαT can affect whether minor criterion is met1 • Cases with BST ≥8 ng/mL when other minor criteria present (MC CD25 expression and spindling)1 • Centralized expert BM sample evaluation suggested1 • Some SM cases are PB KIT–D816V negative, <5% MCs in the BM biopsy2 • MMAS has some pathophysiologic characteristics that overlap with SM criteria, including presence of KIT D816V and CD25 on MCs3 – Patients with MMAS won’t meet criteria for SM

BST, basal serum tryptase.

1. Boggs NA, et al. Blood Advances. 2023;7(13):3150-3154; 2. Jara-Acevedo M, et al. Mod Pathol. 2015;28(8):1138-1149; 3. Jackson CW, et al. Int J Mol Sci. 2021;22(20):11270.

Classifying Subtypes of SM 2022 WHO Criteria

BMM

No additional findings • Absence of skin lesions • Serum tryptase <125 ng/mL

ISM

No additional findings

+

SM diagnostic criteria met ≥20% MCs on BM aspirate smear

MCLa

≥2 B-findings SSM

• Biopsy BM MCs ≥30% or serum tryptase >200 ng/mL • KIT D816V with VAF ≥10% in BM cells or PB leukocytes • BM hypercellularity or dysmyelopoiesis • Organomegaly (without organ impairments)

≥1 C-finding

ASM

• Cytopenias present (ANC <1.0×109/L, hemoglobin <10 g/dL, or platelets <100×109/L) • Hepatomegaly with portal hypertension/ascites • Splenomegaly with hypersplenism • Osteolysis that may be associated with osteoporosis and pathologic fractures • Malabsorption with weight loss

WHO criteria for associated hematologic neoplasm met

SM-AHNa • SM-acute myeloid leukemia • SM-myelodysplastic syndrome • SM-myeloproliferative neoplasm • SM-chronic myelomonocytic leukemia

aB- and C-findings possible.

ANC, absolute neutrophil count; VAF, variant allele fraction.

Figure adapted from Mannelli F. Ann Hematol. 2021;100(2):337-344; Khoury JD, et al. Leukeumia. 2022;36(7):1703-1719; Zanotti R, et al. Leukemia. 2022;36(2):516-524.

QoL and Symptom Assessment Tools for Nonadvanced SM • QoL: Mastocytosis Quality-of-Life Questionnaire (MQLQ)1 • HRQoL: Mastocytosis Quality of Life Questionnaire (MC-QoL)2 • Symptom assessment: – Mastocytosis Symptom Assessment Form (MSAF)1 – Mastocytosis Activity Score (MAS)3 – ISM Symptom Assessment Form (ISM-SAF)4,5 • Assesses 11 signs and symptoms of ISM and SSM • Can determine moderate vs severe symptoms

HRQoL, health-related quality of life; QoL, quality of life.

1. Van Anrooij B, et al. Allergy. 2016;71(11):1585-1593; 2. Siebenhaar F, et al. Allergy. 2016;71(6):869-877; 3. Siebenhaar F, et al. Allergy. 2018;73(7):1489-1496; 4. Taylor F, et al. Orphanet J Rare Dis. 2021;16(1):414; 5. Shields AL, et al. Orphanet J Rare Dis. 2023;18(1):69.

Potential Predictors of Poor Prognosis in SM • Disease subtype1 • Basal serum tryptase level1 • Higher allele burden (VAF) of KIT D816V in PB1 • Aged >60 years2 • Elevated serum alkaline phosphatase (>100 U/L)2

Other genetic mutations are associated with progression to advanced SM3 Nonadvanced SM Subtype

Risk of Progression1

BMM

Very Low

ISM

Low

SSM

Intermediate

1. Valent P, et al. J Allergy Clin Immunol Pract. 2022;10(8):1999-2012; 2. Reiter A, et al. Blood. 2020;135(16):1365-1376; 3. Monaldi C, et al. Mediterr J Hematol Infect Dis. 2021;13:e2021046.

NEW TREATMENT STRATEGIES FOR NONADVANCED SYSTEMIC MASTOCYTOSIS Anne Maitland, MD

Stepwise Approach to Treat Mediator-Induced Symptoms Related to MC Activation Basic Management

Indication(s)

• Avoidance of any triggers Prophylaxis against MC activation events, including anaphylaxis • Basic therapy with histamine receptor blockade (H1 and H2 Prophylaxis against anaphylaxis, mediator-related symptoms receptor blockade) Additional therapies and measures • Add a proton pump inhibitor to H2 receptor blocker Gastrointestinal symptoms not controlled by H2 receptor blocker • Add cromolyn sodium Refractory skin or gastrointestinal symptoms • Referral to allergy/immunology specialist; add ketotifen, Refractory flushing, tachycardia, aspirin, or a leukotriene receptor antagonist (eg, montelukast, hypotension, or bone pain zafirlukast) • Add corticosteroids Refractory allergic symptoms, anaphylaxis, MCAS • Bone mineral density assessment; add calcium and vitamin D Osteoporosis supplementation, bisphosphonates, denosumab, interferon-α or osteopenia MCAS, MC activation syndrome.

Valent P, et al. J Allergy Clin Immunol Pract. 2022;10(8):1999-2012.

Stepwise Approach to Treat Mediator-Induced Symptoms Related to MC Activation Basic Management Additional specific therapies • Insect VIT • Omalizumaba • Epinephrine and other emergency drugs used for anaphylaxis • Avapritinib

Indication(s) Honeybee, yellow jacket, wasp, or fire ant venom allergy Multiresistant MC activation symptoms, therapy-refractory MCAS, confirmed IgE-dependent allergy in high-risk patients (prophylaxis) Anaphylaxis (MC activation event) Adults with ISM

aOmalizumab is not FDA approved for SM or recurrent anaphylaxis. Omalizumab is FDA approved to treat moderate to severe persistent allergic asthma, nasal polyps in adults, and

chronic urticaria.

VIT, venom immunotherapy.

Valent P, et al. J Allergy Clin Immunol Pract. 2022;10(8):1999-2012.

Therapeutic Targets of Targeted Agents in Nonadvanced SM MC1,2 C3a, C5a

Avapritinib

KIT

• Avapritinib was approved by the FDA for use in adult patients with ISM in May 20233 – Not recommended for patients with platelet counts <50 x 109/L

IgE IgG Tryptase

Histamine

• 25 mg orally once daily3 • Avoid coadministration with strong and moderate CYP3A inhibitors and inducers3

CYP, cytochrome P450; FDA, US Food and Drug Administration; 1. Figure adapted from Castells M, Akin C. Nat Med. 2021;27(12):2081-2082; 2. Nicolosi M, et al. Medicina (Kaunas). 2021;57(11):1135; 3. Drugs@FDA. https://www.blueprintmedicines.com/wp-content/uploads/uspi/AYVAKIT.pdf.

Avapritinib Met Primary Endpoint in Patients With ISM Phase 2 PIONEER Trial

Avapritinib Significantly Improves TSS Score TSS Score Change

Placebo

a

0 -2 -4 -6 -8 -10 -12 -14 -16 -18

Avapritinib

-9.2

-15.6a

• ISM-SAF TSS – Bone pain – Abdominal pain – Nausea – Spots – Itching – Flushing – Fatigue – Dizziness – Brain fog – Headache – Diarrhea severity

P=0.003.

BSC, best supportive care; TSS, total symptom score.

N=212 adults with confirmed ISM with inadequately controlled symptoms despite receiving BSC with ≥2 antimediator drugs; n=141 received 25 mg avapritinib daily + BSC or n=71 placebo + BSC for 24 weeks. Patients could then continue to an open-label extension where they receive 25 mg avapritinib daily.

Gotlib J, et al. NEJM Evid. 2023;2(6):EVIDoa2200339.

Avapritinib Met Key Secondary Endpoints in Patients With ISM Phase 2 PIONEER Trial

Avapritinib Significantly Improved Clinical Markers and Symptoms 68

70 60

54

Avapritinib

53

50 40 30

25

23

20 10 0

6

0 Serum tryptasea

BM MC aggregatesa

KIT D816 VAF a

80

Placebo

10

Reduction in TSS score b

Patients Achieving ≥30% Reduction, %

Patients Achieving ≥50% Reduction, %

80

Avapritinib Improved on a 30% Reduction in Symptoms vs Placebo 70 60 50 40 30

45 30

20 10 0 Reduction in TSS score

c

aP<0.001; bP=0.005; cP=0.009.

N=212 adults with confirmed ISM with inadequately controlled symptoms despite receiving BSC with ≥2 antimediator drugs; n=141 received 25 mg avapritinib daily + BSC or n=71 placebo + BSC for 24 weeks. Patients could then continue to an open-label extension where they receive 25 mg avapritinib daily.

Gotlib J, et al. NEJM Evid. 2023;2(6):EVIDoa2200339.

Treatment Considerations for Nonadvanced SM Asymptomatic Patients Observation or clinical trial Counsel patient and monitor for signs and symptoms of disease, including QoL: • H&P, regular labs • CBC/Diff, CMP • DEXA scan • Total IgE and insect venom IgE panel • Rescue and prevention plans for anaphylaxis • Assess symptom burden DEXA, dual-energy X-ray absorptiometry; H&P, history and physical.

Adapted from NCCN Guidelines®. https://www.nccn.org/professionals/physician_gls/pdf/mastocytosis.pdf.

Treatment Considerations for Nonadvanced SM Symptomatic Patients Treat MCA symptoms with antimediator drug therapy •Preferred regimen: avapritiniba for ISM or clinical trial Counsel patient and monitor, including QoL Restage in case of no adequate response or progression

Continue treatment if adequate response without progression

Referral to specialized center with expertise in SM. aShould not be used in patients with platelets <50 x 109/L.

MCA, mast cell activation.

Adapted from NCCN Guidelines®. https://www.nccn.org/professionals/physician_gls/pdf/mastocytosis.pdf.

Considerations for the Use of Targeted Therapies • There is a both a bleeding risk and a thromboembolism risk associated with tyrosine kinase inhibitors1 • Risk varies depending on the therapy1 • To date, increased bleeding has not been reported in patients with ISM who are taking avapritinib2

• A subset of patients with ISM show faster progression and would benefit more from earlier treatment with targeted therapy3 • Currently, targeted therapies are available only through specialty pharmacies4

– Ensure patient does not have a history of intracranial hemorrhage before prescribing 1. Deb S, et al. Cancer Med. 2020;9(1):313-323; 2. Drugs@FDA. https://www.blueprintmedicines.com/wp-content/uploads/uspi/AYVAKIT.pdf; 3. Mukherjee S, et al. J Allergy Clin Immunol.

2023;151(2 suppl):AB49; 4. Blueprint Medicines. https://www.ayvakithcp.com/wp-content/uploads/01-AYVAKIT_AdvSM_Product_Order_Sheet.pdf.

Investigational Agents in Nonadvanced SM Investigational Therapies4

MC1,2 C3a, C5a KIT

Masitinib Elenestinib

Hydroxychloroquine

Therapeutic Target

KIT

Bezuclastinib IgE

Midostaurin

IgG IL-6

Tryptase Histamine

Sarilumab

Investigational Agents

Phase of Development

Bezuclastinib2,3

Phase 2 (Summit)

Elenestinib (BLU-263)2

Phase 2/3 (HARBOR)

Masitinib2

Phase 3

Midostaurin2 IL-6 Receptor

Sarilumab2

Phase 2

Tryptase/ Cytokines

Hydroxychloroquine5

Phase 2/3 (HCQMa)

HCQMa, hydroxychloroquine in isolated cutaneous mastocytosis patients or indolent systemic mastocytosis with associated skin involvement patients.

1. Figure adapted from Castells M, Akin C. Nat Med. 2021;27(12):2081-2082; 2. Nicolosi M, et al. Medicina (Kaunas). 2021;57(11):1135; 3. Akin C, et al. 64th Annual ASH Conference 2022.

Poster 3041; 4. www.clinicaltrials.gov. 5. Espinosa E, et al. Clin Immunol. 2018;194:75-79.

Patient-Centered Management of Nonadvanced SM

Suboptimal Identification and Delayed Diagnoses Increase Overall Patient Burden

Years

Median Time From Symptom Onset to Diagnosis1 10 9 8 7 6 5 4 3 2 1 0

9.5

– Puts patients at risk of life-threatening anaphylaxis, organ dysfunction, and severe osteoporosis2

6

• Prior to diagnosis, patients had seen a median of 3 HCPs4

4

BMM

• Delayed diagnosis due to the rarity of SM and the broad spectrum of signs and symptoms that are shared by other, more-common disorders2,3

ISM

SSM

HCP, health care provider.

1. Van Anrooij B, et al. Allergy. 2016;71(11):1585-1593; 2. Ungerstedt J, et al. Cancers (Basel). 2022;14(16)3942; 3. Mikkelsen CS, et al. Dermatol Reports. 2014;6(1):5199; 4. Jennings SV, et al. Immunol Allergy Clin North Am. 2018;38(3):505-525.

Medication Considerations in Patients With SM Medication Type

Avoid or Use With Caution

Medications That Are Typically Tolerated

General Medications

• Alcohol • Amphotericin B • Dextran • Dextromethorphan • Polymyxin B

• Quinine • Vancomycin IV • Alpha-adrenergic blockers • Beta-adrenergic blockers

Pain Medications

• Opioid narcotics (may be tolerated by some individuals) • Ketorolac

• NSAIDs (unless the patient is already taking a drug from this class)

• Fentanyl (may require adjunctive treatment with ondansetron) • Tramadol

General Anesthetics

• Atracurium • Doxacurium

• Rocuronium • Mivacurium

• Pancuronium • Vecuronium

Local Anesthetics

• Benzocaine • Chloroprocaine

• Procaine • Tetracaine

• Bupivacaine • Lidocaine • Levobupivacaine

• Calcium channel blockers • Centrally acting alpha 2 adrenergic stimulants • Aldosterone antagonists • Oral doses of vancomycin

Intraoperative Induction Medications

• Ketamine • Midazolam • Propofol

Inhaled Anesthetics

• Sevoflurane

IV, intravenous.

The Mast Cell Disease Society (TMS). https://tmsforacure.org/wp-content/uploads/TMS_Full-Patient-Guide_2022.pdf.

• Mepivacaine • Prilocaine • Ropivacaine

Routine Monitoring • Patients with stable SSMa should be monitored every 6 months and those with stable ISMa every 12 months, for changes in: – Serum tryptase levels – CBC/Diff – CMP – Weight – Physical examination, including skin/lesions • Regression of MPCM lesions does not correlate with changes in underlying ISM

– QoL/Symptom burden: ability to participate in daily activities, ability to eat, respiratory symptoms under control, sleep • Use MSAF or MQLQ

• DEXA scan every 1 to 3 years for patients with osteopenia/osteoporosis

If laboratory results or symptoms change, therapeutic adjustment should be considered. a

Patients with unstable SSM or ISM should be seen more frequently until stabilized.

Adapted from Brockow K, et al. Arch Dermatol. 2002;138(6):785-790; NCCN Guidelines®. https://www.nccn.org/professionals/physician_gls/pdf/mastocytosis.pdf.

Patient Education Is Critical to Successful Management • Trigger avoidance – Identifying potential triggers – Unpredictability of response

• Periprocedural precautions • Anaphylaxis action plan – Recognition – Supine position – How to administer epinephrine – Medical alert tag

• Medication adherence • Support groups TMS. 2022. https://tmsforacure.org/

Anaphylaxis Management Is Critical to Successful Management • All patients with SM should be assessed for venom allergy with skin and/or in vitro venom-specific IgE tests: – If positive, treat with VIT indefinitely1 • Omalizumab may be considered if patient does not tolerate VIT2

– VIT benefits outweigh risks in patients with SM3 – If negative, retest after each sting3

Classification

Risk of Anaphylaxis4

BMM ISM SSM

High Intermediate Intermediate

1. Niedoszytko M, et al. Allergy. 2009;64(9):1237-1242. Ricciardi L. Int J Immunopathol Pharmacol. 2016;29(4):726-728; 3. Jarkvist J, et al. Allergy. 2020;75(1):169-177; 4. Valent P, et al. J Allergy Clin Immunol Pract. 2022;10(8):1999-2012.

Patient Resources and Action Plans NCCN Guidelines for Patients® Systemic Mastocytosis, 2022 https://www.nccn.org/patientresources/patientresources/guidelines-for-patients

TMS provides multifaceted support to patients, families, and medical professionals through education, advocacy, and collaboration. https://tmsforacure.org/

GARD helps patients find information, services, experts, financial aid, and support groups. https://rarediseases.info.nih.gov/

NORD is a patient advocacy organization committed to the identification, treatment, and cure of rare disorders through programs of education, advocacy, research, and patient services. https://rarediseases.org/

Summary • Nonadvanced SM has a complex pathophysiology and clinical presentation, with a significant negative impact on QoL and activities of daily living • Traditional management of nonadvanced SM is largely preventive and symptom directed • Avapritinib is approved to specifically target the pathophysiology of ISM – Other targeted agents are under investigation and may soon provide additional therapeutic options

• The multisystemic manifestations of nonadvanced SM necessitate multidisciplinary management