Making the Rounds on Systemic Mastocytosis

Learning Objectives • Discuss SM pathophysiology, including implications for potential clinical presentations and new targeted therapies • Evaluate patients with nonadvanced SM to characterize symptoms, disease burdens, and results from ancillary testing • Discuss recent clinical trial evidence for new targeted treatment options in nonadvanced SM • Individualize ongoing therapeutic regimens for nonadvanced SM based on symptomatology, patient-reported outcomes, and shared clinical decision making

SM, systemic mastocytosis.

DIAGNOSING NONADVANCED SM Patricia Lugar, MD, MS

Clinical Characteristics of Nonadvanced SM % Patient-Reported Signs and Symptoms by SM Subtype Urticaria pigmentosa/MPCM

64

Cutaneous symptoms

64

85 69

GI symptoms Other MC mediator-related symptoms

67

50

Musculoskeletal symptoms

Lymphadenopathy

0

Splenomegaly

0

Hepatomegaly

0 0

86

45

ISM (n=101)

41

11

SSM (n=22)

68

10 10

72 77

78

15 14 13

Constitutional symptoms

78

36

19 23 18 21

Idiopathic/recurrent anaphylaxis

72

BMM (n=36)

55 20

30

40

50

60

70

80

Patients, % BMM, bone marrow mastocytosis; GI, gastrointestinal; ISM, Indolent SM; MC, mast cell(s); MPCM, maculopapular cutaneous mastocytosis; SSM, smoldering SM. Pardanani A, et al. Blood. 2010;115(1):150-151.

90

100

Clinical Characteristics of Nonadvanced SM 20% 18%

Most Bothersome Symptoms 18% 16%

Patients, %

16%

13%

14%

11%

12% 10% 8% 6% 4% 2% 0% Anaphylactic episodes

Abdominal/ stomach pain

Diarrhea/ loose stools

Fatigue

Patients can experience up to 14 different symptoms during the course of their illness.

Mesa RA, et al. Cancer. 2022;128(20):3691-3699.

Diagnostic Algorithm for SM1 • Suspected MC activation-associated symptoms OR • Anaphylaxis AND/OR • Increased serum tryptase level (no mastocytosis in the skin, B- or Cfindings, or abnormal blood counts) OR • Biopsy-proven adult onset mastocytosis in the skin

• Evaluation for SM – BM biopsy or biopsy of organ with suspected extracutaneous involvement – High sensitivity molecular testing for KIT D816V; if needed, additional KIT gene sequencing – MC immunophenotyping using flow cytometry and/or immunohistochemistry – Screen for FIP1L1-PDGFRA if eosinophilia is present and KIT D816V is negative

BM, bone marrow; FIP1L1-PDGFRA, factor interacting with PAPOLA and CPSF1-platelet derived growth factor receptor α.

1. National Comprehensive Cancer Network (NCCN). https://www.nccn.org/professionals/physician_gls/pdf/mastocytosis.pdf. Accessed December 19, 2022.

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

• FISH FIPIL1-PDGFRA, if eosinophilia present • HαT • High-sensitivity mutation analysis (ddPCR, ASO-qPCR) or qPCR for KIT D816V • Myeloid gene panel (NGS)

• 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, CBC/Diff, complete blood count with differential; CMP, comprehensive metabolic panel; ddPCR, droplet digital PCR; FISH, fluorescence in situ hybridization; HαT, hereditary α tryptasemia; NGS, next-generation sequencing; PCR, polymerase chain reaction; qPCR, quantitative PCR. Adapted from NCCN Guidelines. Systemic Mastocytosis Version 2.2022. https://www.nccn.org/professionals/physician_gls/pdf/mastocytosis.pdf. Accessed January 3, 2023.

Differential Diagnoses • Hereditary α Tryptasemia (HαT) – Due to multiplication of TPSAB1 which increases basal serum tryptase levels (>8 ng/mL)1,2 – Symptoms consistent with MC activation, including abdominal pain and bloating, anaphylaxis, brain fog, flushing, urticaria3 – KIT D816V negative, no evidence of MC aggregates or markers of MC activation in bone marrow biopsy3 – Patients do not have elevated MC urinary metabolites as seen with SM3

a

• Other Conditions to Consider4-6 – Cardiovascular: Coronary hypersensitivitya, labile hypertension, orthostatic hypotension, paroxysmal arrhythmias – Digestive: Adverse food reactiona, celiac disease, gastroesophageal reflux disease, gluten enteropathy, IBS – Endocrinological: Fibromyalgia, carcinoid syndrome, insulinoma, parathyroid/thyroid carcinoma, pheochromocytoma, thyroxicosis – Immunological: Autoinflammatory disordersa, 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

Localized MC activation can occur.

IBS, irritable bowel syndrome; IgE, immunoglobulin E. 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. Scherber RM, Borate U. Br J Haematol. 2018;180(1):11-23; 5. Theoharides TC, et al. N Engl J Med. 2015;373(2):163-172; 6. Castells M, Butterfield J. J Allergy Clin Immunol Pract.

2019;7(4):1097-1106.

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 peripheral blood (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 D816V KIT mutational analysis on peripheral blood (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

Classifying Subtypes of SM 2022 WHO Criteria

BMM

ISM

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

No additional findings

+

SM diagnostic criteria met ≥20% mast cells on BM aspirate smear

MCLa

≥2 B-findings SSM

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

≥1 C-finding

ASM

a

• Cytopenias present (ANC <1.0x109/L, hemoglobin <10 g/dL, or platelets <100x109/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

B- and C-findings possible.

ANC, absolute neutrophil count; ASM, aggressive SM; BMM, bone marrow mastocytosis; ISM, Indolent SM; MC, mast cell(s); MCL, mast cell leukemia; MPCM, maculopapular cutaneous mastocytosis; SSM, smoldering SM; SM-AHN, systemic mastocytosis with associated hematologic neoplasm; VAF, variant allele fraction; WHO, World Health Organization.

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.

Potential Predictors of Poor Prognosis in SM • Disease subtype1 • Number and severity of cytopenia(s)1 • Basal serum tryptase level1 • Higher allele burden (VAF) of KIT D816V in peripheral blood1 • >60 years of age2 • Elevated serum alkaline phosphatase (>100 U/L)2

• Other genetic mutations are associated with progression to advanced SM3 – Epigenetic regulators: ASXL1, DNMT3, EZH2, TET2 – Transcription factors: RUNX1 – Signaling molecules: CBL, JAK2, KRAS, NRAS – Splicing factors: SRSF2, SF3B1, U2AF1

Nonadvanced SM Subtype

Risk of Progression1

BMM ISM SSM

Very Low Low Intermediate

ASXL1, ASXL transcriptional regulator 1; DNMT3A, DNA methyltransferase 3α; EZH2, enhancer of zeste 2 polycomb repressive complex 2 subunit; TET2, tet methylcytosine dioxygenase 2; RUNX1, RUNX family transcription factor 1; CBL, Cbl proto-oncogene; JAK2, Janus kinase 2; KRAS, KRAS proto-oncogene, GTPase; NRAS, NRAS proto-oncogene, GTPase; SRSF2, serine and arginine rich splicing factor 2; SF3B1, splicing factor 3b subunit 1; U2AF1, U2 small nuclear RNA auxiliary factor 1.

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.

Diagnosing Nonadvanced SM Clinical Pearls

þ Familiarize yourself with typical and atypical clinical presentations of SM þ Conduct a thorough physical exam, including the skin, when there is a high suspicion of index for SM þ Determine baseline serum tryptase levels è KIT D816V mutation analysis è BM biopsy to confirm SM

QoL 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

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.

TREATMENT STRATEGIES FOR NONADVANCED SM Anne Maitland, MD, PhD

Treatment Considerations for Nonadvanced SM Asymptomatic

Symptomatic

Observation

Treat MCA symptoms with anti-MC/anti-MC mediator drug therapy or clinical trial

Counsel patient and monitor for signs and symptoms of disease: • CBC/Diff, CMP, KIT D816V • Bone DEXA • Total IgE and insect venom IgE panel • Rescue and prevention plans for anaphylaxis

Counsel patient and monitor response vs progression

Restage in case of no adequate response or progression

Continue treatment if adequate response without progression

Referral to specialized center with expertise in SM. DEXA, dual-energy X-ray absorptiometry; MCA, mast cell activation.

Adapted from NCCN Guidelines. Systemic Mastocytosis Version 2.2022. https://www.nccn.org/professionals/physician_gls/pdf/mastocytosis.pdf. Accessed January 3, 2023.

Symptom-Directed Treatment Strategies Symptom

First Line

Additional Options

Pruritus, flushing

H1R antagonist

H2R antagonist, LT/PG inhibitors, PUVA, omalizumab, cromolyn ointment

Abdominal pain, cramping, diarrhea, heartburn, nausea, vomiting

H2R antagonist

Proton pump inhibitor, cromolyn, ondansetron/olanzapine

Headache, cognitive impairment, depression

H1R and H2R antagonist

Tricyclic agents, cromolyn

Hypotensive episodes

Epinephrine IM (acutely), supine positioning

Chronic H1R and H2R antagonists, LT/PG inhibitors, CS-A, omalizumab, MC cytoreductive agents

Bisphosphonate

Denosumab, interferon-α inhibitor, cytoreductive agent

Osteoporosis

Cromolyn, cromolyn sodium; CS-A, cyclosporin A; IM, intramuscular; LT/PG, leukotriene/prostaglandin; PUVA, psolaren plus ultraviolet A. Scherber RM, Borate U. Br J Haematol. 2018;180(1):11-23; Courtesy of Lawrence Schwartz, MD, PhD.

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 receptor blockade)

Prophylaxis against anaphylaxis, mediator-related symptoms

Additional therapies and measures • Add a proton pump inhibitor to H2 receptor blocker • Add cromolyn sodium • Referral to allergy/immunology specialist; add ketotifen, aspirin, or a leukotriene receptor antagonist (eg, montelukast, zafirlukast) • Add corticosteroids

Gastrointestinal symptoms not controlled by H2 receptor blocker Refractory skin or gastrointestinal symptoms Refractory flushing, tachycardia, hypotension, or bone pain Refractory allergic symptoms, anaphylaxis, MCAS

Additional specific therapies • Insect venom immunotherapy • Omalizumaba therapy • Epinephrine and other emergency drugs used in anaphylaxis • Midostaurin or avapritinib a

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) MCAS in patients with advanced or refractory nonadvanced SM (reducing target cells and releasability)

Omalizumab 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.

FDA, US Food and Drug Administration; LTE4, leukotriene E4; MCAS, MC activation syndrome; PGF2, prostaglandin F2.

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

Other Management Strategies Reduce osteoporosis/osteopenia

Bone mineral density assessment; calcium & vitamin D supplementation, bisphosphonates, denosumab, interferon-α, vertebroplasty/kyphoplasty

Perioperative management

Consult with anesthesia and surgical teams, review prior anesthetic records, use “safer” agents

Clinical Trial

Selective mutant KIT inhibitor (eg, avapritinib)

Pardanani A. Am J Hematol. 2021;96(4):508-525.

Medications to Be Avoided 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

• Nonsteroidal anti-inflammatory drugs (unless the patient is already taking a drug from this class)

• Fentanyl (may require adjunct 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). 2022. https://tmsforacure.org/wp-content/uploads/TMS_Full-Patient-Guide_2022.pdf Accessed January 18, 2023.

• Mepivacaine • Prilocaine • Ropivacaine

Overcoming the Challenges Associated With Treating Nonadvanced SM • Currently approved nonadvanced SM treatments do not include KIT mutation-directed therapy • ISM/SSM patients with higher risk of progression and/or with symptoms refractory to current treatments have limited options unless they develop C-findings • However, promising targeted therapies are on the horizon

Therapeutic Targets and Investigational Agents in Nonadvanced SM Mast Cell1,2

Investigational Therapies4 Therapeutic Target

KIT

Investigational Agents

Phase of Development

Avapritinib2

Phase 2 sNDA submitted

Bezuclastinib2,3

Phase 2

Elenestinib (BLU-263)2

Phase 2/3

Masitinib2

Phase 3

Midostaurin2 IL-6 Receptor

Sarilumab2

Tryptase/ Cytokines

Hydroxychloroquine5

Phase 2 Phase 2/3

IgE and IgG, immunoglobulins; IL-6, interleukin 6; PDGFRα, platelet-derived growth factor receptor alpha; SCF, stem cell factor.

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.

Midostaurin Inhibits Kinase Activity of Mutant and Wild-Type KIT • Open-label phase 2 trial of midostaurin treatment for nonadvanced SM • Primary endpoint: symptomatic response rate according to MSAF score: average 38% reduction in symptom severity that lasted through week 24 (P<0.01) • Secondary endpoint: disease-specific quality of life measured using MQLQ: median 29% improvement (P<0.001)

N=20 patients with ISM refractory to antihistamine treatment, monitored for 24 weeks. van Anrooij B, et al. J Allergy Clin Immunol. 2018;142(3):1006-1008.

Midostaurin Has Clinical Benefit in ISM/SSM Patients Demonstrating Response, %

90%

Retrospective review of Mayo Clinic Experience 82%

80% 70%

62%

60% 50%

50%

44%

40% 30% 20% 10% 0% MC skin lesion improvement

MC mediator symptom improvement

BM MC decrease

Serum tryptase level decrease

Some tolerability issues due to gastrointestinal adverse effects resulting in dose reductions but no concomitant loss of response.

N=13, ISM n=11, SSM n=2 patients monitored up to 46 months. Treatment discontinued in 6 patients (46%) due to complete response (1), adverse effects (1), no response (2) and adverse effects-suboptimal response (2).

Farrukh F, et al. Am J Hematol. 2022;97(4):E138-E140.

PIONEER Trial

A 3-Part, Phase 2 Study of Avapritinib in ISM • Enrollment: Patients with confirmed ISM who have moderate-to-severe symptoms despite receiving ≥2 best supportive care (BSC) medications • Study design

• ISM-SAF TSS

– Part 1: Dose escalation Avapritinib 25 mg QD + BSC (n=10) Randomized 1:1:1:1

Avapritinib 50 mg QD + BSC (n=10)

Primary endpoint Determination of recommended phase 2 dose

Avapritinib 100 mg QD + BSC (n=10)

Secondary endpoints

Placebo QD + BSC (n=9)

– Part 2: Pivotal efficacy Randomized 2:1

Avapritinib 25 mg QD + BSC (n=141) Placebo QD + BSC (n=71)

Rollover Avapritinib 25 mg QD + BSC Long-term safety and efficacy

Pharmacokinetics, safety, changes in mast cell burden, and patient-reported outcomes

Primary endpoint Mean change in TSS

Rollover Avapritinib 25 mg QD + BSC Long-term safety and efficacy

Key secondary endpoints

Proportions of patients achieving >30% and >50% TSS reduction; >50% reduction in serum tryptase, bone marrow MC burden, and blood KIT D816V VAF; safety

– Bone pain – Abdominal pain – Nausea – Spots – Itching – Flushing – Fatigue – Dizziness – Brain fog – Headache – Diarrhea severity Mean TSS 53/110

– Part 3: Patients who complete PIONEER part 1 or part 2 will be eligible to enter an open-label extension (rollover) to evaluate the long-term safety and efficacy of avapritinib 25 mg QD TSS, total symptom severity; QD, once daily.

Akin C, et al. Blood. 2020;136(suppl 1):41-42; Akin C, et al. American Academy of Allergy Asthma & Immunology (AAAAI) Annual Meeting; February 24-27, 2023. Abstract 151; Castells M, et al. AAAAI Annual Meeting; February 24-27, 2023. Abstract 627; ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03731260.

Efficacy and Safety of Avapritinib in ISM Phase 2 PIONEER Trial, Part 1

Mean Change From Baseline, %

ISM-SAF TSS1

• At 16 weeks, patients treated with avapritinib 25 mg QD had clinically meaningful improvements in1

10 0

– Total symptom severity – QoL, as measured by MC-QoL – Bone marrow MC burden, serum tryptase, and blood KIT D816V allele fraction

-10 -20 Placebo (n=9) Avapritinib 25 mg (n=10) Avapritinib 50 mg (n=10) Avapritinib 100 mg (n=10)

-30 -40 -50 0

4

8

Weeks

12

16

• Avapritinib had a favorable safety profile and was well-tolerated across all doses1

In June 2021, avapritinib was FDA-approved for the treatment of advanced SM in adults.2 N=39 adults with confirmed ISM who have moderate-to-severe symptoms despite receiving ≥2 BSC medications were randomized to either 25 mg, 50 mg, or 100 mg avapritinib QD + BSC or placebo for 16 weeks.

BSC, best supportive care.

1. Akin C, et al. American Society of Hematology Virtual Conference; December 5-8, 2020. Abstract 1248; 2. FDA. 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/212608s007lbl.pdf.

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

TSS Score Change

Avapritinib

Placebo

0 -2 -4 -6 -8 -10

-9.2

-12 -14 -16 -18

-15.6

A Supplemental New Drug Application was accepted for priority review in January 2023.

P=0.003.

N=212 adults with confirmed ISM with inadequately controlled symptoms despite receiving BSC, n=141 received 25 mg avapritinib QD + BSC or n=71 placebo + BSC for 24 weeks.

Akin C, et al. American Academy of Allergy Asthma & Immunology (AAAAI) Annual Meeting; February 24-27, 2023. Abstract 151; Castells M, et al. AAAAI Annual Meeting; February 2427, 2023. Abstract 627.

Patients Achieving ≥50% Reductions, %

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

80%

68%

70% 60%

Avapritinib

54%

Placebo

53%

50% 40% 30%

23%

20% 10% 0%

6%

0% Serum Tryptase

Bone Marrow MC Aggregates

KIT D816 VAF

Overall adverse events and serious adverse events were lower in avapritinib vs placebo.

P<0.0001.

N=212 adults with confirmed ISM with inadequately controlled symptoms despite receiving BSC, n=141 received 25 mg avapritinib QD + BSC or n=71 placebo + BSC for 24 weeks.

Castells M, et al. AAAAI Annual Meeting; February 24-27, 2023. Abstract 627.

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

Spot severity

Skin symptom domain

-1 -2

-1.86

-3

-2.64

-4 -5 -6 -7

a

-0.63

Avapritinib Placebo

Mean Change, %

ISM-SAF Score Changea

0

100%

Avapritinib

80%

Placebo

86%

60% 40% 20%

10%

0%

0% -20% -40%

-0.5%

-2% -14%

-22% -37%

-60%

-5.87

MC burden

Lesion Lightened surface area skin lesion color

CD30+ MC in skin lesionsb

P<0.0001, bP=0.0015.

N=212 adults with confirmed ISM with inadequately controlled symptoms despite receiving BSC, n=141 received 25 mg avapritinib daily + BSC or n=71 placebo + BSC for 24 weeks.

Maurer M, et al. AAAAI Annual Meeting; February 24-27, 2023. Abstract L69.

PATIENT-CENTERED MANAGEMENT OF NONADVANCED SM Patricia Lugar, MD, MS

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

6

– Puts patients at risk of lifethreatening anaphylaxis, organ dysfunction, and severe osteoporosis2

4

BMM

ISM

• 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

SSM

• Prior to diagnosis, patients saw a median of 3 HCPs4

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.

Multidisciplinary Management of Nonadvanced SM • The presence of multisystemic manifestations of symptoms requires multidisciplinary collaboration between – Allergy/Immunology – Dermatology – Gastroenterology – Hematology/Oncology – Primary care – Rheumatology – Endocrinology – Psychiatry Zanotti R, et al. Cancers (Basel). 2021;13(24):6380; Valent P, et al. Int J Mol Sci. 2019;20(12):2976.

Routine Monitoring • Patients with stablea SSM should be monitored every 6 months and those with stablea ISM every 12 months, for changes in1 – Serum tryptase levels – CBC/Diff – CMP – Weight – Physical examination, including skin/lesions3 • Regression of MPCM lesions does not correlate with changes in underlying ISM2

– QoL/symptom burden: ability to participate in daily activities, ability to eat, respiratory symptoms under control, sleep1,3

• DEXA scan every 1-3 years for patients with osteopenia/osteoporosis1

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

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

1. NCCN Guidelines. Systemic Mastocytosis Version 2.2022. https://www.nccn.org/professionals/physician_gls/pdf/mastocytosis.pdf. Accessed January 3, 2023; 2. Dr. Anne Maitland, personal communication; 3. Brockow K, et al. Arch Dermatol. 2002;138(6):785-790.

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 • Finding support groups TMS. 2022. https://tmsforacure.org/.

Long-term Management of Anaphylaxis • All SM patients should be trained in supine positioning • All SM patients should be advised to carry 1 or 2 epinephrine autoinjectors to manage anaphylaxis • Omalizumab, an anti-IgE mAb, has been shown to be effective for treating recurrent anaphylaxis1

• All SM patients should be assessed for venom allergy with skin and/or in vitro venom-specific IgE tests – If positive, treat with VIT indefinitely2 • Omalizumaba may be considered if patient is not tolerating VIT3

– VIT benefits outweigh the risks in SM patients4 – If negative, retest after each sting Risk of Anaphylaxis5

BMM

High

ISM

Intermediate

SSM

Intermediate

aOmalizumab is not FDA-approved for SM or recurrent anaphylaxis.

VIT, venom immunotherapy.

1. Jendoubi F, et al. Clin Exp Allergy. 2020;50(6):654-661; 2. Niedoszytko M, et al. Allergy. 2009;64(9):1237-1245; 3. Ricciardi L. Int J Immunopathol Pharmacol. 2016;29(4):726-728; 4. Jarkvist J, et al. Allergy. 2020;75(1):169-177; 5. Valent P, et al. J Allergy Clin Immunol Pract. 2022;10(8):1999-2012.

Patient Action Plans

TMS. 2022. https://tmsforacure.org/.

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

The Mast Cell Disease Society (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, making identification and diagnosis difficult • Physical and/or neuropsychiatric symptoms disrupt daily activities and reduce quality of life • Disease management must be personalized and largely preventive and symptom-directed • Targeted agents are under investigation for treatment of nonadvanced SM and may soon provide therapeutic alternatives • The multisystemic manifestations of nonadvanced SM necessitate multidisciplinary management