Systemic Mastocytosis (SM)

Systemic mastocytosis (SM) is a heterogeneous condition that results from multifocal infiltration of clonally derived mast cells (MCs) in cutaneous and extracutaneous tissues. The abnormal MCs usually contain an activating mutation at codon 816 of the KIT gene. The most frequent mutation is the KITD816V mutation, detectable in >80% of all SM patients and in >90% of patients with indolent SM. KIT is considered a driver of MC maturation in normal MCs; however, in patients with SM, the KIT D816V mutation appears to also promote cell survival and proliferation in neoplastic MCs.¹ Symptoms of SM are due to mediator release from MCs and infiltration into various organs. Therapeutics for SM are highly individualized and center around treating symptoms associated with MC degranulation and infiltration. There are novel drugs under development that also target mutant KIT receptors and the KIT gene.²

Systemic Mastocytosis Symptom Control

Pruritus/Flushing

For patients with pruritus/flushing, the first-line option is an H1-antagonist. Recommended drugs and dosing options include²:

• Cetirizine 5-10 mg per day
• Fexofenadine 60 mg twice a day or 180 mg once a day
• Hydroxyzine 25 mg every 6 hours

Doses may be increased with supervision. In addition, the cholinergic effects of hydroxyzine should be taken into consideration when prescribing, and caution should be exercised when prescribing hydroxyzine to geriatric patients, patients with glaucoma, and patients with benign prostate hyperplasia.² 

Second-line options include leukotriene antagonists such as montelukast (10 mg per day) or zafirlukast (20 mg twice a day). A third-line option is aspirin, although caution should be exercised as some patients may have aspirin hypersensitivity or develop anaphylaxis or gastrointestinal bleeding, and children may develop Reye’s syndrome. Another third-line option is psoralen plus ultraviolet A photochemotherapy, which is contraindicated in pregnancy, systemic lupus erythematosus, and photosensitivity.²

Abdominal Pain/Cramping, Diarrhea, Nausea, and Heartburn

The first-line medication for patients with abdominal pain and/or cramping includes the use of an H2-antagonist. Second-line medications are proton pump inhibitors. Table 1 summarizes their recommended dosages and important safety information.²

Table 1. First- and second-line medications for the symptomatic treatment of gastrointestinal symptoms in SM²

Treatment ladder	Medication and dose	Safety information
First-line	Ranitidine 150 mg BID orFamotidine 10 mg BID orCimetidine 400 mg BID	May cause headache, abdominal pain, dizziness, constipation, and/or diarrhea
Second-line	Omeprazole 20 mg/d orPantoprazole 40 mg/d orRabeprazole 20 mg/d	May cause headache, abdominal pain, nausea, vomiting, diarrhea, and/or flatulence

The third-line medication is sodium cromolyn (100-200 mg 4 times a day) 30 minutes before meals and bedtime. Fourth-line medications are corticosteroids such as prednisone (0.5-1 mg/kg/d), which should be tapered over time based on patient response and tolerance.²

Headache, Cognitive Impairment, and Depression

First-line medications include H1- and H2-antagonists, and the second-line medication is sodium cromolyn; these should be dosed as listed above.²

Recurrent Hypotension

Treatment will depend on symptom severity. Options include epinephrine (for anaphylaxis), H1- and H2-blockers, corticosteroids, and cytoreductive therapy.²

Osteoporosis 

Bisphosphonates are the first-line treatment for osteoporosis associated with SM. Treatment options include²:

• Alendronate 70 mg once a week or
• Risedronate 35 mg once a week or
• Pamidronic acid 90 mg intravenously every 4 weeks or
• Zoledronic acid 4 mg intravenously every 4 weeks

Adverse events associated with bisphosphonate therapy include flu-like symptoms, abdominal pain, nausea, vomiting, diarrhea, asthenia, hypocalcemia, rash, musculoskeletal pain, headache, osteonecrosis of the jaw, and nephrotoxicity.²

Cytokine/immunomodulatory therapy or purine nucleoside analogue therapy with interferon alpha and 2-chlorodeoxyadenosine are second- and third-line options, respectively.²

Read more about systemic mastocytosis symptoms

Targeted Therapies

Midostaurin – Midostaurin is a multikinase/KIT inhibitor that inhibits the protein products of KIT, including the kinases encoded by the D816V and D816Y mutations. It is US Food and Drug Administration (FDA)-approved and reserved for patients with aggressive SM. Midostaurin has a response rate of 75% in these patients. Clinical trials have determined the response rates for mast cell leukemia and SM with an associated hematologic neoplasm to be 50% and 58%, respectively.²

Cladribine (chlorodeoxyadenosine) – Cladribine is a purine nucleoside analog that appears to have therapeutic properties due to its antineoplastic activity against neoplastic MCs. It has activity in all subtypes of SM, with response rates comparable to Midostaurin. Potential toxicities of cladribine include myelosuppression and lymphopenia with an increased risk of opportunistic infections.²

Interferon alpha (IFN-α) – IFN-α has activity against all SM types and is useful for improving systemic, dermatological, hematological, and gastrointestinal symptoms associated with MC mediator release. IFN-α is also useful for increasing bone mineral density in patients with SM-associated osteoporosis or osteopenia.²

Read more about systemic mastocytosis therapies

Investigational Agents

Avapritinib/BLU-285 – Avapritinib is a small molecule kinase inhibitor that selectively inhibits activation-loop mutants of KIT, including KITD816V, at subnanomolar concentrations.²

DCC-2618 – This is an experimental drug that falls into a unique category called type II switch pocket control inhibitors. DCC-2618 is a potent exon 17 KIT mutation inhibitor, used in patients who are resistant to conventional kinase inhibitors.²

References

1. Valent P, Akin C, Metcalfe DD. Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts. Blood. 2017;129(11):1420-1427. doi:10.1182/blood-2016-09-731893

2. Pardanani A. Systemic mastocytosis in adults: 2021 update on diagnosis, risk stratification and management. Am J Hematol. 2021;96(4):508-525. doi:10.1002/ajh.26118

Reviewed by Harshi Dhingra, MD, on 4/15/2022.

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Kyle Habet, MD

Kyle Habet, MD, is a physician at Belize International Institute of Neuroscience where he is a member of a multidisciplinary group of healthcare professionals involved in the care of patients with an array of neurological and psychiatric diseases. He is a published author, researcher and instructor of neuroscience and clinical medicine at Washington University of Health and Science.