What is the treatment approach for mast cell disorders?

Treatment Approach for Mast Cell Disorders

All patients with mast cell disorders require anti-mediator drug therapy to control symptoms of mast cell activation, while cytoreductive therapy is reserved specifically for advanced systemic mastocytosis (ASM, SM-AHN, MCL) where organ damage and shortened survival necessitate reduction of mast cell burden. 1

Initial Assessment and Risk Stratification

The treatment strategy depends fundamentally on disease classification:

• Indolent/Smoldering Systemic Mastocytosis (ISM/SSM): Manage with anti-mediator therapy alone 1
• Advanced Systemic Mastocytosis (ASM, SM-AHN, MCL): Requires cytoreductive therapy in addition to anti-mediator therapy 1
• Mast Cell Activation Syndrome (MCAS): Treat with anti-mediator therapy using stepwise escalation 1

All patients must carry 2 epinephrine auto-injectors to manage anaphylaxis, as surgery, endoscopy, and invasive procedures can trigger mast cell activation 1

Anti-Mediator Drug Therapy (Foundation for All Patients)

First-Line Agents

H1 and H2 receptor antagonists form the cornerstone of symptom management and should be initiated in all patients with mast cell disorders 1:

• H1 antihistamines (cetirizine, fexofenadine): Use at 2-4 times FDA-approved doses to control pruritus, flushing, urticaria, tachycardia, abdominal discomfort, and neurologic symptoms 1
• H2 antihistamines (famotidine, ranitidine): Add to prevent histamine-mediated acid secretion and enhance control of gastrointestinal and vascular symptoms 1

Important caveat: First-generation H1 antihistamines (diphenhydramine, hydroxyzine) cause sedation and cognitive decline, particularly problematic in elderly patients, and raise concerns in patients prone to cardiovascular events 1

Mast Cell Stabilizers

Cromolyn sodium is FDA-approved for mastocytosis and effectively manages cutaneous, gastrointestinal, and neurologic symptoms 2:

• Marked improvement in pruritus, whealing, flushing, diarrhea, abdominal pain, and cognitive dysfunction demonstrated in double-blind crossover studies 1
• Can be used topically as ointment/cream to decrease flare-ups triggered by specific exposures 1

Second-Line Mediator-Targeted Agents

When symptoms remain refractory to H1/H2 blockers and cromolyn:

• Leukotriene receptor antagonists (montelukast) or 5-lipoxygenase inhibitors (zileuton): Particularly effective when urinary LTE4 levels are elevated, targeting bronchospasm and gastrointestinal symptoms 1
• Aspirin: Beneficial when urinary prostaglandin levels are elevated, but must be used cautiously as it can trigger mast cell activation in some patients 1
• Omalizumab (anti-IgE antibody): Consider for mast cell activation symptoms insufficiently controlled by other agents 1
• Corticosteroids: Reserve for severe refractory symptoms; can give 50 mg prednisone at 13,7, and 1 hour before procedures when mast cell activation has been problematic 1

Cytoreductive Therapy for Advanced Systemic Mastocytosis

Cytoreductive therapy is mandatory for ASM, SM-AHN, and MCL due to organ damage and poor prognosis 1:

First-Line Cytoreductive Options

• Midostaurin: Preferred targeted KIT inhibitor for advanced SM 1
• Cladribine: Alternative cytoreductive agent 1
• Imatinib: Only if KIT D816V mutation negative/unknown OR if eosinophilia present with FIP1L1-PDGFRA fusion gene 1, 3
  • Critical distinction: Patients harboring D816V mutation (most common) are NOT sensitive to imatinib and should not receive it 3
  • Imatinib achieves 100% complete hematologic response in patients with FIP1L1-PDGFRα fusion kinase 3
• Interferon-alpha (interferon alfa-2b, peginterferon alfa-2a, or peginterferon alfa-2b) ± prednisone 1

Note: Cladribine and interferon-alfa are generally reserved for advanced SM, but may be useful in selected ISM/SSM patients with severe, refractory mediator symptoms or bone disease unresponsive to anti-mediator therapy or bisphosphonates 1

Response Assessment and Restaging

After initiating cytoreductive therapy, restage if 1:

• Return or progression of SM-related organ damage
• Symptomatic or progressive hepatomegaly/splenomegaly
• Progressive disease-related symptoms
• Intolerance to drug therapy

Allogeneic Hematopoietic Cell Transplantation

Allogeneic HCT should be considered for advanced SM patients after adequate response to prior treatment 1:

• 3-year overall survival: 57% for all advanced SM patients (74% for SM-AHN, 43% for ASM, 17% for MCL) 1
• MCL subtype represents the strongest risk factor for poor outcomes 1
• Myeloablative conditioning superior to reduced-intensity regimens 1

For SM-AHN specifically: Consider allogeneic HCT as part of initial treatment when the AHN component requires HCT or if the AHN component progresses 1

For inadequate response or loss of response: Proceed to second-line therapy and consider allogeneic HCT after restaging 1

Prophylactic anti-mediator therapy (corticosteroids, antihistamines, anti-IgE antibody, epinephrine) must be used with conditioning regimen 1

Special Considerations

Bone Disease Management

• Supplement with calcium and vitamin D for osteopenia/osteoporosis 1
• Bisphosphonates can improve vertebral bone mineral density and resolve bone pain 1

Procedural Premedication

Premedications are mandatory for surgery, endoscopy, and invasive/radiologic procedures to prevent procedure-induced mast cell activation and anaphylaxis 1

Pain Management

Opioids (codeine, morphine) should be used with caution due to potential for triggering mast cell activation, but should NOT be withheld if needed since pain itself triggers mast cell activation 1

Monitoring

• ISM/SSM patients: H&P and labs every 6-12 months; DEXA scan every 1-3 years for osteopenia/osteoporosis 1
• Assess symptom burden using validated instruments (MSAF, MQLQ) 1

Multidisciplinary Management

Referral to specialized centers with expertise in mast cell disorders is strongly recommended, particularly for advanced SM 1. Comprehensive care requires collaboration among dermatologists, hematologists, pathologists, gastroenterologists, allergists, and immunologists 1

Enrollment in clinical trials investigating selective KIT D816 inhibitors is encouraged to enable further therapeutic advances 1