What is the treatment for systemic mastocytosis?

Treatment of Systemic Mastocytosis

The treatment of systemic mastocytosis should be tailored to the specific disease variant, with indolent forms managed primarily with anti-mediator therapy while advanced forms require cytoreductive agents such as midostaurin, cladribine, or interferons. 1

Disease Classification and Initial Approach

Systemic mastocytosis (SM) is classified into several variants that guide treatment:

• Indolent systemic mastocytosis (ISM)
• Smoldering systemic mastocytosis (SSM)
• Advanced systemic mastocytosis (AdvSM):
  • Aggressive systemic mastocytosis (ASM)
  • Systemic mastocytosis with associated hematologic neoplasm (SM-AHN)
  • Mast cell leukemia (MCL)

For All Patients with Systemic Mastocytosis:

• Referral to specialized centers with expertise in mastocytosis is strongly recommended 1
• All patients should carry two epinephrine auto-injectors for emergency management of anaphylaxis 1
• Patients should be counseled about mast cell activation triggers to avoid 1
• Multidisciplinary collaboration with subspecialists is essential, especially for procedures requiring anesthesia 1

Treatment Algorithm for Indolent and Smoldering SM

First-Line Approach:

• Anti-mediator drug therapy to control mast cell activation symptoms 1
• Regular monitoring with physical examination and labs every 6-12 months 1
• DEXA scan every 1-3 years for patients with osteopenia/osteoporosis 1
• Assessment of symptom burden using validated tools (MSAF and MQLQ) 1

Anti-Mediator Drug Therapy Options:

1. H1 antihistamines for skin symptoms (pruritus, flushing, urticaria), neurologic symptoms, and cardiovascular symptoms 1
2. H2 antihistamines for gastrointestinal symptoms and to complement H1 blockers 1
3. Cromolyn sodium for gastrointestinal symptoms (diarrhea, abdominal pain, nausea) and some cutaneous symptoms 1
4. Leukotriene receptor antagonists for symptoms refractory to antihistamines 1
5. Aspirin for symptoms associated with elevated prostaglandin levels (caution: may trigger mast cell activation in some patients) 1
6. Omalizumab for refractory symptoms 1

For Inadequate Response or Disease Progression:

• Re-staging and consideration of cytoreductive therapy if progressing to advanced forms 1
• In selected cases of ISM/SSM with severe refractory symptoms or bone disease, cladribine or interferon-alfa may be considered 1

Treatment Algorithm for Advanced Systemic Mastocytosis

First-Line Options:

• Midostaurin - FDA-approved for advanced SM 1, 2
• Cladribine - particularly useful when rapid debulking of disease is required 1
• Imatinib - only if KIT D816V mutation negative or if eosinophilia is present with FIP1L1-PDGFRA fusion gene 1
• Interferons (interferon alfa-2b, peginterferon alfa-2a, or peginterferon alfa-2b) ± prednisone - more suitable for slowly progressive disease 1
• Clinical trials of novel agents should be considered 1, 2

For SM with Associated Hematologic Neoplasm (SM-AHN):

• Initial assessment to determine whether SM or AHN component requires more immediate treatment 1
• Treatment may target either or both components depending on disease burden 1

For Mast Cell Leukemia (MCL):

• Aggressive cytoreductive therapy 1
• Consider allogeneic hematopoietic stem cell transplantation 1, 3

Monitoring and Response Assessment

• Response assessment based on improvement of disease-related symptoms and/or B-findings in ISM/SSM 1
• For advanced SM, monitor for organ damage, hepatosplenomegaly, and disease-related symptoms 1
• Bone marrow biopsy, serum tryptase levels, and additional staging studies as clinically indicated 1

Emerging Therapies

Recent advances have led to new targeted therapies:

• Avapritinib - recently approved for advanced SM and now also for indolent SM 2
• Novel KIT inhibitors in development (ripretinib, bezuclastinib, elenestinib, masitinib) 2
• Other targets under investigation include Bruton's kinase, IL-6, and CD33 2

Common Pitfalls and Caveats

• Misdiagnosis or delayed diagnosis due to heterogeneous presentation 3
• Failure to recognize and manage anaphylaxis risk in all SM patients 1
• Undertreatment of bone complications (osteoporosis is common in SM) 1
• Not considering cytoreductive therapy in chronic MCL despite its indolent course 1
• Overlooking the need for premedications before procedures 1
• Failing to monitor for progression from indolent to advanced disease 1

Remember that while indolent SM patients have near-normal life expectancy, advanced SM significantly reduces survival, making appropriate treatment selection critical 3.