What is the best treatment approach for a patient with mastocytosis?

Treatment of Mastocytosis

The optimal treatment approach for mastocytosis depends critically on disease subtype: for cutaneous mastocytosis (especially pediatric), use symptomatic management with H1/H2 antihistamines and trigger avoidance; for indolent systemic mastocytosis, employ anti-mediator therapy with H1/H2 blockers ± cromolyn sodium; for advanced systemic mastocytosis, initiate cytoreductive therapy with KIT inhibitors, with allogeneic hematopoietic cell transplantation reserved for inadequate responders. 1

Disease Classification Determines Treatment Strategy

The 2024 NCCN guidelines emphasize that mastocytosis encompasses distinct entities requiring different therapeutic approaches 1:

• Cutaneous mastocytosis (CM): Primarily pediatric, generally benign with high spontaneous regression rates
• Systemic mastocytosis (SM): Most common adult form, subdivided into indolent (ISM/SSM) and advanced variants (ASM, SM-AHN, MCL)
• Mast cell sarcoma: Extremely rare malignant variant

Referral to specialized centers with multidisciplinary expertise (hematology, dermatology, allergy/immunology, gastroenterology) is strongly recommended for all mastocytosis patients. 1

Pediatric Cutaneous Mastocytosis: Conservative Management

Primary Approach

Cytoreductive therapy is strongly discouraged in pediatric cutaneous mastocytosis except in rare life-threatening aggressive variants, given the benign natural history and 75% complete resolution rate for mastocytomas and 56% resolution rate for urticaria pigmentosa. 2

Symptomatic Treatment

• H1 antihistamines are first-line for pruritus, flushing, urticaria, and tachycardia 2
• H1 + H2 antihistamine combination for severe pruritus and wheal formation refractory to H1 blockers alone 2
• Trigger avoidance: Control exposure to extreme temperatures, stress, and anxiety 2

Emergency Preparedness

All pediatric patients must carry two epinephrine auto-injectors for anaphylaxis management. During acute attacks with hypotension, wheezing, or laryngeal edema, administer intramuscular epinephrine in supine position 2

Monitoring Thresholds

• Baseline serum tryptase measurement is mandatory 2
• Tryptase >20 μg/L indicates increased mast cell burden requiring close observation, thorough evaluation, and sometimes hospitalization 2
• Bone marrow investigation is indicated if: tryptase significantly elevated, severe systemic symptoms present, organomegaly detected, or no response to initial symptomatic therapy 2

Indolent Systemic Mastocytosis: Anti-Mediator Therapy

Stepwise Symptom Management

All patients with systemic mastocytosis require anti-mediator drug therapy regardless of disease burden. 1 Treatment should be titrated based on symptom severity:

First-Line: Antihistamine Combination

• H1 + H2 blockers control skin symptoms (pruritus, flushing, urticaria, angioedema), gastrointestinal symptoms (diarrhea, cramping, nausea, vomiting), neurologic symptoms (headache, cognitive dysfunction), cardiovascular symptoms (presyncope, syncope, tachycardia), and pulmonary symptoms (wheezing, throat swelling) 1
• Standard doses should be titrated; higher doses may be necessary for refractory symptoms 1

Second-Line: Cromolyn Sodium

Cromolyn sodium is FDA-approved for mastocytosis and effective for gastrointestinal, cutaneous, and neurologic symptoms. 3 Clinical trials demonstrated:

• Improvement in diarrhea, abdominal pain, nausea, vomiting, urticaria, pruritus, flushing, headaches, and cognitive function 3
• Clinical benefit occurs within 2-6 weeks of treatment initiation 3
• Dosing: 200 mg four times daily 3
• Topical cromolyn cream/ointment reduces cutaneous flare-ups 1

Third-Line: Additional Agents

For symptoms refractory to antihistamines and cromolyn 1:

• Leukotriene receptor antagonists for skin and gastrointestinal symptoms
• Aspirin for symptoms associated with elevated urinary prostaglandin levels (caution: can trigger mast cell activation in some patients)
• Corticosteroids for severe refractory symptoms
• Omalizumab (anti-IgE) for mast cell activation symptoms insufficiently controlled by other therapies

Procedural Premedication

Premedications are mandatory for surgery, endoscopy, and invasive/radiologic procedures to prevent procedure-induced mast cell activation and anaphylaxis. 1 Use prophylactic antimediator therapy (corticosteroids, antihistamines, anti-IgE antibody, epinephrine as needed) 1

Advanced Systemic Mastocytosis: Cytoreductive Therapy

Treatment Indications

Cytoreductive therapy is recommended for all patients with advanced SM (ASM, SM-AHN, MCL) due to frequent organ damage and shortened survival. 1 This includes chronic MCL despite more indolent course compared to acute MCL 1

KIT Mutation-Directed Therapy

The presence of KIT D816V mutation (found in >80% of SM patients) guides treatment selection 1:

• KIT D816V-positive disease: Selective KIT D816 inhibitors are preferred agents 1
• KIT D816V-negative, well-differentiated SM with wild-type KIT: Imatinib achieved 50% overall response rate including complete responses 1
• Enrollment in clinical trials investigating highly selective KIT D816 inhibitors is strongly encouraged 1

SM-AHN Management Algorithm

Initial assessment must determine whether the SM component or associated hematologic neoplasm (AHN) component requires more immediate treatment. 1 This determination requires:

• Comprehensive evaluation of relative disease burden/stage of SM and AHN components in bone marrow and extracutaneous organs
• Consider organ-directed biopsy (e.g., liver biopsy for liver function abnormalities) to determine whether organ damage relates to SM, AHN, or both 1

Allogeneic Hematopoietic Cell Transplantation

Allogeneic HCT should be considered for advanced SM patients after adequate response to prior treatment, or as second-line therapy with restaging for those with inadequate response or loss of response. 1

Key HCT considerations 1:

• Myeloablative conditioning regimens associated with better survival than reduced-intensity regimens
• 3-year overall survival: 74% for SM-AHN, 43% for ASM, 17% for MCL
• MCL subtype is the strongest risk factor for poor overall survival
• For SM-AHN: Consider HCT as part of initial treatment when AHN component requires HCT or if AHN component progresses
• Prophylactic antimediator therapy (corticosteroids, antihistamines, anti-IgE antibody, epinephrine) should be used with conditioning regimen

Critical Caveat

The role of KIT inhibitors post-transplant to minimize relapse has not been formally studied 1

Universal Recommendations Across All Subtypes

All mastocytosis patients should carry two epinephrine auto-injectors for anaphylaxis management. 1 Patient and family education regarding trigger avoidance, emergency management protocols, and disease-specific considerations for infections, vaccinations, dental procedures, and surgery is fundamental 2