Systemic Mastocytosis Treatment & Management

Updated: Jun 21, 2021
  • Author: Devapiran Jaishankar, MBBS; Chief Editor: Emmanuel C Besa, MD  more...
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Treatment

Medical Care

Therapy for systemic mastocytosis (systemic mast cell disease) is primarily symptomatic; no therapy is curative. Treatment modalities include the management of (1) anaphylaxis and related symptoms, (2) pruritus and flushing, and (3) intestinal malabsorption. The principles of treatment include control of symptoms with measures to decrease mast cell activation. [39]

Treatment of anaphylaxis and other signs and symptoms

Epinephrine is used in acute anaphylaxis. H1 and H2 receptor blockers are used to control anaphylactic symptoms. Acute anaphylaxis can be treated with 0.3 mL of a 1:1000 dilution of epinephrine. In children, the dose is 0.01 mL/kg (up to 0.3 mL) administered every 10-15 minutes as needed.

Corticosteroids have been used to control malabsorption, ascites, and bone pain and to prevent anaphylaxis. Oral prednisone (40-60 mg/d) for 10-20 days has been used in the treatment of malabsorption. Cromolyn is also helpful for decreasing bone pain and headaches and for improving skin symptoms. Patients with osteopenia that does not respond to therapy may receive a trial of interferon alfa-2b.

Classic H1 antagonists, such as diphenhydramine and hydroxyzine, have been used to treat pruritus and flushing. Mast cell stabilizers, such as ketotifen, have also been used to treat pruritus and whealing. Aspirin can be used in conditions in which H1 and H2 receptor blockers do not prevent vascular collapse. Leukotriene antagonists, such as zafirlukast and montelukast, have also been used in the treatment of systemic mastocytosis.

In patients with anaphylaxis that is recurrent or refractory to conventional therapies, omalizumab (anti-immunoglobulin E [IgE]), a humanized monoclonal antibody that inhibits the binding of IgE to mast cells, reduced the frequency of anaphylaxis in some patients with systemic mastocytosis. [40, 41] This use of omalizumab is not approved by the US Food and Drug Administration (FDA) but deserves further study. 

H2 receptor blockers have been used to treat gastric hypersecretion and peptic ulcer disease associated with systemic mastocytosis. Proton pump inhibitors are also useful.

Psoralen ultraviolet A therapy may provide transient relief of pruritus and may cause fading of skin lesions in some patients.

Anticholinergics have been used in the treatment of diarrhea. Disodium cromolyn has been used in the treatment of abdominal cramping and diarrhea.

Osteoporotic fractures are common in patients with mastocytosis. In contrast to osteoporosis in the general population, males are heavily affected. The risk of osteoporotic fractures increases with age, as in the general population, but starts at younger ages. Patients with mastocytosis should be monitored for osteoporosis. [42]

Antiresorptive treatment with bisphosphonates is a rational treatment for osteoporosis in patients with systemic mastocytosis. A few small studies support this approach, most of which have used zoledronic acid. [22]

Treatment of Primary Disease

Medical therapy for systemic mastocytosis is generally considered as initial treatment for patients with advanced systemic mastocytosis (aggressive systemic mastocytosis, systemic mastocytosis with an associated hematological neoplasm, mast cell leukemia), as bridging treatment to undergo allogenic hematopoietic cell transplantation, or in selected patients with indolent systemic mastocytosis or smoldering systemic mastocytosis who suffer recurrent anaphylaxis despite treatment with all other options.

Various chemotherapy regimens have been used in the treatment of advanced systemic mastocytosis. Chemotherapy has not been particularly successful in the management of this disease. [11]

Tyrosine kinase inhibitors (TKIs) have shown benefit in treatment of systemic mastocytosis. In 2017, the FDA approved midostaurin (Rydapt), which inhibits multiple receptor tyrosine kinases, for aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL), collectively referred to as advanced systemic mastocytosis.

Approval of midostaurin was based on an open-label study in 89 patients with mastocytosis-related organ damage. Of those, 16 had ASM, 57 had SM-AHN, and 16 had MCL. The overall response rate was 60% (95% confidence interval [CI], 49-70%); 45% of the patients had a major response, which was defined as complete resolution of at least one type of mastocytosis-related organ damage. Response rates were similar regardless of the subtype of advanced systemic mastocytosis, KIT mutation status, or exposure to previous therapy. The median overall survival was 28.7 months, and the median progression-free survival was 14.1 months. In the 16 patients with MCL, the median overall survival was 9.4 months (95% CI, 7.5 to not estimated). Dose reduction owing to toxic effects occurred in 56% of the patients; re-escalation to the starting dose was feasible in 32% of those patients. [13]

In June 2021, the FDA approved avapritinib (Ayvakit) for treatment of adult patients with advanced systemic mastocytosis. [43] Avapritinib is an oral type I multi-kinase inhibitor with highly selective and potent activity against mutated KIT (including D816V) and PDGFRA A-loop mutants. Approval was based on findings from the single-arm, open-label EXPLORER and PATHFINDER trials, in which the combined overall response rate in all evaluable patients was 57%, with 28% complete remissions and 28% partial remissions. Median time to response was 2.1 months, and median duration of response was 38.3 months. Avapritinib is not recommended for the treatment of patients with advanced systemic mastocytosis with platelet counts of less than 50 × 109/L. [44] {ref4767-INVALID REFERENCE}

Ripretinib, a type II switch control kinase inhibitor with activity against multiple KIT and PDGFR mutants, showed antineoplastic activity in preclinical models. A phase II study (NCT02571036) for advanced systemic mastocytosis is in progress. Based on the expression of CD123 (interleukin 3 [IL-3] receptor-alpha) on neoplastic mast cells, an anti-CD123 antibody linked to diphtheria toxin, SL-401, is being evaluated in clinical trials for patients with advanced systemic mastocytosis.

The TKI imatinib mesylate (Gleevec) may be useful in those types of systemic mastocytosis that do not have mutations of the codon 816 on the c-kit gene and carry the wild-type kit. The common mutation KIT D816V is resistant to imatinib. Case reports have reported sensitivity to imatinib for systemic mastocytosis with mutations in exons 8 to 10 of KIT. Imatinib mesylate may also be useful in a subtype of systemic mastocytosis that carries the FIP1L1-PDGFRA rearrangement. [12]  Knowledge of the types of systemic mastocytosis that respond to tyrosine kinase inhibition continues to evolve.

Interferon-alfa may be beneficial. Responses—including major responses—have been seen in some patients with smoldering systemic mastocytosis or slowly progressing ASM, but usually no response is seen in ASM or MCL with rapid progression. [45] In a retrospective analysis, 57% had treatment responses but only 21% had a major response. Other published studies show no response to interferon-alfa. It is perhaps not indicated in patients with indolent disease.

Cladribine was reported to have yielded a major response in one patient. Responses may be transient. Cladaribine has myelosuppressive properties and, at this time, is not recommended for patients with indolent disease. [46]

There have been anecdotal reports of thalidomide use in advanced systemic mastocytosis.

Dowse et al reported that treatment with the JAK 1/2 inhibitor ruxolitinib objectively improved symptom burden and splenomegaly in a patient with systemic mastocytosis and associated clonal hematological non–mast cell lineage disease. Mutation analyses demonstrated no evidence of JAK2, kit,MPL, or CALR mutations. After 4 months of treatment, ruxolitinib was tapered over a 10-day period with no symptom flare. These authors note that many of the inflammatory cytokines produced by mast cells utilize the JAK1/JAK2-STAT pathway for signaling, and that reduction in cytokine levels could explain the abatement of systemic symptoms seen in this case. [47]

Allogeneic hematopoietic cell transplantation is the only treatment that has the proven ability to cure advanced systemic mastocytosis but is considered experimental and is being pursued in clinical trials at the US National Institutes of Health (NIH). The largest retrospective series, with 57 patients, reported 70% overall response rate (28% complete response, 21% stable disease) and 57% 3-year overall survival (OS). The following rates of 3-year OS were reported: SM-AHN (38 patients) 74%; MCL (12 patients) 43%; ASM (7 patients) 17%. [48]

 

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Surgical Care

Some surgical procedures, such as laparoscopy and bone marrow biopsy (and sometimes endoscopy), can precipitate anaphylaxis, and patients undergoing these procedures should be closely monitored. [49]

Administration of beta-blockers is contraindicated in patients with systemic mastocytosis who are undergoing surgery, because these agents may interfere with endogenous epinephrine and may precipitate anaphylaxis. Also avoid alpha-blockers and cholinergic antagonists.

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Consultations

Patients thought to have severe systemic mastocytosis that requires chemotherapy may need consultation with hematologists, dermatologists, and immunologists. A bone marrow biopsy is necessary in such cases, and supervision by a hematology/oncology specialist may be needed.

Patients with severe GI symptoms may need endoscopic procedures and biopsies to exclude other causes of malabsorption. Consultation with a gastroenterologist is helpful in such situations.

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Activity

Insect stings can precipitate anaphylaxis; therefore, patients with systemic mastocytosis should exercise great care in avoiding stings when engaging in outdoor activities.

Patients should carry an epinephrine autoinjector at all times and should be taught to use the device in case of emergency.

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