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. [45]
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.
Antihistamines (H1 and H2 receptor blockers) are part of initial pharmacologic treatment in systemic mastocytosis. [46] H1 antagonists are used to treat pruritus and flushing. Nonsedating antihistamines (eg, cetirizine, desloratadine) may be recommended for daytime use, and sedating ones (eg, diphenhydramine, hydroxyzine) for nighttime use. [47] Aspirin can be used in patients with flushing that is unresponsive to antihistamines. [46]
H2 receptor blockers have been used to treat gastric hypersecretion and peptic ulcer disease associated with systemic mastocytosis. Proton pump inhibitors are also useful for this.
Cromolyn sodium has demonstrated mutliple benefits in systemic mastocytosis. It has proved useful for relieving abdominal pain and diarrhea; pruritus, whealing, and flushing; and impaired cognition.
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. [48, 49] This use of omalizumab is not approved by the US Food and Drug Administration (FDA) but deserves further study. A randomized controlled trial of omalizumab in treatment-resistant systemic and cutaneous mastocytosis is in progress. [50]
Leukotriene antagonists, such as zafirlukast and montelukast, have also been used in the treatment of systemic mastocytosis.nPsoralen ultraviolet A therapy may provide transient relief of pruritus and may cause fading of skin lesions in some patients. Leukotriene antagonists, such as zafirlukast and montelukast, have also been used in the treatment of systemic mastocytosis. Anticholinergics have been used in the treatment of diarrhea.
Corticosteroids have been used to control malabsorption, ascites, abdominal pain refractory to cromolyn, bone pain, and diffuse cutaneous disease refractory to topical therapy, and to prevent anaphylaxis. [47] Oral prednisone (40-60 mg/d) for 10-20 days has been used in the treatment of malabsorption. Patients with osteopenia that does not respond to therapy may receive a trial of interferon alfa-2b.,
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. [51]
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. [25]
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. [12]
Tyrosine kinase inhibitors
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 hematologic 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 2021, the FDA approved avapritinib (Ayvakit) for treatment of adult patients with advanced systemic mastocytosis (AdvSM). [14] 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 AdvSM or indolent systemic mastocytosis in patients with platelet counts less than 50 × 109/L. [52]
In May 2023, the FDA extended approval of avapritinib to treatment of adults with indolent systemic mastocytosis. Approval was based on data from the double-blind, placebo-controlled PIONEER trial. [15] From baseline to week 24, avapritinib-treated patients had a decrease of 15.6 points in total symptom score (TSS) compared with a decrease of 9.2 points in the placebo group (P < 0.003). Over that period, the serum tryptase level fell by 50% or more in 76/141 patients (54%) in the avapritinib group, but in none of the 71 patients in the placebo group (P < 0.001). [53]
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. [16]
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.
Knowledge of the types of systemic mastocytosis that respond to tyrosine kinase inhibition continues to evolve, with new TKIs entering clinical trials. [54]
Other agents
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. [55] 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, a purine analog, has shown activity in all systemic mastocytosis subtypes, albeit in small numbers of patients. [56] National Comprehensive Cancer Network (NCCN) guidelines recommend cladribine as particularly useful in patients with systemic mastocytosis with an associated hematologic neoplasm who require rapid debulking of disease. [57] Cladribine is also used as salvage treatment in patients whose disease progresses after treatment with interferon-alpha, midostaurin, or other cytoreductive therapy. [56] Cladribine has myelosuppressive properties and may increase the risk of opportunistic infections. [56]
Thalidomide use has been studied in advanced systemic mastocytosis. [58]
In case reports, the Janus-associated kinase (JAK) inhibitor ruxolitinib has been shown to improve symptoms and quality of life in patients with systemic mastocytosis. [59] Dowse et al reported that ruxolitinib therapy objectively improved symptom burden and splenomegaly in a patient with systemic mastocytosis and associated clonal hematologic 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. [60]
Transplantation
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%. [61]
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. [62]
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.
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.
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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Systemic mastocytosis. Bone marrow aspirate, Romanowsky stain, high-definition magnification. Diagnosis is mastocytosis, and morphology is abnormal mast cells. This is a bone marrow smear from a patient with systemic mastocytosis. Several mast cells are present in this photograph. These mast cells are larger than normal mast cells and have more irregularly shaped nuclear outlines and less densely packed mast cell granules. Courtesy of the American Society of Hematology Slide Bank. Used with permission.
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Systemic mastocytosis. Bone marrow aspirate, toluidine stain, low magnification. Diagnosis is mastocytosis, and morphology is abnormal mast cells. This is a toluidine blue stain of a bone marrow smear from a patient with marrow involvement by systemic mastocytosis. Five mast cells are present in this field. The mast cell granules are metachromatic with the toluidine blue reaction. Courtesy of the American Society of Hematology Slide Bank. Used with permission.
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Systemic mastocytosis. Bone marrow biopsy, toluidine stain, low magnification. Diagnosis is mastocytosis, and morphology is abnormal mast cell infiltrate. This is a toluidine blue stain of a bone marrow biopsy from a patient with systemic mastocytosis. The mast cells are metachromatic with toluidine blue and contain numerous purple granules. Courtesy of the American Society of Hematology Slide Bank. Used with permission.
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Systemic mastocytosis. Lymph node biopsy. Diagnosis is mastocytosis, morphology is mast cell infiltrate, and the organ is the lymph nodes. This is a lymph node biopsy from a person with systemic mastocytosis. The mast cells have a characteristic perifollicular distribution. Courtesy of the American Society of Hematology Slide Bank. Used with permission.
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Systemic mastocytosis. Lymph node biopsy, chloroacetate esterase stain. Diagnosis is mastocytosis, and morphology is mast cell infiltrate. This is a portion of a lymph node biopsy from a patient with systemic mastocytosis. The mast cells are chloroacetate esterase positive, which is characterized by an orange granular appearance. Courtesy of the American Society of Hematology Slide Bank. Used with permission.
Tables
| Criteria | WHO | ICC |
|---|---|---|
| Major Criterion | Presence of multifocal and dense infiltrates of mast cells in bone marrow or in other extracutaneous tissues. Mast cells should be seen in aggregates of 15 cells or more. | Presence of multifocal dense infiltrates of tryptase- and/or CD117 positive mast cells detected in bone marrow or in other extracutaneous tissues. Mast cells should be seen in aggregates of 15 cells or more. |
Minor Criteria |
Spindle shape or atypical mast cell morphology (type I or type II) in 25% or more of the mast cells in biopsy sections of bone marrow or other extracutaneous organs | Spindle shaped or atypical immature morphology in more than 25% of mast cells in biopsy sections of bone marrow or other extracutaneous organs |
| Minor Criteria | Presence KIT-activating KIT point mutation(s) at codon 816 or in other critical regions of KIT in bone marrow or another extracutaneous organ |
Presence of KIT D816V mutation or other activating KIT mutation in bone marrow, peripheral blood, or other extracutaneous organs |
| Minor Criteria | Expression of CD25 and/or CD2 and/or CD30 in addition to normal mast cell markers |
Expression of CD25 and/or CD2 and/or CD30 in addition to normal mast cell markers |
| Minor Criteria | Serum/plasma total tryptase levels persistently greater than 20 ng/mL | Serum tryptase level persistently greater than 20 ng/mL. In cases of SM-AMN an elevated tryptase does not count as a SM minor criterion. |
