Systemic Mastocytosis 

Systemic mastocytosis is a heterogeneous clonal disorder of the mast cell and its precursor cells. The clinical symptoms and signs of systemic mastocytosis result from mediator release and the accumulation of these clonally derived mast cells in different tissues, including bone marrow, skin, the GI tract, the liver, and the spleen.[1, 2, 14, 3, 4]

Systemic mastocytosis is characterized by mast cell infiltration of extracutaneous organs, which is in contrast to cutaneous mast cell disorders, which involve only the skin. Ehrlich first described mast cells in 1877 when he found cells that stained metachromatically with aniline dyes.[15] He called these cells "mast Zellen" because the cells were distended with granules (ie, the botanical definition of mast, which refers to an accumulation of nuts on the forest floor).

Cutaneous mastocytosis was identified in the late 19th century. Sangster first described urticaria pigmentosa, which is one of the cutaneous mast cell disorders, in 1878. In 1933, Touraine suggested that this disease could involve internal organs. In 1949, Ellis first established at autopsy that cutaneous mastocytosis can also involve internal organs. An autopsy of a 1-year-old infant revealed mast cell infiltration of the bone marrow, lymph nodes, spleen, kidneys, and pancreas.

Systemic mastocytosis (systemic mast cell disease) is characterized by mast cell infiltration of skin and extracutaneous organs. Mast cells typically infiltrate the bone marrow and consequently affect the peripheral blood and coagulation system.[16] Mast cells are derived from CD34+/ KIT+ pluripotent hematopoietic cells in the bone marrow.[17] The neoplastic clones of mast cells express abnormal cell surface markers CD25 and/or CD2.

Mueller et al reported that the adhesion molecule CD44 is expressed in systemic mastocytosis cell lines and correlates with the aggressiveness of the disorder. They found that serum levels of soluble CD44 were higher in advanced systemic mastocytosis compared with indolent systemic mastocytosis or cutaneous mastocytosis, and correlated with overall and progression-free survival.[18]

The marrow cellularity ranges from normocellular to markedly hypercellular changes. Erythropoiesis is usually normoblastic without any significant abnormalities. Eosinophilia is a common bone marrow histology finding (see Workup, Histologic Findings). Hypocellular bone marrow and myelofibrosis can be observed in late stages of systemic mastocytosis.

Ho et al evaluated the plasma level of pro–major basic protein (proMBP), a precursor of major basic protein that is contained in eosinophil cytoplasmic granules, in eosinophilic and chronic myeloproliferative disorders.[19] They found that the plasma proMBP level was significantly higher in patients with systemic mastocytosis with eosinophilia, idiopathic eosinophilia, and myeloproliferative disorders with eosinophilia than in healthy controls. In addition, the median proMBP level of patients with postpolycythemic myeloid metaplasia and those with postthrombocythemic myeloid metaplasia was significantly higher than in those with polycythemia vera and essential thrombocythemia.[19]

Ho et al also reported that the presence and size of splenomegaly correlated with proMBP levels in certain conditions. In patients with idiopathic eosinophilia, the presence of splenomegaly was significantly associated with elevated proMBP.[19] In 76 patients with de novo myelofibrosis, the proMBP level correlated with spleen size and the presence of hypercatabolic symptoms. All of these findings led the investigators to conclude that "significantly elevated levels of proMBP in myelofibrosis patients implies that proMBP could be an important stromal cytokine in bone marrow fibrosis."[19]

Focal mast cell lesions in the bone marrow are found in approximately 90% of adult patients with systemic mastocytosis. A typical mast cell has a spindle-shaped nucleus and fine eosinophilic granules, which can be visualized at high magnification. These cells are likely to return positive findings upon Giemsa staining. Peripheral blood can show anemia, leukopenia, thrombocytopenia, and lymphopenia. The most common abnormality found in the peripheral blood is anemia. In some patients, eosinophilia, leukocytosis, basophilia, thrombocytosis, and monocytosis can be observed.

Spleen and lymphoid tissue involvement is a significant manifestation of systemic mastocytosis. Mast cell infiltrates in the spleen can cause nodular areas that could be confused with lymphomas. A biopsy specimen from the spleen can reveal findings similar to a myeloproliferative disorder or hairy cell leukemia. Histopathology studies of the spleen can reveal two types of involvement: (1) diffuse infiltration of the red pulp and sinuses and (2) focal infiltration of the white pulp. Lymph node biopsy can show mast cell infiltrates, particularly in the paracortex. Follicles and medullary involvement can be observed in some cases.

The immune system is affected as a consequence of the previously mentioned pathology. Mast cell products, such as interleukin 4 (IL-4) and IL-3, may induce immunoglobulin E (IgE) synthesis and augment T-cell differentiation toward an allergic phenotype. Mast cells also release histamine, which results in inhibition of IL-2.

GI manifestations result from microscopic infiltration of the liver, pancreas, and intestines by mast cells.[20, 21] Abdominal pain has been attributed to peptic ulcer disease, involvement of the GI tract by mast cells, mediators released by mast cells, and motility disorders. GI involvement includes the following:

• Esophagus (eg, esophagitis, stricture, varices)
• Stomach (eg, peptic ulcer disease, mucosal lesions)
• Small intestine (eg, dilatated small bowel, malabsorption)
• Colon and rectum (eg, multiple polyposis, diverticulitis)
• Liver (eg, hepatomegaly and portal hypertension, ascites, sclerosing cholangitis, Budd-Chiari syndrome)

Osteoporosis is a common manifestations of systemic mastocytosis, particularly in adults, and can result in vertebral fractures. The mechanism of bone loss is not yet fully elucidated, but stimulation of osteoclast activity through RANK-RANKL signaling appears to be most important. Histamine and other cytokines also play significant roles.[22]

Systemic mastocytosis has many features in common with myeloproliferative disorders. However, the 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia no longer lists mastocytosis under the broad heading of  myeloproliferative neoplasms (MPNs), and instead assigns it to a separate category.[23]

More than 95% of adults with systemic mastocytosis have exon 17 KIT mutations, most commonly the KIT D816V mutation. This gain of function mutation in the KIT receptor was detected by polymerase chain reaction (PCR) techniques in 68% of bone marrow specimens in patients with systemic mastocytosis.[9] Additional molecular aberrations are frequently identified in TET2, SRSF2, ASXL1, CBL, RUNX1, DNMT3A, and in the RAS pathway.[24]

The association between JAK2 V617F and systemic mastocytosis is weak and was noted in just 4% of patients with systemic mastocytosis (all had associated non–mast cell hematological disease).[9] The incidence of TET2 mutations (reportedly as high as 29% in KIT-positive systemic mastocytosis) seems to influence the phenotype without affecting the prognosis.[25] Another finding that may prove relevant to the pathogenesis of systemic mastocytosis is a constitutive expression of the stress-related survival factor heat-shock protein 32 (Hsp32) in a human mast cell tumor line.[26]

Frequency

Systemic mastocytosis is an extremely rare disorder in the United States; the specific incidence has not been reported. Likewise, epidemiologic data on the incidence of systemic mastocytosis are lacking. Some studies in Great Britain showed two cases per year from a study population of 300,000.

Mortality/morbidity

Systemic mastocytosis is a progressive neoplastic disorder that has no known curative therapy. Survival in patients with indolent systemic mastocytosis, with a median survival of 198 months, is not significantly different from the general population. However, median survival with aggressive systemic mastocytosis (ASM) is 41 months and that with systemic mastocytosis with associated hematological non–mast cell disorder (SM-AHNMD) is 24 months. Acute mast cell leukemia has the poorest prognosis, with a median survival of 2 months.

Early evolution into acute leukemia may occur in as many as 32% of patients with aggressive mastocytosis.[14] Leukemic transformation is rare with indolent systemic mastocytosis.[9]

Sex- and age-related demographics

A slight male preponderance in the incidence of mastocytosis is noted.[9] Mastocytosis is more common in children than in adults, and it is usually transient and self-limited in children compared with the adult version. Onset is before age 2 years in 55% of patients and is from 2 and 15 years in 10% of patients.

In pediatric patients, progression of cutaneous mastocytosis to systemic mastocytosis is uncommon. In adults, however, cutaneous mastocytosis frequently progresses to systemic disease.[3]

In adults, the median age at diagnosis of systemic mastocytosis is 55 years. Lim et al reported that patients with indolent systemic mastocytosis were younger and symptomatic for a longer duration of time as compared with patients with ASM or SM-AHNMD.[9]

Patients with systemic mastocytosis (systemic mast cell disease) can have signs and symptoms related to involvement of the hematopoietic system, the gastrointestinal (GI) tract, the skin, and the immune system. Additional coexistent hematologic disorders may also be a source of clinical manifestations. Systemic mastocytosis is known to be associated with a number of other hematologic diseases, including the following:

• Hypereosinophilic syndrome
• Castleman disease
• Monoclonal gammopathy
• Hairy Cell leukemia
• Non-Hodgkin lymphoma
• Polycythemia vera
• Primary thrombocythemia

The incidence of various symptoms reported in one of the largest case series of systemic mastocytosis is as follows[9] :

• GI symptoms - 65%
• Cutaneous symptoms - 53%
• Mediator-related symptoms - 47%
• Constitutional complaints - 42%
• Urticaria pigmentosa - 41%
• Musculoskeletal symptoms - 31%
• Idiopathic and/or recurrent anaphylactoid reactions - 17%

Many GI manifestations are observed in patients with systemic mastocytosis. Abdominal pain is the most common GI symptom, followed, by diarrhea, nausea, and vomiting. Symptoms and signs of gastroesophageal reflux disease (GERD) and malabsorption are noted in some patients. Duodenal ulceration and severe duodenitis is seen in 30% to 50% of untreated cases.[24]

Some studies show precipitation of GI manifestations by agents such as penicillin, narcotics, cocaine, aspirin,[27] nonsteroidal anti-inflammatory drugs (NSAIDs), and dipyridamole (Persantine). These drugs can also provoke anaphylaxis, vascular collapse, or syncope.

Pruritus seem to be as common as GI complaints in patients with systemic mastocytosis. Patients may present with pruritus and flushing if their mastocytosis is associated with cutaneous abnormalities.

While the risk of recurrent anaphylactoid reaction is well known, it appears that the association with Hymenoptera (eg, bee, wasp) stings is stronger than the association with other food- and drug-induced systemic reactions.[5]

Caution during anesthesia in the endoscopic and surgical suites is advised. Rare anaphylactoid reactions to intravenous contrast have been reported.[6]

Anemia and coagulopathy (eg, acquired von Willebrand syndrome[28] ) may be observed.

Physical examination findings in patients with systemic mastocytosis (systemic mast cell disease) may include the following:

• Signs of anemia, such as pallor, can be noted in some patients.

• Hepatomegaly (27%), splenomegaly (37%), and lymphadenopathy (21%) can be found in adult patients.[9]

• GI bleeding may be present; contributing factors may include thrombocytopenia caused by splenomegaly, hypersplenism, and a rise in portal pressure; heparin release from mucosal mast cells; and vitamin K malabsorption resulting from mast cell involvement.

• Patients may have signs of urticaria (41%) if the mastocytosis is associated with cutaneous involvement; in these situations, flushing can be noted upon physical examination.

• Osteolysis and pathological fractures are rarely noted (7%).

Mutations of the c-kit proto-oncogene may cause some forms of mastocytosis.[29, 30, 21] Mutations of c-kit in mast cell tumor lines and the ability of c-kit to cause mast cell proliferation and transformation suggest that these mutations are necessary in most forms of mastocytosis.

Several types of somatic activating and nonactivating mutations in c-kit have been demonstrated to cause systemic mastocytosis. One of the common mutations found in systemic mastocytosis is an exon 17 D816V KIT receptor mutation. Most, if not all, adult patients with systemic mastocytosis carry this mutation.[31] In the majority of patients, mastocytosis does not appear to be inherited, but rare familial cases with KIT mutations have been reported.

The complete blood cell count can show anemia, thrombocytopenia, and leukocytosis. The most common abnormality found in the peripheral blood is anemia (45%). In some patients with systemic mastocytosis, the following abnormalities can be observed in peripheral blood:

• Eosinophilia
• Basophilia
• Thrombocytosis
• Monocytosis

Total serum tryptase levels of 20 ng/mL or higher in a baseline serum sample that is associated with a ratio of total–to–beta-tryptase ratio greater than 20:1 is suggestive of systemic mastocytosis.[10] More than 50% of patients have a high tryptase level using the cut-off value of 11.5 ng/mL. However, a normal serum tryptase level does not exclude the diagnosis of systemic mastocytosis.[32]

Measurements of urinary N-methylimidazole are useful in some patients with systemic mastocytosis. Donker et al reported that this marker had 95% accuracy for predicting bone marrow involvement in patients with clinical findings suggestive of indolent systemic mastocytosis.[33]

Lueke et al developed an assay for measurement of urinary leukotriene E4 (LTE4) and confirmed that median urine LTE4 concentrations were significantly higher in patients with systemic mastocytosis (median 97 pg per mg creatinine versus 50 pg/mg cr.; P< 0.01), with 48% sensitivity and 84% specificity for the disorder. These authors incorporated LTE4 into a panel of urinary biomarkers to provide a screening tool for systemic mastocytosis.[34] Additional biomarker results and accuracy were as follows:

• N-methyl histamine (NMH): >200 ng/mL – Clinical sensitivity 71%
• 11ß-prostaglandin F2α (BPG): >1000 ng/mL  – Clinical sensitivity  53%  

Some imaging studies may be necessary in patients with systemic mastocytosis in order to identify the extent and stage of the disease, as follows:

• Patients with abdominal pain may require GI radiography, ultrasonography, or liver-spleen computed tomography (CT) scanning

• Skeletal surveys and bone CT scanning may be necessary in patients with suspected bone involvement.

Cytogenetic data indicate that about 20% of patients with systemic mastocytosis have an abnormal karyotype. These include trisomy 8; monosomy 7; del (13q); del(5q); trisomy 10, 6, and 19; del(20q); and trisomy X. Cytogenetic abnormalities are more often seen with aggressive systemic mastocytosis (ASM) and systemic mastocytosis with associated hematological non–mast cell disorder (SM-AHNMD) than with indolent systemic mastocytosis.[9]

Molecular testing for KIT D816V mutation is universally positive, whereas JAK2 V617F is rarely positive (4%). In the absence of the typical KIT D816V mutation, a search for other mutations by sequencing the entire KIT gene should be considered, as this can influence the choice of treatment.[35]

The mast cell clone is CD117 positive and CD25 and/or CD2 positive.

Bone marrow mast cells reveal 54% CD2 positivity and 93% CD25 positivity on flow cytometry, whereas on immunohistochemistry CD2 positivity is 17% and CD25 positivity is 100%.[9]

Expression of CD25 on mast cells is seen in systemic mastocytosis but is not noted in reactive states of mast cell hyperplasia.[36]

Bone marrow aspiration and biopsy is essential for the diagnosis of systemic mastocytosis.[37] The following procedures may also be indicated in patients with systemic mastocytosis:

• When GI symptoms are present, perform GI procedures (eg, barium studies, endoscopy) to help confirm the diagnosis. Interpretation of GI biopsies is difficult because mast cells are normally abundant in these tissues; in contrast to mast cell numbers, however, expression of CD25 on GI mast cells is a useful diagnostic marker for presence of systemic mastocytosis.[38]

• Patients with hepatomegaly can show evidence of mast cell infiltration on liver biopsy specimens.

• Skin biopsy may be warranted in patients with skin manifestations.

Marrow cellularity ranges from normocellular to markedly hypercellular changes. Erythropoiesis is usually complete without any significant changes. Eosinophilia is a common finding from bone marrow histology. Hypocellular bone marrow and myelofibrosis are usually observed in late stages of systemic mastocytosis. Focal mast cell lesions in the bone marrow are found in approximately 90% of affected adult patients. A bone marrow smear is shown below.

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.

A typical mast cell has a spindle-shaped nucleus and fine eosinophilic granules visualized at high magnification. These cells are likely to return positive findings upon Giemsa staining. Other stains used to identify mast cells are toluidine blue, chloroacetate esterase, aminocaproate esterase, and tartrate-resistant acid phosphatase. Examples are shown in the images below.

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.

Spleen and lymphoid tissue involvement is an important manifestation in systemic mastocytosis. Mast cell infiltrates in the spleen can cause nodular areas that could be confused with lymphomas. A biopsy sample from the spleen can reveal findings similar to a myeloproliferative disorder or hairy cell leukemia. Histopathology of the spleen can show two types of involvement: (1) diffuse infiltration of the red pulp and sinuses and (2) focal infiltration of the white pulp.

Lymph node biopsy can show mast cell infiltrates, particularly in the paracortex. Follicles and medullary involvement can be observed in some cases. Lymph node biopsy samples are shown below.

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.

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.

Diagnostic criteria

Diagnosis of systemic mastocytosis requires the presence of a major criterion plus one minor criterion, or the presence of three minor criteria. The major diagnostic criteria are the 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. Tryptase immunohistochemistry or metachromatic staining (eg, Giemsa, toluidine blue) should be used to confirm the presence of mast cells; immunohistochemical staining for mast cells is more reliable than metachromatic staining.

The major criteria may be absent in early disease. In this situation, the minor criteria are used to make the pathological diagnosis. Three of the following four minor criteria are required to make the diagnosis:

• Spindle shape or atypical mast cell morphology in 25% or more of the mast cells
• Expression of CD25, with or without CD2, in addition to normal mast cell markers
• Serum/plasma tryptase levels persistently greater than 20 ng/mL
• A codon-816 c- kit mutation in peripheral blood, bone marrow, or involved tissue

Types of mastocytosis

The WHO classifies systemic mastocytosis into subtypes, depending on the presence of typical clinical findings (B and C findings). B findings, which refer to organ involvement without organ failure, are as follows:

• Elevated grade of mast cell infiltration - Bone marrow biopsy showing >30% infiltration by mast cells (focal, dense aggregates) and/or serum total tryptase level >200 mg/mL.
• Dysmyelopoiesis - Signs of myelodysplasia or myeloproliferation in non–mast cell lineage(s) but insufficient criteria for definitive diagnosis of an associated hematologic neoplasm , with the blood picture normal or only slightly abnormal.
• Organomegaly on palpation or imaging - Hepatomegaly without impairment of liver function, and/or palpable splenomegaly without hypersplenism, and/or lymphadenopathy.

C findings, which refer to organ involvement with organ dysfunction, are as follows:

• Cytopenias – Bone marrow dysfunction manifested by one or more cytopenia (neutrophil count [ANC] < 1 × 10 ⁹/L, hemoglobin < 10 g/dL, or platelets < 100 × 10 ⁹/L) with no obvious non–mast cell hematopoietic malignancy.
• Palpable hepatomegaly with elevated liver enzyme levels, ascites, and/or portal hypertension.
• Skeletal involvement with large osteolytic lesions and/or severe osteoporosis and pathologic fractures.
• Palpable splenomegaly with hypersplenism.
• Malabsorption with hypoalbuminemia and weight loss due to gastrointestinal mast cell infiltrates.

WHO subtypes of systemic mastocytosis are as follows:

• Indolent systemic mastocytosis (ISM) – This is the most common form of systemic mastocytosis. No C findings are present. ISM follows a stable or slowly progressing clinical course and carries a good prognosis in most patients.
• Smoldering systemic mastocytosis (SSM) – Diagnostic criteria include the presence oftwo or more B findings and the absence of C findings.
• Systemic mastocytosis with an associated hematological neoplasm (SM-AHN) – Diagnostic criteria include the presence of aclonal hematologic non–mast cell lineage disorder (eg, myelodysplastic syndrome [MDS], myeloproliferative neoplasm [MPN], acute myeloid leukemia [AML], lymphoma)
• Aggressive systemic mastocytosis (ASM) – Diagnostic criteria include the presence of C findings, with no features of mast cell leukemia.
• Mast cell leukemia (MCL) – Bone marrow biopsy shows a diffuse infiltration, usually compact, by atypical, immature mast cells. Bone marrow aspirate smears show ≥20% mast cells.

SM-AHN, ASM, and MCL are collectively referred to as advanced systemic mastocytosis.

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]

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.

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.

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.

The tyrosine kinase inhibitors (TKIs) midostaurin and imatinib have each been approved by the US Food and Drug Administration (FDA) for various types of mastocytosis.[12, 13, 50] In a case report, the Janus-associated kinase (JAK) inhibitor ruxolitinib was shown to improve symptoms and quality of life in a patient with systemic mastocytosis.[51] A phase I study with the TKI avapritinib has shown favorable reponses, with improvement in symptom burden and quality of life scores.[52]

Class Summary

The tyrosine kinase inhibitors midostaurin and imatinib have each been approved by the FDA for various types of mastocytosis. A case report of ruxolitinib, a Janus Associated Kinase (JAK) inhibitor, was shown to improve symptoms and quality of life a patient with systemic mastocytosis.

Midostaurin (Rydapt)

Midostaurin has demonstrated the ability to inhibit KIT signaling, cell proliferation, and histamine release and induce apoptosis in mast cells. It is indicated for adults with advanced mastocytosis which includes aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL).

Imatinib (Gleevec)

Imatinib is a protein-tyrosine kinase inhibitor that inhibits the BCR-ABL tyrosine kinase. It is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-kit, and inhibits PDGF-and SCF-mediated cellular events. In vitro, imatinib inhibits proliferation and induces apoptosis in GIST cells, which express an activating c-kit mutation. It is indicated for adults with aggressive systemic mastocytosis without the D816V c-Kit mutation as determined with an FDA-approved test.

Avapritinib (Ayvakit)

Avapritinib is a tyrosine kinase inhibitor that binds to and inhibits specific mutant forms of PDGFRα and c-Kit, including the PDGFRα D842V mutant and various KIT exon 17 mutants. This results in the inhibition of PDGFRa- and c-Kit-mediated signal transduction pathways and the inhibition of proliferation in tumor cells that express these PDGFRa and c-Kit mutants. It is indicated for the treatment of adults with AdvSM. AdvSM includes patients with ASM, SM-AHN, and MCL. Not recommended for treatment of patients with AdvSM with platelet counts 9</sup>/L.

Class Summary

Sympathomimetic agents are used in the treatment of anaphylaxis.

Epinephrine (Adrenalin, Bronitin, EpiPen)

Drug of choice for treating anaphylactoid reactions. Has alpha-agonist effects that include increased peripheral vascular resistance, reversed peripheral vasodilatation, systemic hypotension, and vascular permeability. Beta-agonist effects of epinephrine include bronchodilatation, chronotropic cardiac activity, and positive inotropic effects.

Class Summary

Mast cell stabilizers prevent release of mediators from mast cells, which cause airway inflammation and bronchospasm.

Cromolyn sodium (Intal, NasalCrom)

Inhibits degranulation of sensitized mast cells following their exposure to specific antigens.

Class Summary

Have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify body's immune response to diverse stimuli.

Prednisone (Deltasone, Orasone, Meticorten)

Immunosuppressant for the treatment of autoimmune disorders. May decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear neutrophil activity.

The prognosis of systemic mastocytosis (systemic mast cell disease) is variable.[53] Several prognostic models for systemic mastocytosis have been developed, but there is no consensus regarding the preferred approach for defining prognosis. Young children and patients who present with primarily cutaneous and flushing manifestations tend to have little or no progression of the disease over a considerable length of time. However, older patients and those with more extensive systemic disease involving organ systems other than the skin have a poorer prognosis.[54] Although their median duration of survival is not known, it appears to be a few years.

On laboratory studies, elevated lactate dehydrogenase levels, are a poor prognostic sign.[54] On multivariate analysis, the following findings have also been shown to portend poor prognosis[9] :

• Anemia (hemoglobin < 10.0 mg/dL)
• Thrombocytopenia (platelet count < 150,000/μ L)
• Hypoalbuminemia (albumin < 3.5 g/dL)
• Excess bone marrow blasts (>5%)

In 2019, Jawhar et al published a validated five-parameter mutation-adjusted risk score (MARS) that defines three risk groups among patients with advanced systemic mastocytosis, which may improve up-front treatment stratification.[55] The MARS parameters and assigned points are as follows

• Age > 60 years – 1 point
• Hemoglobin < 10 g/dL) – 1 point
• Platelet count < 100 × 10 ⁹/L) – 1 point
• Presence of one high molecular risk gene mutation (ie, in SRSF2, ASXL1, and/or RUNX1­ – 1 point
• Presence of two or more high molecular risk gene mutations – 2 points

These weighted scores are used to classify patients into one of the following three risk categories:

• Low risk: 0 to 1 point
• Intermediate risk: 2 points
• High risk: 3 - 5 points

Median overall survival (OS) in the three risk categories were as follows:

• Low risk - Median OS not reached
• Intermediate risk - Median OS 3.9 years (95% CI, 2.1 to 5.7 years)
• High risk -  Median OS 1.9 years (95% CI, 1.3 to 2.6 years

Patients should carry epinephrine-filled syringes at all times and should be taught to administer epinephrine in cases of emergency.