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Keywords:

  • mastocytosis;
  • classification;
  • tryptase;
  • c-kit;
  • mediator symptoms

Biology of disease – current status

  1. Top of page
  2. Biology of disease – current status
  3. Diagnostic parameters, prognostic variables and classification
  4. Management of mediator-related symptoms
  5. Therapy of cutaneous involvement
  6. Who should receive systemic glucocorticoids?
  7. Selection of patients for cytoreductive therapy
  8. Who should receive interferon-alpha?
  9. Alternatives to interferon-alpha for treatment of aggressive mastocytosis
  10. Treatment options for patients with mast cell leukaemia
  11. Mast cell sarcoma
  12. Treatment of associated haematopoietic malignancies (ahnmd)
  13. Disease monitoring and follow-up
  14. Response criteria
  15. Final remarks and future perspectives
  16. References

Mast cells are tissue-fixed cells originating from uncommitted and mast cell-committed haematopoietic progenitors (Kitamura et al, 1981; Kirshenbaum et al, 1992; Agis et al, 1993; Rottem et al, 1994; Kempuraj et al, 1999). Mast cell-committed progenitors co-express CD13 and KIT with CD34 (Kirshenbaum et al, 1999) and are detectable in the bone marrow as well as in the peripheral blood (Valent et al, 1992; Rottem et al, 1994; Valent, 1994). Homing, differentiation and maturation of mast cell progenitor cells are regulated by a complex network of growth factors, receptors and other antigens (Galli, 1990; Valent, 1994). The most important growth factor for human mast cells appears to be stem cell factor (SCF) (Irani et al, 1992; Kirshenbaum et al, 1992; Valent et al, 1992; Mitsui et al, 1993). This cytokine is a natural ligand for the c-kit proto-oncogene product, KIT, a tyrosine kinase receptor expressed on the surface of precommitted myelopoietic progenitor cells, mast cell-committed progenitor cells as well as mature mast cells (Galli et al, 1993; Simmons et al, 1994; Valent, 1994).

Based on their unique phenotype and distinct functional properties, mast cells represent a distinct myeloid cell lineage within lympho-haematopoietic tissues. Likewise, mast cells express a unique composition of CD antigens and granular mediators when compared with other myeloid cells (Schwartz, 1985; Valent et al, 1989; Valent & Bettelheim, 1992; Agis et al, 1996) (Table I). Moreover, in contrast to blood basophils and other myeloid cells, mast cells exhibit an extremely long life span in vivo ranging from several months to years (Galli, 1990; Födinger et al, 1994). In contrast to other haematopoietic cells, mast cells produce substantial amounts of histamine and heparin and express the high-affinity IgE receptor on their surface (Ishizaka & Ishizaka, 1984; Schwartz, 1985; Galli, 1990).

Table I.  CD antigen phenotype of normal mast cells and neoplastic mast cells in patients with systemic mastocytosis (SM): comparison with other cells.
CDAntigenNeoplastic MCs (SM)Normal MCs*Cultured MC progenitorsBlood basophilsBlood monocytes
CD2LFA-2+
CD3TcR
CD4T4+/−+/−+/−
CD9MRP-1+++++
CD13AP-N+/−+++
CD14LPSR+
CD153-FAL+
CD25IL-2Rα+++/−
CD33Siglec-3+++++
CD34HPCA-1+/−
CD35CR1+/−+/−++
CD45CLA+++++
CD63LIMP+++++
CD88C5aR++/−++
CD116G-CSFRα+/−+/−+
CD117KIT+++
CD123IL-3Rα+/−++

The concept that mast cells represent a unique myeloid lineage is in line with the notion that systemic mastocytosis (SM) is a distinct haematopoietic (myeloid) neoplasm with unique pathogenetic and clinical features (Lennert & Parwaresch, 1979; Parwaresch et al, 1985; Metcalfe, 1991a; Valent, 1996). The clonal nature of the disease has been reinforced by the association with the somatic c-kit mutation Asp-816-Val (Nagata et al, 1995; Longley et al, 1996, 1999; Buttner et al, 1998). This transforming mutation is detectable in the bone marrow (mast cells) in a majority of patients with SM but usually is not found in other myeloid neoplasms (Fritsche-Polanz et al, 2001). Remarkably, in a group of patients with (advanced) SM, the c-kit mutation Asp-816-Val is detectable not only in mast cells but also in other haematopoietic lineages, including blood monocytes (Akin et al, 2000a; Sotlar et al, 2000; Yavuz et al, 2002). Based on this notion and several clinical observations, SM can be regarded as a myeloproliferative disorder. In line with this concept, patients with SM are at a certain risk of acquiring a secondary myeloid leukaemia (Travis et al, 1988a,b; Horny et al, 1990a; Lawrence et al, 1991; Sperr et al, 2000).

In the management of patients with SM, two major problems have to be faced. The first is mediator release from mast cells with respective clinical symptoms that can be observed frequently in these patients (Horan & Austen, 1991; Metcalfe, 1991a; Austen, 1992; Valent, 1996). In fact, mast cells store (in their granules) or generate a number of vasoactive mediators [histamine, tumour necrosis factor-α (TNFα), vascular endothelial growth factor (VEGF), leukotrienes, prostaglandin D2 (PGD2)] and other biologically active molecules (interleukins, proteases, heparin) (Roberts et al, 1980; Lewis & Austen, 1981; Serafin & Austen, 1987; Burd et al, 1989; Plaut et al, 1989; Wodnar-Filipowicz et al, 1989; Gordon et al, 1990; Gordon & Galli, 1990) (Table II). In response to activating stimuli, mast cells can generate and/or release their mediator substances (Lewis & Austen, 1981; Ishizaka & Ishizaka, 1984; Schwartz, 1985; Burd et al, 1989; Plaut et al, 1989; Wodnar-Filipowicz et al, 1989; Gordon et al, 1990). Resulting clinical symptoms include headache, flushing, pruritus, diarrhoea, vascular instability, hypotension and shock (Austen, 1992) (Table II). Such symptoms may be grave and life threatening, especially in patients with SM who also have a co-existing disease predisposing for mediator secretion (allergies).

Table II.  Mast cell-derived mediators and mediator-related findings in patients with SM.
Mediator(s)Proposed mechanisms and site of actionClinical and pathological findings considered to be mediator related
  1. GI tract, gastrointestinal tract; PG, prostaglandin; LT, leukotriene; VEGF, vascular endothelial growth factor; bFGF, basic fibroblast growth factor; tPA, tissue type plasminogen activator, TNF, tumour necrosis factor; TGF, transforming growth factor; IL, interleukin, GM-CSF, granulocyte–macrophage colony-stimulating factor; MCP-1, monocyte chemoattractant protein-1; MIP-1α, macrophage inflammatory protein-1α.

HistamineH1-receptors on vascular and perivascular cells as well as epithelial cells in various organs H2-receptors on epithelial and other cells in the GI tract H3-receptors in brain and GI tractVascular instability, headache, oedema, flushing, (acute) urticaria, bronchoconstriction, mucus secretion, leucocyte margination before transmigration (selectins) Gastric acid hypersecretion, peptic ulcer disease, diarrhoea, abdominal pain, cramping Neurological abnormalities, abdominal pain, diarrhoea
PGD2, LTC4 and other leukotrienesPG and LT receptors on vascular and perivascular cells and other cell typesOedema, (acute) urticaria, flushing, bronchoconstriction, abdominal discomfort, cramping
VEGFVEGF receptors on endothelial cells in diverse organsOedema, increased angiogenesis in the bone marrow and other organs (in SM infiltrates)
bFGFbFGF receptors on fibroblasts, endothelial cells and other cell types in various organsBone marrow fibrosis, tissue fibrosis, increased angiogenesis, osteosclerosis
TryptasesDiverse effects on fibroblasts, endothelial cells, leucocytes and other mesenchymal cells, and their productsFibrosis, angiogenesis, tissue remodelling, degradation of matrix molecules, abnormal coagulation, bone resorption, osteopenia, osteolysis
tPA HeparinPlasmin activation ATIII-cofactor, anti- coagulant, cofactor for tPA, FGF and other growth factorsHyperfibrinolysis Coagulation abnormalities, bleeding diathesis, fibrosis, angiogenesis, osteoporosis, osteopenia
TNF-αTNF receptors on endothelial cells and other cell typesEndothelial cell activation and CAM expression with transmigration of leucocytes, cachexia, vascular instability
TGF-β Interleukins (IL-1/-2/-3/-5/ -6/-9/-10/-13, GM-CSF)TGF-β receptors on various cells in tissues IL receptors on leucocytes and other cell typesTissue fibrosis, abnormal bone remodelling, osteopenia Leucocyte differentiation and activation, eosinophilia, accumulation of eosinophils, growth and accumulation of lymphocytes in bone marrow, tissue fibrosis and activation of various stromal cells, myeloid hyperplasia
Chemokines (IL-8, MCP-1, MIP-1α, others)Chemokine receptors on leucocytes and stromal cellsActivation and chemotaxis of leucocytes, accumulation of lymphocytes, monocytes and eosinophils

The second management problem in SM results from the uncontrolled (aggressive) growth and infiltration of mast cells in diverse organs with consecutive organopathy (Lennert & Parwaresch, 1979; Parwaresch et al, 1985; Metcalfe, 1991a; Valent, 1996). Such organopathies are seen in patients with aggressive systemic mastocytosis (ASM), mast cell leukaemia (MCL) and in a group of patients with an associated clonal haematological non-mast cell lineage disease (SM-AHNMD), but not in those with indolent systemic mastocytosis (ISM). The organ systems most frequently affected in patients with aggressive disease variants are the liver, bone marrow, skeletal system, spleen and the gastrointestinal (GI) tract (Parwaresch et al, 1985; Travis et al, 1988a; Travis & Li, 1988; Horny et al, 1989; Metcalfe, 1991b; Horny et al, 1992a; Valent, 1996). Respective clinical findings include ascites, cytopenias, osteolysis, pathological fractures, hypersplenism and malabsorption (Rafii et al, 1983; Roth et al, 1985; Reisberg & Oyakawa, 1987; Floman & Amir, 1991; Mican et al, 1995; Kyriakou et al, 1998; Valent et al, 2001a). These organopathy-related clinical consequences have been termed C-Findings (Table III). It is of importance to be aware that organomegaly per se is not considered as ‘C-Finding-organopathy’. Rather, in the absence of C-Findings, organomegalies (palpable splenomegaly, hepatomegaly or lymphadenopathy) are recorded as B-Finding and may be indicative of smouldering mastocytosis, a novel subtype of ISM defined by an excessive burden of neoplastic cells, organomegaly and slow progression (Akin et al, 2001; Jordan et al, 2001a; Valent et al, 2002a) (Table III).

Table III.  Clinical and laboratory findings in patients with SM.
FindingTypically found in patients with
ISMBMMSSMSM-AHNMDASMMCL
  1. ISM, indolent systemic mastocytosis; BMM (isolated) bone marrow mastocytosis; SSM, smouldering systemic mastocytosis; SM-AHNMD, systemic mastocytosis with an associated haematological clonal non-mast cell lineage disease; ASM, aggressive systemic mastocytosis; MCL, mast cell leukaemia; ANC, absolute neutrophil count; UP, urticaria pigmentosa; LDH, lactate dehydrogenase.

B-Findings
 Hepatomegaly+/−+/−+/−+/−
 Splenomegaly++/−++/−
 Lymphadenopathy+/−−/++/−−/+
 Hypercellular marrow++++
 Mild dysplasia++/−+/−+
 Myeloproliferation+++/−+
 Mast cell infiltration in bone marrow > 30%++/−++
 Tryptase > 200 ng/ml++/−+/−+
C-Findings
 Anaemia (Hb < 10 g/dl)+/−++
 Thrombocytopenia (< 100 × 109/l)+/−++
 ANC < 1 × 109/l+/−++
 Hepatopathy with ascites or portal hypertension++
 Splenomegaly with hypersplenism+/−++/−
 Malabsorption with weight loss+/−+
 Osteolysis – pathological bone fractures++/−
Other clinical and laboratory findings
 UP-like skin lesions++/−+/−−/+
 Osteoporosis+/−+/−+/−+/−+/−
 Elevated alkaline phosphatase levels−/+++
 Elevated LDH levels+/−+/−+
 Abnormal coagulation−/+−/++/−+

Considering clinical symptoms in aggressive systemic mastocytosis, it is also of importance to distinguish carefully between mediator-related symptoms and organopathy caused by mast cell infiltrates. Thus, mediator-related symptoms, even if life threatening, are not considered to represent C-Findings (Valent et al, 2001a). Sometimes, however, it may be quite difficult to distinguish between mediator effects and organopathy caused by a local aggressive infiltrate of mast cells (GI symptoms, hypersplenism, pathologic fracture). In these cases, a tissue biopsy may lead to the correct diagnosis.

One paradox is that patients with aggressive mast cell disease often lack urticaria pigmentosa-like skin lesions, whereas those with ISM exhibit skin lesions in a high proportion of cases (Lennert & Parwaresch, 1979; Parwaresch et al, 1985; Metcalfe, 1991a). This paradox may explain why patients with aggressive systemic mastocytosis or mast cell leukaemia are often misdiagnosed by confusion with endocrinological, rheumatological, hepatic or infectious disorders (Table IV), and why it may take some time until the correct diagnosis is established. Moreover, SM shows considerable disease heterogeneity (Metcalfe & Akin, 2001). Thus, under various circumstances and clinical conditions, SM should also be considered as a potential diagnosis in the absence of skin lesions.

Table IV.  Clinical findings in patients with suspected systemic mastocytosis and important differential diagnoses to be considered at first presentation.
FindingsDifferential diagnoses
  • *

    In most paediatric cases, the diagnosis will be cutaneous mastocytosis, whereas in the majority of adults, the diagnosis will be systemic mastocytosis.

Skin
 Unexplained flushing  Unexplained urticaria or oedema  Benign cutaneous flushing, allergies, hereditary or acquired angioedema, carcinoid syndrome, autonomic neuropathy
 Occurrence of cutaneous mast  cell lesions after puberty*Cutaneous mastocytosis*
Cardiovascular system
 Unexplained anaphylactoid reactionAllergies, idiopathic anaphylaxis
 Unexplained syncope and tachycardia  with or without hypotensionAortic stenosis, vascular disorders, cardiac diseases, neurological disorders
 Severe recurrent allergic shockSevere allergic disorder
 Hypotension of unknown aetiologyCardiac, infectious, or neurological disease
 Hypertension of unknown aetiologyEssential hypertension, adrenal tumour
Liver, spleen and lymph nodes
 Unexplained hepatosplenomegaly  with or without ascites or  elevated enzyme levelsHepatitis, liver cirrhosis, hepatic tumour, lymphoma, carcinosis (metastasis), cholecystitis, cholecystolithiasis
 LymphadenopathyMalignant lymphoma, infectious disease
Gastrointestinal tract
 Unexplained diarrhoea    Inflammatory bowel disease, gluten-sensitive enteropathy, lactase deficiency, parasitic diseases, eosinophilic gastroenteritis
 Recurrent peptic ulcerHelicobacter pylori infection, gastrinoma
Skeletal system
 Diffuse osteoporosisHormone deficiency, drug effects, idiopathic
 Osteolysis of unknown aetiologyMultiple myeloma, histiocytosis, metastases
 Recurrent severe bone or  musculoskeletal painBone tumour, myeloma, tumour metastases, fibromyalgia, autoimmune disorders
Constitutional and others
 Headache, neurological abnormalitiesNeurological or psychiatric disorders
 Weight lossNeoplastic diseases including lymphomas
 FeverInfectious diseases, lymphomas
 Nausea  Intoxication, neurological disorder, peptic ulcer disease, drug effects

In addition, even in patients in whom an increase in mast cells in the bone marrow or mast cell-related markers can be demonstrated, the question often remains whether a primary mast cell disease (mastocytosis) is present. This holds especially true for cases with an apparently unrelated myeloid neoplasm and a major increase in immature highly atypical mast cells (myelomastocytic disorders) (Prokocimer & Polliack, 1981; Wimazal et al, 1999; Valent et al 2001b, 2002b) (Table V).

Table V.  Systemic mastocytosis: differential diagnoses to be considered during the haematological and haematopathological work up.
DiagnosisMajor considerations
Systemic mastocytosisa. At least one major and one minor or three minor SM criteria are fulfilled (for SM criteria see Table X)
Reactive mast cell hyperplasiaa. Underlying disease; typical examples: lymphomas, helminth infection, basal cell carcinoma, melanoma, tissue inflammation
b. SM criteria to diagnose SM not fulfilled
Myelomastocytic leukaemiaa. Diagnosis of non-mast cell lineage myeloid neoplasm established (FAB/WHO criteria): MDS, AML or MPD
b. Increase in immature metachromatic cells in bone marrow smears or blood (> 10%)
c. These metachromatic cells are mast cells defined by their phenotype or ultrastructure
d. SM criteria to diagnose SM not fulfilled
Tryptase+ myeloid neoplasma. Diagnosis of non-mast cell lineage myeloid neoplasm established (FAB/WHO criteria): MDS, AML or MPD
b. No increase in metachromatic cells
c. Serum tryptase level > 20 ng/ml
d. SM criteria to diagnose SM not fulfilled
AML with aberrant expression of c-kit point mutation Asp-816-Vala. Diagnosis AML established (WHO criteria)
b. No increase in metachromatic cells
c. SM criteria to diagnose SM not fulfilled
d. Asp-816-Val mutation detectable
Acute/chronic basophilic leukaemiaa. Criteria to diagnose basophilic leukaemia
b. SM criteria to diagnose SM not fulfilled
c. Metachromatic cells are basophils defined by their phenotype and/or ultrastructure
Non-Hodgkin's lymphoma with reactive focal increase in bone marrow mast cellsa. Minor SM criteria missing even in cases with focal dense mast cell accumulation at lymphoma infiltrates (major criterion)

Diagnostic parameters, prognostic variables and classification

  1. Top of page
  2. Biology of disease – current status
  3. Diagnostic parameters, prognostic variables and classification
  4. Management of mediator-related symptoms
  5. Therapy of cutaneous involvement
  6. Who should receive systemic glucocorticoids?
  7. Selection of patients for cytoreductive therapy
  8. Who should receive interferon-alpha?
  9. Alternatives to interferon-alpha for treatment of aggressive mastocytosis
  10. Treatment options for patients with mast cell leukaemia
  11. Mast cell sarcoma
  12. Treatment of associated haematopoietic malignancies (ahnmd)
  13. Disease monitoring and follow-up
  14. Response criteria
  15. Final remarks and future perspectives
  16. References

A number of cell-specific and disease-related parameters appear to be helpful in the diagnostic work up of patients with SM (Valent et al, 1999). When SM is suspected, a first important step is the evaluation of the serum tryptase level. This parameter is normal (< 20 ng/ml) in most patients with cutaneous mastocytosis (CM) but is almost invariably > 20 ng/ml in those with SM (a minor SM criterion) (Schwartz et al, 1987, 1995; Schwartz & Irani, 2000; Sperr et al, 2002a; Akin & Metcalfe, 2002). Moreover, tryptase levels reflect the total burden of mast cells in SM and correlate with mast cell infiltration in the bone marrow (Akin et al, 2000b; Schwartz & Irani, 2000; Schwartz, 2001; Sperr et al, 2002a). However, a persistently elevated serum tryptase level is not specific for SM. Rather, such elevated tryptase levels are also found in other myeloid neoplasms in the absence of SM (Sperr et al, 2001a, 2002b) (Table VI). This is of particular importance for patients with SM who show additional haematological abnormalities. In fact, an elevated serum tryptase level should not count as an indication (criterion) of SM in patients who have an unrelated (non-mast cell lineage) myeloid neoplasm (Valent et al, 2001a,c). Another important aspect is that tryptase levels increase (transiently) during significant mast cell activation that may, for example, occur during a systemic allergic reaction (Schwartz et al, 1987; Schwartz, 2001). In such cases, it is recommended to repeat the test a few weeks later. If the tryptase level is persistently elevated, SM (or another myeloid neoplasm) should be considered as an underlying disease (Schwartz & Irani, 2000; Schwartz, 2001).

Table VI.  Serum tryptase levels in myeloid neoplasms *.
NeoplasmAbbreviation% of patients with tryptase > 20 ng/ml
  1. *Data refer to the available literature (Schwartz et al, 1995; Schwartz, 2001; Sperr et al, 2001a, 2002a,b).

Systemic mastocytosisSM> 90
Acute myeloid leukaemiaAML30–40
AML-M050–60
AML-M120–30
AML-M260–70
AML-M350–60
AML-M410–20
AML-M4eo> 80
AML-M5< 20
AML-M6< 20
AML-M7< 50
Acute lymphoblastic leukaemiaALL< 10
Chronic myeloid leukaemiaCML30–40
Chronic myelomonocytic leukaemiaCMML30–40
Refractory anaemiaRA20–30
RA with ringed sideroblastsRARS20–30
RA with excess of blastsRAEB< 10

In paediatric patients, a baseline serum tryptase level < 20 ng/ml is a relatively safe indication of CM without systemic involvement (Schwartz & Irani, 2000; Sperr et al, 2002a). In these cases, bone marrow examination is not required. In adult patients, however, an examination of the bone marrow is required to establish or exclude the diagnosis of SM, and to determine the subtype of disease. In those with a clearly elevated serum tryptase level (> 30 ng/ml), the likelihood of SM is > 90%.

Diagnostic review of the bone marrow in an adult patient with suspected SM includes a histological and cytochemical assessment of a bone marrow section, morphological investigation of neoplastic cells on a bone marrow smear, an immunophenotypic examination of mast cells by immunohistochemistry or by flow cytometry and a molecular analysis for the presence of the c-kit point mutation Asp-816-Val. In suspected SM-AHNMD, a chromosome analysis (karyotyping) and determination of numbers of colony-forming progenitor cells is also recommended.

A thorough histological investigation of the bone marrow remains the most important investigation in suspected SM (Lennert & Parwaresch, 1979; Horny et al, 1985; Parwaresch et al, 1985; Horny & Valent, 2001; Li, 2001). In fact, the demonstration of multifocal dense infiltrates of mast cells in a representative bone marrow biopsy section is a diagnostic finding (major criterion of SM) (Horny & Valent, 2001; Valent et al, 2001a) (Fig 1). In a majority of cases, the mast cells in these infiltrates are spindle-shaped (minor SM criterion), thereby confirming the diagnosis of SM. Sometimes, however, the focal mast cell infiltrates are small and composed of round (but not spindle-shaped) cells or are accompanied by a diffuse component (Horny et al, 1998; Horny & Valent, 2001). In other patients, the mast cells may be extremely immature and hypogranulated, and therefore escape conventional staining techniques (Horny et al, 1998; Horny & Valent, 2001). Therefore, the use of an antitryptase antibody is recommended (Fukuda et al, 1995; Li et al, 1996; Horny et al, 1998). In fact, antitryptase antibodies appear to be sufficient to detect even small infiltrates or those composed of immature non-granulated mast cells (Horny et al, 1998; Horny & Valent, 2001). Other immunohistochemical markers to be considered in SM include CD25 (IL2Rα), CD68 (macrosialin), CD117 (KIT) and CD2 (LFA-2) (Horny et al, 1990b, 1993, 1998; Fukuda et al, 1995; Li et al, 1996; Jordan et al, 2001b; Horny & Valent, 2002). CD2 and CD25 appear to be particularly helpful as these antigens are almost exclusively detectable in mast cells in SM, but not in mast cells in normal or reactive bone marrow (minor SM criteria) (Jordan et al, 2001b; Horny & Valent, 2002) (Tables I and VII). The KIT antigen may be helpful in the discrimination between mast cells and basophils (Fukuda et al, 1995) (Table I). Depending on the characteristics of the infiltrate and cytomorphological aspects of mast cells, a number of different infiltration patterns can be distinguished in SM (Horny & Valent, 2001, 2002) (Table VII). Figure 1 shows representative examples for such patterns. Another important histopathological aspect is the accompanying (non-specific) reaction of the surrounding microenvironment. Such reactive changes include osteosclerosis with thickening of adjacent bony trabeculae, bone marrow fibrosis, increased bone marrow angiogenesis, eosinophilia and focal accumulation of lymphocytes (Horny et al, 1985; Horny & Valent, 2001; Baek et al, 2002; Wimazal et al, 2002) (Table VII). These changes are sometimes excessive, thereby masking the underlying mast cell disease. From a pathophysiological point of view, these changes are most likely to result from effects of cytokines [VEGF, basic fibroblast growth factor (bFGF), others] derived from local neoplastic mast cells (Table II).

image

Figure 1. Infiltration patterns of mast cells in the bone marrow of patients with indolent systemic mastocytosis (A and C), mast cell leukaemia (B) and myelomastocytic leukaemia (D). Bone marrow sections were stained with an antibody against mast cell tryptase. The multifocal dense mast cell infiltrate is typically found in patients with indolent disease. Note the prominent spindling of mast cells in (A). In some cases, the infiltrate shows an additional diffuse component (C). However, this diffuse component does not alter the underlying normal bone marrow architecture in indolent mastocytosis (C). In contrast, in patients with mast cell leukaemia (B) or myelomastocytic leukaemia (D), the diffuse infiltrate of mast cells is typically associated with a significant alteration in the architecture of the surrounding bone marrow. In mast cell leukaemia, mast cells form a dense and diffuse pattern of infiltration (B). Original magnification × 100.

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Table VII.  Histopathological and immunohistochemical findings in patients with systemic mastocytosis (SM).
FindingTypically found in patients with
ISMBMMSSMSM-AHNMDASMMCL
  • *

    A diagnostic infiltrate (major criterion) is defined as a cluster composed of at least 15–20 mast cells.

  • A diffuse pattern with loosely scattered mast cells is rarely found in patients with SM, i.e. in those with primary extramedullary (e.g. splenic) involvement or those who have additional three minor criteria to fulfil the diagnosis SM.

  • In the immunohistochemical examination of mast cells in SM, the sensitivity of CD25 exceeds that of CD2 (contrasting flow cytometry).

  • ISM, indolent systemic mastocytosis; BMM, isolated bone marrow mastocytosis; SSM, smouldering systemic mastocytosis; SM-AHNMD, systemic mastocytosis with an associated haematological clonal non-mast cell lineage disease; ASM, aggressive systemic mastocytosis; MCL, mast cell leukaemia.

Multifocal mast cell infiltrates*
 Dense focal++−/+−/+−/+
 Dense plus diffuse+/−+/−++
 Dense plus focal with diffuse component (mixed pattern)−/+++/−++
 Loosely diffuse
Paratrabecular mast cells++++++
Infiltration grade > 30%++/−++
Increased angiogenesis+++++
Focal accumulations of polyclonal lymphocytes follicle-like aggregates++/−−/++/−
Bone marrow eosinophilia+/−++/−++
Bone marrow fibrosis++++/−−/+
Osteosclerosis, thickening of bony trabeculae++/−+++
Myeloproliferation with loss of fat cells in non-affected bone marrow+++/−+/−
Dysplastic changes in the erythropoietic or megakaryopoietic compartment++/−+/−+/−
Expression of CD25 in mast cell infiltrates++++++
Expression of CD2 in neoplastic mast cells+/−+/−+/−+/−−/+−/+
Expression of CD68 in neoplastic mast cells++++++

The morphological assessment of a representative bone marrow smear is a crucial diagnostic procedure in SM. First, the recorded percentage of mast cells in a bone marrow smear (for counting mast cells, areas examined should be located away from any bone marrow particles) is an important diagnostic and prognostic parameter (Sperr et al, 2001b). Notably, in most cases of ISM, the percentage of mast cells is below 5%, whereas in aggressive mast cell disease, the percentage of mast cells will often exceed 5%(Table VIII). Moreover, an inverse correlation between the percentage of mast cells and survival in SM has been described (Sperr et al, 2001b). In those patients with SM who have ≥ 20% mast cells in their bone marrow smear, circulating mast cells are usually detected, and the final diagnosis is mast cell leukaemia (Valent et al, 2001a,c; Sperr et al, 2001b) (Table VIII). The morphology of mast cells may yield additional information. In most patients with ISM, the majority of mast cells appear to be ‘spindle-shaped’ with oval nuclei and a hypogranulated cytoplasm (atypical mast cells type I; minor SM criterion) (Sperr et al, 2001b) (Table VIII). In some patients with ISM, mast cells are round and indistinguishable from normal tissue mast cells. In contrast, in most patients with aggressive systemic mastocytosis and mast cell leukaemia, mast cells appear to be immature with bi- or multilobed nuclei (atypical mast cells type II; promastocytes) or even have a blast-like morphology (metachromatic blasts) (Sperr et al, 2001b). Table IX provides cytomorphological criteria for the classification of various types of mast cells that can be detected on bone marrow smears in patients with SM. All in all, the cytomorphological and histological assessment of bone marrow (mast) cells remains the most important diagnostic approach in suspected SM. Lastly, the investigation of the bone marrow may reveal a co-existing myeloid neoplasm [French–American–British (FAB) or World Health Organization (WHO) criteria] thereby leading to the final diagnosis of SM-AHNMD.

Table VIII.  Typical cytomorphological findings on bone marrow and peripheral blood smears in patients with systemic mastocytosis (SM).
FindingTypically found in patients with
ISMBMMSSMSM-AHNMDASMMCL
  • *

    Immature (agranular) mast cells may be counted as atypical monocytes in routine bone marrow and blood counts.

  • ISM, indolent systemic mastocytosis; BMM (isolated) bone marrow mastocytosis; SSM, smouldering systemic mastocytosis; SM-AHNMD, systemic mastocytosis with an associated haematological clonal non-mast cell lineage disease; ASM, aggressive systemic mastocytosis; MCL, mast cell leukaemia.

Bone marrow
 Percentage of mast cells
  < 1%+/−+−/+
  < 5%+++/−++/−
  > 5%+/−+/−+/−+
  > 10%−/++
  > 20%+
Spindle-shaped mast cells predominant++/−+++/−−/+
A substantial portion of mast cells have bi- or multilobed nuclei = promastocytes−/++/−+/−+
Metachromatic blasts−/++/−+
Blast cells > 5%+/−
Eosinophilia+/−++/−++
Monocytosis*+/−+/−+/−+/−+/−
Myelodysplasia−/++/−−/+−/+
Peripheral blood
 Circulating mast cells+
 Eosinophilia+/−++/−++
 Monocytosis*−/++/−+/−+/−+/−
 Circulating blasts+/−+/−
Table IX.  Cytomorphological criteria of subsets of mast cells (MCs) detectable in the bone marrow of patients with systemic mastocytosis (SM).
Cell typeCriteriaProposed normal counterpart
  1. The nomenclature and criteria refer to the published literature and recently defined WHO criteria: Sperr et al (2001b); Valent et al (2001a, c).

Typical mast cellRound cells, well granulated, central round nucleusMature tissue mast cell
Atypical mast cell type Ia. Elongated surface projections, often spindle-shaped cells, b. Hypogranulated with focal granule accumulations c. Oval decentralized nucleus. Out of a, b and c, at least two must be fulfilled to call a cell atypical MC type IUnknown; spindle-shaped normal mast cells are often found in histological analyses (MCs lining tissue elements) but usually not on bone marrow smears in the absence of SM
Atypical mast cell type II  = promastocyte Mostly immature, with bi- or multi-lobed nucleiImmature mast cell
Metachromatic blastMyeloblast with a few metachromatic granulesImmature mast cell- committed progenitor

Apart from histological and morphological studies, it is helpful to define the cell surface phenotype of aspirated bone marrow mast cells by flow cytometry in patients with suspected SM (Escribano et al, 1998, 2001). This may be crucial when sufficient biopsy material cannot be obtained or when the histological analysis is indeterminate. As described above, mast cells in most patients with SM express an aberrant phenotype including CD2 and CD25 (Escribano et al, 1998, 2001) (Table I). Thus, using a multicolour flow cytometry staining technique and antibodies against KIT for mast cell detection, and CD2 and CD25, expression of these antigens on mast cells can easily be demonstrated, consistent with the diagnosis of SM (Escribano et al, 2001). However, these antigens are not expressed on mast cells in all patients with SM. Thus, a negative staining result for CD2 and/or CD25 on mast cells does not exclude the diagnosis of SM.

Another disease-related parameter (minor criterion) is the transforming c-kit mutation Asp-816-Val. This c-kit mutation is detectable in the bone marrow in a majority of patients with SM, but is not detectable in most patients with CM or those with a ‘non-mast cell lineage’ haematopoietic neoplasm in the absence of SM (Nagata et al, 1995; Longley et al, 1996, 1999; Buttner et al, 1998; Fritsche-Polanz et al, 2001). Therefore, this mutation is helpful in the diagnostic work up in patients with suspected SM. In most cases of SM, the c-kit mutation Asp-816-Val is detectable in aspirated bone marrow cells, but is not detectable in the peripheral blood. In some cases, however, the clonal disease process disseminates into multiple haematopoietic cell lineages [smouldering SM, SM-chronic myelomonocytic leukaemia (SM-CMML), some cases with aggressive mastocytosis or MCL] so that the mutation is also found in peripheral blood cells (Nagata et al, 1995; Akin et al, 2000a; Jordan et al, 2001a; Hauswirth et al, 2002; Yavuz et al, 2002). Nevertheless, it is recommended that bone marrow cells (not only blood-derived cells) should always be analysed for the c-kit mutation Asp-816-Val in the work up of suspected SM (SM criteria). Apart from the recurrent c-kit mutation Asp-816-Val, several other c-kit mutations have been described in patients with SM (Longley et al, 2001; Feger et al, 2002). However, these mutations occur with much lower frequency and therefore are not included in routine screening tests in patients with suspected SM.

Based on the disease-related histopathological, molecular and biochemical markers described above, criteria for the diagnosis of SM (SM criteria) have been established by the WHO (Table X). The major criterion is ‘positive histology’ as defined by multifocal dense infiltrates of mast cells in one or more extracutaneous organ biopsies (in most cases, the bone marrow is the primary site of detection of SM) (Valent et al, 2001a,c). Minor criteria of SM include (i) the presence of atypical spindle-shaped or promastocytic mast cells in the bone marrow (> 25%); (ii) an elevated serum tryptase level (> 20 ng/ml) (not valid in the presence of an AHNMD); (iii) presence of the c-kit mutation Asp-816-Val in one or more extracutaneous organs (in most cases, the bone marrow is examined); and (iv) expression of CD2 or/and CD25 by bone marrow mast cells. If at least one major and one minor or three minor criteria are fulfilled, the diagnosis of SM is established (Valent et al, 2001a,c) (Table X).

Table X.  Criteria to diagnose systemic mastocytosis (SM criteria) *.
  1. If at least one major and one minor or three minor criteria are fulfilled, then the diagnosis is systemic mastocytosis = SM.

  2. *SM criteria have recently been published and have been adopted by the WHO: Valent et al (2001a, c).

Major criterionMultifocal dense infiltrates of mast cells (> 15 mast cells in aggregates) in bone marrow biopsies and/or in sections of other extracutaneous organ(s)
Minor criteriaa. > 25% of all mast cells are atypical cells (type I or type II) on bone marrow smears or are spindle-shaped in mast cell infiltrates detected on sections of visceral organs
b. c-kit point mutation at codon 816 in the bone marrow or another extracutaneous organ
c. mast cells in bone marrow or blood or another extracutaneous organ express CD2 or/and CD25
d. Baseline serum tryptase concentration > 20 ng/ml (in the case of an unrelated myeloid neoplasm, (d) is not valid as an SM criterion)

Once the diagnosis SM has been established, the subtype needs to be determined. In fact, SM variants appear to vary greatly in their clinical behaviour and in prognosis. Thus, a number of prognostic factors concerning survival have been identified in patients with SM (Lawrence et al, 1991; Sperr et al, 2001b). These parameters include an elevated lactate dehydrogenase (LDH) or alkaline phosphatase level, occurrence of significant haematological abnormalities or an AHNMD, a high percentage of mast cells in bone marrow smears and absence of urticaria pigmentosa (UP)-like skin lesions. Some of these disease-related markers have (among others) been used as the basis to define criteria and subvariants for patients with SM (Valent et al, 2001a). Based on these criteria and the WHO consensus classification of mastocytosis, four major groups of patients with SM and several subvariants have been defined: indolent systemic mastocytosis (ISM), SM-AHNMD, aggressive systemic mastocytosis (ASM) and mast cell leukaemia (MCL) (Valent et al, 2001a,c).

Typical ISM is defined by SM criteria, presence of skin lesions and absence of clinical or laboratory signs of (i) smouldering disease (B-Findings); (ii) aggressive disease (C-Findings); (iii) MCL; and (iv) an AHNMD. In some patients with ISM, mastocytosis is confined to the bone marrow and is then termed isolated bone marrow mastocytosis (BMM). These patients fulfil the criteria for ISM, lack skin lesions, have low tryptase levels and exhibit small mast cell infiltrates in bone marrow biopsies. In smouldering systemic mastocytosis (SSM), another subentity of ISM, SM criteria are fulfilled and B-Findings (Table II) are detectable, whereas (i) no C-Findings, (ii) no signs of MCL and (iii) no signs of an AHNMD are found. B-Findings are indicative of a large burden of neoplastic cells and include: (i) a high serum tryptase level together with a high infiltration grade of mast cells in the bone marrow; (ii) a hypercellular marrow with a loss of fat cells and with signs of myeloproliferation; and (iii) organomegaly (hepato/splenomegaly, lymphadenopathy) that is attributable to mast cell infiltration (Valent et al, 2001a,c). If two out of these three B-Findings are detectable, the diagnosis of SSM is established. Aggressive systemic mastocytosis (ASM) is defined by organopathy with C-Findings, a percentage of bone marrow mast cells of < 20% in bone marrow smears (excluding MCL) and no signs of an AHNMD. As mentioned, C-Findings are indicative of organopathy caused by ‘aggressive’ mast cell infiltration. The organ systems most frequently involved are the bone marrow, skeletal system, liver, spleen and the GI tract (Parwaresch et al, 1985; Travis & Li, 1988; Horny et al, 1989, 1992a,b; Metcalfe, 1991b; Valent, 1996). A special subvariant of aggressive systemic mastocytosis is lymphadenopathic mastocytosis with eosinophilia (Metcalfe, 1991a). In patients with SM-AHNMD, WHO criteria to diagnose the AHNMD are fulfilled together with SM criteria. MCL is defined by circulating mast cells and ≥ 20% mast cells in bone marrow smears (Valent et al, 2001a). Table XI shows a summary of SM variants.

Table XI.  WHO classification of systemic mastocytosis.
Variants and subvariantsProposed abbreviation
  • The classification of SM is part of the recently established WHO consensus classification of mastocytosis (Valent et al, 2001a, b).

  • *

    Criteria and the classification of AML, MDS and other haematopoietic malignancies have to be applied according to guidelines provided by the French–American–British co-operative study group (FAB) and the WHO.

  • IMF, idiopathic myelofibrosis; ET, essential thrombocythaemia, PV, polycythaemia vera.

Indolent systemic mastocytosisISM
 Provisional subvariants:
 Isolated bone marrow mastocytosisBMM
 Smouldering systemic mastocytosisSSM
SM with an associated haematopoietic clonal non-mast cell lineage diseaseSM-AHNMD
 Proposed subvariants:
 SM – acute myeloid leukaemia*SM-AML
 SM – myelodysplastic syndrome (–RA, –RARS, …)*SM-MDS
 SM – myeloproliferative disease (–IMF, –ET, –PV, …)*SM-MPD
 SM – chronic myeloid leukaemia*SM-CML
 SM – chronic myelomonocytic leukaemia*SM-CMML
 SM – non-Hodgkin's lymphoma* (diverse subentities)*SM-NHL
Aggressive systemic mastocytosisASM
 Proposed subvariant:
 Lymphadenopathic mastocytosis with eosinophilia
Mast cell leukaemiaMCL

The WHO criteria to diagnose SM and SM variants are helpful in discriminating patients with SM from those with a ‘mast cell activation syndrome’ or a ‘reactive mast cell hyperplasia’ (Jordan et al, 2002) as well as in discriminating SM from myelomastocytic disorders (Prokocimer & Polliack, 1981; Valent et al, 2001a,b,c, 2002b) or myeloid neoplasms that express tryptase or the c-kit mutation Asp-816-Val without convincing morphological evidence of mast cell lineage involvement (Valent et al, 2001b) (Table V).

An exact knowledge about the disease and the particular SM variant is an important basis for the management of these patients. However, only a few recommendations for the treatment of SM are based on solid evidence. Especially in the rare aggressive disease variants, no significant database exists, and all drugs and therapies applied to these rare variants must be judged ‘experimental in nature’. In the following sections, we discuss briefly aspects of the management and treatment of SM with an attempt to provide and discuss available treatment options.

Management of mediator-related symptoms

  1. Top of page
  2. Biology of disease – current status
  3. Diagnostic parameters, prognostic variables and classification
  4. Management of mediator-related symptoms
  5. Therapy of cutaneous involvement
  6. Who should receive systemic glucocorticoids?
  7. Selection of patients for cytoreductive therapy
  8. Who should receive interferon-alpha?
  9. Alternatives to interferon-alpha for treatment of aggressive mastocytosis
  10. Treatment options for patients with mast cell leukaemia
  11. Mast cell sarcoma
  12. Treatment of associated haematopoietic malignancies (ahnmd)
  13. Disease monitoring and follow-up
  14. Response criteria
  15. Final remarks and future perspectives
  16. References

Mediator-related symptoms occur in patients with all subtypes of SM (Austen, 1992; Marone et al, 2001; Castells & Austen, 2002). Symptoms that are recurrent, severe and require continuous medical treatment should be recognized as a distinct disease-related problem by the physician. One approach has been to define these patients by adding the subscript SY in the final diagnosis (ISMSY, SM-AHNMDSY, ASMSY, MCLSY) (Valent et al, 2001a). Mediator-related symptoms in patients with SM are treated with agents that interfere with mediator function, mediator production or mediator release (Metcalfe, 1991c; Austen, 1992; Worobec, 2000; Marone et al, 2001; Castells & Austen, 2002; Escribano et al, 2002a; Worobec & Metcalfe, 2002). Histamine-related symptoms generally respond to H1- and H2-histamine receptor antagonists (Metcalfe, 1991c; Austen, 1992; Worobec, 2000; Marone et al, 2001). Other ‘antimediator’ drugs include glucocorticoids, cromolyn sodium, acetylsalicylic acid (aspirin) and leukotriene antagonists (Metcalfe, 1991c; Austen, 1992; Worobec, 2000; Escribano et al, 2002a; Worobec & Metcalfe, 2002). In general, these drugs are prescribed based on the organ(s) and mediator(s) involved (Metcalfe, 1991c; Austen, 1992; Marone et al, 2001; Castells & Austen, 2002; Escribano et al, 2002a) (Table XII). Likewise, peptic ulcer disease requires the use of a proton pump inhibitor and/or H2-antihistamines (Frieri et al, 1985; Gasior-Chrzan & Falk, 1992; Worobec, 2000; Escribano et al, 2002a). H1-blockers are used to control pruritus in patients with SM (Worobec, 2000; Escribano et al, 2002a). Oral cromolyn sodium has been reported to be effective in patients with SM suffering from abdominal pain, diarrhoea, nausea or vomiting (Dolovich et al, 1974; Soter et al, 1979; Horan et al, 1990) (Table XII). In addition, this drug may be effective in some patients with SM suffering from pruritus or bone pain (Alexander, 1985; Miner, 1991; Escribano et al, 2002a). In patients with recurrent and severe mediator-associated symptoms (SMSY), short-term glucocorticoids (25–50 mg prednisone p.o. daily for several weeks) may be considered (Worobec, 2000). In those who have developed or are at apparent risk of developing anaphylactoid shock, the administration of epinephrine on demand through a self-injector (Epi-Pen) seems an appropriate recommendation (Metcalfe, 1991c; Austen, 1992; Worobec, 2000; Worobec & Metcalfe, 2002). Aspirin, a compound that interferes with prostaglandin production, has been proposed for patients with severe flushing, tachycardia and syncope (Austen, 1992). However, aspirin must be used with great caution. First, the starting dose may itself cause vascular collapse in an idiosyncratic response. Moreover, the risk of gastrointestinal bleeding has to be taken into account, especially in patients with a known peptic ulcer, thrombocytopenia or hyperheparinaemia. Therefore, aspirin cannot be routinely recommended to all patients with SM. Together, a number of ‘antimediator’ drugs are available for the treatment of SM. In contrast, mediator-related symptoms should usually not be treated with cytoreductive drugs, i.e. cytostatic agents or chemotherapy, although such an approach has been considered for some patients with severe and recurrent life-threatening episodes of mediator-related events resistant against ‘antimediator drugs’. In such cases, the hazards and risks of side-effects of the cytostatic drug have to be calculated carefully and balanced against the benefit that may result from a reduction in the mast cell burden. In addition, some of these drugs may again cause the release of mediators from mast cells in these patients. Similarly, in patients with aggressive mast cell disease, cytoreductive drugs or polychemotherapy may quite often lead to (an increased) release of mast cell mediators. In these patients, mediator-targeting drugs should be used as important prophylactic adjuncts to cytoreductive drugs (chemotherapy).

Table XII.  Mediator-targeting drugs prescribed in patients with systemic mastocytosis (after diagnosis is confirmed).
Clinical symptoms and mediator effectsStepDrugs to be considered
Skin
 Pruritus, flushing1H1 + H2-histamine receptor antagonists
2Ketotifen, topical glucocorticoids
3PUVA
Cardiovascular system
 Recurrent hypotension and tachycardia1H1 + H2-histamine receptor antagonists
2Glucocorticoids
3Aspirin in selected cases (if tolerable)
 Recurrent shock1H1 + H2-histamine receptor antagonists +  epinephrine on demand (self injector)
2Oral glucocorticoids + epinephrine on demand (self injector)
3Aspirin in select cases (if tolerable) + epinephrine on demand (self injector)
 Co-existing allergy1H1 + H2-histamine receptor antagonists
2Short-term oral glucocorticoids
Consider also:
Hyposensitization/immunotherapy
Avoidance of triggering factors
Gastrointestinal tract
 Peptic ulcer disease1H2-histamine receptor antagonists
2Proton pump inhibitors + H2-blockers
 Diarrhoea, abdominal pain, abdominal cramping, nausea, vomiting1H1 + H2-histamine receptor antagonists
2Oral cromolyn sodium
3Consider trial with leukotriene antagonists
4Short-term glucocorticoids
Skeletal system
 Bone pain1Analgesias, aspirin-like drugs (if tolerable)
Also consider radiation for severe localized bone pain
 Osteopenia, diffuse osteoporosis1Vitamin D + calcium or oestrogen/testosterone on demand
2Biphosphonates
3Consider IFN-α (suspected aggressive disease)
Neurological symptoms
 1H1 + H2-histamine receptor antagonists
2Oral cromolyn sodium

Apart from cytostatic drugs, a number of other ‘triggering’ factors and compounds may variably induce or promote mediator release from mast cells in patients with SM. These factors include environmental or emotional stress, some drugs (aspirin, morphine and its derivatives, tubocurarin-type muscle relaxants, some antibiotics, amphotericin B and others), alcohol or radiographic contrast media (Benyon et al, 1987; Lawrence et al, 1987; Stellato et al, 1991, 1992, 1996; Marone & Stellato, 1992; Stellato & Marone, 1995; Peachell & Morcos, 1998; Marone et al, 2001; Escribano et al, 2002a). In patients with a co-existing allergy, mediator release may be a significant and life-threatening problem (Fricker et al, 1997; Oude-Elberink et al, 1997; Biedermann et al, 1999; Metcalfe, 2000). Therefore, it is of particular importance to be aware of these reactions, and to avoid possible triggering factors in patients with SM (Escribano et al, 2002a). In addition, it is important to be aware of such reactions in patients who undergo surgery (anaesthesia). Respective perioperative recommendations have been proposed (Scott et al, 1983; James et al, 1987; Greenblatt & Chen, 1990; Lerno et al, 1990; Goins, 1991; Yaniv et al, 1992; Borgeat & Ruetsch, 1998).

Therapy of cutaneous involvement

  1. Top of page
  2. Biology of disease – current status
  3. Diagnostic parameters, prognostic variables and classification
  4. Management of mediator-related symptoms
  5. Therapy of cutaneous involvement
  6. Who should receive systemic glucocorticoids?
  7. Selection of patients for cytoreductive therapy
  8. Who should receive interferon-alpha?
  9. Alternatives to interferon-alpha for treatment of aggressive mastocytosis
  10. Treatment options for patients with mast cell leukaemia
  11. Mast cell sarcoma
  12. Treatment of associated haematopoietic malignancies (ahnmd)
  13. Disease monitoring and follow-up
  14. Response criteria
  15. Final remarks and future perspectives
  16. References

Typical cutaneous lesions in SM are maculopapular and indistinguishable from that detectable in patients with CM. The extent of involvement of the skin is variable, ranging from a few lesions to extensive generalized exanthema (Hartmann et al, 2001; Wolff et al, 2001; Hartmann & Henz, 2002). Unlike in the paediatric age groups, skin lesions in SM in adults are persistent in most cases. In fact, only a few adult patients (roughly 10%) appear to have spontaneous regression (Metcalfe, 1991a; Brockow et al, 2002). In some of these individuals, disappearance of cutaneous lesions is accompanied by a progression of visceral mastocytosis (Brockow et al, 2002). This observation is consistent with the paradox that patients with aggressive mast cell disease typically lack urticaria pigmentosa-like skin lesions (Parwaresch et al, 1985; Metcalfe, 1991a; Valent, 1996).

In most patients with SM, the skin lesions primarily represent a cosmetic problem. In other patients, however, the lesions do cause severe discomfort or are accompanied by severe mediator-related symptoms including flushing and itching (Hartmann et al, 2001; Wolff et al, 2001). A number of strategies have been proposed for the treatment of ‘urticaria pigmentosa-like’ skin lesions. Mild symptoms may respond to antihistamines. A more intensive and effective treatment is oral psoralen + UV-A = PUVA (Hartmann et al, 2001; Wolff et al, 2001) (Table XII). Thus, in response to PUVA, a substantial regression of skin lesions is seen in many patients (Christophers et al, 1978; Kolde et al, 1984; Czarnetzki et al, 1985; Godt et al, 1997; Wolff, 2002). However, responses are variable in duration, and most patients require long-term treatment, with repeated cycles of PUVA. An alternative to PUVA is the application of topical glucocorticoids (Hartmann et al, 2001; Wolff, 2002) (Table XII). In patients with severe systemic symptoms, mediator-targeting drugs including H1- plus H2-antihistamines and short-term oral glucocorticoids may be required.

Who should receive systemic glucocorticoids?

  1. Top of page
  2. Biology of disease – current status
  3. Diagnostic parameters, prognostic variables and classification
  4. Management of mediator-related symptoms
  5. Therapy of cutaneous involvement
  6. Who should receive systemic glucocorticoids?
  7. Selection of patients for cytoreductive therapy
  8. Who should receive interferon-alpha?
  9. Alternatives to interferon-alpha for treatment of aggressive mastocytosis
  10. Treatment options for patients with mast cell leukaemia
  11. Mast cell sarcoma
  12. Treatment of associated haematopoietic malignancies (ahnmd)
  13. Disease monitoring and follow-up
  14. Response criteria
  15. Final remarks and future perspectives
  16. References

Glucocorticoids counteract the growth of mast cells through multiple mechanisms, including a direct inhibitory effect on mast cells, as well as a suppressive effect on SCF-producing cells in tissues (Daeron et al, 1982; Robin et al, 1985; Finotto et al, 1987; Wershil et al, 1995; Eklund et al, 1997). However, as long-term treatment is often associated with severe side-effects, the administration of systemic glucocorticoids in SM should be restricted to distinct clinical situations, and the dose kept as low and brief as possible in all cases (Escribano et al, 2002a; Valent et al, 2003). Apart from significant mediator-related symptoms, glucocorticoids should be considered for patients with aggressive systemic mastocytosis and MCL (Valent et al, 2003) (Table XIII). In fact, the initiation of prednisolone (50–60 mg p.o. daily) without other drugs may improve SM-related organopathy, especially in patients with GI tract involvement and malabsorption or hepatomegaly with ascites (Metcalfe, 1991a; Worobec, 2000). However, glucocorticoids are usually not prescribed as a single agent in aggressive SM, but are usually combined with cytoreductive drugs. In most cases of aggressive systemic mastocytosis, prednisone (or prednisolone) is combined with interferon-alpha-2b (IFN-α2b) (see below). We recommend starting glucocorticoids a few days before initiating IFN-α2b (Valent et al, 2003). In addition, glucocorticoids have been considered as an adjunct to polychemotherapy in patients with MCL. In responding patients, the glucocorticoid dose can (sometimes) be tapered down to a low maintenance dose (e.g. 5–10 mg of prednisone p.o. daily) after some weeks (or months), and then possibly be discontinued. In those with diffuse osteoporosis, the use of glucocorticoids should be avoided if possible.

Table XIII.  Options for cytoreductive treatment in patients with systemic mastocytosis (SM).
Disease variantTreatment options
  • IFN, interferon; SM-AHNMD, systemic mastocytosis with an associated haematological clonal-non-mast cell lineage disease.

  • *

    In some studies, IFN-α was also found to improve mediator-related symptoms, and therefore was recommended for patients with ISM (Casassus et al, 2002). However, in these cases, the side-effects of the drug have to be taken into account and balanced against beneficial effects.

Typical indolent systemic mastocytosis (ISM)No cytoreductive treatment required* Exception: consider IFN-α2b for severe osteoporosis even if no histology documenting ASM is available, these cases are considered as ‘probably ASM’
Smouldering systemic mastocytosis (SSM)Watch and wait in most cases. However, in selected cases (rapidly progressive B-Findings), IFN-α2b ± glucocorticoids can be considered
SM-AHNMDTreat AHNMD as if no SM is present and also treat SM as if no AHNMD is found If splenomegaly and hypersplenism prohibit therapy – consider splenectomy
Aggressive systemic mastocytosis (ASM) with slow progressionIFN-α2b ± glucocorticoids or cladribine = 2CdA. If splenomegaly and hypersplenism prohibit therapy – consider splenectomy
ASM – rapid progression and patients who do not respond to IFN-α2bPolychemotherapy (± IFN-α2b); consider bone marrow transplantation in select cases. If splenomegaly and hypersplenism prohibit therapy – consider splenectomy Consider cladribine (2CdA) Consider hydroxyurea as palliative drug
Mast cell leukaemia (MCL)Polychemotherapy or 2CdA (± IFN-α2b) Consider bone marrow transplantation If splenomegaly and hypersplenism prohibit therapy – consider splenectomy Consider hydroxyurea as palliative drug

Selection of patients for cytoreductive therapy

  1. Top of page
  2. Biology of disease – current status
  3. Diagnostic parameters, prognostic variables and classification
  4. Management of mediator-related symptoms
  5. Therapy of cutaneous involvement
  6. Who should receive systemic glucocorticoids?
  7. Selection of patients for cytoreductive therapy
  8. Who should receive interferon-alpha?
  9. Alternatives to interferon-alpha for treatment of aggressive mastocytosis
  10. Treatment options for patients with mast cell leukaemia
  11. Mast cell sarcoma
  12. Treatment of associated haematopoietic malignancies (ahnmd)
  13. Disease monitoring and follow-up
  14. Response criteria
  15. Final remarks and future perspectives
  16. References

Cytoreductive drugs have multiple side-effects, and most of them are considered to be mutagenic, thereby potentially increasing the risk of disease progression and the development of secondary leukaemias. Many have to be used in various countries on a ‘humanitarian basis’ as they may not be recognized therapy, there being insufficient numbers of patients to permit clinical trials. These drugs should thus be administered only to those patients with SM who have clear signs of an aggressive disease (C-Findings) and only after the full information regarding the potential risks and side-effects is understood by the patient and medical care team. In this regard, it is important to document the presence of C-Findings that are reflective of significant organopathy (impaired organ function) caused by mast cell infiltration and thus are a reliable indication for an aggressive SM variant. Sometimes it may be necessary to perform organ biopsies to confirm the diagnosis of aggressive systemic mastocytosis (C-Findings).

In contrast to aggressive mastocytosis, patients with ISM should usually not be considered for cytoreductive therapy. An exception may be smouldering SM. In these patients, clinical and laboratory signs of a significant proliferation of neoplastic cells (hepatomegaly, splenomegaly, lymphadenopathy, hypercellular marrow, leucocytosis, mild cytopenias) without frank organopathy (no C-Findings) are found (Akin et al, 2001; Jordan et al, 2001a; Valent et al, 2002a). In these patients, it is difficult to predict the clinical course and thus to decide on cytoreductive therapy at first presentation. These cases should be followed carefully over time in order to determine whether the disease process shows rapid progression. In some patients, it may then be justified to recommend cytoreductive therapy, even if no overt impairment of organ function is found (Table XIII). For most patients with smouldering SM, the approach is to watch and wait until clear signs of organopathy (shift to aggressive category of SM) develop.

Once the diagnosis of aggressive mast cell disease (ASM, MCL or ASM-AHNMD) has been established, patients should be considered for treatment with cytoreductive drugs. It must be noted, however, that all available drugs are experimental in nature. Experimental cytoreductive drugs that have been proposed include interferon-alpha, cytosine arabinoside (ARA-C), cladribine (2CdA), doxorubicin, daunorubicin, hydroxyurea and vincristine (Travis et al, 1986; Kluin-Nelemans et al, 1992; Worobec, 2000; Tefferi et al, 2001; Valent et al, 2003). These drugs have been used alone or in combination (Travis et al, 1986; Worobec, 2000; Valent et al, 2003). The treatment outcome in SM using such drugs appears to be variable and to depend on the subtype of disease. Thus, it is of importance to determine the subtype of SM before initiating treatment. When considering these drugs, it should also be kept in mind that SM cannot be cured using currently available compounds, and that no evidence-based approach or standard therapy exists.

Who should receive interferon-alpha?

  1. Top of page
  2. Biology of disease – current status
  3. Diagnostic parameters, prognostic variables and classification
  4. Management of mediator-related symptoms
  5. Therapy of cutaneous involvement
  6. Who should receive systemic glucocorticoids?
  7. Selection of patients for cytoreductive therapy
  8. Who should receive interferon-alpha?
  9. Alternatives to interferon-alpha for treatment of aggressive mastocytosis
  10. Treatment options for patients with mast cell leukaemia
  11. Mast cell sarcoma
  12. Treatment of associated haematopoietic malignancies (ahnmd)
  13. Disease monitoring and follow-up
  14. Response criteria
  15. Final remarks and future perspectives
  16. References

Over the past several years, interferon alpha (IFN-α) has been introduced successfully as a ‘stem cell targeting’ and probably non-mutagenic cytoreductive drug for patients with myeloproliferative disorders. The view that SM is related to this group of myeloid neoplasms encouraged clinicians to use this drug also in patients with aggressive systemic mastocytosis or mast cell leukaemia. Indeed, in some patients with aggressive mastocytosis, IFN-α2b, administered in combination with or without glucocorticoids, produced long-lasting depression in mast cells (Kluin-Nelemans et al, 1992; Pulik et al, 1994; Delaporte et al, 1995; Fiehn et al, 1995; Lehmann et al, 1996; Weide et al, 1996; Worobec et al, 1996; Butterfield, 1998; Chosidow et al, 1998). Moreover, IFN-α may improve mediator-related symptoms in patients with SM (Casassus et al, 2002). As no other effective treatment has become available for patients with aggressive mastocytosis to date, it seems appropriate to start with a combination of IFN-α2b and glucocorticoids in these patients (Table XIII). One approach is to start with prednisolone (50–75 mg p.o. daily) a few days before IFN-α2b is introduced and to keep the patient hospitalized initially. During the first weeks, IFN-α2b is usually administered at 3 million units three times a week. Depending on the response and occurrence of side-effects, the dose of IFN-α2b is then increased, whereas prednisolone should be tapered to a low maintenance dose, or discontinued if possible. In patients with MCL, IFN-α2b may also be administered together with glucocorticoids, although the response may not be long-lasting. In fact, more aggressive therapy appears to be required to treat patients with MCL (Table XIII). In patients with severe diffuse osteopenia (osteoporosis) and multiple bone fractures considered to be a result of mast cell infiltration (C-Finding), it may be appropriate to prescribe IFN-α2b without glucocorticoids (Lehmann et al, 1996; Escribano et al, 2002a).

Alternatives to interferon-alpha for treatment of aggressive mastocytosis

  1. Top of page
  2. Biology of disease – current status
  3. Diagnostic parameters, prognostic variables and classification
  4. Management of mediator-related symptoms
  5. Therapy of cutaneous involvement
  6. Who should receive systemic glucocorticoids?
  7. Selection of patients for cytoreductive therapy
  8. Who should receive interferon-alpha?
  9. Alternatives to interferon-alpha for treatment of aggressive mastocytosis
  10. Treatment options for patients with mast cell leukaemia
  11. Mast cell sarcoma
  12. Treatment of associated haematopoietic malignancies (ahnmd)
  13. Disease monitoring and follow-up
  14. Response criteria
  15. Final remarks and future perspectives
  16. References

Based on the current literature, only a subgroup of patients with aggressive systemic mastocytosis have exhibited long-lasting clinical responses to IFN-α2b (Worobec et al, 1996; Butterfield, 1998; Tefferi et al, 2001; Valent et al, 2003). For non-responding patients, a number of treatment options have been proposed (Table XIII). For those patients who show a rapid progression despite IFN-α2b, more aggressive treatment such as polychemotherapy or even bone marrow transplantation should be considered (similar to patients with MCL) (Table XIII). In patients with slowly progressing disease, a number of experimental drugs such as 2-chlorodeoxy-adenosine (cladribine = 2CdA) or cyclosporin A may be used (Tefferi et al, 2001; Escribano et al, 2002b; Valent et al, 2003). Especially, 2CdA appears to be an effective agent and may significantly reduce the mast cell burden, albeit temporarily, in a subgroup of patients with SM. Palliative cytoreductive treatment with hydroxyurea (on demand) is an alternative for those patients who do not respond to IFN-α or 2CdA (or other drugs) (Worobec, 2000; Valent et al, 2003). The use of the tyrosine kinase inhibitor STI571 (Imatinib) has also been proposed. However, although STI571 can effectively kill mast cells bearing the wild-type c-kit (Akin et al, 2003), the presence of the Asp-816-Val mutation causes resistance to STI571 (Ma et al, 2002). Thus, such therapy may only be considered for those (minor group) SM patients in whom no transforming mutation at codon 816 was found. In line with this notion, patients with aggressive systemic mastocytosis or mast cell leukaemia in whom the c-kit mutation Asp-816-Val is found fail to show clinical responses to Imatinib (unpublished observation). However, a number of other tyrosine kinase inhibitors are currently being developed, and some of them appear to counteract not only wild-type KIT, but also the tyrosine kinase activity of the Asp-816-Val-mutated form of KIT (Liao et al, 2002).

Apart from drug therapies, a number of other palliative treatment options have been proposed for patients with aggressive mastocytosis or mast cell leukaemia. In case of severe bone pain and local osteodestruction, radiation therapy is a treatment option. In patients with massive splenomegaly and resulting severe thrombocytopenia, splenectomy may be considered in an attempt to increase platelet counts and to maintain cytoreductive therapy at the required dose (Friedman et al, 1990).

Treatment options for patients with mast cell leukaemia

  1. Top of page
  2. Biology of disease – current status
  3. Diagnostic parameters, prognostic variables and classification
  4. Management of mediator-related symptoms
  5. Therapy of cutaneous involvement
  6. Who should receive systemic glucocorticoids?
  7. Selection of patients for cytoreductive therapy
  8. Who should receive interferon-alpha?
  9. Alternatives to interferon-alpha for treatment of aggressive mastocytosis
  10. Treatment options for patients with mast cell leukaemia
  11. Mast cell sarcoma
  12. Treatment of associated haematopoietic malignancies (ahnmd)
  13. Disease monitoring and follow-up
  14. Response criteria
  15. Final remarks and future perspectives
  16. References

MCL is a rare disease characterized by the rapid growth of neoplastic cells in the bone marrow as well as in visceral organs, with resultant organopathy (Lennert & Parwaresch, 1979; Parwaresch et al, 1985; Dalton et al, 1986; Travis et al, 1986; Metcalfe, 1991b; Valent, 1996). As in other aggressive variants of SM, skin lesions are usually absent (Parwaresch et al, 1985). In contrast to other SM variants, circulating mast cells are detectable in MCL, and the bone marrow smear contains ≥ 20% mast cells (Travis et al, 1986; Sperr et al, 2001b; Valent et al, 2001a). The prognosis in MCL is grave, and no effective treatment is yet available for these patients (Travis et al, 1986). Thus, in contrast to aggressive mastocytosis, patients with MCL may not have long-lasting remissions when treated with IFN-α2b and glucocorticoids. Monotherapy with other conventional cytoreductive drugs may also be without a long-lasting effect (Travis et al, 1986). However, in some patients with MCL, short-term remission has been achieved using polychemotherapy regimens or using IFN-α2b in combination with other drugs (Travis et al, 1986; Worobec, 2000). Therefore, administration of aggressive polychemotherapy should be considered in patients with MCL in an attempt to induce remission or at least lead to a significant reduction in the tumour burden (Table XIII). Chemotherapy regimens similar to those used to treat high-risk acute myeloid leukaemia (AML) patients may be an option (Travis et al, 1986; Sperr et al, 2000; Worobec, 2000). The application of 2CdA together with other drugs may also be considered. In each case, the patient must be able to tolerate chemotherapy. If a bone marrow donor is available, responding patients may be considered for bone marrow transplantation (Table XIII), although no reported experience with this experimental therapeutic manoeuvre in MCL is available. Another strategy would be to apply consolidation chemotherapy as for AML in the responding patients or to introduce maintenance treatment with IFN-α and glucocorticoids or other experimental drugs.

Mast cell sarcoma

  1. Top of page
  2. Biology of disease – current status
  3. Diagnostic parameters, prognostic variables and classification
  4. Management of mediator-related symptoms
  5. Therapy of cutaneous involvement
  6. Who should receive systemic glucocorticoids?
  7. Selection of patients for cytoreductive therapy
  8. Who should receive interferon-alpha?
  9. Alternatives to interferon-alpha for treatment of aggressive mastocytosis
  10. Treatment options for patients with mast cell leukaemia
  11. Mast cell sarcoma
  12. Treatment of associated haematopoietic malignancies (ahnmd)
  13. Disease monitoring and follow-up
  14. Response criteria
  15. Final remarks and future perspectives
  16. References

Mast cell sarcoma (MCS) is an extremely rare mast cell disease. In contrast to SM, MCS is a local tumour that consists of immature atypical mast cells and shows a destructive growth pattern (Parwaresch et al, 1985). Therefore, MCS is considered as a separate disease entity (Parwaresch et al, 1985; Horny et al, 1986; Valent et al, 2001a). However, the biology and pathology of the afflicted cells and the clinical course suggest that mast cell sarcoma is related to the group of aggressive mast cell disorders (ASM, MCL). Moreover, in all cases recorded, secondary dissemination with involvement of visceral organs has been reported, and the terminal phase may closely resemble aggressive systemic mastocytosis or mast cell leukaemia (Horny et al, 1986; Kojima et al, 1999; Günther et al, 2001). Treatment options for patients with MCS appear to be limited. In the few cases reported, survival time was short despite surgery, radiation and polychemotherapy (Horny et al, 1986; Kojima et al, 1999; Günther et al, 2001). Once secondary generalization has occurred (transition to aggressive mastocytosis or MCL), the management and treatment should follow the guidelines described above for the management of aggressive mastocytosis and mast cell leukaemia.

Treatment of associated haematopoietic malignancies (ahnmd)

  1. Top of page
  2. Biology of disease – current status
  3. Diagnostic parameters, prognostic variables and classification
  4. Management of mediator-related symptoms
  5. Therapy of cutaneous involvement
  6. Who should receive systemic glucocorticoids?
  7. Selection of patients for cytoreductive therapy
  8. Who should receive interferon-alpha?
  9. Alternatives to interferon-alpha for treatment of aggressive mastocytosis
  10. Treatment options for patients with mast cell leukaemia
  11. Mast cell sarcoma
  12. Treatment of associated haematopoietic malignancies (ahnmd)
  13. Disease monitoring and follow-up
  14. Response criteria
  15. Final remarks and future perspectives
  16. References

The frequent occurrence of an AHNMD in patients with SM is consistent with the notion that SM behaves as a myeloproliferative disease. In most patients, a myeloid neoplasm such as a myelodysplastic syndrome (MDS), a myeloproliferative disease (MPD) or an AML is diagnosed (Travis et al, 1988b; Horny et al, 1990a; Lawrence et al, 1991; Sperr et al, 2000). Lymphoid neoplasms may also develop, but less frequently compared with myeloid malignancies. Such lymphoid neoplasms are mostly of B-cell origin. In all cases, WHO criteria to diagnose myeloid or lymphoid neoplasms should be applied. In most patients, it will be easy to diagnose an AHNMD in SM. However, sometimes it may be difficult to distinguish between SM-AHNMD and smouldering mastocytosis, or between aggressive systemic mastocytosis and SM-AHNMD. In such cases, additional disease characteristics (karyotype, colony-forming progenitors) and the clinical course may ultimately lead to the correct diagnosis. Once the diagnosis of SM-AHNMD has been established, separate treatment plans for SM and the AHNMD have to be established (Parker, 1991; Sperr et al, 2000; Worobec, 2000; Valent et al, 2001a). In this process, it is of importance to be aware that the mast cell component of the disease (= SM) in patients with SM-AHNMD can be indolent (ISM-AHMD) or aggressive (ASM-AHNMD) and, similarly, the AHNMD can be an aggressive or indolent disorder (Valent et al, 2003). The general approach for patients with SM-AHNMD is to treat SM as if no AHNM is present, and the AHNMD as if no SM has been diagnosed (Sperr et al, 2000; Valent et al, 2001a,c; Escribano et al, 2002a) (Table XIII). For example, it has been reported that standard polychemotherapy is quite effective in producing complete remission of AML in patients with SM-AML (although SM may not respond to this therapy) (Sperr et al, 1998, 2000). Sometimes, both SM and AHNMD may be responsive to a single drug such as IFN-α2b. Thus, the treatment of patients with SM-AHNMD depends on the nature and course of the SM and the AHNMD, as well as on the overall status of the patient (Parker, 1991; Valent et al, 2001a).

Disease monitoring and follow-up

  1. Top of page
  2. Biology of disease – current status
  3. Diagnostic parameters, prognostic variables and classification
  4. Management of mediator-related symptoms
  5. Therapy of cutaneous involvement
  6. Who should receive systemic glucocorticoids?
  7. Selection of patients for cytoreductive therapy
  8. Who should receive interferon-alpha?
  9. Alternatives to interferon-alpha for treatment of aggressive mastocytosis
  10. Treatment options for patients with mast cell leukaemia
  11. Mast cell sarcoma
  12. Treatment of associated haematopoietic malignancies (ahnmd)
  13. Disease monitoring and follow-up
  14. Response criteria
  15. Final remarks and future perspectives
  16. References

Patients with SM should be evaluated at routine intervals, depending on the type of SM, presence of mediator-related symptoms, co-existing disorders and therapy. In ISM without significant medical complications, annual determinations of the serum tryptase level and monitoring of blood counts and liver function is appropriate. For patients with ISM suffering from severe mediator-related symptoms (ISMSY), it may sometimes be helpful to monitor serum tryptase levels. In patients who have the smouldering subtype of ISM, more frequent evaluations may be required to monitor the course (progression) of disease (B-Findings). Important parameters include the serum tryptase levels, blood counts and degree of organomegaly (spleen, liver, lymph nodes). In patients with suspected progression to MCL or SM-AHNMD, a repeat bone marrow aspirate and biopsy should be performed. Patients with aggressive systemic mastocytosis and mast cell leukaemia must be monitored closely before and during treatment with cytoreductive drugs. In these patients, a number of parameters should be followed, namely those reflecting C-Findings (such as liver enzymes, serum calcium, haemoglobin, abnormal X-rays, others) and those reflecting the burden of neoplastic mast cells (bone marrow histology, serum tryptase levels). During treatment with cytoreductive drugs, C-Finding-related parameters may show significant improvement (clinical response). In responding patients, the mast cell-related parameters may also improve or even return to normal (complete remission). However, such complete remissions are only seen in exceptional cases using currently available forms of treatment. Notably, even when using polychemotherapy, mast cell infiltrates often remain unchanged.

Response criteria

  1. Top of page
  2. Biology of disease – current status
  3. Diagnostic parameters, prognostic variables and classification
  4. Management of mediator-related symptoms
  5. Therapy of cutaneous involvement
  6. Who should receive systemic glucocorticoids?
  7. Selection of patients for cytoreductive therapy
  8. Who should receive interferon-alpha?
  9. Alternatives to interferon-alpha for treatment of aggressive mastocytosis
  10. Treatment options for patients with mast cell leukaemia
  11. Mast cell sarcoma
  12. Treatment of associated haematopoietic malignancies (ahnmd)
  13. Disease monitoring and follow-up
  14. Response criteria
  15. Final remarks and future perspectives
  16. References

The response to mediator-targeting drugs is judged on clinical criteria including the patient's subjective assessment of improvement, and thus is difficult to quantify. Concerning organopathy and the effect of cytoreductive drugs, however, objective treatment response criteria have been proposed (Valent et al, 2003). Thus, a major response, a partial response and the failure of treatment have been defined. Respective criteria can be applied to patients with aggressive systemic mastocytosis (ASM), mast cell leukaemia (MCL) and ASM-AHNMD. Table XIV shows a summary of proposed response criteria. A major response (MR) is defined by complete regression of organopathy (defined by resolution of C-Finding/s). Patients exhibiting such a major clinical response can be divided further into those achieving complete remission (pathologically confirmed response = disappearance of mast cell infiltrates and surrogate markers), incomplete remission (incomplete regression of mast cell infiltrates) and an isolated clinical response (disappearance of organopathy without changes in mast cell infiltrates). A partial response (PR) is defined by a measurable improvement in organopathies. This group of patients can be divided further into those with a good partial response (regression of C-Findings to > 50%) and those with a minor response (regression of C-Findings to < 50%). Patients without a response can either exhibit stable disease (no change in organopathy) or progressive disease. Table XIV provides a summary of response types and respective criteria. Applying these criteria, patients treated with IFN-α ± glucocorticoids show an actual rate of major response of approximately 20% (Valent et al, 2003).

Table XIV.  Proposed response criteria for patients with systemic mastocytosis treated with cytoreductive drugs.
ResponseCriteria
  • *

    With or without decrease in mast cell infiltrates, serum tryptase levels and organomegaly.

  • †In case of progressive C-Findings and documented response in other C-Finding(s), the final diagnosis is still progressive disease. For details concerning response criteria, see Valent et al (2003).

I. Major responseComplete resolution of one or more C-Findings and no progression of other organopathies
 a. Complete remission    Disappearance of mast cell infiltrates and decrease in tryptase to < 20 ng/ml; Disappearance of organomegaly
 b. Incomplete remission      Decrease in mast cell infiltrates in affected organs and/or substantial decrease in serum tryptase and/or visible regression of organomegaly
 c. Pure clinical response    No decrease in mast cell infiltrates, no decrease in tryptase levels and no regression of organomegaly
II. Partial responseIncomplete regression of one or more C-Finding(s)* without complete regression and no progress in other C-Findings
 a. Good (significant) partial response> 50% regression
 b. Minor response≤ 50% regression
III. No responseC-Finding(s) persistent or progressive
 a. Stable diseaseC-Findings show constant range
 b. Progressive diseaseC-Finding(s) show(s) progression

Final remarks and future perspectives

  1. Top of page
  2. Biology of disease – current status
  3. Diagnostic parameters, prognostic variables and classification
  4. Management of mediator-related symptoms
  5. Therapy of cutaneous involvement
  6. Who should receive systemic glucocorticoids?
  7. Selection of patients for cytoreductive therapy
  8. Who should receive interferon-alpha?
  9. Alternatives to interferon-alpha for treatment of aggressive mastocytosis
  10. Treatment options for patients with mast cell leukaemia
  11. Mast cell sarcoma
  12. Treatment of associated haematopoietic malignancies (ahnmd)
  13. Disease monitoring and follow-up
  14. Response criteria
  15. Final remarks and future perspectives
  16. References

Systemic mastocytosis is a heterogeneous disease of myelomastocytic progenitors with clonal expansion and a relationship to myeloproliferative disorders. The course of the disease and prognosis vary among patients. The treatment of patients with SM has to be selected based on the subtype of disease, presence of mediator-related symptoms and occurrence of an associated haematopoietic non-mast cell lineage disease. Mediator-related symptoms are managed using ‘mediator-targeting’ drugs. Uncontrolled growth of mast cells in aggressive disease variants is treated with (experimental) cytoreductive drugs such as IFN-α, 2CdA or polychemotherapy. Based on available information, the tyrosine kinase inhibitor STI571 (Imatinib) does not appear to inhibit the autophosphorylation of KIT bearing the Asp-816-Val mutation, and is thus not predicted to be useful in the majority of patients with aggressive mastocytosis. However, there may be occasional patients who are found to lack a mutation in KIT at codon 816 after careful molecular analysis of lesional mast cells. Such patients may be potential candidates for experimental therapy with Imatinib, although this possibility has yet to be explored. In addition, new treatment options may become available with the generation of more specific targeted therapy, including those drugs that inhibit the tyrosine kinase activity of KIT exhibiting transforming mutations at codon 816.

References

  1. Top of page
  2. Biology of disease – current status
  3. Diagnostic parameters, prognostic variables and classification
  4. Management of mediator-related symptoms
  5. Therapy of cutaneous involvement
  6. Who should receive systemic glucocorticoids?
  7. Selection of patients for cytoreductive therapy
  8. Who should receive interferon-alpha?
  9. Alternatives to interferon-alpha for treatment of aggressive mastocytosis
  10. Treatment options for patients with mast cell leukaemia
  11. Mast cell sarcoma
  12. Treatment of associated haematopoietic malignancies (ahnmd)
  13. Disease monitoring and follow-up
  14. Response criteria
  15. Final remarks and future perspectives
  16. References
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