Systemic mastocytosis: overview and new insights in prognosis and therapy

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1 3 Systemic mastocytosis: overview and new insights in prognosis and therapy G. Deslypere, MD 1, T. Devos, MD, PhD 2, M. Delforge, MD, PhD 2, G. Verhoef, MD, PhD 2 Systemic mastocytosis is an orphan myeloproliferative disease characterised by an excessive mast cell accumulation. Benign forms present with urticaria pigmentosa while aggressive subtypes or leukaemic variants lead to organ dysfunction. In patients with unexplained hypotensive syncope s or anaphylaxis, flushing and angio-oedema with a basal tryptase >20 ng/ml, one should think of systemic mastocytosis. Pathophysiology is based on mutations in KIT, encoding the c-kit receptor (CD117) on the surface of mast cells. Diagnosis is based on bone marrow biopsies with clusters of atypical mast cells and co-expression of CD2 or CD25 and/or a KIT mutation. Treatment consists of avoiding triggers of mast cell release and antihistaminic drugs. Patients with aggressive subtypes are candidates for cytoreductive therapies. CD30 is thought to be a novel predictor of prognosis. (Belg J Hematol 2013;4(3):85-89) Introduction Mastocytosis is a group of diseases characterised by an excessive mast cell accumulation in the skin and/or in the bone marrow or other solid organs. 1 Cutaneous mastocytosis patients present only with skin laesions, called urticaria pigmentosa or maculopapular cutaneous mastocytosis. Diffuse cutaneous infiltration of mast cells is less frequent and usually seen in children. The systemic variant presents with obligate bone marrow invasion and possible skin or other organ infiltration. 2 Mastocytosis is an orphan disease with unknown prevalence. Men and women are equally affected. In children the disease presents most often with only skin manifestations that can decrease or resolve in adulthood while adults present almost always with the systemic form. The systemic form cannot be cured and is very heterogeneous in presentation and prognosis. The disease is characterised by episodes of overwhelming mast cell degranulation, resembling an allergic or anaphylactic reaction and, in cases of aggressive variants, with organ dysfunction. 2 Pathogenesis The pathogenesis of systemic mastocytosis is not fully understood. It is known that in patients with systemic mastocytosis there is an excessive mast cell accumulation frequently associated with somatic activating point mutations in KIT encoding the c-kit receptor (CD117), a tyrosine kinase type III at the surface of the mast cells. 2,4,5 CD117 is important in the development and proliferation of mast cells. These special blood cells are the only hematopoietic cells not losing the expression of CD117 during maturation. 1 In >80% of patients with systemic mastocytosis this receptor has a gain of function mutation resulting in the stimulation of CD117 without the binding of stem cell factor (SCF). Nearly thirty KIT mutations have been described. The most commonly observed mutation shows substitution of Val for Asp at codon 816 (D816V) and is identified in the mast cells of 95% or more of adults with systemic mastocytosis when sensitive methods are used. These somatic mutations can be important for the development of specific treatments of systemic mastocytosis like 1 Department of Internal Medicine, University Hospital Leuven, Leuven, Belgium 2 Department of Haematology, University Hospital Leuven, Leuven, Belgium. Please send all correspondence to: G. Deslypere, MD, UZ Leuven, Department of Haematology, Herestraat 49, 3000 Leuven, Belgium, tel: , Griet.deslypere@student.kuleuven.be. Conflict of interest: The authors have nothing to disclose and indicate no potential conflict of interest. Key words: anaphylaxis, systemic mastocytosis, tyrosin kinase inhibitor. 85

2 Table 1. WHO classification of systemic mastocytosis Variant and abbreviation: Subvariant with abbreviation *Indolent Systemic Mastocytosis (ISM) Smouldering SM (SSM) Isolated Bone Marrow Mastocytosis (BMM) Systemic Mastocytosis with Acute Myeloid Leukaemia (SM-AML) Systemic Mastocytosis with Myelodysplastic Syndrome (SM-MDS) *Systemic Mastocytosis with an associated clonal haematologic non-mast cell lineage disease (SM-AHNMD) Systemic Mastocytosis with Myeloproliferative Disorder (SM-MPD) Systemic Mastocytosis with Chronic Myelomonocytic Leukaemia (SM-CMML) Systemic Mastocytosis with Non-Hodgkin s Lymphoma (SM-NHL) Systemic Mastocytosis with Hypereosinophilic Syndrome (SM-HES) *Aggressive Systemic Mastocytosis (ASM) *Mast Cell Leukaemia (MCL) Lymphadenopathic SM with eosinophilia (In a few cases, the FIP1L1/PDGFRAfusion gene may be detected) Aleukaemic MCL tyrosin kinase inhibitors (see below). Mast cells contain numerous granules with vaso-active mediators like proteases, cytokines, histamine, leukotrienes, prostaglandins etcetera. They are the sentinel of the immune system and prevent invasion of micro-organisms. Mast cells do not circulate in the peripheral blood but are positioned in or near the mucosae of all organ systems, close to blood vessels. 1 Degranulation in patients with systemic mastocytosis is mainly triggered by certain drugs, temperature change, insect stings, food products, infections (bacterial, viral and parasitic) and invasive procedures. 1,2 Degranulation of mast cells leads to an early wheal-and-flare reaction due to histamines, leukotrienes, prostaglandins and proteases. In a later phase there is interaction with neutrophils, eosinophils, smooth muscle cells and neuronal cells resulting in bronchoconstriction, hyperperistalsis, pain and itching. 6 Classification system Systemic mastocytosis (SM) can be divided into four main subtypes with their own presentation and prognosis (Table 1). 1,3,7 Indolent SM is the most frequent subgroup and accounts for 46% of all SM patients. The average age at presentation is 49 years. These patients present with cutaneous laesions in 66-75% and episodes of anaphylactic or severe allergic reactions. Two rare subtypes are described; a smouldering variant with high mast cell load and organ invasion without dysfunction, and a variant with solitary bone marrow involvement. 4 The second most frequent subtype (40%) is the one with an associated haematological non mast cell lineage disorder (SM-AHNMD). Mainly myeloproliferative neoplasms (SM-MPN) (45%) but also myelomonocytic leukaemia (SM-CMML) (29%) and myelodysplastic neoplasms (SM-MDS) (23%) are associated with this variant of SM. 4 The aggressive SM subvariant accounts for 12% of all SM patients and causes not only organ invasion but also dysfunction resulting in liver fibrosis, malabsorption, lymfadenopathies and/or cytopaenias. 2-4 Mast cell leukaemia is the rarest subtype (only 1% of SM patients) and has to be considered as an acute leukaemia with a very bad prognosis. 4 Clinical presentation Patients with systemic mastocytosis present with three different types of symptoms. Symptoms of skin infiltration (especially the less aggressive subtypes), signs of mediator release and signs of organ infiltration. 1,2 Skin infiltration presents mainly as urticaria pigmentosa; hyper-pigmented maculopapular laesions preferably on the extremities. Typical of these laesions is the Darier sign; erythema/urticaria after local friction on the laesions as a consequence of local mediator release. Most patients complain of pruritus after showering or in relation to emotional stress or exercise. 86

3 3 Table 2. symptoms 1 Table 3. symptoms 1 B symptoms 1. >30% mast cells in bone marrow (normally 1%) and/or tryptase >200ng/ml 2. Hypercellular or dysplastic bone marrow, but insufficient criteria for definitive diagnosis of a hematopoietic neoplasm 3. Hepatosplenomegaly without ascites/hypersplenism or liver dysfunction and/or lymphadenopathy (ultrasound/ct) Mast cell mediator release leads to signs of vasodilation (flushing, hypotension), urticaria, angio-oedema, nausea, diarrhoea and fatigue. Degranulation is mainly triggered by drugs (ACE-inhibitors, opioids, vancomycin, etc.), high temperature, insect stings, infection, exercise, ethanol and stress. 1 Eighty percent of patients complain of chronic abdominal pain and/or diarrhoea which is thought to be mediated by prostaglandin 2 causing hyperperistalsis. Duodenal ulceration and duodenitis due to histamine induced gastric acid overproduction is also a very frequent finding. Rather underdiagnosed are the neuropsychiatric symptoms like concentration difficulties, memory problems, emotional instability and less frequently a depressive mood. They are named as mixed organ brain dysfunction and thought to be initiated by prostaglandins. 8 Another important set of symptoms are the musculoskeletal problems these patients encounter. Histamine, heparin and other cytokines make them very susceptible to osteoporosis and osteolytic or osteosclerotic laesions, especially in men. 1,9 Lymphadenopathies are present in 20-60% of patients with indolent SM and even more frequent in patients with the more aggressive forms. Organ infiltration (cf. B and C symptoms) can result in cytopaenias (anaemia, leukopenia and thrombopenia), portal hypertension, hepatosplenomegaly, hypersplenism, ascites and malabsorption. Bone infiltration can lead to lytic laesions and pathological fractures. 1 Diagnosis Adults with unexplained hypotensive syncope s, flushing, anaphylactic reactions or cutaneous mastocytosis need to be evaluated for underlying systemic mastocytosis by performing a bone marrow examination. 2 The diagnosis is based on the 2008 criteria of the World Health Organization (WHO) with major and minor criteria. One major and one minor, or three minor criteria C symptoms 1. Cytopenia: <1x10E9/L neutrophils, Hemoglobin <10 g/dl, platelet count <100x10E9/L 2. Hepatomegaly with ascites, liver dysfunction (AST/ALT, AF and LDH), hypoalbuminemia, clotting problems, portal hypertension 3. Splenomegaly with hypersplenism 4. Malabsorption with weight loss due to GI mast cell infiltrates on biopsy 5. Bone lesions, osteoporosis, fractures are needed to make the diagnosis. The major criterion is the presence of multifocal, dense infiltrates of at least fifteen mast cells in bone marrow and/or extracutaneous tissue confirmed by tryptase staining. A minimum of 25% morphologically atypical or spindle shaped mast cells in bone marrow aspirate/biopsy is a minor criterion. A KIT mutation in codon 816, co-expression of CD117 with CD2 or CD25 in bone marrow, blood or other extracutaneous tissues and a serum tryptase >20ng/ml are the other minor criteria. The last one does not account for further subtype differentiation when it is associated with a haematological malignancy. 3 Basal tryptase >20ng/ml can also be seen in patients with myeloproliferative/dysplastic syndromes, chronic eosinophilic leukaemia and chronic kidney and liver dysfunction. 2 Further classification of SM depends on the absence or presence of B or C symptoms (Table 2 and 3). B and C symptoms present as organ enlargement without or with dysfunction, respectively. The smouldering variant of indolent SM presents with two or more B findings. The aggressive subtype typically presents with one or more C findings. 1 Differential diagnosis One has to differentiate between disorders associated with and without mast cell activation. Monoclonal mast cell activation syndrome for example presents with recurrent flushing, gastro-intestinal cramps, hypotension and one or two minor criteria for SM. 10 Anaphylaxis is an exclusion diagnosis because first an underlying haematological disease should be excluded. Non mast cell associated diseases mimicking SM are: hereditary angio- 87

4 Key messages for clinical practice Mastocytosis: excessive mast cell accumulation in skin/bone marrow/gastro-intestinal tract/bones. Heterogeneous presentation and prognosis. Symptoms: urticaria pigmentosa, pruritus, angio-oedema, anaphylaxis, diarrhoea, peptic ulceration, ascites, lymphadenopathies, osteoporosis and lytic bone laesions. Diagnosis: bone marrow examination, skin biopsy and basal tryptase. Non-curable condition. Prevention of triggers, antihistaminic drugs, 2CDA, IFN-α, TKIs (limited indications), chemotherapy in agressive forms and corticosteroids for exacerbations. oedema (congenital deficiency of C1 esterase inhibitor), carcinoid syndrome (elevated 5-HIAA in 24hr urine sample) or a pheochromocytoma (hypertension, headache and flushing). 2 Treatment options No curative treatment is available for SM. For an individual patient, it is important to look for factors that can trigger a flare of SM. For the indolent forms with good prognosis, the first step is to avoid contact with these triggers. Antihistaminic drugs (H1 and H2 blockers) are given to most patients with SM to avoid severe allergic/anaphylactic reactions. 4 If this is insufficient to control symptoms, Montelukast (an anti-leukotriene drug) is advised. Chromoglycate (mast cell stabiliser) and protein pump inhibitors may control gastro-intestinal complaints. 4 Corticosteroids are reserved for episodes of flare up. For severe skin laesions, psoralen UV A (PUVA) is an option. 1,4 Calcium and vitamin D supplements in combination with bisphosphonates are indicated in patients with osteoporosis. Especially in patients with a history of an anaphylactic reaction, prescription of an EpiPen and explanation of its use, is strongly advised. Before invasive procedures (endoscopy, radiology with contrast) or operations in patients with SM, it is advised to give prophylactic antihistaminic drugs and eventually an anti-leukotriene one hour before the procedure. In case of insufficient effect, corticosteroids should be given 24 hours and 2 hours before the procedure. 1 Associated clonal haematological non-mast cell lineage diseases should be treated separately from the SM symptoms. Tyrosin kinase inhibitors (TKIs) are promising agents for the treatment since mastocytosis is frequently associated with somatic activating point mutations within KIT encoding CD117, a tyrosin kinase. However, overall results of TKI studies are rather disappointing in SM patients. Imatinib and Nilotinib are resistant to the frequent (D816V) KIT mutation. Imatinib is the first TKI used in SM and has good results in those with a FIPIL1-PDGFRA (in chronic eosinophilic leukaemia too) or V560G KIT mutation. 5 Midostaurin, a new TKI, shows promising results in patients with the (D816V) KIT mutation. One prospective multicentre study with Midostaurin (n=26) describes an improved clinical response in 69%, consisting of 10 patients (38%) with a major response rate (MR), 5 patients (19%) with a good partial response (GPR), and 3 patients (12%) with a minor partial response (PR). 5 The aggressive subtype needs cytoreductive therapy. IFN-α one to three million units 3/week is considered the first line treatment and demonstrated a 20-30% MR and up to 53% overall response rate (ORR). The median duration of response was eleven months. 11 Cladribine (2-CDA) is an alternative option for every subtype of SM with an ORR of 55%. 11,12 Mast cell leukaemia needs to be treated as an acute leukaemia with intensive chemotherapy. 4 Prognosis Patients diagnosed over the age of two years tend to have a persistent disease. Ninety percent of adults with cutaneous laesions have a systemic variant. The indolent forms have a normal survival rate compared to the healthy population but in 1-5% there is an evolution towards a more aggressive subtype of SM. The smouldering subtype is associated with a worse prognosis 88

5 3 because of the advanced age at diagnosis. 4 Yearly monitoring is enough for the indolent forms of SM. SM- AHNMD have an overall median survival of 24 months. Patients with SM-MPN have a median survival of 31 months, while patients with SM-CMML and SM-MDS have a worse median prognosis of respectively fifteen and thirteen months. 4 The aggressive subtype of SM has a variable prognosis with a median survival of 41 months, ranging from months to several years. Patients with a mast cell leukaemia only have a median survival of two months. 4 They often progress to multiple organ failure. In recent literature, the presence of the activation marker CD30 (Ki-1 antigen) on the surface of mast cells is found to be a possible prognostic marker in SM. CD30 is frequently present in patients with the aggressive subtype and in mast cell leukaemia but not in the indolent forms. In future, the Ki-1 antigen may be a novel therapeutic target in SM. Anti-CD30 monoclonal antibodies are already a treatment option in refractory Hodgkin s lymphoma and anaplastic large cellular lymphoma (ALK + or -). 13,14 Conclusion Systemic mastocytosis is a rare and heterogeneous group of diseases. One has to think about this disease in cases of unexplained flushing, tachycardia, hypotensive syncope s, anaphylactic reactions and cutaneous mastocytosis in adults. Symptoms arise from mast cell mediator release, organ invasion/dysfunction and skin laesions with pruritus as predominant symptom. Diagnosis is based on specific bone marrow and peripheral blood characteristics. No curative treatment is available. Prognosis varies from several months to a survival as seen in the general population. References 1. Andersen CL, Kristensen TK, Severinsen MT, et al. Systemic mastocytosis-a systematic review. Dan Med 2012; 3: Valent P, Sperr WR, Schwarts RB, et al. Diagnosis and classification of mast cell proliferative disorders: Delineation from immunologic and non mast cell hematopoietic neoplasms. J Allergy Clin Immunol 2004;114: mastocytosis.htm 4. Pardanani A, Tefferi A. Systemic mastocytosis in adults: a review on prognosis and treatment based on 342 Mayo clinic patients and current literature. Curr Opin Hematol 2010: Ustun C, De Remer DL, Akin C. Tyrosine kinase inhibitors in the treatment of systemic mastocytosis. Leuk Res 2011;35: Bischoff SC. Role of mast cells in allergic and non-allergic immune responses: comparison of human and murine data. Nature 2007;7: Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, Fourth EditionWHO classification of Tumours, Volume 2. IARC Lyon. 8. Rogers MP, Bloomingdale K, Murawski BJ. Mixed organic brain syndrome as a manifestation of systemic mastocytosis. Psychosom Med.1986;6: Van der Veer E, van der Goot W, de Monchy JG, et al. High prevalence of fractures and osteoporosis in patients with indolent systemic mastocytosis. Allergy 2012;3: Akin C, Valent P, Metcalfe DD. Mast cell activation syndrome: Proposed diagnostic criteria. J Allergy Clin Immunol 2010 ;126: e4. Epub 2010 Oct Pardanani A. Systemic mastocytosis in adults: 2012 Update on diagnosis, risk stratification, and management. Am J Hematol 2012;87: Lim KH, Pardanani A, Butterfield JH, et al. Cytoreductive therapy in 108 adults with systemic mastocytosis: Outcome analysis and response prediction during treatment with interferon-alpha, hydroxyurea, imatinib mesylate or 2-chlorodeoxyadenosine. Am J Hematol 2009;84: Maric I, Calvo KR. Mastocytosis: the new differential diagnosis of CD30 positive neoplasms. Leuk Lymphoma2011;5: Valent P, Sotlar K, Horny HP. Aberrant expression of CD30 in aggressive systemic mastocytosis and mast cel leukemia: a differential diagnosis to consider in aggressive hematopoietic CD30 positive neoplasms. Leuk Lyphoma, 2011;5: All published articles can be found on our website: where you may also find articles published in our other journals. 89