Indolent systemic mastocytosis D47.0

Systemic mastocytosis is a rare disease characterized by pathological proliferation and increased activity of neoplastic mast cells in bone marrow and in various other organ systems, potentially also in the skin. Cutaneous involvement(maculopapular mastocytosis = in the older nomenclature called urticaria pigmentosa) is found mainly in indolent systemic mastocytosis (ISM). It is completely absent in mast cell leukemia.

The diagnosis of "systemic mastocytosis" is made on the basis of the 2016 WHO classification criteria. To diagnose SM, either one major criterion and at least one of four minor criteria or three minor criteria must be met.

Main criterion

• Histological evidence of multifocal, compact infiltrates of mast cells (≥15) in the BM or in an extracutaneous organ.

Ancillary criteria

• Detection of atypical spindle-shaped mast cells (≥25% of all mast cells): histologically in the BM or in other extracutaneous organs or cytologically in the BM smear.
• Detection of KIT D816 point mutation in peripheral blood, KM or other extracutaneous organs.
• Detection of the surface marker CD2 and/or CD25 on mast cells in the BM, peripheral blood or in another extracutaneous organ
• Serum tryptase level persistently ≥ 20μg/l

The classification and subtyping of mastocytoses is according to the current WHO classification from 2016.

Cutaneous mastocytosis (CM)

• Cutaneous mastocytoma (findings in young children)
• Maculopapular cutaneous mastocytosis (MPCM = Urticaria pigmentosa of the old nomenclature), without detectable extracutaneous manifestations

Systemic mastocytosis (SM)

• Indolent SM (ISM) - most patients have cutaneous involvement
• Smoldering SM (SSM)
• SM with associated hematologic neoplasia (SM-AHN)* ⁺
• Aggressive SM (ASM⁾⁺
• Mast cell leukemia (MCL⁾⁺
• Mast cell sarcoma+

⁺ In clinical practice, the term "advanced SM (AdvSM)" has become the generic term for ASM, SM-AHN, and MCL.

*Systemic mastocytosis with associated hematologic neoplasia (SM-AHN): The hematologic neoplasia associated in rare SM-AHN is of myeloid origin in >95% of patients(SM-MDS; SM-CMML; SM-CEL; less commonly SM-AML). It reflects multilineage involvement of the KIT D816V mutation. The basis for subtyping is the extent of organ involvement and dysfunction.

Detectable somatic mutations, e.g., SRSF2, ASXL1, and RUNX1, among others, have now assumed increasing importance in phenotype, treatment response, and prognosis (Valent P et al. 2017; Jawhar M et al. 2019).

Systemic mastocytosis is a rare disease. Epidemiological figures on incidence and prevalence are imprecise. For indolent systemic mastocytosis, the incidence is thought to be around 1/100,000/year; for advanced systemic mastocytosis (AdvSM), the incidence is reported to be 1-2/1 million population/year.

Mastcells: Mast cells are derived from CD34 -positive bone marrow progenitor cells. These immature mast cell volcano cells enter the connective tissue of skin and mucous membranes of their end organs (skin, bronchial mucous membranes, mucous membranes of the GI tract) via the blood vessels. Mast cells express the tyrosine kinase receptor KIT (CD117), which in turn binds stem cell factor (SCF). SCF is a growth factor. It is essential for proliferation and differentiation of mast cells. In the tissue of their end organs, the immature cells differentiate into mature mast cells. Mutations that lead to a defect of SCF or KIT result in mast cell deficiency.

Activation of mast cells: Mast cells can be activated by various stimuli, such as allergens, food components, infections, drugs, physical stimuli, insect venom. This stimulation usually leads to a controlled release of mast cell mediators. These include biogenic amines such as histamine, heparin, tryptase, chymase, cytokines such as TNF-alpha, chemokines and prostanoids. However, in rare cases, uncontrolled release of mast cell mediators may occur with flushing, urticaria, or angioedema (see also under mast cell).

An extreme and uncontrolled release of mast cell mediators occurs in the so-called mast cell activation syndrome with possibly severe life-threatening conditions, e.g. hypotension/anaphylactic shock.

In contrast to these mediator-mediated symptoms, AdvSM often results in direct impairment of organ function due to mast cell infiltration itself and, in some cases, associated inflammation.

KIT mutation: The KIT D816 mutation (>95% KIT D816V in exon 17) is an activating mutation detectable in 80-95% of SM patients. The mutation leads to stem cell factor-independent receptor activation with clonal expansion and accumulation of tissue mast cells.

In childhood mastocytosis, mutations are also found in 50% of cases . However, in other regions of the KIT gene (exons 8, 9, 11).

KIT D816V mutation and mutation burden: KIT D816V mutation is detectable in mast cells in the vast majority of patients with ISM and SSM and in many patients with advancedSM without AHN. In general, quantitative KIT D816V mutation load correlates with mast cell load in KM. Genetic studies have shown that somatic mutations are often an early event, while KIT D816V mutation is a rather late event in the disease evolution of multimutated AdvSM patients (Jawhar M et al. 2016).

In adults, ISM most commonly manifests between the ages of 20 and 40, and AdvSM between the ages of 60 and 70.

The clinical picture differs significantly between "indolent systemic mastocytosis" (ISM) and "advanced systemic mastocytosis" (AdvSM).

In indolent systemic mastocytosis, the complaints and symptoms caused by the release of mast cell mediators are clinically in the foreground:

• Skin: pruritus, flushing, urticaria.
• GI tract: nausea, vomiting, ulcers, diarrhoea, abdominal cramps, food intolerance especially to histamine-containing foods such as cheese, red wine, chocolate, nuts, etc.
• Bronchial system: swelling of the nasopharynx, swelling of the larynx, possibly dyspnoea.
• Cardiovascular system: Syncope, dizziness, palpitations, tachycardia, anaphylactic reactions (especially after bee and wasp stings) with circulatory shock up to cardiac arrest (primary mast cell activation syndrome).
• Neurology: memory and concentration disorders, depression, headaches, sleep disorders
• Bones: diffuse bone pain, arthralgias, osteopenia, osteoporosis, osteoporotic fractures (especially of the spine)
• Constitutional: general weakness, fatigue

The following examinations are standard for the diagnosis "systemic mastocytosis" according to "WHO criteria 2016":

Laboratory parameters: tryptase, albumin, AP, GGT, bilirubin, LDH, ferritin, vitamin D, vitamin B12, folic acid, CRP, ß2-microglobulin, protein electrophoresis, immunofixation, IgE, plasmatic coagulation.

Blood count: blood and differential blood count (especially monocytes, eosinophils), possibly mast cells; dysplasia signs (MDS); leuko-/thrombocytosis (MPN)

Imaging: osteodensitometry (only with confirmed diagnosis)

Abdominal and lymph node sonography

If necessary CT/MRT (suspicion of osteolysis)

Bone marrow cytology: detection or exclusion of mast cell leukemia (mast cells ≥20%) or ASM-t (mast cells 5-19%) and degree of maturity of mast cells (metachromatic blasts, promastocytes, atypical spindle forms - mature cell or immature cell), dysplasias, blasts

Histology: mast cell load (quantitative), dysplasia, proliferation, AHN (yes/no?), blasts, fibrosis

Immunohistochemistry: tryptase, CD117, CD2, CD14, CD15, CD25, CD30, CD34, CD61

flow cytometry: determination/confirmation of mast cell number and phenotype of KIT+/CD34- mast cells: CD2, CD25, CD30, CD33; in AHN possibly also typing of monocytes, other AHN cells (depending on AHN type) and blasts

Molecular genetics: KIT D816V mutation analysis (qualitative and quantitative) from BM and peripheral blood.

In KIT D816V negative patients sequencing of KIT gene (rarely other KIT mutations possible)

Extended mutation analysis (myeloid NGS panel) in suspected SSM, AdvSM and mast cell sarcoma. Conventional cytogenetics, possibly FISH analysis - especially in case of (suspected) AHN.

Indolent SM (ISM): Within ISM, the individual clinical courses differ considerably. A part of the patients suffers from no symptoms at all . Mostly, it is the comorbidities that cause symptoms, e.g. IgE-dependent allergy. Especially the hymenoptera venom allergy is associated with a considerable morbidity and sometimes mortality. Other typical findings and symptoms are food and drug intolerance, skin manifestations, gastrointestinal complaints and osteopenia/osteoporosis with/without sintering fractures. Prophylactic antimediator therapy is initially administered as in patients with low-impact allergies, e.g. with 1 tablet/capsule of an HR1 blocker per day (e.g. cetirizine, fexofenadine, desloratadine, rupatadine) and an HR2 blocker per day (e.g. ranitidine 2 x 150 mg/day - currently (as of 02/2020) unfortunately not available.

Alternative: famotidine 2-3 x 40 mg/day). The dose is adjusted according to efficacy and tolerability. In severe cases (e.g. anaphylaxis) the dose is set (at least) as high as in severe allergies (these patients often primarily suffer from severe allergies). In some cases, different HR1 blockers can be combined so that, for example, centrally acting substances are used more in the evening to support the sleep that is often restricted in ISM patients. More importantly, HR2 blockers are taken in the evening. If efficacy is lacking or declining, a dose increase or a change in preparation may be helpful.

One HR2 blocker is sufficient to control symptoms in most cases with gastrointestinal symptoms. If symptoms are pronounced and/or resistant, the dose can be increased or a PPH can be prescribed in addition. A mere switch to a PPH, however, is not effective. In completely refractory cases, the primary diagnosis must be questioned and the GI tract examined again if necessary (only ISM or ASM after all - but also: additional active GI disease?).

In the next stage (while maintaining HR1/HR2 + PPH therapy) the use of a mast cell stabilizer (e.g. cromoglicic acid) or budesonide may be considered.

Consistent avoidance of potentially triggering substances (histamine-rich foods, allergens, triggers of intolerance reactions) must be required as a supportive basis for all therapies. Every patient should carry a list of all potentially triggering medications and foods, allergens, etc., as well as medications that have been well tolerated so far (e.g. painkillers).

The therapy of osteoporosis and its primary and secondary prophylaxis with regard to osteoporotic sintering fractures is of particular importance. In principle, these measures can be taken in accordance with the recommendations of the Osteoporosis Guideline of the German Osteological Association (Dachverband Osteologie e.V.). (DVO), mastocytosis represents a high-risk situation.

Every patient with proven vitamin D deficiency should receive vitamin D . In the case of pronounced vitamin D deficiency and high vitamin D dosage, attention should be paid to an additional supply of vitamin K2 (avoidance of vascular complications due to worsening of arteriosclerosis). Bisphosphonate therapy should be considered early.

Another alternative for these patients is therapy with interferon-alpha (Valent P et al. 2017).

The WHO classification with the distinction between ISM, SSM and the different subtypes of AdvSM represented until recently the only possibility to distinguish between different prognosis groups. Patients with ISM are characterized by a normal life expectancy. The median life expectancy of AdvSM is usually months to a few years.

Clinical examination (height, weight, qualitative and quantitative skin involvement, liver/spleen size, ascites, LK status).

blood and differential blood count, tryptase, AP, albumin, ß2-microglobulin, vitamin D3, fibrinogen, CRP

KIT D816V Mutation load

Individual: allergy status (total IgE, possibly specific IgE) [3, 9, 11, 14].

Osteodensitometry, sono-abdomen, BM cytology/histology, possibly CT/MRI.

Response parameters: C-findings, tryptase, monocytosis/eosinophilia, organomegaly/dysfunction, KM infiltration, KIT D816V mutation load

V.a. resistance/progression: KM puncture cytology, histology, possibly cytogenetics; myeloid panel (known mutations, novel mutations, e.g. K/N-RAS, TP53).

1. Akin C (2014) Mast cell activation disorders. J Allergy Clin Immunol Pract 2:252-257.
2. Bohm A et al (2010) In vitro and in vivo growth-inhibitory effects of cladribine on neoplastic mast cells exhibiting the imatinib-resistant KIT mutation D816V. Exp Hematol 38:744-755.
3. Erben P et al (2014) The KIT D816V expressed allele burden for diagnosis and disease monitoring of systemic mastocytosis. Ann Hematol 93:81-88
4. Hadzijusufovic E et al (2010) H1-receptor antagonists terfenadine and loratadine inhibit spontaneous growth of neoplastic mast cells. Exp Hematol 38:896-907.
5. Jawhar M et al. (2016) Additional mutations in SRSF2, ASXL1 and/or RUNX1 identify a high-risk group of patients with KIT D816V(+) advanced systemic mastocytosis. Leukemia 30:136-143.
6. Jawhar M et al. (2017) The clinical and molecular diversity of mast cell leukemia with or without associated hematologic neoplasm. Haematologica 102:1035-1043.
7. Jawhar M et al. (2019) MARS: mutation-adjusted risk score for advanced systemic mastocytosis. J Clin Oncol 37:2846-2856.
8. Jawhar M et al. (2019) KIT D816 mutated/CBF-negative acute myeloid leukemia: a poor-risk subtype associated with systemic mastocytosis. Leukemia 33:1124-1134.
9. Kluin-Nelemans HC et al (2003) Cladribine therapy for systemic mastocytosis. Blood 102:4270-4276.
10. Lubke J et al. (2019) Inhibitory effects of midostaurin and avapritinib on myeloid progenitors derived from patients with KIT D816V positive advanced systemic mastocytosis. Leukemia 33:1195-1205.
11. Naumann N et al. (2018) Incidence and prognostic impact of cytogenetic aberrations in patients with systemic mastocytosis. Genes Chromosomes Cancer 57:252-259.
12. Riffel P et al (2019) Magnetic resonance imaging reveals distinct bone marrow patterns in indolent and advanced systemic mastocytosis. Ann Hematol 98:2693-2701.
13. Sotlar K et al (2010) Variable presence of KITD816V in clonal haematological non-mast cell lineage diseases associated with systemic mastocytosis (SM-AHNMD). J Pathol 220:586-595.
14. Valent P et al (2017) Advances in the Classification and Treatment of Mastocytosis: Current Status and Outlook toward the Future. Cancer Res 77:1261-1270.
15. Ustun C et al (2016) Consensus Opinion on Allogeneic Hematopoietic Cell Transplantation in Advanced Systemic Mastocytosis. Biol Blood Marrow Transplant 22:1348-1356
16. Valent P et al. (2007) Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. European journal of clinical investigation 37:435-453.
17. Valent P et al. (2017) Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts. Blood 129:1420-1427.