Advanced systemic mastocytosisQ47.0; C96.2

Systemic mastocytosis is a rare group of diseases characterized by pathological proliferation and increased activity of neoplastic mast cells in the BM and in various other organ systems. Cutaneous involvement is less common in advanced systemic mastocytosis (AdvSM) than in indolent systemic mastocytosis. The diagnosis is made on the basis of the criteria of the WHO classification 2016.

Classification and subtyping is according to the current WHO classification from 2016.

Cutaneous mastocytosis (CM)

• Maculopapular CM (MPCM) = Urticaria pigmentosa of the older nomenclature(UP).
• Cutaneous mastocytoma

Systemic mastocytosis (SM)

• Indolent SM (ISM)
• Smoldering SM (SSM)
• SM with associated hematologic neoplasia (SM-AHN)*
• Aggressive SM (ASM)+
• Mast cell leukemia (MCL)+
• (advanced systemic mastocytosis)
• Mast cell sarcoma

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

SM is a rare disease. Epidemiological figures on incidence and prevalence are imprecise. For "advanced systemic mastocytosis (AdvSM)", an incidence of 1-2/1 million population/year is reported. In AdvSM, men are more frequently affected than women.

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 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: Thus, an activating KIT D816 mutation (>95% KIT D816V in exon 17) is detectable in 80-95% of SM patients. The mutation leads to SCF-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 AdvSM without AHN. In general, quantitative KIT D816V mutation load correlates with mast cell load in KM. In AdvSM, especially in SM-AHN, and in SSM, the KIT D816V mutation is detectable in mast cells, but also in non-mast cell fractions (e.g., myeloid progenitor cells, monocytes, eosinophils, and others). In these cases, the KIT D816V mutation is always detectable in peripheral blood as well, and the KIT D816V mutation load in peripheral blood can reach levels of 50% and above.

Other mutations: In 60-80% of patients with AdvSM, additional somatic mutations are detectable in addition to KIT D816V. The most commonly affected genes are TET2, SRSF2, ASXL1, RUNX1, JAK2, CBL, N/KRAS, EZH2, IDH1/2 and SF3B1. Detection of at least one mutation in the SRSF2, ASXL1, RUNX1 gene panel has a significant impact on phenotype, treatment response, progression and prognosis. Genetic studies have shown that the somatic mutations often represent an early event, while the KIT D816V mutation represents a rather late event in the disease evolution of multimutated AdvSM patients (Jawhar M et al. 2016).

AdvSM manifests itself between the ages of 60 and 70.

The clinical picture of "advanced systemic mastocytosis" (AdvSM) is clearly different from "indolent systemic mastocytosis" (ISM) and the cutaneous forms of mastocytosis. In indolent systemic mastocytosis, the focus is on symptoms caused by the release of mast cell mediators . Furthermore, this variant is characterized by a high skin involvement.

In AdvSM), the organomegaly caused by organ infiltration and the typically occurring organ dysfunctions are in the foreground:

• Bone marrow: cytopenias (anemia, thrombocytopenia, neutropenia).
• Spleen/Liver: Splenomegaly with/without hypersplenism, hepatomegaly with/without elevated liver enzymes (especially alkaline phosphatase (AP), possibly bilirubin, rarely ALAT and ASAT), hypoalbuminemia and ascites.
• Gastrointestinal: Malabsorption with hypoalbuminemia, weight loss, ventricular ulcer, duodenal ulcer, intestinal perforation (rare).
• Lymph nodes: lymphadenopathy (especially abdominal, retroperitoneal)
• Bones: often osteosclerosis, osteopenia or osteoporosis rather rare, very rarely large osteolyses with pathological fractures

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, 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.

KIT inhibitors: Midostaurin: the only drug approved in Germany for the treatment of AdvSM (ASM, SM-AHN and MCL). The effect is independent of previous therapies and KIT mutation status. Significant reduction of KM mast cell infiltration, serum tryptase, splenomegaly and KIT D816V mutation load as well as improvement of C-findings. The response rate is 60% and can last for several months, sometimes years. However, primary resistance or early progression are also observed. Over the long-term, improved survival appears to be associated with the absence of pathogenetically relevant, somatic additional mutations (e.g. SRSF2, ASXL1, RUNX1), the achievement of a conventional response, and with a >25% reduction in KIT D816V mutation burden at 6 months.

The initial dose is 2 x 100mg/day (in 25mg capsules), depending on e.g. age, comorbidity and/or general condition possibly starting with 2 x 50mg/day and further adjustment according to effect and side effects. Many patients report nausea, sometimes considerable, which requires regular prophylaxis with a 5-HT₃ antagonist, e.g. ondansetron 2 x 4-8 mg/day. The hematological toxicity of midostaurin is rather low; anemia and thrombocytopenia that increase during the course often cannot be distinguished from disease progression.

Imatinib/nilotinib/dasatinib(off-label): The KIT D816V mutation confers primary imatinib resistance. Potentially, these TKIs are effective in KIT wild-type (approval in US), KIT K509I, KIT F522C, and KIT V560G (<2% of patients). There are also single case reports of complete remissions here.

Conventional cytoreductive therapy.

Hydroxyurea: palliative therapy of refractory, non-transplant AdvSM. In SM-AHN mainly for therapy of AHN, e.g. leukocytosis, blasts, splenomegaly. No long-lasting remissions. In rare cases, there is also a temporary response in cases of otherwise uncontrollable splenomegaly.

Interferon-alpha (off-label): There are isolated case reports of positive response in ASM-AHN when the AHN component of the disease can in principle respond to IFN-alpha, e.g. MPN, or in slowly progressing ASM, especially with predominant liver and/or GI involvement. AdvSM patients who only have ascites respond particularly well (here the combination of IFN-alpha + glucocorticosteroids is particularly effective).

Cladribine (off-label): Indication in SSM with signs of incipient ASM and any form of AdvSM without a rapidly progressive course. Dosage 3-6 cycles; 0.14mg/kg s.c. or i.v. over 5 days). Caveat: Additional medication with cotrimoxazole and aciclovir in usual dosage. Overall, cladribine shows relatively good tolerability (Kluin-Nelemans HC et al 2003; Bohm A et al 2010).

Intensive polychemotherapy: in rapidly progressive or refractory ASM, SM-AML and MCL ± AHN (e.g. rapid rise in tryptase or rapid rise in mast cells in the blood), polychemotherapy is indicated and may need to be initiated rapidly. The regimens are based on those of de novo AML therapy. Additional therapy with midostaurin (as in FLT3-mutated AML) is not standard, but may be used in individual cases. Complete remissions have been described for MCL or ASM as well as for AHN (AML) (Kluin-Nelemans HC et al. 2003).

Allogeneic stem cell transplantation: The exact value of allogeneic SCT as the only potentially curative form of therapy in AdvSM has not yet been clarified due to the lack of prospective studies. A donor should be sought in all young and fit patients, and once a donor is found, this therapeutic option should be discussed. The 3-year overall survival was 57% for all patients, 74% for SM-AHN, 43% for ASM and 17% for MCL.

Lack of complete remissions or early relapses after remission: maintenance therapy with midostaurin, e.g. after 6 months for further 12-24 months. In general, all suitable (age, comorbidity) patients with AdvSM should therefore be presented early to a transplant center (Ustun C et al. 2016).

The median life expectancy of AdvSM is usually months to a few years. Patients with MCL ± AHN have the worst prognosis. Most recently, several unfavorable prognostic factors independent of the WHO classification have been identified. From a molecular point of view, an S/A/R gene panel consisting of three (SRSF2/ASXL1/RUNX1) prognostically essential genes can be used, in which a mutation per se as well as the number of mutations are associated with an aggressive clinical presentation as well as reduced survival.

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.