Systemic Mastocytosis: Multidisciplinary Approach

Roberta Zanotti1,2, Ilaria Tanasi1,2, Lara Crosera1, Massimiliano Bonifacio1,2 Donatella Schena2,3, Giovanni Orsolini2,4, Francesca Mastropaolo2,4, Morena Tebaldi2,5, Elisa Olivieri2,6 and Patrizia Bonadonna2,6.

1 Hematology Unit, Department of Medicine, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy.
2 Interdisciplinary Study Group for Mastocytosis (GISM), Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy.
3 Dermatology Unit, Department of Medicine, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy.
4 Rheumatology Unit, Department of Medicine, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy.
5 Gastroenterology Unit, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy.
6 Allergy Unit, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy.

Correspondence to: Roberta Zanotti. Department of Medicine and Interdisciplinary Study Group for Mastocytosis (GISM), Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy. E-mail: roberta.zanotti@univr.it

Published: November 1, 2021
Received: September 23, 2021
Accepted: October 20, 2021
Mediterr J Hematol Infect Dis 2021, 13(1): e2021068 DOI 10.4084/MJHID.2021.068

This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(
https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Systemic Mastocytosis (SM) is a heterogeneous group of diseases that affect almost exclusively adults and are defined by the proliferation and accumulation of clonal mast cells (MC) in various tissues. Disease subtypes range from indolent to rare but aggressive forms. Although SM is classified as a rare disease, it is believed to be likely underdiagnosed. Major signs and symptoms mainly depend on MC activation and less frequent organ infiltration, typical of more aggressive variants. Diagnosis may be challenging, and symptoms can be aspecific and involve several organs. Therefore, it is advisable to refer patients to specialized centers, having sufficient knowledge of the disease, sensitive diagnostic procedures, offering a personalized and multidisciplinary diagnostic approach, including at least hematological, allergological, dermatological, and rheumatological evaluations. A precise and timely diagnosis is required for: a) adequate counseling of patients and their physicians; b) beginning of symptomatic treatment (anti-mediator therapy); c) prevention of severe manifestations of the disease (i.e., recurrent anaphylaxis, osteoporosis, and bone fractures); d) cytoreductive treatment of advanced SM variants.
This review summarizes the disease's main manifestations and describes the ideal diagnostic approach for adult patients with suspected SM, giving physicians the main notions for correct patient diagnosis and management. This review also highlights the importance of a multidisciplinary approach in this very complex disease.



Introduction

The term mastocytosis comprises a heterogeneous group of clonal diseases characterized by proliferation and accumulation of mast cells (MC) in different tissues, mainly skin and bone marrow (BM).[1] Cutaneous Mastocytosis (CM) is a skin-limited disease, typical of childhood, that may spontaneously regress during puberty.[2] Conversely, more than 90% of adults have a systemic disease (SM) involving one or more extracutaneous organs [BM, gastrointestinal tract (GI), lymph nodes, and spleen)], with or without skin involvement.[1] The great majority of SM shows a "self-activating" somatic point mutation at codon 816 of the c-Kit receptor gene.[3,4]
SM may present with a variety of clinical manifestations due to inappropriate release of MC mediators (i.e., pruritus, urticaria, angioedema, flushing, nausea, vomiting, abdominal pain, diarrhea, episodic anaphylactoid attacks, osteopenia or osteoporosis) and skin diseases (urticaria pigmentosa – UP or maculopapular CM - MPCM); in the rare cases of aggressive disease, clinical features are due to MC tissue infiltration and subsequent organ dysfunction (i.e., hypersplenism, pathological bone fractures, ascites, malabsorption, cytopenia).[1]

Classification

The 2016 World Health Organization (WHO) distinguishes upon major categories and subvariants of Mastocytosis. Diagnosis of SM is based on one major and four minor criteria (Table 1) and requires the presence of the major histological criterion, together with at least one minor criterion.

Table 1 Table 1.  Criteria for diagnosis and definition of major clinical variants in systemic Mastocytosis (SM) (WHO, 2008; updated in 2016).[5]

In the absence of the major criterion, at least three out of four minor criteria need to be satisfied.[5,6] SM patients can be further sub-classified depending on the presence of B or C findings, defining the MCs' burden and the disease aggressiveness, respectively (Table 2).[5,6] Based on histological criteria, clinical parameters, and organ involvement, SM is divided into indolent SM (ISM), smoldering SM (SSM), and advanced SM variants (AdvSM). AdvSM are subclassified into SM with associated hematologic neoplasia (SM-AHN), aggressive SM (ASM), and MC leukemia (MCL) (Table 2). ISM is the most common subtype and has a relatively benign prognosis, although a small percentage of patients progress to SSM or AdvSM. Bone marrow mastocytosis (BMM) represents a provisional variant of ISM, without skin involvement, and characterized by low MC burden, low serum tryptase levels, and frequent association with anaphylaxis, mainly after hymenoptera sting.[7] The prognosis of this variant is considered particularly good, but no significant difference in survival compared to typical ISM with skin involvement has been documented until now.[8] Recent data from the European Competence Network on Mastocytosis (ECNM) suggest that patients with BMM and low disease burden (defined as the absence of any B-Finding and a tryptase level <125 ng/ml) have a better prognosis than patients with typical ISM. As a consequence, the authors proposed redefining BMM with these characteristics as a different SM variant.[9]

Table 2 Table 2. Classification of systemic Mastocytosis.[1,5

SSM is characterized by a higher disease burden than ISM, but the actual prognostic relevance of SSM is debated: a first report documented an inferior survival of SSM with respect to ISM,[10] but in a recent large retrospective study by the ECNM, the estimated survival of SSM patients was similar to that of ISM.[8]
ASM is characterized by signs of organ damage due to MC infiltration, and patients have a reduced life expectancy and poor prognosis.
SM-AHN represents a very complex SM variant. In 85-90% of cases, SM is associated with a myeloid disease (i.e., myelodysplastic/myeloproliferative neoplasms, myelodysplasia, acute myeloid leukemia, myeloproliferative neoplasms), more rarely with lymphomas or myelomas.[5,6] It is generally considered an advanced variant, multilineage-mutated myeloid neoplasia with a fatal outcome. However, the prognosis of SM-AHN depends on both the SM variant and the associated disease. For example, the prognosis may not be severe when ISM is associated with a relatively indolent disease (such as essential thrombocythemia). It is also often challenging to accurately correlate the B/C findings to the SM or the associated disease, and therefore the correct classification of the SM variant. Therefore, the incidence of SM-AHN is probably underestimated, especially when the MC burden is low.
ASM accounts for approximately 5% of all SM and has a poor prognosis, with an average survival rate of 2-4 years.[11] Skin lesions are frequently absent, while "C" findings such as hepatosplenomegaly associated with signs of organ failure, malabsorption with weight loss, blood count cytopenias or extensive osteolysis may be dominant aspects of the clinical picture.[1]
MCL is the leukemic form of SM, a rare entity characterized by diffuse medullary infiltration of MCs (> 20% in the medullary smear), often with an immature or blastic appearance.[1,12] Skin lesions are absent in almost all patients, and the course is fatal, with a reported prognosis of fewer than six months. However, a "chronic" form of MCL was recently defined, characterized by the absence of "C" findings and less aggressive clinical course, with survival even longer than two years.

Epidemiology

Reports on epidemiological aspects of Mastocytosis in adults are limited, and it is widely believed that the disease is highly underdiagnosed due to a lack of knowledge about it and the very heterogeneous clinical presentation. A nationwide study based on Danish health registries reported an estimated prevalence of SM in adults of 10 per 100.000 inhabitants,[13] and a similar prevalence of ISM had been reported in the Groningen region adult population (13.0 per 100,000 inhabitants).[14]
We believe that the growing diffusion of sensitive diagnostic methods and the creation of multidisciplinary groups dedicated to Mastocytosis will allow us to document a greater number of SM diagnoses. Based on the database of our Interdisciplinary Study Group for Mastocytosis (GISM), the estimated prevalence of SM in the adult population of the Italian province of Verona is 16.1 per 100.000 inhabitants (unpublished data based on ISTAT report of Verona province population at Jan 1, 2021).
No apparent gender predominance has been documented in adult mastocytosis.
Although Mastocytosis is considered a non-hereditary somatic disease, familial cases have been reported in pediatric series, with an estimated frequency of 11–13%.[15,16] Recently, a study conducted on a large series of adult patients reported an estimated prevalence of familial cases of 1.5%.[17]

Pathogenesis

MC progenitor cells express the tyrosine kinase receptor KIT, involved in the development of MC by binding its ligand, the stem cell factor (SCF).[18] The majority of adult patients with SM harbor an activating KIT receptor mutation responsible for the autonomous growth and expansion of neoplastic MC.[3] D816V mutation of KIT is the most frequently detected, independently of the SM variant and the aggressiveness; moreover, it is documented in about 40% of pediatric CM.[4,15,19] Although KIT D816V mutation is undoubtedly the major driver of SM pathogenesis, it is not considered a fully transforming oncoprotein.
Additional non-KIT mutations not specific for SM (i.e., ASXL1, SRFS2, RUNX1, CBL, EZH2 mutations) are detected mainly in advanced SM and associated with poorer prognosis.[20–22] The role of these mutations in SM pathogenesis is still unclear.


Hematologic Diagnostic Workup

The diagnostic pathway should begin with the search for characteristic skin lesions, that even if isolated constitute an indication to perform a complete BM assessment.[23] Skin biopsy is not strictly necessary if skin lesions are typical.[2]
In the absence of typical skin lesions, the diagnostic pathway varies according to the tryptase value detected. However, it must be taken into account that, during and following an anaphylactic event, tryptase increases, and therefore, it is necessary to re-evaluate it 24 hours after the complete resolution of the symptoms.[23,24] If the basal serum tryptase value is higher than 25 ng/ml, a complete BM evaluation is immediately indicated, while if the value is inferior to 15 ng/ml, it could be monitored over time. For tryptase values ranging from 15 to 25 ng/ml, the indication to proceed with the BM evaluation depends upon additional parameters, such as a REMA score ≥2 (Table 3), the detection of the D816V mutation on peripheral blood (PB), or the presence of extra symptoms suggestive of the disease.[25]


Table 3 Table 3. The REMA Score (Red Española de Mastocitosis).[64]

Table 4 Table 4. Factors that can lead to mast cells mediators release.[114

BM and PB diagnostic workup is detailed in Table 5. They should include:
o    Morphological examination of BM smear, using the classic staining with May Grunwald-Giemsa.[26] BM smear examination is necessary to evaluate the percentage of MC and their morphology that it was classified in four subtypes: a) spindly shaped with hypo-granulated cytoplasm, b) well-differentiated (round, hyper-granulated), c) immature (promastocytes with a bilobed or indented nucleus), and d) metachromatic blasts.[26] The BM smear should also be reviewed for AHN features. The stain with Toluidine Blue could allow to easily identify atypical MC distinguish them from basophils for the presence of the typical metachromatic granules.[6]
o    Morphological examination of PB smear. PB smears should  be  examined  for  the presence of circulating MC and eventually for excluding signs of an associated hematological neoplasm (i.e., dysplasia, monocytosis, eosinophilia).[1]
o    Histological and immunohistochemical examination of the BM biopsy that must include, in addition to the normal Giemsa and Hematoxylin-eosin stains, the following immunohistochemical investigations: tryptase, CD117, CD25 (and CD2).[1,27] In fact, neoplastic MC aberrantly express, in addition to CD117 and Tryptase, antigens related to the lymphoid lineage, such as CD2 and CD25, absent in the normal MC.[28,29] In particular, CD25 showed high sensitivity and specificity (close to 100%) for the diagnosis of SM[30] and is therefore considered the best immunohistochemical diagnostic marker.[27] Recently, the abnormal MC expression of CD30 has emerged as a useful feature, especially in advanced forms of SM.[31] Furthermore, recent reports have shown that CD30 is also frequently expressed in CM and all subtypes of SM, being useful in diagnosing CD25 negative well-differentiated SM.[32] The BM evaluation should also include the extent of infiltration, the atypia of MCs, the presence of fibrosis, and signs of other associated hematological neoplasms.[1] An accurate diagnosis of SM can be challenging in some cases, particularly when the major histological criterion is not fulfilled and only isolated atypical MC or small sub-diagnostic aggregates are observed. (Figure 1)
o    Multi-parameter flow cytometry on BM samples requires a panel including at least monoclonal antibodies anti-CD45, CD34, CD117, CD25, CD2 (and optionally CD30).[27,32,33] In case of minimal MC infiltration, a high number of events should be acquired (up to 3-6 million events).[33,34]
o    Detection of KIT D16V mutation in BM with highly sensitive KIT mutation assay to minimize the risk of false-negative results. For instance, in ISM the allelic burden can be very low and often less than 0.01%.[25,35] Currently, the allele-specific oligonucleotide quantitative polymerase chain reaction (ASO-qPCR) is considered the most sensitive technique (0.01%). Droplet Digital PCR (ddPCR) is a promising method for quantifying KIT D816V mutation with similar sensitivity to RT-qPCR (0.01%) and without the need for standardization.[36] Both these techniques detect the D816V KIT mutation only. At this moment, Next Generation Sequencing (NGS) is not routinely recommended for the search of the D816V KIT mutation, as it has been proved to be less sensitive than RT-qPCR (sensitivity 1-5%).[37] Approximately 5-10% of SM are negative for the D816V KIT mutation,[4] generally because of a) false-negative results due to low MC burden or sub-optimal sample or the use of a less sensitive method; b) Wild-type KIT; c) presence of another rare KIT mutation at codon 816 (F/ H/ I/Y) or in other codons. In the case of D816V negativity and strong suspicion of SM, other KIT mutations at position 816 (i.e., D816Y, D816H, etc.) should be ruled out with PNA-mediated PCR technique on BM samples or sorted MC with a sensitivity of 0.1%.[4,19,38–40] Moreover, mutations in other regions of a KIT gene may be assessed by NGS.[40] Molecular testing in PB with an RT-qPCR-based method or ddPCR may be used as a screening method in patients with suspicion of SM.[36,41] However, it must be taken into account that about 30% of BMM and 10% of ISM patients result negative for the mutation assessed in PB, also with sensitive techniques.[39]
o    BM conventional cytogenetics analysis is indicated in patients with suspected or confirmed advanced SM, especially in SM-AHN cases.[27]
o    NGS study for other myeloid gene mutations is recommended to search for mutations of other myeloid genes in advanced forms, mainly for prognostic purposes.[27,42,43]


Table 5 Table 5. Workup for suspected systemic Mastocytosis; modified from Gotlib et al 2018.

Figure 1 Figure 1.  Bone marrow histology of two patients with D816V KIT-mutated ISM. Case 1 (upper panel) shows an aggregate of more than 15 mast cells, i.e. the major diagnostic criterion (A: H&E; B: CD117 staining, C: CD25 staining). Case 2 (lower panel) shows isolated spindle-shaped paratrabecular atypical mast cells (A: H&E; B: tryptase staining, C: CD25 staining). (courtesy of dr Alice Parisi).


Prognosis

Several clinical, serological, cytomorphological, immunological have been reported to be prognostic in SM. Some of these variables have been included in the WHO classification, such as cytopenia and organomegaly.[1,5] Other variables associated with poorer prognosis are age >60 years, low albumin serum level, increased serum β2-microglobulin and alkaline phosphatase.[44–46]
Some biological parameters have been proposed and tested in SM to improve WHO-based risk stratification: poorer prognosis is associated with a multilineage KIT mutation involvement, high KIT D816V allele burden, and presence and number of mutations in genes other than KIT (e.g., SRSF2, ASXL1, RUNX1).[20,46,47] Several integrated prognostic models, as IPSM, MAPS, MARS, GPSM score have been still proposed, all demonstrated on large retrospective patient cohorts and also confirmed in external series.[48–51] Some models include only clinical information and are particularly useful in routine practice, while other scores include both mutational and clinical data. Further longitudinal studies in a large series of SM patients with long follow-up may help select better scores for adequate patient stratification, treatment decisions, and clinical management of MS patients.

Multidisciplinary Evaluation and Treatment

General considerations. Mastocytosis is a complex disease presenting with several clinical manifestations and with a variable clinical course. In non-advanced variants, patients mainly refer to skin symptoms (i.e., pruritus, flushing) or other mediators-release symptoms (i.e., anaphylaxis, osteoarticular pain, GI symptoms), and management often relies upon symptoms control and elimination of additional risk factors and comorbidities. In advanced forms of SM, organ damage prevails, and cytoreductive treatment is needed. Thus, a multidisciplinary diagnostic approach is needed for all these reasons, and a treatment strategy should be tailored to a single patient. Additionally, these patients may need psychological or psychiatric support.
The approach to the patient with SM must include adequate counseling addressed to patients and relatives and physicians involved in the treatment. In addition, information should be given on the natural history of disease and related problems, the drugs to be avoided, and the management of patients requiring anesthesia or surgical treatment. Furthermore, patients should be instructed to avoid triggers for acute mediator release (Table 5) and the emergency use of steroids associated with fast-acting antihistamines and self-injectable adrenaline, mainly if they present a high risk of anaphylaxis (i.e., patients allergic to Hymenoptera venom).
Complete workup of patients with SM at diagnosis is detailed in Table 5.
History, physical exam, assessment of symptoms burden, laboratory evaluations (annually for patients with ISM and every six months for SSM), and DEXA scan every 1-3 years are recommended for ISM and SSM patients. In addition, patients with ISM and SSM should also be monitored for the development of signs of disease progression to advanced SM (e.g., development of B or C findings).[27] The frequency of monitoring patients with advanced variants of SM should be individualized on the patient conditions and cytoreductive treatment.
Skin manifestations. The classification of CM includes the following variants[2]
•    Maculopapular Cutaneous Mastocytosis (MPCM) or Urticaria Pigmentosa, subclassified into monomorphic and polymorphic variants.
•    Diffuse Cutaneous Mastocytosis.
•    Isolated Mastocytoma.
The presence of telangiectasia, along with MPCM-like skin lesions, has traditionally been termed Telangiectasia Macularis Eruptiva Perstans (TMEP), though the term TMEP should no longer be used.[2] Adult patients with CM who have not undergone BM assessment are more correctly and provisionally referred to as having Mastocytosis in the skin (MIS).[1]
The most common presenting symptom in adult mastocytosis is the gradual onset of pigmented, reddish-brown, monomorphic, small-sized (up to 5 mm in diameter) skin lesions (MPCM) (Figure 2).[2] Some cases result from the persistence in adulthood of pediatric CM. The frequency of these cases remains to be determined; in clinical practice, monomorphic MCPM generally persists in adulthood, while polymorphic MPCM tends to resolve in puberty, as well as the cutaneous Mastocytoma.[2,52] Skin lesions typically show a wheal-and-flare reaction upon rubbing or stroking, the so-called Darier's sign.[2]


Figure 2 Figure 2. Maculopapular cutaneous Mastocytosis (or Urticaria Pigmentosa) (courtesy of dr Donatella Schena).

Skin symptoms include pruritus, flushing, and wheeling, often triggered by physical stimuli, such as heat, cold, sunlight, and friction.[1] Skin symptoms due to MC mediators release can usually be controlled by H1- antihistamines alone or in association with H2-inhibitors.
Cosmetic complaints could be a significant issue in many patients, especially younger adults, and should not be minimized. Moreover, symptoms could not respond to anti-mediator therapy. At present, ultraviolet A therapy or Psoralen plus ultraviolet A (PUVA) photochemotherapy can be employed,[1,43,53,54] to reduce MC mediator skin symptoms and visibility of skin lesions, although the effect is temporary. This treatment should be used with caution due to its potential cutaneous side effects.
Anaphylaxis. The prevalence of anaphylaxis in adult patients with Mastocytosis ranges from 20% to 49%,[55–57] much higher than the 0.05–2% estimated frequency in the general population.[58,59] Discrepancies between different studies might be a result of the heterogeneity of the patient cohorts, the definition of anaphylaxis, varying recruitment strategies but also be due to the sensitivity of the diagnostic techniques. Allergic/anaphylactic symptoms are mostly present in patients with BMM, often representing the initial clinical manifestation and the indication for BM evaluation in most cases.[60]
The triggers that can induce a massive degranulation of MC and subsequent anaphylaxis in adult SM patients are numerous, Hymenoptera stings being the more frequent (19-60% of cases of anaphylaxis), followed by foods (3-16% of cases) and drugs (5-9%).[55–57,60] alcohol, exercise and temperature changes are other possible triggering factors of anaphylaxis in Mastocytosis, acting mainly as co-factors.[56]
Idiopathic anaphylaxis is not infrequent in SM, reported in up to 29-39% of cases.[57,60]
The higher prevalence of HVA confirms a significant association between HVA and SM in SM patients (up to 20-30%) compared to the general population (00.5-3.3% of adults in the US and 0.3-7.5% of adults in Europe).[61–63] Patients with SM and severe HVA are typically affected by indolent SM lacking skin lesions in the majority of cases (i.e., BMM), are mainly of the male gender, have not very high basal tryptase levels, and allergic reaction is characterized by hypotension with the absence of urticaria and angioedema.[64,65] Early diagnosis of SM in patients with severe HVA represents a substantial advantage because they are at high risk of severe osteoporosis, and early therapy can be immediately started to prevent vertebral fracture. Furthermore, proper advice and prescription of adrenaline (two autoinjectors) can be assessed. Finally, venom immunotherapy should be continued lifelong to prevent fatal events.[66]
Gastrointestinal symptoms. Patients with SM frequently complain of GI symptoms, including abdominal pain, cramping, diarrhea and gastritis.[1,67] Symptoms may be mild or severe, and differential diagnosis with other GI diseases could be difficult. The pathogenesis of GI symptoms in SM is, in most cases, related to MC mediator release, but especially in advanced forms, it could also involve the accumulation of clonal MC in the GI tract. Various stimuli may trigger GI symptoms, i.e., foods, alcohol, stress, but they also can occur spontaneously.
In patients with SM, endoscopic abnormalities are frequently nonspecific. Histological features may include the presence of MC in aggregates or sheets in the lamina propria and the detection of aberrant CD25-expressing MC.[68] However, the involvement can be focal and subtle, making the diagnosis challenging. Moreover, clinical symptoms do not always correlate with histological findings.
Treatment options include H2 blockers, proton-pump inhibitors, and oral sodium cromolyn, alone or in combination. Complete patient history is helpful to identify the triggers of symptoms. In the rare, aggressive subtypes of SM, severe MC infiltration in the GI tract may lead to malabsorption and weight loss. In these cases, cytoreductive therapy is indicated.[1]
Bone involvement: diagnosis and treatment of related symptoms. According to the cohort of Hermans et al.,[69] osteoporosis and bone lesions are among the most frequent manifestations of SM. On the other hand, a recent study on over 8000 osteoporotic patients recognized SM as its cause in 0.5% of the population.[70] Osteoporosis' prevalence settles down to 8-40% in patients affected by SM while fractures to 3-41%.[71–76] Useful imaging modalities in this context are dual-energy X-ray absorptiometry, radiography (skeleton in toto or at least axial), CT, and magnetic resonance imaging advanced techniques such as PET could be reserved for special cases.[77] Alongside imaging, it is therefore very important to evaluate laboratory tests (such as the serum dosage of 25-OH-vitamin D, s-CTX, Parathormone, alkaline phosphatase, calcemia, phosphoremia, 24-hour calciuria, and phosphaturia, see Table 3).
SM-related fragility involves most prominently the spine, provoking frequently vertebral fragility fractures.[77] Given this, SM diagnosis should be considered when approaching a patient with unexplained fragility fractures, osteoporosis, or inappropriate low bone mineral density (BMD), as a possible underlying etiology.[78] The presence of osteoporosis in male patients or young premenopausal women should induce the suspect of SM.[70] Osteoporosis secondary to SM frequently causes a lower BMD at the lumbar spine than the hip, indicating a greater loss of trabecular with respect to cortical bone. This could be due to either a higher sensitivity of trabecular bone to local factors synthesized by MC or MC's development from BM, which is predominantly localized in the trabecular bone.[70] Furthermore, both the Z-score and the T-score should be considered in these patients since the latter could be misleading due to the low sensitivity and specificity to detect secondary bone disease, especially in men and premenopausal women.[79] When facing a low BMD with a Z-score < -2, secondary causes of osteoporosis should be excluded with further diagnostic examinations. Likewise, fragility fractures occurring in the context of normal or almost normal BMD values should be investigated to rule out possible secondary causes.[78] Bone involvement in patients affected by Mastocytosis comprises both a qualitative and a quantitative problem, as shown by the occurrence of fractures in osteopenic patients or those with normal values of BMD. Patients affected by osteoporosis secondary to SM often display a high bone turnover. Interestingly, many studies evidenced a correlation of C-telopeptide and osteoprotegerin to tryptase levels, highlighting a possible correlation to the number of MC.[70,80,81] Of note, serum tryptase elevation (>25 ng/mL) is considered a useful screening tool to predict systemic Mastocytosis and select patients who should undergo BM biopsy. In cases of mild increase of serum tryptase levels (15-25 ng/mL), BM biopsy should also be considered based on the concomitant clinical elements of suspicion. However, it is not completely reliable as with any biomarker due to possible false positive and negative results. Data from Carosi et al. described serum tryptase elevation in a large cohort of patients with osteoporosis, but only a small percentage (19%) of those who underwent BM biopsy was confirmed to have Mastocytosis.[81] Therefore, as serum tryptase values lack the high reliability needed in this group of patients when a high clinical suspicion is present, BM biopsy should be considered regardless of serum tryptase value. The picture is even more complicated because, according to recent data, the absence of skin involvement represents a significant risk factor for fractures in SM. This is probably due to a higher diagnostic delay and misdiagnosis in patients not presenting typical skin lesions.[74,79] It must be remembered that osteoporosis and fragility fractures are not the only bone manifestations of SM. A minority of patients present with a diffuse osteosclerotic pattern, characterized by high BMD, high bone turnover, and diffuse bone scintigraphy uptake ("super scan").[78,82] In most cases, these patients also display a very high level of serum tryptase and have a higher chance to be affected by advanced forms of SM.[83] It may also happen that in the context of a sclerotic bone, small lytic lesions may appear, not having the classical appearance of "C-criteria" lytic lesions. A small percentage of patients may also have single or multiple focal sclerotic or lytic lesions.[77,78,82] Antiresorptive drugs are the mainstay of treatment in osteoporosis induced by Mastocytosis. In particular, 5 mg zoledronate IV per year seems to be an effective therapeutic option to reduce bone turnover markers and prevent bone loss,[84] but in aggressive forms with lytic involvement and recurrent fracture a monthly protocol for myeloma could be applied. The most frequent side effect, which occurs more frequently than in the general population, is the acute phase reaction to the first administration of zoledronate. However, this reaction is transient, manageable with symptoms and with adequate patient information before administration. Given the pivotal role that the RANK-RANKL system seems to play in the pathogenesis of osteoporosis caused by SM, denosumab might be a further therapeutic option.[77,85]
In patients with severe osteoporosis or refractory to bisphosphonates, therapy with alpha-interferon is suggested based on some studies which reported a good efficacy of the combined use of bisphosphonates and interferon, also if with tolerance problems.86 In the future, the role of alpha-interferon could be replaced by more innovative drugs.
If the diet is low in calcium, the prescription of vitamin D supplements and even calcium supplements remains pivotal in all conditions ranging from mild osteopenia to severe osteoporosis.

Special Aspects

Anesthesia. Currently, there are no reliable data on the safety of anesthetic drugs in patients with Mastocytosis, and it is impossible to provide general recommendations on the safety of drugs, or drug families, used in the perioperative period.
The risk appears to be greater in adult patients with Mastocytosis than in children, regardless of skin involvement, particularly in those with a history of previous adverse drug reactions.[87,88] From a practical point of view, a detailed allergological history is necessary. In patients who have undergone previous surgery under general anesthesia, it may be advisable to consult the medical record and learn about the drugs used during surgery and in the postoperative period.[88] However, routine preoperative skin testing with drugs to be used is not recommended.[88] Prudentially, a reasonable approach is to choose those drugs with low capacity to elicit MC degranulation in each pharmacologic group and to use drugs with known tolerance by individual patients. The following drugs, employed for general anesthesia, are considered safe: propofol, a sedative-hypnotic anesthetic; sevoflurane and isoflurane, inhaled anesthetic agents; fentanyl, sufentanil, remifentanil and alfentanil, opioid anesthetics; local anesthetics such as lidocaine and bupivacaine; skin antiseptics such as povidone-iodine. Finally, curares drugs such as Vecuronium, pancuronium, and cisatracurium have been less frequently associated with the risk of adverse reactions.[88,89]
In SM patients, it is also recommended to avoid potential physical triggers, such as sudden temperature changes, cold fluid infusions, extensive tissue trauma, vigorous skin rubbing, and other mechanical factors.[88] In addition, anxiety can trigger MC degranulation so that patients could be premedicated with sedatives (benzodiazepines) before the surgical procedure.[89]
There is no consensus about the routine administration of premedication before anesthesia or its efficacy to prevent or reduce the severity of reactions. Premedication is recommended in patients with previous perioperative anaphylaxis and in general, depending on the individual patient's risk.[87,88]
Venom Immunotherapy. Venom immunotherapy (VIT) is recognized as a life-saving treatment for HVA patients. After some debate, mainly due to safety concerns, it is now generally accepted that VIT should be given anyway.[90] SM patients who had experienced systemic reactions after Hymenoptera sting should undergo allergological workup. The tests can be performed following the standard protocols (in vivo and in vitro), currently used for patients without Mastocytosis. Although skin tests are generally safe, considering the increased risk of patients with SM, they should be performed in a hospital setting.[66] It is also helpful to perform the dosage of specific IgE towards the whole extracts of the poisons of the main Hymenoptera, as well as the dosage of the specific IgE towards the single species-specific molecular markers available (Api m1-2-3-5-10 for the bee, Ves v1, and Ves v 5 for Vespula spp and Pol d 5 for Polistes Dominulus), and the cross-reactive carbohydrate determinants (CCD).[91]
This helps define the individual sensitization profile and discriminate among the poison molecules involved in the allergic reaction and the cross-reactive ones. As SM patients may have very low specific IgE levels, a cut-off level of specific IgE for recombinant molecules lower than 0.10 kUA/L is preferable to ensure better sensitivity and specificity.[92]
Venom immunotherapy (VIT) is universally considered the only life-saving and effective treatment in patients with Hymenoptera venom allergy, even in SM patients, protecting them from severe allergic reactions to subsequent punctures.[90]
Given many reports on fatal Hymenoptera sting reactions after discontinuation of treatment, it is advisable to continue the VIT life-long in patients with SM.[66]
To reduce the number and severity of extensive local reactions or mild systemic reactions to VIT, premedication with an H1 antihistamine can be used in patients with Mastocytosis, while Omalizumab can be used in case of more severe systemic reactions (i.e., urticaria or angioedema) occurring during immunotherapy.[93,94]
Pregnancy. Diagnosis of SM does not appear to affect fertility.[95] There is little evidence regarding the impact of Mastocytosis on pregnancy compared to the general population.[95] Based on limited reports, patients with Mastocytosis seem not to show a significant increase of maternal-fetal adverse events during pregnancy and delivery (i.e., miscarriage, preterm birth, complications of labor and delivery) compared to the general population.[95,96] Patients with nonaggressive categories of Mastocytosis should not be advised against pregnancy,[95] but they must be evaluated before conception, during pregnancy, and postpartum by a multidisciplinary team (which also includes a midwife and an anesthetist).[95]
The management of symptoms of women with SM during pregnancy and early postpartum should combine drugs with no or very limited teratogenic potential to relieve symptoms of MC activation, avoid known triggers, and eventually use prophylactic anti-mediator drugs (steroids, antihistamines), as needed.[27] Interferon-alpha cytoreductive therapy may be considered for pregnant women with severe symptoms and refractory to conventional treatments. The use of cladribine or tyrosine kinase inhibitors (TKI) is not recommended.[27]
Vaccination. Patients with Mastocytosis generally have an increased incidence of adverse reactions to exogenous agents. Although there are no data on the prevalence of adverse reactions to vaccines in adult patients with Mastocytosis (i.e., influenza, hepatitis B, or travel-related vaccinations), experts have a consensus that Mastocytosis does not represent a contraindication to vaccinations in adults.[97]
In a few cases, reactions were observed, particularly in children. Although patients with Mastocytosis can be vaccinated according to the standard schedule, precautions to prevent MC activation and degranulation have been formulated by experts, under observation with medications available to treat anaphylaxis, particularly in cases of diffuse skin manifestations. Protocols for premedication with steroids, antihistamines, and leukotriene receptor antagonists or cromolyn therapy have been applied to prevent complications, but official guidelines have not to be released.[98]
Although the reported frequency of severe side effects is low, there is an emerging discussion about the safety of Covid-19 vaccination in patients with severe allergies and Mastocytosis. However, severe adverse reactions are rare even in these patients, and the general use of Covid-19 vaccination in patients with Mastocytosis is recommended globally. The only well-established exception is a known or suspected allergy against a constituent of the vaccine. Safety measures, including premedication with anti-H1 and post-vaccination observation, should be considered in all patients with Mastocytosis, depending on the individual risk.[99]


Treatment of Advanced Systemic Mastocytosis

Cytoreductive therapy is indicated in patients with advanced Mastocytosis and includes chemotherapeutics, such as cladribine, biologics, alpha-interferon, and tyrosine kinase (TK) inhibitors, such as imatinib, and the multitarget oral TK inhibitor midostaurin.[43]
Interferon-alpha (IFN-α) appears to be of limited efficacy and has its indication in treating slow-progressing forms or, in non-advanced forms, severe osteoporosis refractory to bisphosphonate therapy.[43,86,100,101] The frequency of major response (i.e., complete resolution of one or more baseline "C" findings) ranges from 20% to 30%. The optimal dose and duration of IFN-α therapy for SM is still unknown (typically 1 to 5 MU subcutaneously, three times/week), although concurrent administration of corticosteroids (i.e., prednisone) may improve its efficacy (up to 40% of major response rate) and tolerability.[43,100,101] The pegylated form of alpha-interferon may be better tolerated and is likely to be preferred.[43,102]
Cladribine administered at a dosage of 0.14 mg/kg/day for five days, as a 2-hours infusion or by subcutaneous administration, and for up to 9 cycles, led to clinical improvement by lowering the secretion of mediators and reducing MC infiltration and serum tryptase levels.[43] The most common side effects include myelosuppression and lymphopenia. Reported overall response rates are 43% in ASM, 53% in SM-AHN, and 0% in MCL; the median response duration was 2.47 years.[103]
Imatinib is indicated only in KIT wild-type SM variants or harboring rare KIT mutations sensitive to this drug and in the rare well-differentiated forms of SM (WDSM).[43,104]
Although the second-generation multi-kinase inhibitor, dasatinib, demonstrated in vitro efficacy against various KIT mutants, including KIT D816V,[105] two clinical trials reported modest efficacy and significant side effects.[106–108]
Midostaurin is a potent pan-inhibitor of TK, approved in 2017 in monotherapy for treating adult patients with advanced forms of SM, at the recommended starting dose of 100 mg twice/day orally, regardless of the KIT mutational status. The registration study demonstrated a high efficacy leading to an overall response rate (including major or partial responses) in 60% of patients, improved symptoms burden and quality of life, and good tolerability.[109] In addition to BM toxicity, the most common side effects are nausea and vomiting, generally well controlled with prophylactic antiemetics, and taking the drug with food. After a median follow-up of 26 months, the median overall survival in the pivotal study was 28.7 months, with improvement over historical survival data, including a median OS not reached in ASM, of 20.7 months in SM-AHN and 9.4 months in MCL.[109]
Ongoing trials, also led in Italy, aim to evaluate the efficacy of other TK inhibitors such as avapritinib, a potent inhibitor of D816V mutated KIT, recently registered in the United States to treat diseases determined by activating KIT mutations, including Mastocytosis and gastrointestinal stromal tumors (GIST). This drug led to a rapid and deeper response in advanced SM, with an overall response rate greater than 70%, of whom 24% of complete response or complete hematological response.[110] The starting treatment dose was established at 200 mg once daily. The most frequently reported side effects are edema, thrombocytopenia, anemia, diarrhea, nausea, and fatigue. One patient in the pivotal study, who had pre-treatment severe thrombocytopenia (platelets <50×109/L), experienced Grade 4 subdural hematoma; consequently, pre-treatment severe thrombocytopenia was defined as an exclusion criterion, and dose interruption for severe thrombocytopenia is recommended.
More than 50% of AdvSM express CD30 on the surface of clonal MC. Nonetheless, a recent phase 2 trial of Brentuximab Vedotin (BV), a CD30-directed antibody-drug conjugate, on ten patients of CD30-positive AdvSM, failed to demonstrate the single-agent activity of BV in this setting.[111]
The treatment of SM-AHN is very complex, and the strategy relies upon both the clinical variant of SM (advanced or indolent) and the type of associated neoplasm. Usually, treatment is tailored against the more aggressive form or consists of a combined treatment,[54] but responses with midostaurin and avapritinib could be obtained regardless of the presence of concomitant AHN.[42,109,110]
Allogeneic stem cell transplantation in advanced SM can be an option if the associated hematological neoplasm itself has an indication or MCL responsive to TK inhibitors, considering the very severe prognosis. In other advanced forms of SM, the decision is tricky, as few studies demonstrated the superiority of transplant over KIT inhibitor maintenance therapy.[42]
In patients with ISM presenting with severe mediator symptoms and refractory to standard therapy, more aggressive therapy may be indicated; the use of KIT inhibitors in patients with non-advanced forms of Mastocytosis will be assessed in ongoing studies.[43] Masitinib, a TKI inhibitor of Lyn, Fyn, PDGFR-α/β, and wild-type KIT, was recently evaluated in phase III, randomized, double-blind trial, in non-advanced SM unresponsive to optimal symptomatic treatments. Masitinib allowed a 75% of sustained improvement in one symptom as pruritus, flushing, depression, or fatigue, in 18.7% of patients compared to 7.4% of patients taking a placebo without severe toxicity. However, an excess incidence of diarrhea and rush of 9% and 4% respectively was reported in the masitinib group.[112] Recent data from a study enrolling ISM patients with moderate or severe mediators related symptoms, refractory to best supportive care drugs, showed that low doses of avapritinib were well tolerated and produced significantly greater symptoms reduction than placebo.[113]

Conclusions

Mastocytosis presents with a plethora of signs and symptoms, mostly related to the secretion of mediators from clonal MC. In many cases, mediator-release symptoms significantly impact patients' quality of life and could be controlled through the instauration of adequate anti-mediator therapy. Consequently, an early and accurate diagnosis is beneficial for most patients. Patients with a positive history of an anaphylactic reaction to Hymenoptera venom should receive immunotherapy continuously to avoid other systemic reactions. Patients with osteoporosis secondary to SM may benefit from antiresorptive therapy.
Furthermore, patients requiring surgical procedures, both in local or general anesthesia, should be adequately managed to prevent massive degranulation of clonal MC and subsequent severe adverse events. Concerning more advanced forms of SM, treating physicians should be able to handle cytoreductive therapies, considering allogeneic stem cell transplant or enrolment in clinical trials in selected cases. Given the complexity of this rare and often misdiagnosed disease, it is of great importance to address the patient to well experienced and specialized center, possibly performing a multidisciplinary diagnostic evaluation. Additionally, the availability of sensitive molecular techniques is essential for a precise diagnosis.
This review provides a compendium of the current knowledge on the disease, aiming to help physicians easily recognize patients with a high probability of SM, which should be addressed to reference centers.

 

References   

  1. Valent, P.; Akin, C.; Escribano, L.; Födinger, M.; Hartmann, K.; Brockow, K.; Castells, M.; Sperr, W.R.; Kluin‐Nelemans, H.C.; Hamdy, N. a. T.; et al. Standards and Standardization in Mastocytosis: Consensus Statements on Diagnostics, Treatment Recommendations and Response Criteria. European Journal of Clinical Investigation 2007, 37, 435-453, doi:10.1111/j.1365-2362.2007.01807.x. https://doi.org/10.1111/j.1365-2362.2007.01807.x PMid:17537151
  2. Hartmann, K.; Escribano, L.; Grattan, C.; Brockow, K.; Carter, M.C.; Alvarez-Twose, I.; Matito, A.; Broesby-Olsen, S.; Siebenhaar, F.; Lange, M.; et al. Cutaneous Manifestations in Patients with Mastocytosis: Consensus Report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology. J Allergy Clin Immunol 2016, 137, 35-45, doi:10.1016/j.jaci.2015.08.034. https://doi.org/10.1016/j.jaci.2015.08.034 PMid:26476479
  3. Longley, B.J.; Tyrrell, L.; Lu, S.Z.; Ma, Y.S.; Langley, K.; Ding, T.G.; Duffy, T.; Jacobs, P.; Tang, L.H.; Modlin, I. Somatic C-KIT Activating Mutation in Urticaria Pigmentosa and Aggressive Mastocytosis: Establishment of Clonality in a Human Mast Cell Neoplasm. Nat Genet 1996, 12, 312-314, doi:10.1038/ng0396-312. https://doi.org/10.1038/ng0396-312 PMid:8589724
  4. Arock, M.; Sotlar, K.; Akin, C.; Broesby-Olsen, S.; Hoermann, G.; Escribano, L.; Kristensen, T.K.; Kluin-Nelemans, H.C.; Hermine, O.; Dubreuil, P.; et al. KIT Mutation Analysis in Mast Cell Neoplasms: Recommendations of the European Competence Network on Mastocytosis. Leukemia 2015, 29, 1223-1232, doi:10.1038/leu.2015.24. https://doi.org/10.1038/leu.2015.24 PMid:25650093 PMCid:PMC4522520
  5. Arber, D.A.; Orazi, A.; Hasserjian, R.; Thiele, J.; Borowitz, M.J.; Beau, M.M.L.; Bloomfield, C.D.; Cazzola, M.; Vardiman, J.W. The 2016 Revision to the World Health Organization Classification of Myeloid Neoplasms and Acute Leukemia. Blood 2016, 127, 2391-2405, doi:10.1182/blood-2016-03-643544. https://doi.org/10.1182/blood-2016-03-643544 PMid:27069254  
  6. Valent, P.; Horny, H.P.; Escribano, L.; Longley, B.J.; Li, C.Y.; Schwartz, L.B.; Marone, G.; Nuñez, R.; Akin, C.; Sotlar, K.; et al. Diagnostic Criteria and Classification of Mastocytosis: A Consensus Proposal. Leuk Res 2001, 25, 603-625, doi:10.1016/s0145-2126(01)00038-8. https://doi.org/10.1016/S0145-2126(01)00038-8  
  7. Zanotti, R.; Bonadonna, P.; Bonifacio, M.; Artuso, A.; Schena, D.; Rossini, M.; Perbellini, O.; Colarossi, S.; Chilosi, M.; Pizzolo, G. Isolated Bone Marrow Mastocytosis: An Underestimated Subvariant of Indolent Systemic Mastocytosis. Haematologica 2011, 96, 482-484, doi:10.3324/haematol.2010.034553. https://doi.org/10.3324/haematol.2010.034553 PMid:21193416 PMCid:PMC3046284
  8. Trizuljak, J.; Sperr, W.R.; Nekvindová, L.; Elberink, H.O.; Gleixner, K.V.; Gorska, A.; Lange, M.; Hartmann, K.; Illerhaus, A.; Bonifacio, M.; et al. Clinical Features and Survival of Patients with Indolent Systemic Mastocytosis Defined by the Updated WHO Classification. Allergy 2020, 75, 1927-1938, doi:10.1111/all.14248. https://doi.org/10.1111/all.14248 PMid:32108361 PMCid:PMC7115854  
  9. Zanotti R, Bonifacio M, Lucchini, G Sperr W, Scaffidi L, van Anrooij B et al. Refined Diagnostic Criteria for Bone Marrow Mastocytosis: A Proposal of the European Competence Network on Mastocytosis.  
  10. Pardanani, A.; Lim, K.-H.; Lasho, T.L.; Finke, C.M.; McClure, R.F.; Li, C.-Y.; Tefferi, A. WHO Subvariants of Indolent Mastocytosis: Clinical Details and Prognostic Evaluation in 159 Consecutive Adults. Blood 2010, 115, 150-151, doi:10.1182/blood-2009-10-249979. https://doi.org/10.1182/blood-2009-10-249979 PMid:20056798
  11. Lim, K.-H.; Tefferi, A.; Lasho, T.L.; Finke, C.; Patnaik, M.; Butterfield, J.H.; McClure, R.F.; Li, C.-Y.; Pardanani, A. Systemic Mastocytosis in 342 Consecutive Adults: Survival Studies and Prognostic Factors. Blood 2009, 113, 5727-5736, doi:10.1182/blood-2009-02-205237. https://doi.org/10.1182/blood-2009-02-205237 PMid:19363219
  12. Valentini, C.G.; Rondoni, M.; Pogliani, E.M.; Van Lint, M.T.; Cattaneo, C.; Marbello, L.; Pulsoni, A.; Giona, F.; Martinelli, G.; Leone, G.; et al. Mast Cell Leukemia: A Report of Ten Cases. Ann Hematol 2008, 87, 505-508, doi:10.1007/s00277-007-0430-3. https://doi.org/10.1007/s00277-007-0430-3 PMid:18172645
  13. Cohen, S.S.; Skovbo, S.; Vestergaard, H.; Kristensen, T.; Møller, M.; Bindslev-Jensen, C.; Fryzek, J.P.; Broesby-Olsen, S. Epidemiology of Systemic Mastocytosis in Denmark. Br J Haematol 2014, 166, 521-528, doi:10.1111/bjh.12916. https://doi.org/10.1111/bjh.12916 PMid:24761987  
  14. van Doormaal, J.J.; Arends, S.; Brunekreeft, K.L.; van der Wal, V.B.; Sietsma, J.; van Voorst Vader, P.C.; Oude Elberink, J.N.G.; Kluin-Nelemans, J.C.; van der Veer, E.; de Monchy, J.G.R. Prevalence of Indolent Systemic Mastocytosis in a Dutch Region. J Allergy Clin Immunol 2013, 131, 1429-1431.e1, doi:10.1016/j.jaci.2012.10.015. https://doi.org/10.1016/j.jaci.2012.10.015 PMid:23219169  
  15. Bodemer, C.; Hermine, O.; Palmérini, F.; Yang, Y.; Grandpeix-Guyodo, C.; Leventhal, P.S.; Hadj-Rabia, S.; Nasca, L.; Georgin-Lavialle, S.; Cohen-Akenine, A.; et al. Pediatric Mastocytosis Is a Clonal Disease Associated with D816V and Other Activating C-KIT Mutations. Journal of Investigative Dermatology 2010, 130, 804-815, doi:10.1038/jid.2009.281. https://doi.org/10.1038/jid.2009.281 PMid:19865100  
  16. Ben-Amitai, D.; Metzker, A.; Cohen, H.A. Pediatric Cutaneous Mastocytosis: A Review of 180 Patients. Isr Med Assoc J 2005, 7, 320-322.  
  17. Tanasi, I.; Bonifacio, M.; Pizzolato, M.; Irene Grifoni, F.; Sciumè, M.; Elena, C.; Benvenuti, P.; Mannelli, F.; Parente, R.; Schena, D.; et al. Familial Occurrence of Systemic and Cutaneous Mastocytosis in an Adult Multicentre Series. Br J Haematol 2021, 193, 845-848, doi:10.1111/bjh.17405. https://doi.org/10.1111/bjh.17405 PMid:33754335
  18. Valent, P. The Riddle of the Mast Cell: Kit(CD117)-Ligand as the Missing Link? Immunology Today 1994, 15, 111-114, doi:10.1016/0167-5699(94)90153-8. https://doi.org/10.1016/0167-5699(94)90153-8  
  19. Garcia-Montero, A.C.; Jara-Acevedo, M.; Teodosio, C.; Sanchez, M.L.; Nunez, R.; Prados, A.; Aldanondo, I.; Sanchez, L.; Dominguez, M.; Botana, L.M.; et al. KIT Mutation in Mast Cells and Other Bone Marrow Hematopoietic Cell Lineages in Systemic Mast Cell Disorders: A Prospective Study of the Spanish Network on Mastocytosis (REMA) in a Series of 113 Patients. Blood 2006, 108, 2366-2372, doi:10.1182/blood-2006-04-015545. https://doi.org/10.1182/blood-2006-04-015545 PMid:16741248  
  20. Jawhar, M.; Schwaab, J.; Schnittger, S.; Meggendorfer, M.; Pfirrmann, M.; Sotlar, K.; Horny, H.-P.; Metzgeroth, G.; Kluger, S.; Naumann, N.; et al. Additional Mutations in SRSF2, ASXL1 and/or RUNX1 Identify a High-Risk Group of Patients with KIT D816V + Advanced Systemic Mastocytosis. Leukemia 2016, 30, 136-143, doi:10.1038/leu.2015.284. https://doi.org/10.1038/leu.2015.284 PMid:26464169
  21. Muñoz-González, J.I.; Jara-Acevedo, M.; Alvarez-Twose, I.; Merker, J.D.; Teodosio, C.; Hou, Y.; Henriques, A.; Roskin, K.M.; Sanchez-Muñoz, L.; Tsai, A.G.; et al. Impact of Somatic and Germline Mutations on the Outcome of Systemic Mastocytosis. Blood Adv 2018, 2, 2814-2828, doi:10.1182/bloodadvances.2018020628. https://doi.org/10.1182/bloodadvances.2018020628 PMid:30373888 PMCid:PMC6234367  
  22. Pardanani, A.; Lasho, T.; Elala, Y.; Wassie, E.; Finke, C.; Reichard, K.K.; Chen, D.; Hanson, C.A.; Ketterling, R.P.; Tefferi, A. Next-Generation Sequencing in Systemic Mastocytosis: Derivation of a Mutation-Augmented Clinical Prognostic Model for Survival. Am J Hematol 2016, 91, 888-893, doi:10.1002/ajh.24426. https://doi.org/10.1002/ajh.24426 PMid:27214377
  23. Valent, P.; Akin, C.; Arock, M.; Brockow, K.; Butterfield, J.H.; Carter, M.C.; Castells, M.; Escribano, L.; Hartmann, K.; Lieberman, P.; et al. Definitions, Criteria and Global Classification of Mast Cell Disorders with Special Reference to Mast Cell Activation Syndromes: A Consensus Proposal. Int Arch Allergy Immunol 2012, 157, 215-225, doi:10.1159/000328760. https://doi.org/10.1159/000328760 PMid:22041891 PMCid:PMC3224511
  24. Shanmugam, G.; Schwartz, L.B.; Khan, D.A. Prolonged Elevation of Serum Tryptase in Idiopathic Anaphylaxis. J Allergy Clin Immunol 2006, 117, 950-951, doi:10.1016/j.jaci.2005.12.1356. https://doi.org/10.1016/j.jaci.2005.12.1356 PMid:16630958
  25. Valent, P.; Escribano, L.; Broesby-Olsen, S.; Hartmann, K.; Grattan, C.; Brockow, K.; Niedoszytko, M.; Nedoszytko, B.; Oude Elberink, J.N.G.; Kristensen, T.; et al. Proposed Diagnostic Algorithm for Patients with Suspected Mastocytosis: A Proposal of the European Competence Network on Mastocytosis. Allergy 2014, 69, 1267-1274, doi:10.1111/all.12436. https://doi.org/10.1111/all.12436 PMid:24836395
  26. Sperr, W.R.; Escribano, L.; Jordan, J.H.; Schernthaner, G.H.; Kundi, M.; Horny, H.P.; Valent, P. Morphologic Properties of Neoplastic Mast Cells: Delineation of Stages of Maturation and Implication for Cytological Grading of Mastocytosis. Leuk Res 2001, 25, 529-536, doi:10.1016/s0145-2126(01)00041-8. https://doi.org/10.1016/S0145-2126(01)00041-8
  27. Gotlib, J.; Gerds, A.T.; Bose, P.; Castells, M.C.; Deininger, M.W.; Gojo, I.; Gundabolu, K.; Hobbs, G.; Jamieson, C.; McMahon, B.; et al. Systemic Mastocytosis, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2018, 16, 1500-1537, doi:10.6004/jnccn.2018.0088. https://doi.org/10.6004/jnccn.2018.0088 PMid:30545997
  28. Escribano, L.; Díaz-Agustín, B.; Bellas, C.; Navalón, R.; Nuñez, R.; Sperr, W.R.; Schernthaner, G.H.; Valent, P.; Orfao, A. Utility of Flow Cytometric Analysis of Mast Cells in the Diagnosis and Classification of Adult Mastocytosis. Leuk Res 2001, 25, 563-570, doi:10.1016/s0145-2126(01)00050-9. https://doi.org/10.1016/S0145-2126(01)00050-9  
  29. Metcalfe, D.D.; Mekori, Y.A. Pathogenesis and Pathology of Mastocytosis. Annu Rev Pathol 2017, 12, 487-514, doi:10.1146/annurev-pathol-052016-100312. https://doi.org/10.1146/annurev-pathol-052016-100312 PMid:28135563
  30. Morgado, J.M.T.; Sánchez-Muñoz, L.; Teodósio, C.G.; Jara-Acevedo, M.; Alvarez-Twose, I.; Matito, A.; Fernández-Nuñez, E.; García-Montero, A.; Orfao, A.; Escribano, L. Immunophenotyping in Systemic Mastocytosis Diagnosis: "CD25 Positive" Alone Is More Informative than the "CD25 and/or CD2" WHO Criterion. Mod Pathol 2012, 25, 516-521, doi:10.1038/modpathol.2011.192. https://doi.org/10.1038/modpathol.2011.192 PMid:22222639  
  31. Sotlar, K.; Cerny-Reiterer, S.; Petat-Dutter, K.; Hessel, H.; Berezowska, S.; Müllauer, L.; Valent, P.; Horny, H.-P. Aberrant Expression of CD30 in Neoplastic Mast Cells in High-Grade Mastocytosis. Mod Pathol 2011, 24, 585-595, doi:10.1038/modpathol.2010.224. https://doi.org/10.1038/modpathol.2010.224 PMid:21186345
  32. Morgado, J.M.; Perbellini, O.; Johnson, R.C.; Teodósio, C.; Matito, A.; Álvarez-Twose, I.; Bonadonna, P.; Zamò, A.; Jara-Acevedo, M.; Mayado, A.; et al. CD30 Expression by Bone Marrow Mast Cells from Different Diagnostic Variants of Systemic Mastocytosis. Histopathology 2013, 63, 780-787, doi:10.1111/his.12221. https://doi.org/10.1111/his.12221 PMid:24111625  
  33. Escribano, L.; Diaz‐Agustin, B.; López, A.; López, R.N.; García‐Montero, A.; Almeida, J.; Prados, A.; Angulo, M.; Herrero, S.; Orfao, A. Immunophenotypic Analysis of Mast Cells in Mastocytosis: When and How to Do It. Proposals of the Spanish Network on Mastocytosis (REMA). Cytometry Part B: Clinical Cytometry 2004, 58B, 1-8, doi:10.1002/cyto.b.10072. https://doi.org/10.1002/cyto.b.10072 PMid:14994369  
  34. Perbellini, O.; Zamò, A.; Colarossi, S.; Zampieri, F.; Zoppi, F.; Bonadonna, P.; Schena, D.; Artuso, A.; Martinelli, G.; Chilosi, M.; et al. Primary Role of Multiparametric Flow Cytometry in the Diagnostic Work-up of Indolent Clonal Mast Cell Disorders. Cytometry B Clin Cytom 2011, 80, 362-368, doi:10.1002/cyto.b.20606. https://doi.org/10.1002/cyto.b.20606 PMid:21656905  
  35. Kristensen, T.; Broesby-Olsen, S.; Vestergaard, H.; Bindslev-Jensen, C.; Møller, M.B.; Mastocytosis Centre Odense University Hospital (MastOUH) Circulating KIT D816V Mutation-Positive Non-Mast Cells in Peripheral Blood Are Characteristic of Indolent Systemic Mastocytosis. Eur J Haematol 2012, 89, 42-46, doi:10.1111/j.1600-0609.2012.01789.x. https://doi.org/10.1111/j.1600-0609.2012.01789.x PMid:22469616  
  36. Greiner, G.; Gurbisz, M.; Ratzinger, F.; Witzeneder, N.; Simonitsch-Klupp, I.; Mitterbauer-Hohendanner, G.; Mayerhofer, M.; Müllauer, L.; Sperr, W.R.; Valent, P.; et al. Digital PCR: A Sensitive and Precise Method for KIT D816V Quantification in Mastocytosis. Clin Chem 2018, 64, 547-555, doi:10.1373/clinchem.2017.277897. https://doi.org/10.1373/clinchem.2017.277897 PMid:29237714 PMCid:PMC7115889  
  37. Kristensen, T.; Broesby-Olsen, S.; Vestergaard, H.; Bindslev-Jensen, C.; Møller, M.B.; Mastocytosis Centre Odense University Hospital (MastOUH) Targeted Ultradeep Next-Generation Sequencing as a Method for KIT D816V Mutation Analysis in Mastocytosis. Eur J Haematol 2016, 96, 381-388, doi:10.1111/ejh.12601. https://doi.org/10.1111/ejh.12601 PMid:26095448
  38. Sotlar, K.; Escribano, L.; Landt, O.; Möhrle, S.; Herrero, S.; Torrelo, A.; Lass, U.; Horny, H.-P.; Bültmann, B. One-Step Detection of c-Kit Point Mutations Using Peptide Nucleic Acid-Mediated Polymerase Chain Reaction Clamping and Hybridization Probes. Am J Pathol 2003, 162, 737-746. https://doi.org/10.1016/S0002-9440(10)63870-9  
  39. Jara-Acevedo, M.; Teodosio, C.; Sanchez-Muñoz, L.; Álvarez-Twose, I.; Mayado, A.; Caldas, C.; Matito, A.; Morgado, J.M.; Muñoz-González, J.I.; Escribano, L.; et al. Detection of the KIT D816V Mutation in Peripheral Blood of Systemic Mastocytosis: Diagnostic Implications. Mod Pathol 2015, 28, 1138-1149, doi:10.1038/modpathol.2015.72. https://doi.org/10.1038/modpathol.2015.72 PMid:26067933
  40. Monaldi, C.; De Santis, S.; Mancini, M.; Bruno, S.; Cavo, M.; Soverini, S. Systemic Mastocytosis: Molecular Landscape and Implications for Treatment. Mediterr J Hematol Infect Dis 2021, 13, e2021046, doi:10.4084/MJHID.2021.046. https://doi.org/10.4084/MJHID.2021.046 PMid:34276915 PMCid:PMC8265368
  41. Kristensen, T.; Vestergaard, H.; Bindslev-Jensen, C.; Mortz, C.G.; Kjaer, H.F.; Ollert, M.; Møller, M.B.; Broesby-Olsen, S.; Mastocytosis Centre Odense University Hospital (MastOUH) Prospective Evaluation of the Diagnostic Value of Sensitive KIT D816V Mutation Analysis of Blood in Adults with Suspected Systemic Mastocytosis. Allergy 2017, 72, 1737-1743, doi:10.1111/all.13187. https://doi.org/10.1111/all.13187 PMid:28432683
  42. Reiter, A.; George, T.I.; Gotlib, J. New Developments in Diagnosis, Prognostication, and Treatment of Advanced Systemic Mastocytosis. Blood 2020, 135, 1365-1376, doi:10.1182/blood.2019000932. https://doi.org/10.1182/blood.2019000932 PMid:32106312 
  43. Pardanani, A. Systemic Mastocytosis in Adults: 2021 Update on Diagnosis, Risk Stratification and Management. Am J Hematol 2021, 96, 508-525, doi:10.1002/ajh.26118. https://doi.org/10.1002/ajh.26118 PMid:33524167  
  44. Lim, K.-H.; Tefferi, A.; Lasho, T.L.; Finke, C.; Patnaik, M.; Butterfield, J.H.; McClure, R.F.; Li, C.-Y.; Pardanani, A. Systemic Mastocytosis in 342 Consecutive Adults: Survival Studies and Prognostic Factors. Blood 2009, 113, 5727-5736, doi:10.1182/blood-2009-02-205237. https://doi.org/10.1182/blood-2009-02-205237 PMid:19363219  
  45. Jawhar, M.; Schwaab, J.; Hausmann, D.; Clemens, J.; Naumann, N.; Henzler, T.; Horny, H.-P.; Sotlar, K.; Schoenberg, S.O.; Cross, N.C.P.; et al. Splenomegaly, Elevated Alkaline Phosphatase and Mutations in the SRSF2/ASXL1/RUNX1 Gene Panel Are Strong Adverse Prognostic Markers in Patients with Systemic Mastocytosis. Leukemia 2016, 30, 2342-2350, doi:10.1038/leu.2016.190. https://doi.org/10.1038/leu.2016.190 PMid:27416984  
  46. Escribano, L.; Alvarez-Twose, I.; Sánchez-Muñoz, L.; Garcia-Montero, A.; Núñez, R.; Almeida, J.; Jara-Acevedo, M.; Teodósio, C.; García-Cosío, M.; Bellas, C.; et al. Prognosis in Adult Indolent Systemic Mastocytosis: A Long-Term Study of the Spanish Network on Mastocytosis in a Series of 145 Patients. J Allergy Clin Immunol 2009, 124, 514-521, doi:10.1016/j.jaci.2009.05.003. https://doi.org/10.1016/j.jaci.2009.05.003 PMid:19541349
  47. Hoermann, G.; Gleixner, K.V.; Dinu, G.E.; Kundi, M.; Greiner, G.; Wimazal, F.; Hadzijusufovic, E.; Mitterbauer, G.; Mannhalter, C.; Valent, P.; et al. The KIT D816V Allele Burden Predicts Survival in Patients with Mastocytosis and Correlates with the WHO Type of the Disease. Allergy 2014, 69, 810-813, doi:10.1111/all.12409. https://doi.org/10.1111/all.12409 PMid:24750133 PMCid:PMC4896381
  48. Sperr, W.R.; Kundi, M.; Alvarez-Twose, I.; van Anrooij, B.; Oude Elberink, J.N.G.; Gorska, A.; Niedoszytko, M.; Gleixner, K.V.; Hadzijusufovic, E.; Zanotti, R.; et al. International Prognostic Scoring System for Mastocytosis (IPSM): A Retrospective Cohort Study. Lancet Haematol 2019, 6, e638-e649, doi:10.1016/S2352-3026(19)30166-8. https://doi.org/10.1016/S2352-3026(19)30166-8  
  49. Pardanani, A.; Shah, S.; Mannelli, F.; Elala, Y.C.; Guglielmelli, P.; Lasho, T.L.; Patnaik, M.M.; Gangat, N.; Ketterling, R.P.; Reichard, K.K.; et al. Mayo Alliance Prognostic System for Mastocytosis: Clinical and Hybrid Clinical-Molecular Models. Blood Adv 2018, 2, 2964-2972, doi:10.1182/bloodadvances.2018026245. https://doi.org/10.1182/bloodadvances.2018026245 PMid:30413432 PMCid:PMC6234360  
  50. Jawhar, M.; Schwaab, J.; Álvarez-Twose, I.; Shoumariyeh, K.; Naumann, N.; Lübke, J.; Perkins, C.; Muñoz-González, J.I.; Meggendorfer, M.; Kennedy, V.; et al. MARS: Mutation-Adjusted Risk Score for Advanced Systemic Mastocytosis. J Clin Oncol 2019, 37, 2846-2856, doi:10.1200/JCO.19.00640. https://doi.org/10.1200/JCO.19.00640 PMid:31509472 PMCid:PMC6823885
  51. Muñoz-González, J.I.; Álvarez-Twose, I.; Jara-Acevedo, M.; Zanotti, R.; Perkins, C.; Jawhar, M.; Sperr, W.R.; Shoumariyeh, K.; Schwaab, J.; Greiner, G.; et al. Proposed Global Prognostic Score for Systemic Mastocytosis: A Retrospective Prognostic Modelling Study. Lancet Haematol 2021, 8, e194-e204, doi:10.1016/S2352-3026(20)30400-2. https://doi.org/10.1016/S2352-3026(20)30400-2
  52. Schena, D.; Galvan, A.; Tessari, G.; Girolomoni, G. Clinical Features and Course of Cutaneous Mastocytosis in 133 Children. Br J Dermatol 2016, 174, 411-413, doi:10.1111/bjd.14004. https://doi.org/10.1111/bjd.14004 PMid:26138896
  53. Godt, O.; Proksch, E.; Streit, V.; Christophers, E. Short- and Long-Term Effectiveness of Oral and Bath PUVA Therapy in Urticaria Pigmentosa and Systemic Mastocytosis. Dermatology 1997, 195, 35-39, doi:10.1159/000245681. https://doi.org/10.1159/000245681 PMid:9267734
  54. Valent, P.; Akin, C.; Gleixner, K.V.; Sperr, W.R.; Reiter, A.; Arock, M.; Triggiani, M. Multidisciplinary Challenges in Mastocytosis and How to Address with Personalized Medicine Approaches. Int J Mol Sci 2019, 20, E2976, doi:10.3390/ijms20122976. https://doi.org/10.3390/ijms20122976 PMid:31216696 PMCid:PMC6627900
  55. González de Olano, D.; de la Hoz Caballer, B.; Núñez López, R.; Sánchez Muñoz, L.; Cuevas Agustín, M.; Diéguez, M.C.; Alvarez Twose, I.; Castells, M.C.; Escribano Mora, L. Prevalence of Allergy and Anaphylactic Symptoms in 210 Adult and Pediatric Patients with Mastocytosis in Spain: A Study of the Spanish Network on Mastocytosis (REMA). Clin. Exp. Allergy 2007, 37, 1547-1555, doi:10.1111/j.1365-2222.2007.02804.x. https://doi.org/10.1111/j.1365-2222.2007.02804.x PMid:17883734
  56. Brockow, K.; Jofer, C.; Behrendt, H.; Ring, J. Anaphylaxis in Patients with Mastocytosis: A Study on History, Clinical Features and Risk Factors in 120 Patients. Allergy 2008, 63, 226-232, doi:10.1111/j.1398-9995.2007.01569.x. https://doi.org/10.1111/j.1398-9995.2007.01569.x PMid:18186813
  57. Gülen, T.; Hägglund, H.; Dahlén, B.; Nilsson, G. High Prevalence of Anaphylaxis in Patients with Systemic Mastocytosis - a Single-Centre Experience. Clin Exp Allergy 2014, 44, 121-129, doi:10.1111/cea.12225. https://doi.org/10.1111/cea.12225 PMid:24164252
  58. Lieberman, P.; Camargo, C.A.; Bohlke, K.; Jick, H.; Miller, R.L.; Sheikh, A.; Simons, F.E.R. Epidemiology of Anaphylaxis: Findings of the American College of Allergy, Asthma and Immunology Epidemiology of Anaphylaxis Working Group. Ann Allergy Asthma Immunol 2006, 97, 596-602, doi:10.1016/S1081-1206(10)61086-1. https://doi.org/10.1016/S1081-1206(10)61086-1
  59. Muraro, A.; Roberts, G.; Worm, M.; Bilò, M.B.; Brockow, K.; Fernández Rivas, M.; Santos, A.F.; Zolkipli, Z.Q.; Bellou, A.; Beyer, K.; et al. Anaphylaxis: Guidelines from the European Academy of Allergy and Clinical Immunology. Allergy 2014, 69, 1026-1045, doi:10.1111/all.12437. https://doi.org/10.1111/all.12437 PMid:24909803
  60. Pieri, L.; Bonadonna, P.; Elena, C.; Papayannidis, C.; Grifoni, F.I.; Rondoni, M.; Girlanda, S.; Mauro, M.; Magliacane, D.; Elli, E.M.; et al. Clinical Presentation and Management Practice of Systemic Mastocytosis. A Survey on 460 Italian Patients. Am J Hematol 2016, 91, 692-699, doi:10.1002/ajh.24382. https://doi.org/10.1002/ajh.24382 PMid:27060898
  61. Biló, B.M.; Rueff, F.; Mosbech, H.; Bonifazi, F.; Oude-Elberink, J.N.G.; EAACI Interest Group on Insect Venom Hypersensitivity Diagnosis of Hymenoptera Venom Allergy. Allergy 2005, 60, 1339-1349, doi:10.1111/j.1398-9995.2005.00963.x. https://doi.org/10.1111/j.1398-9995.2005.00963.x PMid:16197464
  62. Niedoszytko, M.; de Monchy, J.; van Doormaal, J.J.; Jassem, E.; Oude Elberink, J.N.G. Mastocytosis and Insect Venom Allergy: Diagnosis, Safety and Efficacy of Venom Immunotherapy. Allergy 2009, 64, 1237-1245, doi:10.1111/j.1398-9995.2009.02118.x. https://doi.org/10.1111/j.1398-9995.2009.02118.x PMid:19627278
  63. Bonadonna, P.; Lombardo, C.; Zanotti, R. Mastocytosis and Allergic Diseases. J Investig Allergol Clin Immunol 2014, 24, 288-297; quiz 3 p preceding 297.  
  64. Alvarez-Twose, I.; González de Olano, D.; Sánchez-Muñoz, L.; Matito, A.; Esteban-López, M.I.; Vega, A.; Mateo, M.B.; Alonso Díaz de Durana, M.D.; de la Hoz, B.; Del Pozo Gil, M.D.; et al. Clinical, Biological, and Molecular Characteristics of Clonal Mast Cell Disorders Presenting with Systemic Mast Cell Activation Symptoms. J Allergy Clin Immunol 2010, 125, 1269-1278.e2, doi:10.1016/j.jaci.2010.02.019. https://doi.org/10.1016/j.jaci.2010.02.019 PMid:20434205
  65. Bonadonna, P.; Perbellini, O.; Passalacqua, G.; Caruso, B.; Colarossi, S.; Dal Fior, D.; Castellani, L.; Bonetto, C.; Frattini, F.; Dama, A.; et al. Clonal Mast Cell Disorders in Patients with Systemic Reactions to Hymenoptera Stings and Increased Serum Tryptase Levels. J Allergy Clin Immunol 2009, 123, 680-686, doi:10.1016/j.jaci.2008.11.018. https://doi.org/10.1016/j.jaci.2008.11.018 PMid:19135713
  66. Bonadonna, P.; Bonifacio, M.; Lombardo, C.; Zanotti, R. Hymenoptera Allergy and Mast Cell Activation Syndromes. Curr Allergy Asthma Rep 2016, 16, 5, doi:10.1007/s11882-015-0582-5. https://doi.org/10.1007/s11882-015-0582-5 PMid:26714690  
  67. Sokol, H.; Georgin-Lavialle, S.; Canioni, D.; Barete, S.; Damaj, G.; Soucie, E.; Bruneau, J.; Chandesris, M.-O.; Suarez, F.; Launay, J.-M.; et al. Gastrointestinal Manifestations in Mastocytosis: A Study of 83 Patients. J Allergy Clin Immunol 2013, 132, 866-873.e1-3, doi:10.1016/j.jaci.2013.05.026. https://doi.org/10.1016/j.jaci.2013.05.026 PMid:23890756
  68. Doyle, L.A.; Sepehr, G.J.; Hamilton, M.J.; Akin, C.; Castells, M.C.; Hornick, J.L. A Clinicopathologic Study of 24 Cases of Systemic Mastocytosis Involving the Gastrointestinal Tract and Assessment of Mucosal Mast Cell Density in Irritable Bowel Syndrome and Asymptomatic Patients. Am J Surg Pathol 2014, 38, 832-843, doi:10.1097/PAS.0000000000000190. https://doi.org/10.1097/PAS.0000000000000190 PMid:24618605 PMCid:PMC4086834
  69. Hermans, M.A.W.; Rietveld, M.J.A.; van Laar, J.A.M.; Dalm, V.A.S.H.; Verburg, M.; Pasmans, S.G.M.A.; Gerth van Wijk, R.; van Hagen, P.M.; van Daele, P.L.A. Systemic Mastocytosis: A Cohort Study on Clinical Characteristics of 136 Patients in a Large Tertiary Centre. Eur J Intern Med 2016, 30, 25-30, doi:10.1016/j.ejim.2016.01.005. https://doi.org/10.1016/j.ejim.2016.01.005 PMid:26809706
  70. Gehlen M, Schmidt N, Pfeifer M, Balasingam S, Schwarz-Eywill M, Maier A, Werner M, Siggelkow H. Osteoporosis Caused by Systemic Mastocytosis: Prevalence in a Cohort of 8392 Patients with Osteoporosis.Calcif Tissue Int. 2021 Jul 5. doi: 10.1007/s00223-021-00887-4. Epub ahead of print. PMID: 34223956. https://doi.org/10.1007/s00223-021-00887-4 PMid:34223956  
  71. Escribano, L.; Alvarez-Twose, I.; Sánchez-Muñoz, L.; Garcia-Montero, A.; Núñez, R.; Almeida, J.; Jara-Acevedo, M.; Teodósio, C.; García-Cosío, M.; Bellas, C.; et al. Prognosis in Adult Indolent Systemic Mastocytosis: A Long-Term Study of the Spanish Network on Mastocytosis in a Series of 145 Patients. J Allergy Clin Immunol 2009, 124, 514-521, doi:10.1016/j.jaci.2009.05.003. https://doi.org/10.1016/j.jaci.2009.05.003 PMid:19541349  
  72. Rossini, M.; Zanotti, R.; Bonadonna, P.; Artuso, A.; Caruso, B.; Schena, D.; Vecchiato, D.; Bonifacio, M.; Viapiana, O.; Gatti, D.; et al. Bone Mineral Density, Bone Turnover Markers and Fractures in Patients with Indolent Systemic Mastocytosis. Bone 2011, 49, 880-885, doi:10.1016/j.bone.2011.07.004. https://doi.org/10.1016/j.bone.2011.07.004 PMid:21782049
  73. Barete, S.; Assous, N.; de Gennes, C.; Grandpeix, C.; Feger, F.; Palmerini, F.; Dubreuil, P.; Arock, M.; Roux, C.; Launay, J.M.; et al. Systemic Mastocytosis and Bone Involvement in a Cohort of 75 Patients. Ann Rheum Dis 2010, 69, 1838-1841, doi:10.1136/ard.2009.124511. https://doi.org/10.1136/ard.2009.124511 PMid:20570833
  74. van der Veer, E.; Arends, S.; van der Hoek, S.; Versluijs, J.B.; de Monchy, J.G.R.; Oude Elberink, J.N.G.; van Doormaal, J.J. Predictors of New Fragility Fractures after Diagnosis of Indolent Systemic Mastocytosis. J Allergy Clin Immunol 2014, 134, 1413-1421, doi:10.1016/j.jaci.2014.05.003. https://doi.org/10.1016/j.jaci.2014.05.003 PMid:24985401
  75. Degboé, Y.; Eischen, M.; Nigon, D.; Apoil, P.-A.; Mailhol, C.; Tournier, E.; Laurent, C.; Hanssens, K.; Hermine, O.; Paul, C.; et al. Prevalence and Risk Factors for Fragility Fracture in Systemic Mastocytosis. Bone 2017, 105, 219-225, doi:10.1016/j.bone.2017.09.005. https://doi.org/10.1016/j.bone.2017.09.005 PMid:28919366
  76. Broesby-Olsen, S.; Kristensen, T.K.; Møller, M.B.; Bindslev-Jensen, C.; Vestergaard, H. Adult-Onset Systemic Mastocytosis in Monozygotic Twins with KIT D816V and JAK2 V617F Mutations. Journal of Allergy and Clinical Immunology 2012, 130, 806-808, doi:10.1016/j.jaci.2012.04.013. https://doi.org/10.1016/j.jaci.2012.04.013 PMid:22608575
  77. Orsolini, G.; Viapiana, O.; Rossini, M.; Bonifacio, M.; Zanotti, R. Bone Disease in Mastocytosis. Immunol Allergy Clin North Am 2018, 38, 443-454, doi:10.1016/j.iac.2018.04.013. https://doi.org/10.1016/j.iac.2018.04.013 PMid:30007462
  78. Zanotti, R.; Tanasi, I.; Bernardelli, A.; Orsolini, G.; Bonadonna, P. Bone Marrow Mastocytosis: A Diagnostic Challenge. J Clin Med 2021, 10, 1420, doi:10.3390/jcm10071420. https://doi.org/10.3390/jcm10071420 PMid:33915965 PMCid:PMC8037514
  79. Rossini, M.; Zanotti, R.; Viapiana, O.; Tripi, G.; Orsolini, G.; Idolazzi, L.; Bonadonna, P.; Schena, D.; Escribano, L.; Adami, S.; et al. Bone Involvement and Osteoporosis in Mastocytosis. Immunol Allergy Clin North Am 2014, 34, 383-396, doi:10.1016/j.iac.2014.01.011. https://doi.org/10.1016/j.iac.2014.01.011 PMid:24745681  
  80. Guillaume, N.; Desoutter, J.; Chandesris, O.; Merlusca, L.; Henry, I.; Georgin-Lavialle, S.; Barete, S.; Hirsch, I.; Bouredji, D.; Royer, B.; et al. Bone Complications of Mastocytosis: A Link between Clinical and Biological Characteristics. Am J Med 2013, 126, 75.e1-7, doi:10.1016/j.amjmed.2012.07.018. https://doi.org/10.1016/j.amjmed.2012.07.018 PMid:23200108
  81. Carosi, G.; Guabello, G.; Longhi, M.; Grifoni, F.; Passeri, E.; Corbetta, S. Hypertryptasemia and Mast Cell-Related Disorders in Severe Osteoporotic Patients. Mediators Inflamm 2020, 2020, doi:10.1155/2020/5785378. https://doi.org/10.1155/2020/5785378 PMid:33144848 PMCid:PMC7599415
  82. Leone, A.; Criscuolo, M.; Gullì, C.; Petrosino, A.; Carlo Bianco, N.; Colosimo, C. Systemic Mastocytosis Revisited with an Emphasis on Skeletal Manifestations. Radiol Med 2020, doi:10.1007/s11547-020-01306-8. https://doi.org/10.1007/s11547-020-01306-8 PMid:33242205
  83. Riffel, P.; Schwaab, J.; Lutz, C.; Naumann, N.; Metzgeroth, G.; Fabarius, A.; Schoenberg, S.O.; Hofmann, W.-K.; Valent, P.; Reiter, A.; et al. An Increased Bone Mineral Density Is an Adverse Prognostic Factor in Patients with Systemic Mastocytosis. J Cancer Res Clin Oncol 2020, 146, 945-951, doi:10.1007/s00432-019-03119-3. https://doi.org/10.1007/s00432-019-03119-3 PMid:31980928 PMCid:PMC7085471  
  84. Rossini, M.; Zanotti, R.; Viapiana, O.; Tripi, G.; Idolazzi, L.; Biondan, M.; Orsolini, G.; Bonadonna, P.; Adami, S.; Gatti, D. Zoledronic Acid in Osteoporosis Secondary to Mastocytosis. Am J Med 2014, 127, 1127.e1-1127.e4, doi:10.1016/j.amjmed.2014.06.015. https://doi.org/10.1016/j.amjmed.2014.06.015 PMid:24954632  
  85. Greene, L.W.; Asadipooya, K.; Corradi, P.F.; Akin, C. Endocrine Manifestations of Systemic Mastocytosis in Bone. Rev Endocr Metab Disord 2016, 17, 419-431, doi:10.1007/s11154-016-9362-3. https://doi.org/10.1007/s11154-016-9362-3 PMid:27239674  
  86. Laroche, M.; Livideanu, C.; Paul, C.; Cantagrel, A. Interferon Alpha and Pamidronate in Osteoporosis with Fracture Secondary to Mastocytosis. Am J Med 2011, 124, 776-778, doi:10.1016/j.amjmed.2011.02.038. https://doi.org/10.1016/j.amjmed.2011.02.038 PMid:21787907  
  87. Matito, A.; Morgado, J.M.; Sánchez-López, P.; Álvarez-Twose, I.; Sánchez-Muñoz, L.; Orfao, A.; Escribano, L. Management of Anesthesia in Adult and Pediatric Mastocytosis: A Study of the Spanish Network on Mastocytosis (REMA) Based on 726 Anesthetic Procedures. IAA 2015, 167, 47-56, doi:10.1159/000436969. https://doi.org/10.1159/000436969 PMid:26160029
  88. Carter, M.C.; Uzzaman, A.; Scott, L.M.; Metcalfe, D.D.; Quezado, Z. Pediatric Mastocytosis: Routine Anesthetic Management for a Complex Disease. Anesth Analg 2008, 107, 422-427, doi:10.1213/ane.0b013e31817e6d7c. https://doi.org/10.1213/ane.0b013e31817e6d7c PMid:18633019 PMCid:PMC2736554
  89. Bonadonna, P.; Zanotti, R.; Varani, A.B.; Pagani, M. Mast Cell Diseases and Drug Hypersensitivity Reactions. Current Treatment Options in Allergy 2017, 2, 258-267, doi:10.1007/s40521-017-0130-8. https://doi.org/10.1007/s40521-017-0130-8  
  90. Bonadonna, P.; Gonzalez-de-Olano, D.; Zanotti, R.; Riccio, A.; De Ferrari, L.; Lombardo, C.; Rogkakou, A.; Escribano, L.; Alvarez-Twose, I.; Matito, A.; et al. Venom Immunotherapy in Patients with Clonal Mast Cell Disorders: Efficacy, Safety, and Practical Considerations. J Allergy Clin Immunol Pract 2013, 1, 474-478, doi:10.1016/j.jaip.2013.06.014. https://doi.org/10.1016/j.jaip.2013.06.014 PMid:24565619  
  91. Bilò, M.B.; Pravettoni, V.; Bignardi, D.; Bonadonna, P.; Mauro, M.; Novembre, E.; Quercia, O.; Cilia, M.; Cortellini, G.; Costantino, M.T.; et al. Hymenoptera Venom Allergy: Management of Children and Adults in Clinical Practice. J Investig Allergol Clin Immunol 2019, 29, 180-205, doi:10.18176/jiaci.0310. https://doi.org/10.18176/jiaci.0310 PMid:30183660  
  92. Michel, J.; Brockow, K.; Darsow, U; Ring, J.; Schmidt-Weber, C.B.; Grunwald, T.; Blank, S.; Ollert, M. Added Sensitivity of Component-Resolved Diagnosis in Hymenoptera Venom-Allergic Patients with Elevated Serum Tryptase and/or Mastocytosis. Allergy 2016, 71, 651-660, doi:10.1111/all.12850. https://doi.org/10.1111/all.12850 PMid:26836051
  93. Kontou-Fili, K. High Omalizumab Dose Controls Recurrent Reactions to Venom Immunotherapy in Indolent Systemic Mastocytosis. Allergy 2008, 63, 376-378, doi:10.1111/j.1398-9995.2007.01604.x. https://doi.org/10.1111/j.1398-9995.2007.01604.x PMid:18269681  
  94. Galera, C.; Soohun, N.; Zankar, N.; Caimmi, S.; Gallen, C.; Demoly, P. Severe Anaphylaxis to Bee Venom Immunotherapy: Efficacy of Pretreatment and Concurrent Treatment with Omalizumab. J Investig Allergol Clin Immunol 2009, 19, 225-229.  
  95. Matito, A.; Álvarez-Twose, I.; Morgado, J.M.; Sánchez-Muñoz, L.; Orfao, A.; Escribano, L. Clinical Impact of Pregnancy in Mastocytosis: A Study of the Spanish Network on Mastocytosis (REMA) in 45 Cases. Int. Arch. Allergy Immunol. 2011, 156, 104-111, doi:10.1159/000321954. https://doi.org/10.1159/000321954 PMid:21447966 
  96. Worobec, A.S.; Akin, C.; Scott, L.M.; Metcalfe, D.D. Mastocytosis Complicating Pregnancy. Obstet Gynecol 2000, 95, 391-395, doi:10.1016/s0029-7844(99)00591-8. https://doi.org/10.1016/S0029-7844(99)00591-8  
  97. Zanoni, G.; Zanotti, R.; Schena, D.; Sabbadini, C.; Opri, R.; Bonadonna, P. Vaccination Management in Children and Adults with Mastocytosis. Clin Exp Allergy 2017, 47, 593-596, doi:10.1111/cea.12882. https://doi.org/10.1111/cea.12882 PMid:28079293
  98. Carter, M.C.; Metcalfe, D.D.; Matito, A.; Escribano, L.; Butterfield, J.H.; Schwartz, L.B.; Bonadonna, P.; Zanotti, R.; Triggiani, M.; Castells, M.; et al. Adverse Reactions to Drugs and Biologics in Patients with Clonal Mast Cell Disorders: A Work Group Report of the Mast Cells Disorder Committee, American Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol 2019, 143, 880-893, doi:10.1016/j.jaci.2018.10.063. https://doi.org/10.1016/j.jaci.2018.10.063 PMid:30528617
  99. Bonadonna, P.; Brockow, K.; Niedoszytko, M.; Elberink, H.O.; Akin, C.; Nedoszytko, B.; Butterfield, J.H.; Alvarez-Twose, I.; Sotlar, K.; Schwaab, J.; et al. COVID-19 Vaccination in Mastocytosis: Recommendations of the European Competence Network on Mastocytosis (ECNM) and American Initiative in Mast Cell Diseases (AIM). J Allergy Clin Immunol Pract 2021, 9, 2139-2144, doi:10.1016/j.jaip.2021.03.041. https://doi.org/10.1016/j.jaip.2021.03.041 PMid:33831618 PMCid:PMC8019658
  100. Casassus, P.; Caillat-Vigneron, N.; Martin, A.; Simon, J.; Gallais, V.; Beaudry, P.; Eclache, V.; Laroche, L.; Lortholary, P.; Raphaël, M.; et al. Treatment of Adult Systemic Mastocytosis with Interferon-α: Results of a Multicentre Phase II Trial on 20 Patients. British Journal of Haematology 2002, 119, 1090-1097, doi:10.1046/j.1365-2141.2002.03944.x. https://doi.org/10.1046/j.1365-2141.2002.03944.x PMid:12472593
  101. Lim, K.H.; Pardanani, A.; Butterfield, J.H.; Li, C.-Y.; Tefferi, A. 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, 790-794, doi:10.1002/ajh.21561. https://doi.org/10.1002/ajh.21561 PMid:19890907
  102. Arun, V.A.; Soni, D.; Bal, A.; Jain, A. Aggressive Systemic Mastocytosis Presenting as Rapidly Progressive Ascites, Generalised Lymphadenopathy and Osteosclerosis. BMJ Case Rep 2021, 14, e238034, doi:10.1136/bcr-2020-238034. https://doi.org/10.1136/bcr-2020-238034 PMid:33558379  
  103. Barete, S.; Lortholary, O.; Damaj, G.; Hirsch, I.; Chandesris, M.O.; Elie, C.; Hamidou, M.; Durieu, I.; Suarez, F.; Grosbois, B.; et al. Long-Term Efficacy and Safety of Cladribine (2-CdA) in Adult Patients with Mastocytosis. Blood 2015, 126, 1009-1016; quiz 1050, doi:10.1182/blood-2014-12-614743. https://doi.org/10.1182/blood-2014-12-614743 PMid:26002962
  104. Alvarez-Twose, I.; Matito, A.; Morgado, J.M.; Sánchez-Muñoz, L.; Jara-Acevedo, M.; García-Montero, A.; Mayado, A.; Caldas, C.; Teodósio, C.; Muñoz-González, J.I.; et al. Imatinib in Systemic Mastocytosis: A Phase IV Clinical Trial in Patients Lacking Exon 17 KIT Mutations and Review of the Literature. Oncotarget 2016, 8, 68950-68963, doi:10.18632/oncotarget.10711. https://doi.org/10.18632/oncotarget.10711 PMid:28978170 PMCid:PMC5620310
  105. Gleixner, K.V.; Mayerhofer, M.; Sonneck, K.; Gruze, A.; Samorapoompichit, P.; Baumgartner, C.; Lee, F.Y.; Aichberger, K.J.; Manley, P.W.; Fabbro, D.; et al. Synergistic Growth-Inhibitory Effects of Two Tyrosine Kinase Inhibitors, Dasatinib and PKC412, on Neoplastic Mast Cells Expressing the D816V-Mutated Oncogenic Variant of KIT. Haematologica 2007, 92, 1451-1459, doi:10.3324/haematol.11339. https://doi.org/10.3324/haematol.11339 PMid:18024392
  106. Verstovsek, S.; Tefferi, A.; Cortes, J.; O'Brien, S.; Garcia-Manero, G.; Pardanani, A.; Akin, C.; Faderl, S.; Manshouri, T.; Thomas, D.; et al. Phase II Study of Dasatinib in Philadelphia Chromosome-Negative Acute and Chronic Myeloid Diseases, Including Systemic Mastocytosis. Clin Cancer Res 2008, 14, 3906-3915, doi:10.1158/1078-0432.CCR-08-0366. https://doi.org/10.1158/1078-0432.CCR-08-0366 PMid:18559612 PMCid:PMC5018899  
  107. Purtill, D.; Cooney, J.; Sinniah, R.; Carnley, B.; Cull, G.; Augustson, B.; Cannell, P. Dasatinib Therapy for Systemic Mastocytosis: Four Cases. Eur J Haematol 2008, 80, 456-458, doi:10.1111/j.1600-0609.2008.01048.x. https://doi.org/10.1111/j.1600-0609.2008.01048.x PMid:18284618  
  108. Bibi, S.; Arock, M. Tyrosine Kinase Inhibition in Mastocytosis: KIT and Beyond KIT. Immunol Allergy Clin North Am 2018, 38, 527-543, doi:10.1016/j.iac.2018.04.007. https://doi.org/10.1016/j.iac.2018.04.007 PMid:30007468  
  109. Gotlib, J.; Kluin-Nelemans, H.C.; George, T.I.; Akin, C.; Sotlar, K.; Hermine, O.; Awan, F.T.; Hexner, E.; Mauro, M.J.; Sternberg, D.W.; et al. Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis. N Engl J Med 2016, 374, 2530-2541, doi:10.1056/NEJMoa1513098. https://doi.org/10.1056/NEJMoa1513098 PMid:27355533
  110. Radia D, Deininger M, Gotlib J, et al. Avapritinib, a potent and selective inhibitor of kit d816v, induces complete and durable responses in patients (pts) with advanced systemic mastocytosis (ADVSM).  
  111. Gotlib, J.; Baird, J.H.; George, T.I.; Langford, C.; Reyes, I.; Abuel, J.; Perkins, C.; Schroeder, K.; Bose, P.; Verstovsek, S. A Phase 2 Study of Brentuximab Vedotin in Patients with CD30-Positive Advanced Systemic Mastocytosis. Blood Adv 2019, 3, 2264-2271, doi:10.1182/bloodadvances.2019000152. https://doi.org/10.1182/bloodadvances.2019000152 PMid:31350306 PMCid:PMC6693006
  112. Lortholary, O.; Chandesris, M.O.; Livideanu, C.B.; Paul, C.; Guillet, G.; Jassem, E.; Niedoszytko, M.; Barete, S.; Verstovsek, S.; Grattan, C.; et al. Masitinib for Treatment of Severely Symptomatic Indolent Systemic Mastocytosis: A Randomised, Placebo-Controlled, Phase 3 Study. Lancet 2017, 389, 612-620, doi:10.1016/S0140-6736(16)31403-9. https://doi.org/10.1016/S0140-6736(16)31403-9
  113. Maurer, M.; Elberink, H.O.; Gotlib, J.; Sabato, V.; Hartmann, K.; Broesby-Olsen, S.; Castells, M.; Deininger, M.W.; Heaney, M.L.; George, T.I.; et al. Results from PIONEER: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study of Avapritinib in Patients with Indolent Systemic Mastocytosis (ISM). Oncology Research and Treatment 2020, 43, 77. 
  114. Escribano, L.; Akin, C.; Castells, M.; Orfao, A.; Metcalfe, D.D. Mastocytosis: Current Concepts in Diagnosis and Treatment. Ann. Hematol. 2002, 81, 677-690, doi:10.1007/s00277-002-0575-z. https://doi.org/10.1007/s00277-002-0575-z PMid:12483363

[TOP]