Pharmacological treatment options for mast cell activation disease

  • Gerhard J. Molderings
  • Britta Haenisch
  • Stefan Brettner
  • Jürgen Homann
  • Markus Menzen
  • Franz Ludwig Dumoulin
  • Jens Panse
  • Joseph Butterfield
  • Lawrence B. Afrin
Open Access
Review

Abstract

Mast cell activation disease (MCAD) is a term referring to a heterogeneous group of disorders characterized by aberrant release of variable subsets of mast cell (MC) mediators together with accumulation of either morphologically altered and immunohistochemically identifiable mutated MCs due to MC proliferation (systemic mastocytosis [SM] and MC leukemia [MCL]) or morphologically ordinary MCs due to decreased apoptosis (MC activation syndrome [MCAS] and well-differentiated SM). Clinical signs and symptoms in MCAD vary depending on disease subtype and result from excessive mediator release by MCs and, in aggressive forms, from organ failure related to MC infiltration. In most cases, treatment of MCAD is directed primarily at controlling the symptoms associated with MC mediator release. In advanced forms, such as aggressive SM and MCL, agents targeting MC proliferation such as kinase inhibitors may be provided. Targeted therapies aimed at blocking mutant protein variants and/or downstream signaling pathways are currently being developed. Other targets, such as specific surface antigens expressed on neoplastic MCs, might be considered for the development of future therapies. Since clinicians are often underprepared to evaluate, diagnose, and effectively treat this clinically heterogeneous disease, we seek to familiarize clinicians with MCAD and review current and future treatment approaches.

Keywords

Mast cell Mast cell activation disease Systemic mastocytosis Systemic mast cell activation syndrome Therapy 

Introduction

Mast cells (MCs, Fig. 1) are immune cells of hematopoietic origin found in all human tissues, especially at the environmental interfaces. They act as both effector and regulatory cells and play a central role in adaptive and innate immunity (Anand et al. 2012; Gri et al. 2012). Their important role in immunological as well as non-immunological processes is reflected by the large number of mediators (>200) including pre-stored ones such as histamine and tryptase as well as numerous mediators synthesized de novo in response to allergic or non-immune triggers such as chemokines and cytokines, by which MCs may influence other cells (Lundequist and Pejler 2011; Ibelgaufts 2016). Their evolved arrays of sensory and response mechanisms engender diverse havoc when MC dysfunction emerges.
Fig. 1

May-Grünwald/Giemsa stain of a resting human mast cell and a mast cell following activation-induced degranulation. Note the loss of granule staining. Mast cells obtained from the human bone marrow, magnification 1000×

The umbrella term mast cell activation disease (MCAD; Akin et al. 2010) comprises the full spectrum of primary systemic MC disease, i.e., systemic mastocytosis (SM) which is further divided into several subtypes (Valent et al. 2007; Tables 1 and 2), primary MC activation syndrome (MCAS; Table 3; Molderings et al. 2011a; Hamilton et al. 2011; Valent et al. 2012), and MC leukemia (MCL). Pathogenetically, MCAD denotes a group of polygenic MC disorders (Molderings 2015, 2016) characterized by aberrant release of variable subsets of MC mediators and also an accumulation of either morphologically altered and immunohistochemically identifiable mutated MCs due to MC proliferation (SM and MCL) or morphologically ordinary MCs due to decreased apoptosis (MCAS; Kohno et al. 2005; Aichberger et al. 2009; Karlberg et al. 2010a). According to recent molecular genetic findings (Molderings 2015, 2016; Haenisch et al. 2014; Lasho et al. 2016), the subclasses and clinical subtypes of MCAD do not represent distinct disease entities but should be more accurately regarded as variable presentations of a common generic state of MC dysfunction (Molderings et al. 2007, 2010; Hermine et al. 2008; Akin et al. 2010). Due to both the widespread distribution of MCs and the great heterogeneity of aberrant mediator expression patterns, symptoms can occur in virtually all organs and tissues; hence, the clinical presentation of MCAD is very diverse, sometimes to the even-further-confounding point of presenting opposite abnormalities in different patients (or even in the same patient at different times, or in different sites in the same patient at the same time). While the prevalence of SM in Europeans ranges between 0.3 and 13 per 100,000 (Haenisch et al. 2012; Cohen et al. 2014; van Doormaal et al. 2013), the prevalence of MCAS may be as high as 17 % (in Germany; Molderings et al. 2013a, b).
Table 1

WHO 2008 diagnostic criteria for systemic mastocytosis (Valent et al. 2001)

Major criterion:

1. Multifocal, dense aggregates of MCs (15 or more) in sections of the bone marrow or other extracutaneous tissues and confirmed by tryptase immunohistochemistry or other special stains

Minor criteria:

1. Atypical or spindled appearance of at least 25 % of the MCs in the diagnostic biopsy

2. Expression of CD2 and/or CD25 by MCs in the marrow, blood, or extracutaneous organs

3. KIT codon 816 mutation in the marrow, blood, or extracutaneous organs

4. Persistent elevation of serum total tryptase >20 ng/ml

Diagnosis of SM made by either (1) the major criterion plus any one of the minor criteria or (2) any three minor criteria

Table 2

Classification of systemic mastocytosis (modified form Valent et al. 2007)

Categories of systemic mastocytosis (SM)

Subtypes

Indolent systemic mastocytosis

• Smoldering systemic mastocytosis

• Isolated bone marrow mastocytosis

• Well-differentiated systemic mastocytosis

Aggressive systemic mastocytosis (ASM)

• ASM in transformation

Systemic mastocytosis with an associated clonal hematological non-mast cell lineage disease

• SM-acute myeloid leukemia

• SM-myelodysplastic syndrome

• SM-myeloproliferative neoplasm

• SM-chronic myelomonocytic leukemia

• SM-chronic eosinophilic leukemia

• SM-non-Hodgkin lymphoma

• SM-multiple myeloma

Table 3

Current provisional criteria to define mast cell activation syndrome (MCAS; modified from Afrin and Molderings 2014)

Major criterion

 

Constellation of clinical complaints attributable to pathologically increased mast cell activity (mast cell mediator release syndrome)

Minor criteria

1.

Focal or disseminated increased number of mast cells in marrow and/or extracutaneous organ(s) (e.g., gastrointestinal tract biopsies; CD117-, tryptase-, and CD25-stained)

2.

Abnormal spindle-shaped morphology in >25 % of mast cells in marrow or other extracutaneous organ(s)

3.

Abnormal mast cell expression of CD2 and/or CD25 (i.e., co-expression of CD117/CD25 or CD117/CD2)

4.

Detection of genetic changes in mast cells from the blood, bone marrow, or extracutaneous organs for which an impact on the state of activity of affected mast cells in terms of an increased activity has been proven

5.

Evidence (typically from body fluids such as whole blood, serum, plasma, or urine) of above-normal levels of mast cell mediators including:

 

Tryptase in the blood

 

Histamine or its metabolites (e.g., N-methylhistamine) in the urine

 

Heparin in the blood

 

Chromogranin A in the blood (potential confounders of cardiac or renal failure, neuroendocrine tumors, or recent proton pump inhibitor use were excluded)

 

Other relatively mast cell-specific mediators (e.g., eicosanoids including prostaglandin PGD2, its metabolite 11-β-PGF, or leukotriene E4)

6.

Symptomatic response to inhibitors of mast cell activation or mast cell mediator production or action (e.g., histamine H1 and/or H2 receptor antagonists, cromolyn)

Diagnosis of MCAS made by either (1) the major criterion plus any one of the minor criteria or (2) any three minor criteria

This review focuses on the current state of drug therapy in SM and MCAS and describes perspectives of promising new approaches for drug treatment. Compounds in various stages of preclinical and clinical development are summarized in tables. We first describe drugs that are currently available and either are used on a regular basis in MCAD therapy or have been used successfully in single MCAD cases. In this context, it should be noted that there is no official guideline for treatment of MCAD.

Treatment options

Due to its genetic roots, MCAD generally is regarded as incurable. Recent mutational studies revealed that each patient has an individual pattern of genetic and epigenetic alterations which may affect the intracellular signal transduction pathways and receptive sites involved in sensory perception. As a consequence, mediator formation and release as well as inhibition of apoptosis and/or increase in proliferation are determined by individual genetic and epigenetic conditions (Fig. 2) and represent potential targets for therapy. Hence, there is need of highly personalized therapy for the disease. Unfortunately (with regard to easy detection), most genetic alterations (with a few exceptions such as certain mutations in tyrosine kinase KIT, e.g., KITD816V) do not alter the morphology and immunohistochemistry of the surface of the affected MCs. Thus, in most cases except for patients with the reliably identifiable D816V mutation, it cannot be decided by simple tests whether MCs found in biopsies are genetically altered MCs or physiological MCs.
Fig. 2

Scheme of conditions responsible in MCAD for the development of individual phenotypes

First-line treatment options

Step 1 in managing most situations of inappropriate MC activation is identifying the individual patient’s unique triggers (chemical, physical, or otherwise) as precisely as possible and then desensitizing when possible (in truth, rarely) and otherwise practicing avoidance. With respect to drug treatment, only a few clinical therapeutic trials have been conducted in SM (midostaurin, cladribine, masitinib; Table 4), and there have been no therapeutic trials in MCAS yet. Most information about therapeutic effectiveness in MCAD has been found in small case series (Table 4) and single case reports, perhaps unsurprising given the mutational heterogeneity of the disease and thus the heterogeneity of its patterns of clinical presentation and therapeutic responsiveness. Therefore, in the future, it may be helpful to establish an international patient registry in partnership with existing registries so that issues related to molecular and clinical MCAD phenotypes can be adequately addressed. As the primary feature of MCAD is inappropriate MC activation (Molderings et al. 2011a, b; Pardanani 2013; Cardet et al. 2013), mainstays of first-line management are identification and avoidance of triggers plus therapies to control MC mediator production (both primary as well as secondary/reactive; Table 5) as well as their action (Table 6).
Table 4

Case series and clinical therapeutic trials in systemic mastocytosis and mast cell activation syndrome

Compound

Number of patients included in the study or case series

References

H1-antihistamines

 Rupatadine

30

Siebenhaar et al. 2013

 Azelastine vs. chlorpheniramine

15

Friedman et al. 1993

 Ketotifen vs. hydroxyzine

8

Kettelhut et al. 1989

 Chlorpheniramine plus cimetidine

8

Frieri et al. 1985

 Continuous diphenhydramine infusion

10

Afrin 2015a

Mast cell stabilizer

 Cromoglicic acid (cromolyn)

5

Soter et al. 1979

11

Horan et al. 1990

4

Mallet et al. 1989

8

Frieri et al. 1985

2

Welch et al. 1983

2

Zachariae et al. 1981

 Tranilast

2

Katoh et al. 1996

Kinase inhibitors

 Imatinib (STI571)

14

Droogendijk et al. 2006

20

Vega-Ruiz et al. 2009

22

Lim et al. 2009

17

Pagano et al. 2008

12

Pardanani et al. 2003

5

Heinrich et al. 2008

3

Hennessy et al. 2004

 Nilotinib (AMN107)

61

Hochhaus et al. 2015

 Dasatinib (BMS-354825)

33

Verstovsek et al. 2008

4

Purtill et al. 2008

 Midostaurin (PKC412)

9

Papayannidis et al. 2014

11

Knapper et al. 2011

22

Chandesris et al. 2014

89

Gotlib et al. 2014

14

Strati et al. 2015

 Masitinib

25

Paul et al. 2010

Cytostatic agents

 Hydroxyurea

26

Lim et al. 2009

5

Afrin 2013a

 Cladribine (2-chlorodeoxyadenosine)

22

Lim et al. 2009

10

Kluin-Nelemans et al. 2003

4

Pardanani et al. 2004

3

Pagano et al. 2008

68

Barete et al. 2015

Immunomodulation

 Interferon-α

20

Casassus et al. 2002

5

Hauswirth et al. 2004

10

Laroche et al. 2011

40

Lim et al. 2009

8

Pagano et al. 2008

6

Giraldo Castellano et al. 1998

9

Hennessy et al. 2004

3

Worobec et al. 1996

 Thalidomide

16

Gruson et al. 2013

IgE antibody

 Omalizumab

4

Molderings et al. 2011ba

2

Carter et al. 2007

2

Lieberoth and Thomsen 2015

ß-Sympathomimetics

 Isoprenaline, terbutaline

5

van Doormaal et al. 1986

Cyclooxygenase inhibitor

 Acetylsalicylic acid

4

Butterfield and Weiler 2008

20

Butterfield 2009

aIt indicates clinical trials performed with patients with mast cell activation syndrome

Table 5

First-line drugs which can potentially be used in the treatment of mast cell (MC) activation disease and their target location and mechanisms of action

 

Target location/mechanisms of action

Growth inhibition

Decrease of mediator release

To relieve symptoms

References

First-line drugs

 

 H1-antihistamines (preferably of the second and third generations)

Block mutual activation of mast cells via H1-histamine receptors; antagonize H1-histamine receptor-mediated symptoms

 

X

X

Church and Gradidge 1980

Valent et al. 2007R

Picard et al. 2013R

Nurmatov et al. 2015

Siebenhaar et al. 2013

Escribano et al. 2006R

 H2-antihistamines

Block mutual activation of mast cells via H2-histamine receptors; antagonize H2-histamine receptor-mediated symptoms

 

X

X

Valent et al. 2007R

Escribano et al. 2006R

 Cromoglicic acid (also known as cromolyn)

GPR35; modulation of chloride current

 

X

X

Soter et al. 1979

Valent et al. 2007R

Yang et al. 2010

Edwards et al. 2011

Edwards and Hagberg 2010

Zhang et al. 2016

Escribano et al. 2006R

 Vitamin C

Increased degradation of histamine; decrease of histamine formation by inhibition of histidine decarboxylase

 

X

X

Hagel et al. 2013

Johnston et al. 1992

Uchida et al. 1989

Chatterjee et al. 1975

As a rule, these drugs should be used in combination to achieve a sufficient reduction of MC activity. All drugs should be tested for tolerance in a low single dose before therapeutic use, if their tolerance in the patient is not known from an earlier application. A precondition for therapeutic success is the avoidance of identifiable triggers of MC activation; in this context, parallel to the beginning of drug therapy, gluten, cow milk protein, and baker’s yeast should be omitted from the diet for 3–4 weeks

R review article (further references therein)

Table 6

Symptomatic treatment (orally as needed) in MCAD (modified from Molderings et al. 2014)

Colitis ⇒ budesonide; for some days, prednisone >20 mg/day

Diarrhea ⇒ c(h)olestyramine; nystatin; montelukast; 5-HT3 receptor inhibitors (e.g. ondansetron); incremental doses of acetylsalicylic acid (50–350 mg/day; extreme caution because of the possibility to induce mast cell degranulation); in steps test each drug for 5 days until improvement of diarrhea

Colicky abdominal pain due to distinct meteorism ⇒ metamizole; butylscopolamine

Angioedema ⇒ tranexamic acid; icatibant

Nausea ⇒ dimenhydrinate; lorazepam; 5-HT3 receptor inhibitors; NK1 antagonists such as aprepitant

Respiratory symptoms (mainly due to increased production of viscous mucus and obstruction with compulsive throat clearing) ⇒ leukotriene receptor blockers such as montelukast; if in a country available, leukotriene synthesis inhibitors such as zileuton; urgent: short-acting ß-sympathomimetic

Gastric complaints ⇒ proton-pump inhibitors (de-escalating dose-finding)

Osteoporosis, osteolysis, bone pain ⇒ bisphosphonates (vitamin D plus calcium application is second-line treatment in MCAD patients because of limited reported success and an increased risk for developing kidney and ureter stones); calcitonin; teriparatide (with caution; cases of cholestatic liver failure due to this drug have been reported); anti-RANKL drugs such as denosumab (dental clearance is required prior to treatment with bisphosphonates and anti-RANKL therapies due to risk for potentially severely morbid osteonecrosis of the jaw in patients with poor dentition or recent invasive dental work)

Non-cardiac chest pain ⇒ when needed, additional dose of a H2-histamine receptor antagonist; also, proton-pump inhibitors for proven gastroesophageal reflux

Tachycardia ⇒ AT1-receptor antagonists; ivabradine

Neuropathic pain and paresthesia ⇒ α-lipoic acid

Itches ⇒ palmitoylethanolamine-containing care products; cromolyn-containing ointment

Rheumatoid symptoms ⇒ COX2 inhibitors such as etoricoxib or celecoxib; paracetamol

Anemia ⇒ in iron-deficiency anemia, iron supplementation (whether oral or parenteral) must be given cautiously due to risk for potentially intense mast cell activation; alternatively, red blood cell transfusion should be considered

Interstitial cystitis ⇒ pentosan, amphetamines

Sleep-onset insomnia/sleep-maintenance insomnia ⇒ triazolam

Conjunctivitis ⇒ exclusion of a secondary disease; otherwise preservative-free eye drops with H1-antihistamine, cromolyn, ketotifen, or glucocorticoid for brief courses

Hypercholesterolemia ⇒ (probably due to inhibition of transport into the cells, thus independent of diet) >300 mg/dL therapeutic trial with HMG-CoA reductase inhibitor atorvastatin

Subordinate therapeutic options

Continuous diphenhydramine infusion

Occasional patients suffer nearly continuous anaphylactoid and/or dysautonomic states poorly controlled by intermittently dosed epinephrine, antihistamines, and steroids. As discussed in more detail below, some such patients are particularly triggered by a wide range of medication excipients, making it challenging for them to tolerate trials of any adulterated (non-pure) medications, and yet some modicum of stability is required to pursue medication trials in such patients. Diphenhydramine is a well-tolerated histamine H1 receptor blocker (that among other non-threatening adverse affects can cause dizziness and an increase in appetite) which can quickly suppress MC activation and is used to treat allergic reactions and anaphylaxis. However, its half-life is as short as 1 h (www.drugbank.ca/drugs/DB01075). Intermittently dosed, though, its initial therapeutic serum level rapidly declines to subtherapeutic levels and the patient seesaws into yet another flare. The safety of continuous diphenhydramine infusion was established in trials of the “BAD” regimen (diphenhydramine [Benadryl], lorazepam [Ativan], and dexamethasone) in refractory chemotherapy-induced emesis in adult and pediatric patients (Dix et al. 1999; Jones et al. 2007). In a small series of ten MCAS patients suffering almost continuous anaphylactoid/dysautonomic flares, continuous diphenhydramine infusion at 10–14.5 mg/h appeared effective in most patients at dramatically reducing flare rates and appeared safely sustainable at stable dosing for at least 21 months (Afrin 2015). Stabilization has enabled successful trials of other helpful medications, but no patient has yet successfully stopped continuous diphenhydramine infusion.

Acute and chronic immunosuppressive therapies

Though typically not first-line, acute and chronic immunosuppressive therapies can be considered (Fig. 3; Table 7) and may be particularly appropriate for patients possibly manifesting an autoimmune component of the disease as might be suggested by the presence, for example, of anti-IgE or anti-IgE-receptor antibodies. Glucocorticoids may exert beneficial effects in MCAD, including a decrease in production of stem cell factor (SCF, and possibly other cytokines) and a decrease in MC activation, by various mechanisms which have been extensively reviewed by Oppong et al. 2013. Glucocorticoids at doses >20 mg prednisone equivalent per day are frequently needed to effectively control otherwise refractory acute (and chronic) symptoms. Their chronic toxicity profile is disadvantageous for long-term use, but such toxicities have to be accepted in some cases. The influence of azathioprine, methotrexate, ciclosporine, hydroxyurea, and tamoxifen on MC activity can vary from no to moderate effect depending on individual disease factors. As in therapy of rheumatoid arthritis, azathioprine and methotrexate can be used in daily doses lower than those used in cancer or immunosuppressive post-transplant therapy. Effective MCAD therapy with ciclosporine requires doses as high as those used in transplantation medicine (M. Raithel, personal communication). Methotrexate has to be administered parenterally to be effective (unpublished observation, G.J. Molderings), and in the risk-benefit analysis, a possible non-immunologic histamine release from MCs (Estévez et al. 1996) has to be considered. Hence, use of the compound should be limited to MCAD with methotrexate-sensitive comorbidities (e.g., rheumatoid arthritis and vasculitis).
Fig. 3

Suggested treatment options for mast cell activation disease. All drugs should be tested for tolerance in a low single dose before therapeutic use, if their tolerance in the patient is not known from an earlier application. For further details of indication, see text

Table 7

Second- and third-line drugs which can potentially be used in the treatment of mast cell activation disease and their target location and mechanisms of action

 

Target location/mechanisms of action

Growth inhibition

Decrease of mediator release

To relieve symptoms

References

Second-line drugs

Immunosuppressive drugs

    

 Azathioprine

Multiple targets

 

X

X

Nolte and Stahl Skov 1988, Own unpublished data

 Ciclosporine

Calcineurin inhibitor

 

X

X

Kurosawa et al. 1999, Broyd et al. 2005, Trojan and Khan 2012, Own unpublished data

 Glucocorticoids

Multiple targets

(X)

X

X

Zen et al. 2011R

 Hydroxyurea

Multiple targets

X

 

X

Lim et al. 2009, Afrin 2013

 Tamoxifen

Precise mechanism of action in MCAD unknown

X

X

In single cases

Butterfield and Chen 2016, Duffy et al. 2003;

 Methotrexate

Multiple targets

 

?

X

Sagi et al. 2011, Vrugt et al. 2000

Third-line drugs

     

 Omalizumab

Anti-IgE antibody

  

X

Molderings et al. 2011b

Bell and Jackson 2012; Kibsgaard et al. 2014

Kontou-Fili et al. 2010

 Etoricoxib

 Acetylsalicylic acid

COX-inhibitors

  

X

Butterfield and Weiler 2008

Breslow et al. 2009

Butterfield 2009

 Montelukast

Antagonist at cys-LT1 receptors

  

X

Tolar et al. 2004

Cikler et al. 2009

Breslow et al. 2009

Turner et al. 2012

 Zileuton

5-Lipoxygenase inhibitor

  

X

Rodriguez et al. 2011

R review article (further references therein)

Recently, the humanized anti-IgE murine monoclonal antibody omalizumab has been described in multiple case reports as safe and effective in MCAD (e.g., Molderings et al. 2011b; Kontou-Fili et al. 2010; Bell and Jackson 2012; Kibsgaard et al. 2014), though a definitive trial has yet to be conducted. Since treatment with omalizumab has an acceptable risk-benefit profile, it should be considered in cases of MCAD resistant to at least a few lines of therapy. The drug’s expense likely consigns it to third-line (or later) treatment (Table 7). If elevated prostaglandin levels induce symptoms such as persistent flushing, inhibition of cyclooxygenases by incremental doses of acetylsalicylic acid (ASA; 50–350 mg/day) may be used with extreme caution, since ASA can induce MC degranulation probably due its chemical property as an organic acid. The leukotriene antagonist montelukast (possibly more effective at twice-daily dosing; personal observation, L.B. Afrin) and the 5-lipoxygenase inhibitor zileuton may be useful adjuvants in people with MCAD, particularly in those with refractory gastrointestinal and urinary symptoms (Tolar et al. 2004; Turner et al. 2012; Akhavein et al. 2012).

Studies of kinase inhibitors, both on-market (e.g., imatinib, nilotinib, dasatinib) and experimental (e.g., midostaurin, masitinib), have yielded variable responses in SM ranging from no response to partial or even complete responses (Fig. 3; Table 8). As with all drugs used in therapy of MCAD, their therapeutic success seems to be strongly dependent on the individual patient, again underscoring the observed mutational heterogeneity of the disease. In formal studies in SM patients, although some kinase inhibitors reduced MC burden as reflected by histological normalization in bone marrow and improved laboratory surrogate markers (e.g., tryptase level in blood), at best only partial improvement of mediator-related symptoms was achieved (Droogendijk et al. 2006; Gotlib et al. 2008; Verstovsek et al. 2008; Vega-Ruiz et al. 2009). There has been repeated suggestion that symptoms in MCAD may be due more to mediator release from normal MCs secondarily activated by pathologically overactive, mutated MCs (Galli and Costa 1995; Rosen and Goetzl 2005; Boyce 2007; Kaneko et al. 2009; Fig. 2 in Molderings et al. 2014), helping to explain why intensity and pattern of symptoms do not correlate with degree of MC proliferation and infiltration (Topar et al. 1998; Hermine et al. 2008; Broesby-Olsen et al. 2013; Erben et al. 2014; Quintás-Cardama et al. 2013). Distinction in pathways in the MC which promote MC proliferation vs. mediator production/release may explain why kinase inhibitors reduce MC burdens and MC-driven symptoms to different degrees (Droogendijk et al. 2006; Gotlib et al. 2008; Verstovsek et al. 2008; Vega-Ruiz et al. 2009; Table 8). However, in some case reports, kinase inhibitors have been significantly effective at relieving symptoms. Thus, in spite of potential serious adverse effects of these drugs, a therapeutic trial may be justified in individual cases at an early stage. Partial and complete responses have been reported with some of these agents in MCAS too (e.g., Afrin 2010, 2011, 2012, 2015; Afrin et al. 2015a). Dosing of the kinase inhibitors in the individual often is considerably lower than how such drugs are dosed for other applications (e.g., imatinib, sunitinib; Afrin et al. 2015a). Possibly due to the causative mutations in multiple genes leading to simultaneous activation of multiple intracellular pathways, multitargeted kinase inhibitors such as midostaurin and sunitinib may be more effective than drugs which selectively downregulate only one intracellular pathway.
Table 8

Kinase inhibitors which can potentially be used as fourth-line drugs in the treatment of mast cell activation disease and their target location and mechanisms of action

 

Target location/mechanisms of action

Growth inhibition

Decrease of mediator release

To relieve symptoms

References

Fourth-line drugs

Inhibitors of tyrosine kinases and other kinases

 Imatinib

KIT (excluding D816X), PDGFR, Bcr-Abl, Arg/Abl2, DDR-1

X

(X)

X

Pardanani et al. 2003

Droogendijk et al. 2006

Lim et al. 2009

Vega-Ruiz et al. 2009

Aman et al. 2012

Vaali et al. 2012

Quintás-Cardama et al. 2011R

Marton et al. 2015

 Nilotinib

KIT, PDGFR, Bcr-Abl

X

 

(X)

Hochhaus et al. 2006

Quintás-Cardama et al. 2011R

Hochhaus et al. 2015

El-Agamy 2012

 Dasatinib

KIT, BCR-ABL1, Lyn, Btk, Tec

X

 

(X)

Verstovsek et al. 2008

Hantschel et al. 2007

Gleixner et al. 2011

Quintás-Cardama et al. 2011R

 Sunitinib

VEGFR, PDGFR, KIT, FLT3, RET, CSF1R, SRC,

313 potential kinase targets

X

X

X

Afrin et al. 2015a

Yamaki and Yoshino 2012

Papaetis and Syrigos 2009

Bairlein 2010

 Masitinib

KIT, PDGFRα, Lck, LYN, FGFR3, FAK

X

 

X

Marech et al. 2014

Moussy and Kinet 2014

Paul et al. 2010

Quintás-Cardama et al. 2011R

 Midostaurin

PKC, FLT3, KIT, PDGFR, VEGFR2

X

X

X

Gotlib et al. 2014

Papayannidis et al. 2014

Knapper et al. 2011

Quintás-Cardama et al. 2011R

 Ponatinib

Bcr-Abl, KIT, FLT3, FGFR1, PDGFRα, Lyn

X

  

Jin et al. 2014

Gleixner et al. 2013

 Bafetinib

KIT (excluding D816X), Abl, Lyn

X

  

Peter et al. 2010a

 Bosutinib

Lyn, Btk

X

 

In ASM patients ineffective

Gleixner et al. 2011

Randall et al. 2015

R review article (further references therein)

In the mastocytosis patient with significant MC burden and/or an aggressive clinical course, cytoreductive drugs are prescribed (Lim et al. 2009; Valent et al. 2010). Unfortunately, effective cytoreductive therapies in SM presently are few in number and typically offer only modest response rates, qualities, and durations. Cytoreductive options include interferon-α and 2-chlorodeoxyadenosine (cladribine, 2-CdA; Fig. 3 and Table 9). Interferon-α is frequently combined with prednisone and is commonly used as cytoreductive therapy for aggressive SM. It ameliorates mastocytosis-related organopathy in a proportion of cases but can be associated with considerable adverse effects (e.g., flu-like symptoms, myelosuppression, depression, hypothyroidism), which may limit its use in MCAD (Simon et al. 2004; Butterfield 2005). PEGylated interferon-α has been shown to be as efficacious as and less toxic than the non-PEGylated form in some myeloproliferative neoplasms, but it has not been specifically studied in MCAD. 2-Chlorodeoxyadenosine is generally reserved for last-choice treatment of patients with aggressive SM who are either refractory or intolerant to interferon-α. Potential toxicities of 2-CdA include significant and potentially prolonged myelosuppression and lymphopenia with increased risk for opportunistic infections.
Table 9

Last-choice drugs which can potentially be used in the treatment of mast cell activation disease and their target location and mechanisms of action. R-review article (further references therein)

 

Target location/mechanisms of action

Growth inhibition

Decrease of mediator release

To relieve symptoms

References

Last-choice drugs

 

 Interferon-α

Multiple targets

X

 

(X)

Simon et al. 2004

Casassus et al. 2002

Hauswirth et al. 2004

Butterfield et al. 2005

Butterfield 2005R

Yoshida et al. 2009

Lim et al. 2009

Quintás-Cardama et al. 2011R

 Cladribine

Nucleoside analog

X

X

X

Tefferi et al. 2001

Kluin-Nelemans et al. 2003

Pardanani et al. 2004

Lim et al. 2009

Böhm et al. 2010

Radojković et al. 2011

Quintás-Cardama et al. 2011R

Lock et al. 2015

Barete et al. 2015

Last resorts

Polychemotherapy, including intensive induction regimens of the kind used in treating acute myeloid leukemia, as well as high-dose therapy with stem cell rescue, are approaches restricted to rare, selected patients. Allogeneic stem cell transplantation sometimes yields remissions in mastocytosis long thought impermanent (Spyridonidis et al. 2004; Nakamura et al. 2006; Bae et al. 2013; Gromke et al. 2013), though recent data may offer new hope (Ustun et al. 2014).

Investigational drugs

There are several drugs approved for indications other than MCAD which already have been successfully used in isolated cases with MCAD (Table 10). In cases of unsuccessful first- to fourth-line therapy, these compounds may be considered as treatment options.
Table 10

Drugs successfully (or not) used off-label to treat isolated cases of mast cell activation disease

 

Target location/mechanisms of action

Growth inhibition

Decrease of mediator release

To relieve symptoms

References

Investigational drugs

 Thalidomide

Precise mechanism of action unknown

  

X

Damaj et al. 2008

Gruson et al. 2013

 Lenalidomide

   

No effect

Kluin-Nelemans et al. 2009

 Flavonoids (e.g., luteolin, quercetin, genistein)

Multiple

X

(X)

(X)

Alexandrakis et al. 2003

Kempuraj et al. 2006

Min et al. 2007

Finn and Walsh 2013R

Weng et al. 2012

Lee et al. 2015

Weng et al. 2015

 Miltefosine

Raft modulator

 

X

(X)

Weller et al. 2009

Maurer et al. 2013R

 Mepolizumab

IL-5 antibody

X

  

Otani et al. 2012

 Rituximab

CD20 antibody

  

X

Borzutzky et al. 2014

 Ruxolitinib

JAK

X

 

X

Yacoub and Prochaska 2016

Kvasnicka et al. 2014

 Cannabinoids

Agonists at the cannabinoid receptors

  

X

De Filippis et al. 2008

Frenkel et al. 2015

Own unpublished experiences

 Methylene blue

Guanylyl cyclase inhibitor

  

Anaphylaxis treatment

Rodrigues et al. 2007

Evora and Simon 2007R

 Pimecrolimus

Calcineurin inhibitor

X

 

Cutaneous symptoms; (mice)

Ma et al. 2010

Correia et al. 2010

 Everolimus

mTOR

  

no effect

Parikh et al. 2010

 Ribavirin

Possibly suppression of activated retroviral elements in the genome which may be involved in the development of the somatic mutations in KIT and other proteins

 

X

X

Marquardt et al. 1987

Molderings 2016

Own unpublished experiences

R review article (further references therein)

A variety of drugs have been shown to inhibit MC growth, to decrease MC mediator release, and/or to relieve mediator-induced symptoms in in vitro and in vivo animal models (Table 11). Some of these drugs are approved for certain indications (such as ambroxol, statins, mefloquine, and ruxolitinib) and, thus, may be used (if accessible given financial considerations for some agents) if MCAD patients suffer from both the disorder of indication (e.g., hypercholesterolemia—statins, mucous congestion—ambroxol, polycythemia vera—ruxolitinib) and MCAD. An important question is what the role of the other compounds without approved indications should be in clinical practice. There are several challenges that may hamper the clinical introduction of novel targeted therapies in general. Some of these challenges include inherent problems in the translation of preclinical findings to the clinic, the presence of multiple coactive deregulated pathways in the disease, and questions related to the optimal design of clinical trials (e.g., eligibility criteria and endpoints). In particular, the testing of novel targeted treatment in an isolated fashion may be problematic and may in fact underestimate the effectiveness of these novel compounds. It is reasonable to assume that combination therapy will be the key to target parallel critical pathways.
Table 11

Investigational drugs which might have activity against mast cell activation disease since they induce apoptosis of mast cells and/or suppress mast cell mediator release in vitro and/or in vivo

 

Target location/mechanisms of action

Growth inhibition

Decrease of mediator release

To relieve symptoms

Investigated in vitro

Investigated in vivo

References

Investigational drugs

 ABT-737 {(R)-4-(3-dimethylamino-1-phenylsulfanylmethyl-propylamino)-N-{4-[4-(4′-chloro-biphenyl-2-ylmethyl)-piperazin-1-yl]-benzoyl}-3-nitro-benzenesulfonamide)}

BH3 mimetic

X

  

Murine BMMC, human cord blood-derived MCs, C57 MC line, MC/9 MC line

Mice

Karlberg et al. 2010b

 17-Allylamino-17-demethoxygeldanamycin,

 Ganetespib (STA-9090)

Binding to heat shock protein 90

X

  

HMC-1, canine BMMC, C2 MC line, BR canine mastocytoma cell lines

 

Fumo et al. 2004

Lin et al. 2008

 Ambroxol

Multiple

 

X

 

Human MCs

 

Gibbs et al. 1999

 Amitriptyline, clomipramine, maprotiline

Yet to be defined in MCAD

 

X

  

Male Wistar rats

Gurgel et al. 2013

Clemons et al. 2011

 Benzodiazepines

Yet to be defined

(X)

X

X

  

Molderings et al. 2013b; Dueñas-Laita et al. 2009; Bidri et al. 1999; Fujimoto et al. 2005; Suzuki-Nishimura et al. 1989; Hoffmann et al. 2013

 BI 2536 {(R)-4-(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide}

Polo-like kinase-1

X

  

HMC-1, primary human neoplastic MCs

 

Peter et al. 2011

 BLU-285 (chemical structure not yet published)

KIT

X

  

HMC-1.2,

P815 mouse mastosarcoma cells

 

Evans et al. 2015

 Botulinum toxin A

Cleavage of the SNARE proteins

X

X

  

SD rats

Park 2013

 Butaprost

EP2 receptor agonist

 

X

 

Human lung MCs

 

Kay et al. 2006

 Cerivastatin, fluvastatin, atorvastatin

Unknown in MCAD

X

X

 

Primary human MCs, HMC-1, P815

 

Krauth et al. 2006

Paez et al. 2015

 Chemokine receptor antagonists

Targeting activating chemokine receptors expressed on MCs

 

X

  

Mice

Koelink et al. 2012R

 Cinnamaldehyde

Signaling molecules, e.g., ERK1/2, JNK, p38, Akt

 

X

 

Human MCs, RBL-2H3 cells

 

Hagenlocher et al. 2015

Bibi et al. 2014R

 Combined arginine and glutamine

Multiple

 

X

 

Human intestinal MCs

 

Lechowski et al. 2013

 Coumarines (scopoletin)

Yet to be defined in MCAD

 

X

 

HMC-1

 

Moon et al. 2007

Finn and Walsh 2013R

 CRA1000 {N-ethyl-4-[4-(3-fluorophenyl)-3,6-dihydro-2H-pyridin-1-yl]-6-methyl-N-(2-methylsulfanyl-4-propan-2-ylphenyl)pyrimidin-2-amine}

Non-peptidic corticotropin-releasing factor antagonist

 

X

  

Mouse dermal MCs

Shimoda et al. 2010

 Crenolanib

FLT3

X

  

HMC-1, p815, MCs from SM patients

 

Schittenhelm et al. 2014

 Curcumin

Multiple

 

X

 

HMC-1, murine BMMC

BALB/c mice

Baek et al. 2003

Kinney et al. 2015

 Demethylating agents (5-azacytidine, 5-aza-2′deoxycytidine)

DNA methylation

X

 

(X)

HMC-1

 

Krug et al. 2010

Meeran et al. 2010R

 EXEL-0862 (WO2004050681 A2)

KIT, STAT3

X

  

HMC-1

 

Pan et al. 2007

 Fedratinib (TG101348)

JAK2 inhibition

X

  

HMC-1

 

Lasho et al. 2010

 GLC756 {(3R,4aR,10aR)-l,2,3,4,4a,5,10,10a-octahydro-6-hydroxy-1-methyl-3-[(2-pyridyl-thio) methyl]-benzo [gq]uinolinehydrochloride)}

Dopamine D1 and D2 receptor agonist

 

X

 

RBL-2H3 cells

 

Laengle et al. 2006

 Gly-Phe-CHN2, PZ610, PZ709, PZ889 (chemical structures not yet published)

Dipeptidylpeptidase-1 inhibitors

   

LAD2 MC

 

El-Feki et al. 2011

 Histamine H4-receptor agonist

Histamine H4-receptor

 

X

X

HMC-1, murine MCs

Ex vivo guinea pig and murine hearts

Aldi et al. 2014

 Histone deacetylase inhibitors: vorinostat, AR-42 {N-hydroxy-4-[[(2S)-3-methyl-2-phenylbutanoyl]amino]benzamide}

Histone deacetylase

X

  

HMC-1.2, primary human MCs, murine, and canine MCs

 

Mühlenberg et al. 2009

Hadzijusufovic et al. 2010

Meeran et al. 2010R

Abdulkadir et al. 2015

Lin et al. 2010

 Hypothemycin

Inhibition of KIT and Btk

 

X

 

Human MCs

Mice

Jensen et al. 2008

 IMD-0354 {N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide}

NF-κB inhibitor

X

  

HMC-1

 

Tanaka et al. 2005

 JTE-052 {3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile mono citrate}

JAK1,2,3 inhibitor, Tyk2 inhibitor

 

X

 

Human MCs

DBA/1J mice, Lewis rats

Tanimoto et al. 2015

 Mefloquine

Permeabilization of secretory granules

X

  

Human and murine MCs

 

Paivandy et al. 2014

 Mylotarg (gemtuzumab ozogamicin)

CD-33 targeting drug

X

  

HMC-1, human cord blood-derived MCs

 

Krauth et al. 2007

 Neramexane

Possibly NMDA antagonist

 

X

 

HMC-1 cells

 

Kurzen 2009

 Obatoclax

BH3 mimetic

X

  

HMC-1, human neoplastic BMMC

 

Aichberger et al. 2009

 ONO-4053 (chemical structure not yet published)

Prostaglandin receptor DP1 antagonist

X

  

Human BMMC

 

Yamaguchi et al. 2016

 8-OH-DPAT (7-(Dipropylamino)-5,6,7,8-tetrahydronaphthalen-1-ol)

5-HT1A receptor

No effect

X

   

Ritter et al. 2012

 Palmitoylethanolamide

PPAR-α, cannabinoid receptors, potassium channels, TRPV1

  

X

rat peritoneal MCs

 

Facci et al. 1995

Mattace Raso et al. 2014R

 PD180970 {6-(2,6-dichlorophenyl)-2-(4-fluoro-3-methylanilino)-8-methylpyrido[2,3-d]pyrimidin-7-one}

KIT, Bcr-Abl, PDGFR

X

  

HMC-1, P815 MCs

 

Corbin et al. 2004

 Phosphodiesterase inhibitors

Phosphodiesterase

 

X

 

Human lung MCs, rat MCs

Wistar rats

Lau and Kam 2005; Eskandari et al. 2015

Babaei and Bayat 2012

 Phosphatidylethanolamine, phosphatidylserine

CD300a

X

  

Human cord blood-derived MCs, human lung MCs, murine BMMC

 

Bachelet et al. 2005

Simhadri et al. 2012

 Prostaglandin D2 receptor antagonists

CRTH2

  

X

  

Harvima et al. 2014R

 Proteases inhibitors

Tryptase, chymase, cathepsins, carboxypeptidase

  

X

Human and murine MCs

Mice

Caughey 2016R

Harvima et al. 2014R

 Rapamycin

mTOR pathway inhibitor

X

  

HMC-1

 

Chan et al. 2013

 RNAi

RNA interference against KIT RNA

X

  

HMC-1

 

Ruano et al. 2010

 Rosiglitazone, pioglitazone

PPARγ

 

X

 

Murine BMMC

 

Tachibana et al. 2008

 Siramesine

Sigma-2 receptor agonist

X

  

Human and murine MCs

 

Spirkoski et al. 2012

 Sitagliptin

Dipeptidylpeptidase-4 inhibitor

 

X

 

Rat peritoneal MCs

 

Nader 2011 1845

 Somatostatin

Somatostatin receptors

  

X

 

Wistar rats

Tang et al. 2005

 Syk kinase inhibitors

Syk kinase

 

X

 

Human, murine, and rat MCs; RBL-2H3

 

Matsubara et al. 2006

Finn and Walsh 2013

 Tandutinib (MLN518)

KIT, STAT3

X

  

HMC-1, P815 MCs

 

Corbin et al. 2004

 Tetracyclines

Multiple

X

 

X

Rat serosal MCs, HMC-1

Human

Sandler et al. 2005

Joks and Durkin 2011R

 α-Tocopherol

Multiple

X

  

HMC-1

 

Kempna et al. 2004

Ruano et al. 2010

 Tranilast

Yet to be defined

 

X

(X)

Rat peritoneal MC

Rats; rabbits

Adachi et al. 1999

Cooper et al. 2007

Baba et al. 2016

 Whi-P131 {4-[(6,7-dimethoxyquinazolin-4-yl)amino]phenol}

JAK3/STAT pathway inhibitor

X

  

HMC-1

 

Chan et al. 2013

Bibi et al. 2014R

R review article (further references therein), MC mast cell, BMMC bone marrow-derived mast cells

General considerations on drug treatment of MCAD

Although no biomarkers of symptomaticity or therapeutic response are yet validated, the tolerability and efficacy of most therapies tried in MCAD (starting, and escalating in dosage and composition, cautiously) become clinically evident within 1–2 months. Modest experiments with alternative dosages and/or dosing frequencies are not unreasonable. Therapies clearly shown clinically helpful should be continued; therapies not meeting this high bar should be halted to avoid the troublesome polypharmacy that can easily develop in such patients. With no predictors of response yet available, a cost-based approach to sequencing therapeutic trials in a given patient seems reasonable. It is not even clear yet that medications targeted at mediators found elevated in diagnostic testing (e.g., antihistamines in patients with elevated histamine, non-steroidal anti-inflammatory drugs in patients with elevated prostaglandins, leukotriene inhibitors in patients with elevated leukotrienes) are reliably effective, again perhaps unsurprising given the multitude of MC mediators and the complexity of the signaling networks dysregulated by the multiple mutations in MC regulatory elements present in most MCAD patients. Successful regimens appear highly personalized.

Multiple simultaneous (or nearly so) changes in the medication regimen are discouraged since such can confound identification of the specific therapy responsible for a given improvement (or deterioration). Ineffective or harmful agents should be stopped promptly. Prescribers should be aware that although rapid demonstration of intolerance of a new medication (or a new formulation of a previously well-tolerated medication) often suggests excipient reactivity as further discussed below, some active drug molecules themselves (e.g., cromolyn) sometimes cause an initial symptom flare which usually soon abates. Temporary waiver of gluten-, yeast-, and cow milk protein-containing foods during the initial 3–4 weeks of drug therapy can improve the response rate (Biesiekierski et al. 2011; Rodrigo et al. 2013; own unpublished experiences). When MCAD is suspected, therapies that strongly activate the immune system (e.g., vaccinations with live vaccines or autohemotherapy) must be given with caution (especially if similar therapies were previously already poorly tolerated), as such interventions sometimes dramatically worsen MCAD acutely and/or chronically.

Any drug can induce intolerance symptoms in the individual MCAD patient. In some MCAD patients, the disease creates such remarkable states of not only constitutive MC activation but also aberrant MC reactivity that such patients unfortunately experience a great propensity to react adversely to a wide variety of medication triggers. Those MCAD patients begin demonstrating (either acutely or subacutely) odd/unusual/weird/strange/bizarre/unexpected symptoms soon after beginning new medications. It is very important to note that such patients often demonstrate even a greater propensity to react to medication excipients (i.e., fillers, binders, dyes, preservatives) than to the active ingredients. When the patient tries one or more alternative formulations of a medication with the same active ingredient but sharing as few as possible (preferably none) of the excipients in the offending formulation, the patient may discover the medication to be at least tolerable and perhaps even quite effective. Furthermore, such a scenario obviously provides the patient (and physician and pharmacist) a great opportunity to identify one or more of the specific excipients which are triggering abnormal reactivity in the patient’s dysfunctional MCs, and it is those specific excipients—not the medication as a whole—that should be added to the patient’s allergy list and screened against all present medications being taken by the patient and against all future medications proposed for the patient. An MCAD patient’s physician would be wise to not assume, just because an excipient is very widely used in many medication products and appears innocuous and well tolerated in the vast majority of patients, that the same excipient will necessarily be tolerated well in MCAD patients (unpublished observation of the authors). Sometimes the specificity of the reaction is quite extraordinary. For example, patients who react to wood-based microcrystalline cellulose might tolerate cotton-based microcrystalline cellulose without any difficulty at all, or vice versa. In some cases, the pharmacist is unable to identify alternative commercially available formulations sharing few to none of the excipients in the offending formulation, and in those cases, a compounding pharmacist may need to be engaged to identify/develop a custom-compounded formulation the patient can tolerate. (There can be geographic and financial challenges in accessing compounding pharmacies, though.) Occasionally, MCAD patients may be so remarkably reactive to such a wide range of excipients that they can only tolerate a given medication when provided as pure drug salt, reconstituted in water (without preservatives). Intolerance symptoms can be mediated by IgE antibodies, though this scenario appears to be rare since the symptoms are usually not ameliorated by the anti-IgE monoclonal antibody omalizumab (unpublished observation, G.J. Molderings). Alternatively, they may be mediated by IgG antibodies, raising the question of whether gamma globulin (if itself tolerable) might be a helpful adjunct therapy in such patients (perhaps by directly targeting the MC surface’s IgG receptors or via indirect pathways). Recently, a MC-specific receptor termed MRGPRX2 has been identified which appears to be crucially involved in pseudo-allergic drug reactions (McNeil et al. 2015; Seifert 2015).

Drugs which should not be used in MCAD

Several drugs have the ability to trigger MC mediator release. A compilation of drugs known to be associated with a high risk of release of mediators from MCs is given in Table 12. However, there often are therapeutic alternatives to these drugs (Table 12).
Table 12

Compilation of drugs associated with a high risk of release of mediators from mast cells and their therapeutic alternatives (compiled from Mousli et al. 1994; Sido et al. 2014; Afrin et al. 2015b; McNeil et al. 2015)

Substance group

Drugs with proven or theoretical high risk of mast cell activation

Therapeutic alternatives

Intravenous narcotics

Methohexital

Phenobarbital

Thiopental

Propofol

Ketamine

Etomidate

Midazolam

Muscle relaxants

Atracurium

Mivacurium

Rocuronium

Cis-atracurium

Vecuronium

Antibiotics

Cefuroxim

Gyrase inhibitors

Vancomycin

Roxithromycin

Selective dopamine- and norepinephrine reuptake inhibitors

Bupropion

Amitriptyline, doxepine, clomipramine, maprotiline

Selective serotonin reuptake inhibitors

All

Anticonvulsive agents

Carbamazepine, topiramate

Clonazepam

Opioid analgesics

meperidine, morphine, codeine

remifentanil, alfentanil, fentanyl, oxycodon, piritramid

Peripheral-acting analgesics

Acidic non-steroidal anti-inflammatory drugs such as ASS or ibuprofen

Paracetamol, metamizol

Local anesthetics

Amide-type: lidocaine

articaine

Ester-type: tetracaine,

procaine

prefer amide-Type, e.g., bupivacaine

Peptidergic drugs

Icatibant, cetrorelix, sermorelin, octreotide, leuprolide

 

X-ray contrast medium

Iodinated contrast medium

Gadolinium chelate

Non-ionic contrast media: iohexol, iopamidol, iopromida, ioxilan, ioversol, idolatran, iodixanol

Plasma substitutes

Hydroxyethyl starch

Gelatine

Albumin solution, 0.9 %-NaCl solution, Ringer’s solution

Cardiovascular drugs

ACE inhibitors

ß-Adrenoceptor antagonists

Sartans, calcium channel antagonists, ivabradine, and much else

Conclusions and future perspectives

The therapeutic management of individuals with MCAD is complex and requires reviewing the entire spectrum of symptoms. The paucity of randomized, controlled studies makes treatment of refractory disease challenging and requires patience, persistence, and a methodical approach on the parts of both patient and managing provider(s). Delayed control of the symptoms may increase morbidity. Effective therapy often consists simply of antihistamines and MC-stabilizing compounds supplemented with medications targeted at specific symptoms and complications (Table 13). Current treatment options for refractory disease are based mainly on observational studies and case reports. Until larger randomized, controlled trials become available to give more guidance on therapy for refractory disease, clinicians should use the available data in conjunction with their clinical expertise and the adverse effect profile of the available drugs to make treatment decisions. More research is certainly needed to better understand MCAD pathobiology, in particular to determine which deregulated genes contribute to a specific symptom or symptom cluster. The greatest challenge in translational research for the discovery of new rational therapies requires a highly interactive interdisciplinary approach engaging basic science labs and clinicians. Understanding of the key components might hasten the progress of novel treatment for all these devastating MCAD phenotypes.
Table 13

Schematic summary of selected potential targets of pharmacological interventions in MCAD

Targets of drugs located in the plasma membrane

 

 Histamine H1 receptor

H1-antihistamines

 Histamine H2 receptor

H2-antihistamines

 CB1/CB2 cannabinoid receptors

Cannabinoids

 cysLTR1 leukotriene receptor

CysLTR1 antagonists, e.g., montelukast

 ß-Adrenoceptor

ß-Sympathomimetics

 EP2 receptor

EP2 receptor agonist, e.g., butaprost

 Chemokine receptors

Chemokines

 FcεRI

IgE antibody, e.g., omalizumab

 FcγRIII

IgG

 Siglec-8

Siglec-8 ligand

 CD300a

Phosphatidylethanolamine, phosphatidylserine

Targetting released mast cell mediators

 

 Tryptase

Tryptase inhibitor, e.g., nafamostat

 Chymase

Chymase inhibitor, e.g., BCEAB (4-[1-[bis-(4-methyl-pheny)-methyl]-3-(2-ethoxy-benzyl)-4-oxo-azetidine-2-yloxy]-benzoic acid)

 Cathepsin G

Cathepsin G inhibitor, e.g., RWJ355871 (β-ketophosphonate 1)

 TNFα

Infliximab, adalimumab

 IL-4

Pascolizumab

 IL-5

e.g., mepolizumab

 IL-6

e.g., sirukumab

 IL-17

e.g., secukinumab

Intracellular inhibition of mediator formation

 

 Histamine

Histidine decarboxylase inhibition, e.g., by vitamin C

 Leukotrienes

5-Lipoxygenase inhibitors, e.g., zileuton

 Prostaglandins

Cyclooxygenase inhibitors, e.g., acetylsalicylic acid, etoricoxib

Inhibition of cytosolic pathways

 

 Signaling pathways containing protein kinases

Inhibitors of protein kinases (see Table 8)

 mTOR pathway

e.g., rapamycin, everolimus

 Apoptotic pathways

Stimulation of apoptosis by, e.g., ABT-737, obatoclax

Intranuclear targets

 

 Histone deacetylase

Histone deacetylase inhibitors, e.g., vorinostat

 DNA methylation

Demethylating agents, e.g., 5-azacytidine, 5-aza-2′deoxycytidine

 DNA

Nucleoside analog cladribine

Notes

Acknowledgments

The publication of this article was financially supported by the Förderclub Mastzellforschung e.V.

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© The Author(s) 2016

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Authors and Affiliations

  • Gerhard J. Molderings
    • 1
  • Britta Haenisch
    • 2
  • Stefan Brettner
    • 3
  • Jürgen Homann
    • 4
  • Markus Menzen
    • 4
  • Franz Ludwig Dumoulin
    • 4
  • Jens Panse
    • 5
  • Joseph Butterfield
    • 6
  • Lawrence B. Afrin
    • 7
  1. 1.Institute of Human GeneticsUniversity Hospital of BonnBonnGermany
  2. 2.German Center for Neurodegenerative Diseases (DZNE)BonnGermany
  3. 3.Department of Oncology, Hematology and Palliative CareKreiskrankenhaus WaldbrölWaldbrölGermany
  4. 4.Allgemeine Innere Medizin, Gastroenterologie und DiabetologieGemeinschaftskrankenhausBonnGermany
  5. 5.Department of Hematology, Oncology and Stem Cell Transplantation, Medical FacultyRWTH Aachen UniversityAachenGermany
  6. 6.Program for the Study of Mast Cell and Eosinophil DisordersMayo ClinicRochesterUSA
  7. 7.Division of Hematology, Oncology, and TransplantationUniversity of MinnesotaMinneapolisUSA

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