Pharmacological treatment options for mast cell activation disease

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.

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., KIT D816V ) 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 H 1 -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 2015 a 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 2013 a 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. 2011b a 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 a It 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 H 1 -antihistamines (preferably of the second and third generations) Block mutual activation of mast cells via H 1 -histamine receptors; antagonize H 1 -histamine receptor-mediated symptoms X X Churc

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. 2011 R 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-LT 1 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 dis

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 2013 R Weng et al. 2012 Lee et al. 2015 Weng et al. 2015 Miltefosine Raft modulator X (X) Weller et al. 2009 Maurer et al. 2013 R 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 2007 R 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 EP 2 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 Koe

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