2014-15 Health Care Professionals SPECIAL EDITION THE SOCIETY CHRONICLES

What’s Inside... Mast Cell Disorders: Mastocytosis

Mast Cell Disorders ...... 01, 03-10 and Mast Cell Activation Syndromes By Valerie Slee, RN, BSN and Susan Jennings, PhD TMS Board of Directors...... 02

TMS Survey...... 10 Overview ICD-10 Progress Report...... 11 Mast cell disorders can cause Pediatric Fact Sheet...... 12, 13 tremendous suffering and disability

History of TMS...... 14 due to symptomatology from daily mast cell (MC) mediator release, Emergency Care Brochure...... 15, 16 and/or symptoms arising from Visual Guide to Skin Manifestations... 17-20 infiltration and accumulation of Systemic Mastocytosis Brochure...... 21, 22 mast cells in major organ systems. The two major forms of mast cell TMS Annual Conference Order Form...... 23 disorders are mastocytosis and mast Mast Cell photo provided Medical & Research Centers...... 24, 25 cell activation syndromes (MCAS), By Mariana Castells, MD, PhD Medical Advisory Board although it is important to note that Contact Information...... 26, 27 the process of mast cell activation can occur with both mastocytosis and with Printed Material Order Forms...... 28, 29 MCAS.1 Although systemic mastocytosis is a rare disease,2 those suffering Medical Resources...... 30, 31 with MCAS have recently been increasingly recognized and diagnosed. As a result, patients with MCAS appear to represent a growing proportion of the 2014 Supporting Members...... 32 mast cell disorder patient population.3, 4 Support Groups...... 33

Membership Application...... 34, 35 MASTOCYTOSIS Definition Mastocytosis has been defined in the literature as an abnormal accumulation of mast cells in one or more organ systems. Broadly separated into two categories – cutaneous mastocytosis (CM) and systemic mastocytosis (SM), the disease occurs in both children and adults. CM is considered a benign skin disease representing the majority of pediatric cases. In 67-80% of pediatric cases seen, resolution will occur before or during puberty.5, 6 In pediatric cases, symptoms of mast cell mediator release may occur systemically as a result of mast cell mediators released from skin lesions. This, however, does not necessarily indicate systemic disease. The incidence of systemic disease in children was previously unknown, but has now been proven to exist in some cases.5, 6 The majority of adult patients are diagnosed with systemic disease. Skin involvement, typically urticaria pigmentosa, is common in adult patients © 2014 The Mastocytosis Society, Inc. and can provide an important clue to accurate diagnosis.7 All rights reserved … Continued on page 3

RESEARCH + EDUCATION + ADVOCACY Special Edition Board of Directors Valerie M. Slee RN, BSN: Chair For Health Care Professionals Medical Advisory Board Liaison Patient Referral Coordinator The Mastocytosis Chronicles is distributed to the members of the [email protected] Mastocytosis Society, Inc. on a quarterly basis, in early February, Rita Barlow: Vice Chair May, August, and mid-to late November. Patient Support and Advocacy [email protected] This special edition of The Mastocytosis Chronicles has been Jim McKee: Treasurer published specifically for physicians and health care professionals. [email protected] This edtion contains diagnostic and treatment protocols for Celeste Thomason: Secretary mastocytosis and mast cell activation disorders, locations of mast [email protected] cell disorder treatment centers, physician contact information, Michele Kress: Director documentation of research articles, and other pertinent information. [email protected] For additional information visit www.tmsforacure.org. Mishele Cunningham, RN, BSN, PHN: Education and Medical Conference Chair Patient Referral Coordinator [email protected] The Mastocytosis Society, Inc. Mission Patricia Beggiato: Fundraising Chair The Mastocytosis Society, Inc. is a 501(c)3 nonprofit organization [email protected] dedicated to supporting patients affected by Mastocytosis or Mast Cell Activation Disorders, as well as their families, caregivers, and Committees physicians through research, education, and advocacy. Special Edition Chronicles Susan Jennings, PhD Valerie M. Slee, RN, BSN TMS Medical Advisory Board Mishele Cunningham RN, BSN, PHN John Gilligan, Design Lawrence B. Afrin, M.D. Norton J. Greenberger, M.D. Drug Shortage Cem Akin, M.D., Ph.D. Richard Horan, M.D. [email protected] Iván Alvarez-Twose, M.D. Nicholas Kounis, M.D., Ph.D. Valerie M. Slee, RN, BSN, Co-Chair Philip Askenase, M.D. Philip B. Miner Jr., M.D. Emily Menard, BA Co-Chair K. Frank Austen, M.D.* Larry Schwartz, M.D., Ph.D. Fundraising Joseph Butterfield, M.D. Peter Valent, M.D. [email protected] Mariana Castells, M.D., Ph.D. Theoharis Theoharides, M.D., Ph.D. Patricia Beggiato, Chair Luis Escribano, M.D., Ph.D. Srdan Verstovsek, M.D., Ph.D. Pediatrics Jason Gotlib, M.D., M.S. Catherine R Weiler, M.D., Ph.D. [email protected] Kelli Foster *Honorary Board Member Stacy Sheldon We thank each of these doctors for their time, caring, and expertise. Research [email protected] Susan Jennings, PhD, Co-Chair Nancy Russell, DrPH, Co-Chair

MPN Advocacy TMS is proud to be a Lay Organization member of The American [email protected] Academy of Allergy Asthma and Immunology (AAAAI) Jennifer Dratch, Chair Valerie M. Slee, RN, BSN, Board Liason Membership [email protected] Rita Barlow, Chair Sandra Frost Melanie Wardell

The Mastocytosis Society is a long-standing member of the National Organization for Rare Disorders (NORD) 2 | The Mastocytosis Chronicles Mast Cell Disorders …continued from page 1 Fact Sheet in this issue). It should be noted that the term “UP” encompasses a variety of clinical manifestations. Diagnosis and Classification In children, some of these varieties will fade away, some CM is diagnosed by the presence of typical skin lesions will develop into indolent systemic mastocytosis and and a positive skin biopsy demonstrating characteristic some will evolve into a newly described entity called clusters of mast cells. The preferred method of well-differentiated systemic mastocytosis.5 diagnosing SM is via bone marrow (BM) biopsy. The World Health Organization (WHO) has established SYSTEMIC MASTOCYTOSIS criteria for diagnosing SM, summarized8 as follows: Systemic mastocytosis consists of a group of rare, heterogeneous disorders involving growth and accumulation Majorª: Multifocal dense infiltrates of mast cells of abnormal mast cells in one or multiple extracutaneous (MCs) (>15 MCs in aggregate) in tryptase stained organ systems (Table 1). Standard technique can be used to biopsy sections of the bone marrow or other obtain an iliac crest bone marrow (BM) biopsy and aspirate extracutaneous organ. smear for diagnosis. Aspirated BM should be allocated for Minorª: flow cytometry to assess for the presence of mast cells • More than 25% of MCs in bone marrow or with aberrant phenotype (i.e., co-expression of CD25). other extracutaneous organ(s) show abnormal Immunohistochemistry for KIT, mast cell tryptase, and morphology (i.e. are atypical MC type 1 or are CD25 should be performed on sections of the biopsy.10-14 spindle–shaped MCs) in multifocal lesions in histologic examination TABLE 1. • KIT mutation at codon 816b in extracutaneous Major Variants of Systemic Mastocytosis15 organ(s) (in most cases bone marrow cells are ISM (Indolent systemic mastocytosis) examined) WHO criteria for SM met, MC burden low, +/- skin + • KIT MCs in bone marrow show aberrant lesions, no C findings, no evidence of AHNMD expression of CD2 and/or CD25 • Bone marrow mastocytosis: ISM with BM • Serum total tryptase > 20 ng/mL (does not count involvement, but no skin lesions in patients who have AHNMD-type disease.) • Smoldering SM: ISM, typically with skin lesions, with 2 or more B findings, but no C findings. Abbreviation Key: SM-AHNMD (SM with associated clonal hematologic KIT: KIT tyrosine kinase receptor non mast cell lineage disease)* MC(s): Mast cells AHNMD: associated (clonal) hematologic non-mast Meets criteria for SM and also criteria for an AHNMD cell lineage disease (MDS, MPN, MDS/MPN, AML), or other WHO- ª If at least one major criterion and one minor defined myeloid hematologic neoplasm, +/- skin criterion OR at least three minor criteria are lesions. fulfilled, the diagnosis of systemic mastocytosis ASM (Aggressive systemic mastocytosis) can be established. Meets criteria for SM with one or more C findings. b Activating mutations at codon 816, in most cases, No evidence of MCL, +/- skin lesions. KIT D816V. MCL (Mast cell ) Diagnostic techniques differentiate mastocytosis into Meets criteria for SM. BM biopsy shows a diffuse the following categories: infiltration, usually compact, by atypical, immature MCs. BM aspirate smears show 20% or more MCs. CUTANEOUS MASTOCYTOSIS This category includes maculopapular cutaneous Typical MCL: MCs comprise 10% or more of peripheral mastocytosis/urticaria pigmentosa (UP), telangiectasia blood white cells. Aleukemic MCL: < 10% of peripheral macularis eruptiva perstans (TMEP), diffuse cutaneous blood white cells are MCs. Usually without skin lesions. mastocytosis (DCM), and solitary .9 Most cases of pediatric mastocytosis fall into one of these * A lymphoproliferative disorder or plasma cell dyscrasia may rarely be diagnosed with SM. categories and may or may not include symptoms of BM: bone marrow systemic mast cell activation as a result of mediators released from the skin (see Pediatric Mast Cell Disorders … Continued on page 4 Special Edition 2014 | 3 18 Mast Cell Disorders …continued from page 3 an increased incidence of anaphylaxis. In SSM, two or more B findings (Table 2) are found and there is a TABLE 2. greater possibility that the disease will progress to a B and C Findings15 more aggressive variant. B Findings BM biopsy showing > 30% infiltration by MCs Well differentiated SM (WDSM), first described in 19 (focal, dense aggregates) and serum total tryptase 2004 , is reported in the literature as a form of level > 200 ng/mL systemic mastocytosis that fulfills the major criterion for SM and continues to be studied by researchers.5, 6 Myeloproliferation or signs of dysplasia in non– A relatively frequent form of mastocytosis in children, MC lineage(s), no prominent cytopenias; criteria it usually has a pediatric onset, nodular or plaque skin for AHNMD not met lesions, possibly extensive, severe mast cell symptoms Hepatomegaly and/or splenomegaly on palpation and goes into adulthood in a low percentage of cases. without impairment of organ function and/or The mast cells do not have the CD25 marker that is lymphadenopathy on palpation/imaging (> 2 cm) part of the minor WHO criterion for SM and roughly C Findings* 90% of WDSM patients don’t have the c-kit D816V Cytopenia(s): ANC < 1 x 109/L, Hb < 10 g/dL, or marker or other exon 17 c-kit mutations. Bone marrow platelets < 100 x 109/L analysis identifies mast cells in WDSM patients as Hepatomegaly on palpation with impairment of notably large, round, mature-appearing mast cells with liver function, ascites, and/or portal hypertension the absence of the spindle-shaped mast cells typically 5 Skeletal lesions: osteolyses and/or pathologic fractures seen in SM. Baseline serum tryptase levels in these Palpable splenomegaly with hypersplenism patients are usually lower than what is frequently detected in SM, except in a variable percentage of Malabsorption with weight loss from gastrointestinal children at onset. Imatinib mesylate has been used tract MC infiltrates in some patients with severe cases of WDSM, since * Must be attributable to the MC infiltrate. these patients do not usually carry the c-kit D816V mutation, which causes resistance to imatinib.20 Indolent Systemic Mastocytosis The majority of adult patients fit into this category, Systemic Mastocytosis with Associated Clonal fulfilling the criteria for indolent systemic mastocytosis Hematologic Non-Mast Cell Lineage Disease (AHNMD) 9, 11, 16, 17 (ISM). The bone marrow, gastrointestinal These patients fit the criteria for SM and they fit the tract, skeletal system, nervous system and skin may WHO criteria for (MDS), be affected. Some patients may have enlarged livers myeloproliferative neoplasm (MPN), MDS/MPN, or and spleens and lymphadenopathy. Mediator-related acute (AML), with or without skin symptoms are common, but the grade of bone marrow lesions.15, 21, 22 infiltration is low (usually less than 5 percent) with the bone marrow fulfilling the criteria for SM and 80-90% of Aggressive Systemic Mastocytosis the patients exhibiting a positive D816V KIT mutation. In this rare variant, aggressive systemic mastocytosis In most patients the serum tryptase concentration (ASM) patients fit the criteria for SM, and their bone exceeds 20 ng/mL, but a normal level of tryptase marrow biopsy reveals abnormal blood cell formation does not rule out either mastocytosis or another mast that does not fit WHO criteria for an AHNMD, as listed cell activation disorder. Treatment usually includes above,15 with or without skin lesions. mediator-targeting drugs, including antihistamines, but does not usually require cytoreductive agents, although there are exceptions. In this rare variant, mast cell leukemia (MCL) patients fit the criteria for SM, and a bone marrow aspirate Isolated bone marrow mastocytosis (BMM) and smear shows that 20% or more of the cells are mast smoldering systemic mastocytosis (SSM) are variants cells, or 10% or more mast cells are seen in circulating 17 of indolent SM . BMM is characterized by the absence blood.15, 23 The mast cells have malignant features. of skin lesions, lack of multiorgan involvement, and Prognosis is poor, although life expectancy has been

4 | The Mastocytosis Chronicles extended, in some cases, beyond 2 months, due to of mediators, such as tryptase, histamine, heparin, advances in cytoreductive therapy. leukotrienes and prostaglandins.28 Triggers of mediator release may include: heat; cold; temperature change; foods; medications; alcohol; friction; environmental, Mast cell sarcoma is a rare tumor and prognosis is emotional, or physical stress; perfumes/odors; viral/ generally very poor. Pathological examination of the bacterial/fungal infections; venoms; and fatigue. Some tumor has shown it to be highly malignant with an patients may experience reactions to medications aggressive growth pattern.24, 25 Patients with this tumor including, but not limited to: opiates, antibiotics and do not fulfill the criteria for SM. The imatinib mesylate- NSAIDs. Use with caution. Mast cell activation can resistant KIT D816V mutation has not been found in occur along with, or independent of, any form of reported mast cell sarcomas, such that use of imatinib mastocytosis. has been attempted in some patients.25 Mast Cell Mediator Symptoms Diagnostic Workup for Aggressive Variants or The myriad symptoms patients experience during Associated Hematological Disorder10, 15, 26 mast cell activation/degranulation can wreak havoc on When aggressive disease or an associated hematological patients on a daily basis, and multiple organ systems, disorder is suspected, further evaluation of the patient including pulmonary, cardiovascular, dermatologic, may include: gastrointestinal, musculoskeletal, and neurologic can be involved.3, 4, 28-32 Symptoms may include, but are 1. Comprehensive bloodwork; not limited to: flushing of the face, neck, and chest; headache; tachycardia and chest pain; abdominal pain, 2. X-ray or CT scan of the chest, looking for evidence bloating, GERD, diarrhea, vomiting; uterine cramps or of significantly enlarged lymph nodes (greater than 2 bleeding; rashes, including UP, TMEP; bone/muscle cm in diameter); pain, osteosclerosis, osteopenia, osteoporosis; itching, +/- rash; blood pressure instability; brain fog, cognitive 3. X-ray or nuclear medicine bone scan of the skeletal dysfunction; anxiety/depression; lightheadedness, system, looking for osteoporosis, osteosclerosis, or syncope; and anaphylaxis. These symptoms may areas where calcium has been completely lost from appear as acute (as in anaphylaxis) or as chronic bone; conditions. It should be noted that the manifestation of anaphylaxis or similar symptoms among infants and 4. CT scan or ultrasound of the abdomen, looking for preschoolers may be more difficult to identify. enlarged liver or spleen, enlarged lymph nodes, or the collection of fluid; Treatment of Mediator Release Symptoms Treatment of mastocytosis depends on the symptoms 5. Endoscopy/colonoscopy and biopsy of the and the classification of disease.6, 9, 33 Symptoms gastrointestinal tract, looking for evidence of mast of mediator release are treated with H1 and H2 cell infiltration, ulcers, or areas of bleeding. Mast cell antihistamines, mast cell stabilizers, leukotriene infiltration can be identified by aggregates of 15 or inhibitors, and possibly aspirin (under direct supervision more abnormal mast cells, or sheets of mast cells. of a physician). All mast cell disease patients should Abnormal mast cells can be identified by the presence carry two doses of injectable epinephrine unless of CD25 on these cells.27 Other tests may be done, as otherwise contraindicated (Glucagon may need to be indicated, if there is a suspected hematologic disorder administered for patients on beta-blockers). Patients or to evaluate the individual patient’s symptoms. By should also be instructed on how to self-administer contrast, further testing should be kept to a minimum epinephrine while in a recumbent position, to maximize when the disease seems to be confined to the skin, and rapid absorption of the drug. in most pediatric cases. Perioperative Management Mast Cell Activation and Triggers While the incidence of hypersensitivity to anesthesia Mast cells can be activated through both IgE and and surgical procedures in patients with mast cell non-IgE-related mechanisms, resulting in the release … Continued on page 6

Special Edition 2014 | 5 Mast Cell Disorders …continued from page 5 Grade IV: Cardiac arrest disorders is unknown, various non-specific triggers Specific management of a mast cell degranulation in the perioperative setting may cause mast cell event in patients with mast cell disorders includes degranulation, and thus immediate hypersensitivity. stopping any suspicious drug being administered, Therefore, the goal of all perioperative management discontinuation of anesthetic agents likely to cause is prevention of mast cell mediator release. This can vasodilation and negative muscular contractility, if be accomplished by careful history taking, excellent possible, and early administration of epinephrine for communication between the anesthesia and surgical Grade III and Grade IV reactions along with 100% staff, avoidance of all known and potential triggers of oxygen and large volume fluid support. mediator release, and careful attention to management of perioperative mast cell degranulation and/or With these measures, patients with mast cell disorders cardiovascular changes.34 Although perioperative can be prepared for surgery with a plan that includes complications due to mast cell mediator release preventing mast cell degranulation by identification of in children with mastocytosis are rare, they are not possible triggers, rapid recognition of degranulation unknown.6 Measures to prevent triggering mast cell when it does occur and immediate appropriate degranulation in adults and children should be utilized intervention. whenever possible. Advanced Disease Considerations Prevention also includes perioperative antianxiety and Treatment medications to avoid precipitating mast cell Advanced disease symptoms may include: anemia, degranulation; maintenance of a steady environmental thrombocytopenia, ascites, bone fractures, temperature throughout the entire surgical experience; gastrointestinal abnormalities, and enlargement of minimizing friction and mechanical trauma (i.e. tape, the liver, spleen, and lymph nodes, which ultimately tourniquet use, etc.) near mastocytosis skin lesions; can lead to organ failure and early death. Therapies careful positioning of the patient, being mindful of of limited effectiveness exist for advanced SM, but possible osteoporosis or osteolysis; avoiding histamine promising new treatments are being developed. releasing drugs such as atracruium and mivacurium; Prominent among these are tyrosine kinase inhibitors aggressive treatment of pain, which is a potent mast (TKIs) targeting the KIT kinase36, 37a (e.g., midostaurin36). cell degranulator, including forms of opioids which are Imatinib is approved therapy for adult ASM patients known to be acceptable (i.e. fentanyl); use of H1 and lacking the KIT D816V mutation or if mutation status H2 receptor antagonists to maintain mast cell stability is unknown. Standard therapies for ASM are interferon until surgery.34 and the chemotherapeutic agent cladribine, employed with antimediator therapy, to reduce disease burden Ring and Messmer have developed a grading scale34, 35 and control symptoms. In patients with SM-AHNMD, to describe clinical severity of perioperative immediate therapy selection usually depends on the associated hypersensitivity in mastocytosis: disease, which is commonly more aggressive than the SM part. MCL requires a polychemotherapy approach. Usually Non-Life Threatening Grade I: Mucocutaneous signs and symptoms only Prognosis All patients with mastocytosis are at increased risk Grade II: Mild mucocutaneous signs, features which for anaphylaxis and potentially a poor outcome. The may be associated with cardiovascular and respiratory prognosis of mastocytosis depends on the specific changes. classification of disease.17 The prognosis for cutaneous mastocytosis and indolent mastocytosis is good. Most Life-Threatening patients with SM have ISM. ISM patients have preserved Grade III: Cardiovascular collapse which may be organ function and their survival is comparable to that associated with mucocutaneous and/or gastrointestinal of the general population. Patients with smoldering signs, and/or bronchospasm. SM may have an increased risk of developing disease

6 | The Mastocytosis Chronicles transformation to aggressive forms of SM. Survival The second required co-criterion for systemic mast of patients with more advanced SM is significantly cell activation depends on documentation that mast shorter than that of the overall population and is cells are directly involved in the symptomatology. affected by disease subtype, with median survival of An increase in the serum level of tryptase, above 41 months for patients with ASM, 24 months for SM- baseline and within a narrow (generally accepted as AHNMD, and 2 months for MCL.26 Patients with ASM one to two hour) window of time after a symptomatic suffer debilitating symptoms and have signs of organ episode, is proposed as the preferred method for dysfunction (C-findings; Table 2). In patients with providing evidence of mast cell involvement according SM-AHNMD, prognosis can differ depending on the to these criteria.1, 48, 49 The consensus article provides particular myeloproliferative neoplasm.37b a method for calculating the required minimum rise in serum tryptase.1 Consensus members also agreed MAST CELL ACTIVATION SYNDROMES that when serum tryptase evaluation is not available Definition or when the tryptase level does not rise sufficiently to Existence of a subset of mast cell disorder patients meet the required increase for the co-criterion, other who experience episodes of mast cell activation mediator tests could suffice. A rise in urinary n-methyl without detectable evidence of a proliferative mast cell histamine, prostaglandin-D2, or its metabolite, 38, 39 11 -prostaglandin-F (24-hour urine test for any of the disorder was postulated over 20 years ago. Over β 2α the last two decades, with development of improved three), is considered an alternative for the co-criterion methodology for identification of abnormal mast related to a requirement for a mast cell mediator level 1 cells,40-43 it became apparent that there were patients rise during a systemic mast cell activation event. who exhibited symptoms of mast cell mediator release who did not fulfill the criteria for SM.44, 45 Thus began Finally, the third co-criterion requires a response (based 10 the evolution of discussions about other forms of on response criteria ) to medications that inhibit the 1 mast cell disorders, both clonal and nonclonal, which action of histamine. In addition, a “complete or became known as Mast Cell Activation Syndromes major” response to drugs that inhibit other mediators (MCAS).46, 47 produced by mast cells or block mast cell mediator release can be regarded as fulfillment of the third co- Diagnosis and Proposed Classification criterion for MCAS. Recognition by specialist physicians of the importance of mast cell activation in disease led to an international PRIMARY MCAS Mast Cell Disorders Working Conference emphasizing Primary MCAS results from a clonal population this topic in September of 2010. Consensus of mast cells and may be due to mastocytosis or statements were published regarding classification of monoclonal Mast Cell Activation Syndrome (MMAS). and diagnostic criteria for mast cell disorders,1 where Primary MCAS with mastocytosis can be diagnosed if mast cell activation plays a prominent role. the patient has symptoms of mast cell activation and fulfills the WHO criteria for mastocytosis. MMAS is a 50 As previously stated, mediators produced by mast cells new, distinct disease characterized by the presence have a considerable effect on specific symptomatology. of abnormal mast cells and fulfillment of criteria for Symptoms, including, but not limited to flushing, mast cell activation, but where sufficient criteria for a 1, 3, 10, 32, 44, pruritis, urticaria, headache, gastrointestinal symptoms diagnosis of mastocytosis are not identified. 45, 50-52 (including diarrhea, nausea, vomiting, abdominal pain, bloating, gastroesophageal reflux), and hypotension, allow a patient to meet the first of three required SECONDARY MCAS 1, 3, 32, 53 co-criterion for systemic mast cell activation when Secondary MCAS is diagnosed when mast cell the patient exhibits symptoms involving two or more activation occurs as an indirect result of another disease organ systems in parallel, which are “recurrent or or condition. Physician awareness of the presence permanent, cannot be explained by other known of secondary MCAS will allow for more appropriate disorders/conditions (other than mast cell activation), mast cell activation-targeted treatments, in addition to and require a therapeutic intervention.”1 primary disease-related medications, to be provided. In … Continued on page 8

Special Edition 2014 | 7 Mast Cell Disorders …continued from page 7 Cardet et al. suggest that, despite lack of proof of elevated mast cell mediators, a response to mast cell addition to the widespread example of atopy as a cause or mast cell mediator blockers should be determined in of secondary MCAS, other diseases that can cause such patients.54 If a patient responds well to treatment, secondary MCAS have been reviewed in the literature.1, a diagnosis of idiopathic MCAS remains open for 3, 53 consideration, as long as other diagnoses continue to be considered. IDIOPATHIC MCAS Idiopathic MCAS is proposed as a final diagnosis Dr. Afrin notes that even the co-criterion requiring a after proposed mast cell activation criteria have been response to mast cell targeted therapy can be lacking fulfilled and a thorough evaluation has excluded the in some patients. In his experience with more than 300 possibility of another known underlying cause for this MCAS patients, diagnostics are not always useful for activation.1, 54 Idiopathic MCAS is therefore nonclonal, guiding specific choices for anti-mediator therapy, such with regard to current diagnostic capabilities related that multiple mast cell (or mast cell mediator) blocking to mast cell analyses, and has been presented and therapies must be tried before successful symptom discussed in the literature by a variety of mast cell resolution is attained.4 Also, in recent work by Picard et disorder specialists.1, 3, 32, 50, 53-55 Review of other al., it is reported that only one third of MCAS patients causes of MCAS to aid physicians in evaluation for the experience a complete resolution with treatment; one exclusionary diagnosis of idiopathic MCAS have also third have a major response and another third have a been provided.1, 3, 50 minor response, and a combination of drugs is usually required to achieve control of symptoms.50 Triggers, Symptoms, Perioperative Management and Treatment of MCAS Prognosis MCAS, in all of its forms, can cause tremendous All patients with MCAS are at increased risk for suffering and disability due to symptomatology from anaphylaxis and a potentially poor outcome. Prognosis daily mast cell mediator release. The triggers, symptoms will likely depend on the type of MCAS. As MMAS is and treatment of MCAS are similar to those listed a newly described entity, no long-term prognostic data above for mastocytosis symptoms related to mast cell are available. The long-term prognosis for patients with activation and mediator release.50, 54, 56 Perioperative idiopathic MCAS is similarly unknown. For secondary management, as listed above for mastocytosis, should MCAS, the prognosis likely depends on the primary also be a consideration. condition causing the MCAS.

Additional Considerations for MCAS CONCLUSIONS It is recognized by researchers that current diagnostic Recognition of mast cell disorders can be difficult methods for capturing a rise in mast cell mediators due to the many possible presentations, often leading after a symptomatic episode are not ideal.54, 57, 58 Some to deferment of proper diagnosis and treatment.4, 26, patients who present with typical and recurrent signs 50, 55, 59 In addition, due to the broad range of signs and symptoms of mast cell activation do not present and symptoms, patients with mast cell disorders may with elevated levels of mediators for which we are be misdiagnosed.1, 4, 11 Awareness of the existence of currently able to test. Non-specialist physicians may mastocytosis and mast cell activation syndromes can most commonly use serum tryptase levels to exclude help physicians recognize potential mast cell disorder a mast cell disorder. However, some MCAS specialists patients for further evaluation,50 provide for more have indicated that tryptase rises are not seen as often accurate diagnoses and would allow for more rapid and in patients with certain forms of MCAS, and that other effective treatment allocation. changes in bloodwork and urine tests can sometimes be more reliable.55, 57 Additionally, there is a very narrow window of time (1-2 hours after symptoms begin) during which to obtain a serum tryptase test to indicate mast cell activation,1 such that obtaining laboratory evidence of the event can prove difficult in many circumstances.

8 | The Mastocytosis Chronicles References 24. Georgin-Lavialle S, Aguilar C, Guieze R, Lhermitte L, Bruneau J, Fraitag S, 1. Valent P, Akin C, Arock M, Brockow K, Butterfield JH, Carter MC, et al. Defi- et al. Mast cell sarcoma: a rare and aggressive entity--report of two cases and nitions, criteria and global classification of mast cell disorders with special review of the literature. J Clin Oncol. 2013 Feb 20;31(6):e90-7. reference to mast cell activation syndromes: a consensus proposal. Int Arch 25. Ryan RJ, Akin C, Castells M, Wills M, Selig MK, Nielsen GP, et al. Mast Allergy Immunol. 2012;157(3):215-25. cell sarcoma: a rare and potentially under-recognized diagnostic entity with 2. Horny HP, Sotlar K, Valent P, Hartmann K. Mastocytosis: a disease of specific therapeutic implications. Mod Pathol. 2013 Apr;26(4):533-43. the hematopoietic stem cell. Deutsches Arzteblatt international. 2008 26. Lim KH, Tefferi A, Lasho TL, Finke C, Patnaik M, Butterfield JH, et al. 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Immunol Allergy 32. Akin C, Metcalfe DD. Mastocytosis and mast cell activation syndromes pre- Clin North Am. 2014 Feb;34(1):181-96. senting as anaphylaxis. In: Castells MC, editor. Anaphylaxis and hypersensi- 10. Valent P, Akin C, Escribano L, Fodinger M, Hartmann K, Brockow K, et tivity reactions. New York: Humana Press; 2011. p. 245-56. al. Standards and standardization in mastocytosis: consensus statements on 33. Cardet JC, Akin C, Lee MJ. Mastocytosis: update on pharmacotherapy and diagnostics, treatment recommendations and response criteria. Eur J Clin future directions. Expert Opin Pharmacother. 2013 Oct;14(15):2033-45. Invest. 2007 Jun;37(6):435-53. 34. Dewachter P, Castells MC, Hepner DL, Mouton-Faivre C. Perioperative 11. Alvarez-Twose I, Morgado JM, Sanchez-Munoz L, Garcia-Montero A, Management of Patients with Mastocytosis. Anesthesiology. 2013 Oct 16. Mollejo M, Orfao A, et al. Current state of biology and diagnosis of clonal 35. Dewachter P, Mouton-Faivre C, Cazalaa JB, Carli P, Lortholary O, Her- mast cell diseases in adults. Int J Lab Hematol. 2012 Oct;34(5):445-60. mine O. [Mastocytosis and anaesthesia]. Ann Fr Anesth Reanim. 2009 12. Horny HP, Sotlar K, Valent P. Mastocytosis: state of the art. Pathobiology. Jan;28(1):61-73. 2007;74(2):121-32. 36. Verstovsek S. Advanced systemic mastocytosis: the impact of KIT mutations 13. Horny HP, Valent P. Diagnosis of mastocytosis: general histopathological in diagnosis, treatment, and progression. Eur J Haematol. 2013 Feb;90(2):89- aspects, morphological criteria, and immunohistochemical findings. Leuk 98. Res. [Review]. 2001 Jul;25(7):543-51. 37a. Ustun C, DeRemer DL, Akin C. Tyrosine kinase inhibitors in the treatment 14. Escribano L, Garcia Montero AC, Nunez R, Orfao A. Flow cytometric of systemic mastocytosis. Leuk Res. 2011 Sep;35(9):1143-52. analysis of normal and neoplastic mast cells: role in diagnosis and follow-up 37b. Pardanani A, Lim KH, Lasho TL, Finke C, McClure RF, Li CY, et al. of mast cell disease. Immunol Allerg y Clin North Am. 2006 Aug;26(3):535- Prognostically relevant breakdown of 123 patients with systemic mas- 47. tocytosis associated with other myeloid malignancies. Blood. 2009 Oct 15. Gotlib J, Pardanani A, Akin C, Reiter A, George T, Hermine O, et al. 29;114(18):3769-72. International Working Group-Myeloproliferative Neoplasms Research and 38. Roberts LJ, 2nd, Oates JA. Biochemical diagnosis of systemic mast cell Treatment (IWG-MRT) & European Competence Network on Mastocytosis disorders. J Invest Dermatol. 1991 Mar;96(3):19S-24S; discussion S-5S. (ECNM) consensus response criteria in advanced systemic mastocytosis. Blood. 2013 Mar 28;121(13):2393-401. 39. Metcalfe DD. Classification and diagnosis of mastocytosis: current status. J Invest Dermatol. 1991 Mar;96(3):2S-4S. 16. Valent P. Mastocytosis: a paradigmatic example of a rare disease with com- plex biology and pathology. Am J Cancer Res. 2013;3(2):159-72. 40. Nagata H, Worobec AS, Oh CK, Chowdhury BA, Tannenbaum S, Suzuki Y, et al. Identification of a point mutation in the catalytic domain of the proto- 17. Pardanani A. Systemic mastocytosis in adults: 2013 update on diagnosis, risk oncogene c-kit in peripheral blood mononuclear cells of patients who have stratification, and management. Am J Hematol. 2013 May 30. mastocytosis with an associated hematologic disorder. Proc Natl Acad Sci U 18. Zanotti R, Bonadonna P, Bonifacio M, Artuso A, Schena D, Rossini M, et al. S A. 1995 Nov 7;92(23):10560-4. Isolated bone marrow mastocytosis: an underestimated subvariant of indolent 41. Longley BJ, Tyrrell L, Lu SZ, Ma YS, Langley K, Ding TG, et al. Somatic c- systemic mastocytosis. Haematologica. 2011 Mar;96(3):482-4. KIT activating mutation in urticaria pigmentosa and aggressive mastocytosis: 19. Akin C, Fumo G, Yavuz AS, Lipsky PE, Neckers L, Metcalfe DD. A novel establishment of clonality in a human mast cell neoplasm. Nat Genet. 1996 form of mastocytosis associated with a transmembrane c-kit mutation and Mar;12(3):312-4. response to imatinib. Blood. 2004 Apr 15;103(8):3222-5. 42. Escribano L, Orfao A, Diaz-Agustin B, Villarrubia J, Cervero C, Lopez A, et 20. Alvarez-Twose I, Gonzalez P, Morgado JM, Jara-Acevedo M, Sanchez-Mu- al. Indolent systemic mast cell disease in adults: immunophenotypic charac- noz L, Matito A, et al. Complete response after imatinib mesylate therapy in terization of bone marrow mast cells and its diagnostic implications. Blood. a patient with well-differentiated systemic mastocytosis. J Clin Oncol. 2012 1998 Apr 15;91(8):2731-6. Apr 20;30(12):e126-9. 43. Horny HP. Mastocytosis: an unusual clonal disorder of bone marrow-derived 21. Stoecker MM, Wang E. Systemic mastocytosis with associated clonal hema- hematopoietic progenitor cells. Am J Clin Pathol. 2009 Sep;132(3):438-47. tologic nonmast cell lineage disease: a clinicopathologic review. Arch Pathol 44. Sonneck K, Florian S, Mullauer L, Wimazal F, Fodinger M, Sperr WR, et al. Lab Med. 2012 Jul;136(7):832-8. Diagnostic and subdiagnostic accumulation of mast cells in the bone marrow 22. Wang SA, Hutchinson L, Tang G, Chen SS, Miron PM, Huh YO, et al. of patients with anaphylaxis: monoclonal mast cell activation syndrome. Int Systemic mastocytosis with associated clonal hematological non-mast Arch Allergy Immunol. 2007;142(2):158-64. cell lineage disease: clinical significance and comparison of chomosomal abnormalities in SM and AHNMD components. Am J Hematol. 2013 Mar;88(3):219-24. … Continued on page 10 23. Georgin-Lavialle S, Lhermitte L, Dubreuil P, Chandesris MO, Hermine O, Damaj G. Mast cell leukemia. Blood. 2013 Feb 21;121(8):1285-95. Special Edition 2014 | 9 52. Alvarez-Twose I, Gonzalez de Olano D, Sanchez-Munoz L, Matito A, Mast Cell Disorders …continued from page 7 Esteban-Lopez MI, Vega A, et al. Clinical, biological, and molecular char- acteristics of clonal mast cell disorders presenting with systemic mast cell 45. Akin C, Scott LM, Kocabas CN, Kushnir-Sukhov N, Brittain E, Noel P, et activation symptoms. J Allergy Clin Immunol. 2010 Jun;125(6):1269-78 e2. al. Demonstration of an aberrant mast-cell population with clonal mark- 53. Valent P, Horny HP, Triggiani M, Arock M. Clinical and laboratory param- ers in a subset of patients with “idiopathic” anaphylaxis. Blood. 2007 Oct eters of mast cell activation as basis for the formulation of diagnostic criteria. 1;110(7):2331-3. Int Arch Allergy Immunol. 2011;156(2):119-27. 46. Horny HP, Sotlar K, Valent P. Evaluation of mast cell activation syndromes: 54. Cardet JC, Castells MC, Hamilton MJ. Immunology and clinical manifesta- impact of pathology and immunohistology. Int Arch Allergy Immunol. tions of non-clonal mast cell activation syndrome. Curr Allergy Asthma Rep. 2012;159(1):1-5. 2013 Feb;13(1):10-8. 47. Valent P. Mast cell activation syndromes: definition and classification. Al- 55. Hamilton MJ, Hornick JL, Akin C, Castells MC, Greenberger NJ. Mast cell lergy. 2013 Apr;68(4):417-24. activation syndrome: a newly recognized disorder with systemic clinical 48. Schwartz LB, Sakai K, Bradford TR, Ren S, Zweiman B, Worobec AS, et al. manifestations. J Allergy Clin Immunol. 2011 Jul;128(1):147-52 e2. The alpha form of human tryptase is the predominant type present in blood at 56. Lee MJ, Akin C. Mast cell activation syndromes. Ann Allergy Asthma Im- baseline in normal subjects and is elevated in those with systemic mastocyto- munol. 2013 Jul;111(1):5-8. sis. J Clin Invest. 1995 Dec;96(6):2702-10. 57. Molderings GJ, Brettner S, Homann J, Afrin LB. Mast cell activation dis- 49. Schwartz LB, Irani AM. Serum tryptase and the laboratory diagnosis of sys- ease: a concise practical guide for diagnostic workup and therapeutic options. temic mastocytosis. Hematol Oncol Clin North Am. 2000 Jun;14(3):641-57. J Hematol Oncol. 2011;4:10. 50. Picard M, Giavina-Bianchi P, Mezzano V, Castells M. Expanding spectrum 58. Afrin LB. Polycythemia from mast cell activation syndrome: lessons learned. of mast cell activation disorders: monoclonal and idiopathic mast cell activa- Am J Med Sci. 2011 Jul;342(1):44-9. tion syndromes. Clin Ther. 2013 May;35(5):548-62. 59. Jennings S, Russell N, Jennings B, Slee V, Sterling L, Castells M, et al. The 51. Bonadonna P, Perbellini O, Passalacqua G, Caruso B, Colarossi S, Dal Fior Mastocytosis Society Survey on Mast Cell Disorders: Patient Experiences D, et al. Clonal mast cell disorders in patients with systemic reactions to Hy- and Perceptions. J Allergy Clin Immunol Pract. 2014;2(1):70-6. menoptera stings and increased serum tryptase levels. The Journal of allergy and clinical immunology. 2009 Mar;123(3):680-6.

The Mastocytosis Society Survey on Mast Cell Disorders: Patient Experiences and Perceptions

Susan Jennings, PhD, Nancy Russell, Brigham and Women’s Hospital through the TMS website between Dr PH, Blair Jennings, BS, Valerie Slee, contacted TMS about a unique April 15 and May 24, 2010. RN, BSN, Lisa Sterling, BS, Mariana opportunity for patients to provide Castells, MD, PhD, Peter Valent, MD input into the establishment and/ Information collected included and Cem Akin, MD, PhD or revision of the diagnostic criteria survey respondents’ demographics, J Allergy Clin Immunol Pract. 2014;2(1):70-6. for mastocytosis and the disorders diagnoses, symptoms, medications, of mast cell activation. He asked comorbid conditions, clinical and The Mastocytosis Society, Inc. (TMS) TMS to create a survey, based laboratory tests, allergies, triggers is happy to announce publication of on a series of questions originally of mast cell symptoms, dietary the first set of results from the 2010 provided by Dr. Peter Valent of concerns, occurrence of mast cell Mast Cell Disorder Patient Survey the Medical University of Vienna. disease in their families, its impact in the Journal of Allergy and Clinical Patients in Europe were invited to on their lives and their perceptions Immunology: In Practice. The article do a similar survey based on the of mast cell related care in the and its online repository (containing same questions. United States. additional data and the original survey questionnaire) are available free A web-based survey was designed The TMS Patient Survey provides an to the public through the journal’s and implemented by TMS. Patients example of patients and specialists website (www.jaci-inpractice.org). of all ages, or caregivers on the working together to learn from the The authors are currently preparing patients’ behalf, living in or outside experiences and perceptions of a second TMS Survey report, the United States (U.S.), with people coping with rare disorders. focusing on clinical experiences, co- cutaneous or systemic mastocytosis, Survey results provide useful morbidities and additional concerns. mast cell activation syndrome or any information for non-specialist other suspected mast cell disorder, clinicians who treat or collaborate in Background were invited to complete the survey the treatment of these patients and In December of 2009, Dr. Cem whether or not they were members for patients to review experiences Akin of Harvard Medical School and of TMS. The survey was posted of others with mast cell disorders.

10 | The Mastocytosis Chronicles ICD-10-CM Progress Report August 2014

Tenth Edition of the International Classification of MCAS and Mastocytosis ICD-10-CM Subcommittee Members: Diseases-Clinical Manifestation (ICD-10-CM) Code Set Joseph Butterfield, MD, Co-Director of the Mayo Clinic Center of for Mast Cell Activation Syndromes and Mastocytosis Excellence for Mast Cell and Eosinophil Disorders; Chair, AAAAI Mast Cell Disorders Committee The Mastocytosis Society, Inc. (TMS), chaired by Valerie Slee, RN, BSN, and the American Academy of Allergy, Arnold Kirshenbaum, MD, Co-Chair, MCAS and Mastocytosis ICD- 10-CM Subcommittee (MCD Committee) Asthma and Immunology (AAAAI) Mast Cell Disorder (MCD) Committee, chaired by Joseph Butterfield, MD, Catherine Weiler, MD, PhD, Co-Director of the Mayo Clinic have joined forces to help create medical codes for Mast Center of Excellence for Mast Cell and Eosinophil Disorders; Co- Chair, MCAS and Mastocytosis ICD-10-CM Subcommittee (MCD Cell Activation Syndromes (MCAS) and update existing Committee) codes for Mastocytosis. The two organizations formed a subcommittee consisting of AAAAI MCD Committee Cem Akin, MD, PhD, Director of the Mastocytosis Center of and TMS Research Committee members, chaired by Excellence at Brigham and Women’s Hospital and Dana-Farber Cancer Institute Arnold Kirshenbaum, MD, and Catherine Weiler, MD, PhD, for the MCD Committee, and Susan Jennings, Dr. Mariana Castells, MD, PhD, Associate Director of the PhD, and Nancy Russell, DrPH, for TMS, to work on Mastocytosis Center of Excellence at Brigham and Women’s the collaborative development of proposals for new Hospital and Dana-Farber Cancer Institute and updated Tenth Edition International Classification Susan Jennings, PhD, Co-Chair, Research Committee, The of Diseases-Clinical Manifestation (ICD-10-CM) codes Mastocytosis Society, Inc.; Co-Chair, MCAS and Mastocytosis for mast cell disorders. A proposal to add MCAS ICD-10-CM Subcommittee (TMS) codes to ICD-10-CM was then jointly submitted to the Nancy Russell, Dr. PH, Co-Chair, Research Committee, The National Center for Health Statistics (NCHS; housed Mastocytosis Society, Inc.; Co-Chair, MCAS and Mastocytosis at the Center for Disease Control and Prevention) in ICD-10-CM Subcommittee (TMS) January 2014 and a second proposal, focused on Valerie Slee, RN, BSN, Chair, Board of Directors and Board of modification and expansion of existing Mastocytosis Directors Liaison to the Research Committee, The Mastocytosis ICD-10-CM codes, was jointly submitted to the NCHS Society, Inc. in July 2014. Both proposals were also co-sponsored and approved by the AAAAI Board of Directors. The Mishele Cunningham, RN, BSN, PHN, Chair, Education Committee, The Mastocytosis Society, Inc. MCAS ICD-10-CM proposal was presented at the March 19-20, 2014 ICD-10 Coordination and Maintenance Committee Meeting of the Centers for Disease Control and Prevention. The deadline for receipt of public comments for proposals discussed at that meeting was June 20, 2014. It is currently anticipated that the Mastocytosis ICD-10-CM proposal will be presented at the September 23-24, 2014 ICD-10 Coordination and Maintenance Committee Meeting of the Centers for Disease Control and Prevention. Regular updates to ICD-10 are currently scheduled to begin on October 1, 2016.

Special Edition 2014 | 11 The Mastocytosis Society Pediatric Mast Cell Disorders Fact Sheet By, Valerie Slee RN, BSN, and Mishele Cunningham RN, BSN, PHN

Pediatric mast cell disorders, a group of rare diseases, Urticaria Pigmentosa/Maculopapular Cutaneous are characterized by either the presence of too many Mastocytosis (UP) mast cells in the skin or other tissues (pediatric • Red maculopapular lesions tend to wheal mastocytosis), or recurrent symptoms arising from when scratched (positive Darier’s sign) release of mast cell mediators in two or more organ • Blister formation can occur with rubbing systems, in parallel (mast cell activation syndrome, or stroking of lesion and is associated with MCAS). Mast cells are instrumental in mediating pruritis2 anaphylaxis, and children with mast cell disorders are at higher risk to develop both provoked and unprovoked • Encompasses several clinical entities episodes of anaphylaxis. A child whose disease appears with different outcomes, including: to be confined to the skin may still exhibit systemic pitted melanotic macules, reddish brown symptoms due to mast cell degranulation and mediator telangiectatic macules, lightly pigmented release.1 Symptoms common to pediatric mastocytosis papules, brownish papules, and small and MCAS include flushing of the face and neck, nodules dermatographism, gastrointestinal complaints [such as diarrhea, abdominal pain, nausea, gastroesophageal Diffuse Cutaneous Mastocytosis (DCM) reflux (GERD)], pruritis, dyspnea, headache, lethargy, • Skin thickened, hyperpigmented and fatigue, and neuropsychiatric symptoms. Many children diffusely infiltrated; can involve up to 100% may not complain of specific symptoms, may not be of the skin with the central area, head and able to identify or localize a symptom, or may have scalp heavily affected every symptom, while others may have very few or none. • Can appear at birth or early infancy Age of Onset: • Blisters, some of which are hemorrhagic; • Pediatric mastocytosis is commonly bullae are present and dermatographism may diagnosed prior to age two. be prominent – Disease is seen in both males and • Flushing is a common symptom females equally.2 • Tryptase may be elevated due to increased – No race has been found to be mast cell burden in the skin, and can be predominant.2 indicative of well differentiated systemic mastocytosis • Pediatric mast cell activation syndrome can be diagnosed at any age. Possible Symptoms • Itching Presentation: • In 90% of the cases, the typical presentation • Flushing involves cutaneous manifestations (skin lesions). • Darier’s Sign and dermatographism These may include: • Abdominal pain, nausea, diarrhea, bloating, colic in infants, GERD Solitary or Multiple • Bone and joint pain • Usually present at birth • Headache • Solitary, elevated lesion which usually • Fatigue resolves during childhood • Neuropsychiatric symptoms, such as: brain fog, • Multiple mastocytomas may evolve into adult ADD/ADHD, behavioral issues, seizures well differentiated systemic mastocytosis • Anaphylaxis (WDSM)1

12 | The Mastocytosis Chronicles Guidelines for Acquiring a Diagnosis: • Mast cell stabilizers • Completion of a thorough patient history - Oral cromolyn sodium • Careful skin examination and biopsy of lesions - Ketotifen with mast cell stains (hematoxylin, eosin, • Injectable epinephrine giemsa stains) and immunohistochemistry for tryptase and KIT - Auvi Q: talking auto injector • Acquisition of labs, including complete blood - EpiPen auto injector count, peripheral smear, serum chemistry, • Topical treatments serum tryptase and liver function tests - Steroid creams • Exam of liver and spleen for - Cromolyn sodium cream 1%-5% hepatosplenomegaly by ultrasound or scan • No chemotherapy is indicated in cutaneous or • Any other exam relevant to individual symptoms indolent systemic disease in children, unless (endoscopy, colonoscopy, bone scan, etc.) indicators of progression to aggressive disease • Bone marrow biopsy and aspirate with flow are identified cytometry, only if clinical suspicion of systemic Prognosis: or progressive disease: • Benign course will be seen in approximately - abnormal peripheral blood counts, 70% of patients.1 organomegaly, significant lymphadenopathy, • Approximately 30% of pediatric mastocytosis severe recurrent systemic mast cell mediator- cases persist into adulthood.1 related symptoms, persistent high tryptase, • Children with extensive bullous lesions appear 2, 3 persistence of disease into adulthood to be at increased risk of shock or sudden death Triggers to Avoid (varies by patient): from anaphylaxis.4 • Changes in temperature, heat and cold • Children with widespread skin lesions (UP & • Friction or pressure on the skin DCM) are at increased risk for severe systemic • Specific foods: very individualized but may reaction due to potential mast cell mediator include shellfish, high histamine foods such release from affected skin.4 as left-overs, salicylate-containing foods, nuts, Support Services: peanuts and other potential allergens • The Mastocytosis Society is a 501(c)3 nonprofit • Medications, which can be problematic, organization dedicated to supporting patients include: opioid narcotics, alcohol as an additive, affected by Mastocytosis or Mast Cell Activation IV vancomycin, neomycin, benzocaine, anti- Disorders, as well as their families, caregivers, cholinergics, and certain anesthetics. See the and physicians through research, education and TMS website for further lists: www.tmsforacure. advocacy. org. • The Mastocytosis Society coordinates support • Insect bites and stings, jellyfish, snake and fire groups in nearly every state. Please visit our ant venoms website at www.tmsforacure.org. • Physical, emotional or environmental stressors • Mastokids.org is a site where parents and • Perfumes, odors and chemical exposures caregivers of children with mastocytosis or mast cell disease can come to learn, find support, Treatment Guidelines: and discover a safe environment to interact with • Avoidance of triggers other families. • H1 and H2 antihistamines References: 1. Torrelo A, Alvarez-Twose I, Escribano L. Childhood mastocytosis. Curr Opin Pediatr. 2012 - H1: loratadine, cetirizine, desloratadine, Aug;24(4):480-6. 2. Castells M, Metcalfe DD, Escribano L. Diagnosis and treatment of cutaneous mastocytosis in diphenhydramine, hydroxyzine, fexofenadine, children: practical recommendations. Am J Clin Dermatol. 2011 Aug 1;12(4):259-70. 3. Fried AJ, Akin C. Primary mast cell disorders in children. Curr Allergy Asthma Rep. 2013 chlorpheniramine maleate, doxepin Dec;13(6):693-701. 4. Alvarez-Twose I, Vano-Galvan S, Sanchez-Munoz L, Morgado JM, Matito A, Torrelo A, et al. - H2: ranitidine, cimetidine, famotidine Increased serum baseline tryptase levels and extensive skin involvement are predictors for the severity of mast cell activation episodes in children with mastocytosis. Allergy. 2012 Jun;67(6):813-21. • Leukotriene inhibitors Pediatric Mastocytosis Fact Sheet - Montelukast, zileuton, zafirlukast Copyright © 2014 The Mastocytosis Society, Inc. All rights reserved. • UVA/UVB photolight therapy Special Edition 2014 | 13

Mission and History of TMS

Mission: The Mastocytosis Society, Inc. is a 501(c)3 nonprofit organization dedicated to supporting patients affected by Mastocytosis or Mast Cell Activation Disorders as well as their families, caregivers, and physicians through research, education, and advocacy.

History: The Mastocytosis Society, Inc. (TMS) was founded in 1995 by Bill Abbottsmith, Linda Buchheit, Olive Clayson, Iris Dissinger, Bill Hingst, and Joe Palk. At that time very little was known about Mastocytosis, so these pioneering individuals sought to fill a massive void with some answers to their multitude of questions about this rare disease. They found one another through NORD, sheer determination and extensive research.

The first support group meeting was held in Baltimore at the Inner Harbor in 1994 and was attended by Linda Buchheit and Bill Hingst. The second meeting was held the following year at Linda Buchheit’s home in Ohio. Fourteen members attended that year. Little did they know how fruitful their efforts would be and what a lifeline they would become as more and more patients joined each year!

Until 1990 many patients diagnosed with Mastocytosis were given a very grim prognosis. Up until that time, Mastocytosis was not often considered when physicians were making a differential diagnosis, and many cases were completely missed, resulting in patient death. At that point, signs of the disease were then discovered on autopsy; however, because so little was known about Mastocytosis, it was presumed that Mastocytosis was one of the causes of death, when in fact the patient had often died of other causes, and the Mastocytosis was an incidental finding! On the other hand, more advanced cases of aggressive Mastocytosis were also recognized during post-mortem exams, leading pathologists to identify all forms of Mastocytosis as having a high associated mortality rate. Fortunately, that prognosis has improved as more patients are diagnosed and treated sooner, and more physicians research and treat this disease. Today, we know that pediatric patients have greater than a 75% chance of outgrowing their disease at or before puberty, and adults with Indolent Systemic Mastocytosis can have a near normal life expectancy if they avoid triggers and take their medication!

Founding Members: Today’s accomplishments are built on the foundations laid by the early volunteers, and we are grateful for their efforts. TMS is where it is today because of the seeds that they planted in 1994 and in the early years. Below are some of the earliest members, but there have been many more champions who have served their fellow patients and families affected by Mastocytosis and Mast Cell Activation Disorders by volunteering for TMS. We salute you!

Past Board Members: THANK YOU to all of our past board members as they are our strong foundation for all the wonderful and exciting things happening now and in the future for TMS!

Linda Buchheit William Hingst Joseph Palk Elizabeth Punsalan Iris Dissinger Bill Abbottsmith Jessica Hobart Olive Clayson Ruth Sampson Joyce McEntire Margaret Thomas Stephanie Shaw Jane Clark Kathy Favorite Mishele Cunningham Kristin Forest Juanita Anderson Marcia Gordon Denise Baun Regis Park Emily Tidball Diana Coleman Candace VanAuken Susan Manchester Cindra Carey Michael Zorska Deborah Wallack Len Levenda Joan Passmore Emily Menard Lisa Kenny Jody Bachiman Erin Cunia Regina Rentz Wanda Hermann Rachael Zinman Lisa Sterling Ethan Bordeaux Janice Chiappone Bill Richers Sandra Frost

14 | The Mastocytosis Chronicles Perf administer with extreme caution. Fentanyl is the opiate with the best profile for mast cell patients; administration should be considered along with epinephrine. coronary vasospasm. If the patient is on β-blockers, glucagon epinephrine can aggravate Kounis syndrome and worsen Epinephrine is the drug of choice for anaphylaxis, however due to the unopposed actions of α heart rate. β blockers can exaggerate coronary vasospasms Nitroglycerin causes decreased blood pressure and increased identified on pathology (Giemsa, hematoxylin-eosin stain) Type 3: Stent thrombosis with eosinophils and mast cells infarction myocardial acute manifesting rupture or erosion, plaque or angina vasospastic either induce can attacks allergic acute whom in disease atheromatous pre-existing Quiescient 2: Type Treatment of the allergic episode can terminate the type 1 variant elevation of cardiac enzymes and troponins OR coronary vasospasm with myocardial infarction with coronary vasospasms without elevations in cardiac enzymes pre-disposing conditions; acute allergic attacks resulting in Type1 :Normal coronary arteries, no coronary disease, no cardiomyopathy during anaphylactic reactions. mediators may initiate Takotsubo Syndrome or stress induced Please note: Coronary artery spasm induced by mast cell cells, which can result in the Kounis syndrome cascade. vessels and together result in hyperresponsiveness of mast Multiple mast cell mediators have direct action on coronary rapid, with the heart and coronary arteries as the primary target. cascade leading to anaphylaxis and Kounis syndrome can be very patients are on a protocol exposing them to many medications, the pre-existing conditions. When patients such as mast cell disorder syndrome are drugs, environmental exposures, and various and can affect patients of any age. The main triggers of Kounis in patients with a wide variety of mast cell activation disorders reactions. One example, called Kounis Syndrome, is highly likely Acute coronary syndromes can occur in allergic and anaphylactic CONSIDERATIONS KOUNIS SYNDROME IN MAST CELL PATIENTS Treatment of stent thrombosis with allergic attack allergic attack Treatment of acute coronary event comes first, then treat - -Mast cell stabilizers -H1 and H2 blockers -corticosteroids -H1 and H2 blockers -corticosteroids -acute coronary event protocol - - H1 and H2 blockers - corticosteroids eosinophils Biopsy of thrombus stained for mast cells and vasospasms and nitrates can decrease hypersensitivity induced Vasodilators such as calcium channel blockers -adrenergic receptors. Fold 15. 14. 13. 12. 11. 10. 9. 8. 7. 6. 5. 4. 3. 2. 1. Copyright @ 2014 The Mastocytosis Society, Inc. Hastings, NE 68902-0129 P.O. Box 129 The Mastocytosis Society, Inc. 501 3 c [email protected] tmsforacure.org for their review of this document. Thank you to the members of the TMS Medical Advisory Board REFERENCES: Apr;112(4):309-16. to cardiac events. Ann Allergy Asthma Immunol. 2014 Alevizos M, et al. Stress triggers coronary mast cells leading 1;161(1):56-8. presenting with Kounis syndrome. Int J Cardiol. 2012 Nov Gonzalez-de-Olano D, et al. Mast cell-related disorders of Allergy, Asthma and Immunology. 2011. College of Allergy, Asthma and Immunology. American Academy Lieberman, P. Anaphylaxis. Guidelines Pocketcard. American Wallet Card. J Allergy Clin Immunol Pract. 2013 Mar;1(2):181-5. anaphylaxis education mini-handout: the AAAAI Anaphylaxis Hernandez-Trujillo V, Simons FE. Prospective evaluation of an Immunol. 2013;162(3):193-204. Guidelines: 2013 update of the evidence base. Int Arch Allergy Simons FE, et al. World Allergy Organization Anaphylaxis from www.acepnow.com/article/anaphylaxis-update. Lanier, BQ. Anaphylaxis Update. ACEP Now. 2013 Mar; Retrieved disease. Future Cardiol. 2011 Nov;7(6):805-24. Kounis NG, et al. Kounis syndrome: a new twist on an old Mar;127(3):587-93 e1-22. guidelines: summary. J Allergy Clin Immunol. 2011 Simons FE, et al. World Allergy Organization anaphylaxis Anesth. 2012 Apr;80(2):129-40. Norred CL. Anesthetic-induced anaphylaxis. J Am Assoc Nurse Immunol. 2010 Sep;126(3):477-80 e1-42. anaphylaxis practice parameter: 2010 update. J Allergy Clin Lieberman P, et al. The diagnosis and management of Allergy Clin Immunol. 2011 Jul;128(1):147-52 e2. recognized disorder with systemic clinical manifestations. J Hamilton MJ, et al. Mast cell activation syndrome: a newly Dec;84(12):779-81. misunderstanding in mastocytosis. Am J Hematol. 2009 Gotlib J. On being metachromatic: mystique and New York: Humana Press; 2011. Castells M, editor. Anaphylaxis and Hypersensitivity Reactions. criteria. J Allergy Clin Immunol. 2010 Dec;126(6):1099-104 e4. Akin C, et al. Mast cell activation syndrome: proposed diagnostic 487-504, 515-529, 541, 549-566. Clin North Am. Philadelphia: Elsevier; 2006 Aug; 26(3):465-476, Akin C, editor. Mast Cells and Mastocytosis. Immunol Allergy Fold THE MASTOCYTOSIS SOCIETY, INC. Mast Cell Disorders For Patients with Emergency Care RESEARCH + EDUCATION + ADVOCACY tmsforacure.org Perf 13

Epinephrine should be administered as soon the diagnosis be administered Epinephrine should Although the diagnosis usually is suspected. of anaphylaxis if even systems, of 2 organ depends on the involvement such as the skin, system, with 1 organ presents anaphylaxis be indicated. may epinephrine administration or respiratory cardiac as an acute present may Anaphylaxis manifestation. as the only with hypotension event, disorder cell a patient with mast When giving epinephrine to be to be given must care anaphylaxis, who is experiencing in the any of the ingredients to the patient is not allergic sure be preferable. epinephrine may free epinephrine. Preservative “Because of the risk of potentially lethal arrhythmias, epinephrine should be administered IV only, in profoundly hypotensive patients or patients in cardio/respiratory arrest who have failed to respond to IV volume replacement and several injected doses of epinephrine.” Oxygen Administer IV access bore large Start if wheezing is present bronchodilators Consider inhaled andH1 H2 Blockers as supportive therapy, preferably IV administration, including diphenhydramine as an H1 blocker, given 25mg-50mg, adults, and 1mg/kg, up to max 50mg dose in children; given very slow IV diluted in normal saline over 2-5 minutes. Hydroxyzine is an alternative blockerH1 in this situation. H2 antagonist, such as Famotidine, IV, should also be given. anaphylaxis, prolonged prevent may Corticosteroids in the initial treatment efficacy not have may although they of anaphylaxis. Assemble an emergency protocol packet, together with the names of doctors, care-givers, phone numbers, medications you take, diagnoses, allergies and mast cell protocol signed by your physician. Have multiple copies of these documents available for emergency personnel. of all copies department, request the emergency go to If you files your for and treatments including labs, x-rays, records in the ambulance. these with you and take and give if possible, go by ambulance If ER visit is required, paperwork. the EMT all of your If someone is driving you, recline as far back as you can or lie down in the back seat, have them pull up to the ER anddoor, alert emergency personnel that you are having anaphylaxis. (Vastus Lateralis muscle) is the drug of muscle) Lateralis IM (Vastus Epinephrine given is 1:1000 concentration of anaphylaxis- treatment for choice and 0.01ml/mg/ adults (1mg/1ml) solution- 0.2mg-0.5mg for if needed. in 5-15 minutes, repeat may children- for kg When to take rescue medications, and what medications to take All mast cell patients must be monitored for biphasic reactions. for be monitored must patients cell All mast ANAPHYLAXIS TREATMENT IN A A IN TREATMENT ANAPHYLAXIS PHYSICIANS FOR SETTING: HOSPITAL > > > > > > > IV fluids if hypotensive. > Administer > > > > > > When to use IM epinephrine > When to call and go to the 911 emergency room > > > >

<92%) 2

cardiac arrest cardiac IV: Grade itching, swelling of lips and/or tongue swelling Mouth: itching, hoarseness closure, tightness, itching, Throat: flushing swelling, redness, hives, Skin: itching, diarrhea, cramps Gut: nausea, vomiting, wheeze cough, of breath, Lung: shortness out passing pulse, dizziness, Heart: weak of mouth/throat or swelling itching I: hives/rash, Grade tachycardia, plus- hypotension, II: any of the above, Grade to: including, but not limited GI distress, presyncope, dyspnea, diarrhea pain, nausea, vomiting, hypotension, plus- profound III: any of the above, Grade collapse, cardiovascular confusion, or tachycardia, bradycardia (SaO hypoxia bronchospasm, Unknown trigger- Idiopathic anaphylaxis trigger- Unknown such as ant, snake, and other venoms venom Hymenoptera and insect jellyfish morphine and to including, but not limited Medications in be tolerated aspirin, NSAIDS; can IV Vancomycin, derivatives, with caution. Proceed some patients. gallamine, D-tubocurarine, drugs (succinylcholine, Anesthesia dyes and radiocontrast decamethonium) including alcohol or beverage, Food anxiety and fatigue Emotional stress, change in temperature e.g., heat, cold, stress, Physical or vibration of skin lesions Friction Exercise odors/perfumes Latex, ANAPHYLAXIS REACTIONS CELL MAST OF TRIGGERS COMMON ANAPHYLAXIS AND GRADES ANAPHYLAXIS A IN TREATMENT ANAPHYLAXIS PRE-HOSPITAL SETTING: FOR PATIENTS FOR SETTING: PRE-HOSPITAL > Triggers can include, but are not limited to: not limited include, but are can Triggers > > > > > > > > > > Anaphylaxis is an acute, life-threatening, systemic reaction that reaction systemic life-threatening, is an acute, Anaphylaxis of mediators release systemic the sudden, rapid, from results and basophils. cells mast from symptoms or worsening as new present symptoms Anaphylaxis including: > > > > > > Only a few of these symptoms may be present. Although the diagnosis usually depends on the involvement of 2 organ systems, even if anaphylaxis presents with 1 organ system, epinephrine administration may be indicated. Anaphylaxis may present as an acute cardiac or respiratory event or with hypotension as the only manifestation of anaphylaxis. FAST! ACT be life-threatening! can Symptoms that a you each patient. If a patient tells unique to are Triggers trigger cell is a mast factor or environmental drug, substance certain if it does not seem plausible. the patient even them, believe for > > > set to physician cell primary mast with your work to It is important anaphylactic/ for protocol room up a signed home and emergency include: should episodes. This protocol degranulation cell mast

What Are Are What Disorders Mast Cell abnormal mast cell proliferation/accumulation (mastocytosis), and/or activation [mastocytosis and (MCAS)], syndrome activation mastor cell adults. and children both affect Mastocytosis can affect skin and internal organs such as the bone marrow, GI tract, liver and spleen, and most patients have either cutaneous or indolent systemic (benign) forms. Others, with more aggressive disease, may have associated hematologic disorders. Mast cell patients may have unpredictable symptoms that require anti-mediator therapy. Diagnosis of mastocytosis is confirmed by a bone marrow or skin biopsy. MCAS patients exhibit similar symptoms, and may or may not have increased measurable mast cell mediators for which we can currently test (serum tryptase, urinary N-methyl histamine, urinary prostaglandin D2 and F2 11-beta alpha) during or immediately after an attack, and do respond to anti-mediator therapy. experience to likely more are disorders cell with mast Patients population. No than the general anaphylaxis life-threatening the signs and symptoms between has been found correlation burden. cell or mast levels and serum tryptase of anaphylaxis idiopathic recurrent are types of anaphylaxis common The most or drug induced anaphylaxis, hymenoptera anaphylaxis, during anesthesia, also occur can Anaphylaxis anaphylaxis. management is critical. perioperative that appropriate indicating by characterized are disorders Mast cell 13 Visual Guide to Diagnosing Mastocytosis

The following pages are a photo journal of examples Pediatric Mastocytosis of how mastocytosis can present. While cutaneous Most cases of pediatric mastocytosis fall into one of mastocytosis can include maculopapular cutaneous these categories and may or may not include symptoms mastocytosis/urticaria pigmentosa (UP), telangiectasia of systemic mast cell activation as a result of mediators macularis eruptiva perstans (TMEP), diffuse cutaneous released from the skin (see Pediatric Mast Cell Disor­ mastocytosis (DCM), and solitary mastocytoma, skin ders Fact Sheet in this issue). It should be noted that manifestations can occur in mast cell activation the term “UP” encompasses a variety of clinical mani­ syndrome (MCAS) and systemic mastocytosis (SM) festations. In children, some of these varieties will fade patients as well. away, some will develop into indolent systemic mas­ tocytosis and some will evolve into a newly described entity called well-differentiated systemic mastocytosis. Epinephrine should be administered as soon the diagnosis be administered Epinephrine should Although the diagnosis usually is suspected. of anaphylaxis if even systems, of 2 organ depends on the involvement such as the skin, system, with 1 organ presents anaphylaxis be indicated. may epinephrine administration or respiratory cardiac as an acute present may Anaphylaxis manifestation. as the only with hypotension event, disorder cell a patient with mast When giving epinephrine to be to be given must care anaphylaxis, who is experiencing in the any of the ingredients to the patient is not allergic sure be preferable. epinephrine may free epinephrine. Preservative “Because of the risk of potentially lethal arrhythmias, epinephrine should be administered IV only, in profoundly hypotensive patients or patients in cardio/respiratory arrest who have failed to respond to IV volume replacement and several injected doses of epinephrine.” Oxygen Administer IV access bore large Start if wheezing is present bronchodilators Consider inhaled andH1 H2 Blockers as supportive therapy, preferably IV administration, including diphenhydramine as an H1 blocker, given 25mg-50mg, adults, and 1mg/kg, up to max 50mg dose in children; given very slow IV diluted in normal saline over 2-5 minutes. Hydroxyzine is an alternative blockerH1 in this situation. H2 antagonist, such as Famotidine, IV, should also be given. anaphylaxis, prolonged prevent may Corticosteroids in the initial treatment efficacy not have may although they of anaphylaxis. Assemble an emergency protocol packet, together with the names of doctors, care-givers, phone numbers, medications you take, diagnoses, allergies and mast cell protocol signed by your physician. Have multiple copies of these documents available for emergency personnel. of all copies department, request the emergency go to If you files your for and treatments including labs, x-rays, records in the ambulance. these with you and take and give if possible, go by ambulance If ER visit is required, paperwork. the EMT all of your If someone is driving you, recline as far back as you can or lie down in the back seat, have them pull up to the ER anddoor, alert emergency personnel that you are having anaphylaxis. (Vastus Lateralis muscle) is the drug of muscle) Lateralis IM (Vastus Epinephrine given is 1:1000 concentration of anaphylaxis- treatment for choice and 0.01ml/mg/ adults (1mg/1ml) solution- 0.2mg-0.5mg for if needed. in 5-15 minutes, repeat may children- for kg When to take rescue medications, and what medications to take All mast cell patients must be monitored for biphasic reactions. for be monitored must patients cell All mast ANAPHYLAXIS TREATMENT IN A A IN TREATMENT ANAPHYLAXIS PHYSICIANS FOR SETTING: HOSPITAL > > > > > > > IV fluids if hypotensive. > Administer > > > > > > When to use IM epinephrine > When to call and go to the 911 emergency room > > > >

<92%) 2

Pic. 1- Female adult with smoldering systemic mastocytosis Pic. 2- Female adult athlete with hives and urticaria cardiac arrest cardiac IV: Grade itching, swelling of lips and/or tongue swelling Mouth: itching, hoarseness closure, tightness, itching, Throat: flushing swelling, redness, hives, Skin: itching, diarrhea, cramps Gut: nausea, vomiting, wheeze cough, of breath, Lung: shortness out passing pulse, dizziness, Heart: weak of mouth/throat or swelling itching I: hives/rash, Grade tachycardia, plus- hypotension, II: any of the above, Grade to: including, but not limited GI distress, presyncope, dyspnea, diarrhea pain, nausea, vomiting, hypotension, plus- profound III: any of the above, Grade collapse, cardiovascular confusion, or tachycardia, bradycardia (SaO hypoxia bronchospasm, Unknown trigger- Idiopathic anaphylaxis trigger- Unknown such as ant, snake, and other venoms venom Hymenoptera and insect jellyfish morphine and to including, but not limited Medications in be tolerated aspirin, NSAIDS; can IV Vancomycin, derivatives, with caution. Proceed some patients. gallamine, D-tubocurarine, drugs (succinylcholine, Anesthesia dyes and radiocontrast decamethonium) including alcohol or beverage, Food anxiety and fatigue Emotional stress, change in temperature e.g., heat, cold, stress, Physical or vibration of skin lesions Friction Exercise odors/perfumes Latex, and urticaria pigmentosa pigmentosa ANAPHYLAXIS REACTIONS CELL MAST OF TRIGGERS COMMON ANAPHYLAXIS AND GRADES ANAPHYLAXIS A IN TREATMENT ANAPHYLAXIS PRE-HOSPITAL SETTING: FOR PATIENTS FOR SETTING: PRE-HOSPITAL > Triggers can include, but are not limited to: not limited include, but are can Triggers > > > > > > > > > > Anaphylaxis is an acute, life-threatening, systemic reaction that reaction systemic life-threatening, is an acute, Anaphylaxis of mediators release systemic the sudden, rapid, from results and basophils. cells mast from symptoms or worsening as new present symptoms Anaphylaxis including: > > > > > > Only a few of these symptoms may be present. Although the diagnosis usually depends on the involvement of 2 organ systems, even if anaphylaxis presents with 1 organ system, epinephrine administration may be indicated. Anaphylaxis may present as an acute cardiac or respiratory event or with hypotension as the only manifestation of anaphylaxis. FAST! ACT be life-threatening! can Symptoms that a you each patient. If a patient tells unique to are Triggers trigger cell is a mast factor or environmental drug, substance certain if it does not seem plausible. the patient even them, believe for > > > set to physician cell primary mast with your work to It is important anaphylactic/ for protocol room up a signed home and emergency include: should episodes. This protocol degranulation cell mast

Pic. 3- Female child with systemic mastocytosis and Pic. 4- Female child with mastocytoma on shoulder urticaria pigmentosa

Special Edition 2014 | 17 What Are Are What Disorders Mast Cell Mastocytosis can affect skin and internal organs such as the bone marrow, GI tract, liver and spleen, and most patients have either cutaneous or indolent systemic (benign) forms. Others, with more aggressive disease, may have associated hematologic disorders. Mast cell patients may have unpredictable symptoms that require anti-mediator therapy. Diagnosis of mastocytosis is confirmed by a bone marrow or skin biopsy. MCAS patients exhibit similar symptoms, and may or may not have increased measurable mast cell mediators for which we can currently test (serum tryptase, urinary N-methyl histamine, urinary prostaglandin D2 and F2 11-beta alpha) during or immediately after an attack, and do respond to anti-mediator therapy. experience to likely more are disorders cell with mast Patients population. No than the general anaphylaxis life-threatening the signs and symptoms between has been found correlation burden. cell or mast levels and serum tryptase of anaphylaxis idiopathic recurrent are types of anaphylaxis common The most or drug induced anaphylaxis, hymenoptera anaphylaxis, during anesthesia, also occur can Anaphylaxis anaphylaxis. management is critical. perioperative that appropriate indicating by characterized are disorders Mast cell abnormal mast cell proliferation/accumulation (mastocytosis), and/or activation [mastocytosis and (MCAS)], syndrome activation mastor cell adults. and children both affect Pic. 7- Female adult with smoldering systemic mastocytosis, urticaria pigmentosa during a flare

Pic. 5- Female adult with indolent systemic mastocytosis and confluent urticaria pigmentosa

Pic. 6- Male child with systemic mastocytosis and Pic. 8- Male child with urticaria pigmentosa mystery rashes

18 | The Mastocytosis Chronicles Pic. 9- Male child with systemic mastocytosis during flare Pic. 10- Male child with mast cell activation syndrome, causing blisters during flushing episode

Pic. 11- Male child with urticaria pigmentosa

Special Edition 2014 | 19 part. MCL requires a polychemotherapy approach. disease, which is commonly more aggressive than the SM therapy selection usually depends on the associated burden and control symptoms. In patients with SM-AHNMD, employed with antimediator therapy to reduce disease interferon and the chemotherapeutic agent cladribine, status is unknown. Standard therapies for ASM are patients lacking the KIT D816V mutation or if mutation midostaurin kinase inhibitors (TKIs) targeting the KIT kinase (e.g., being developed. Prominent among these are tyrosine for advanced SM, but promising new treatments are and early death. Therapies of limited effectiveness exist and lymph nodes, which ultimately lead to organ failure abnormalities, and enlargement of the liver, spleen, thrombocytopenia, ascites, bone fractures, gastrointestinal Advanced disease symptoms may include: anemia, administered for patients on beta-blockers). otherwise contraindicated (Glucagon may need to be should carry two doses of injectable epinephrine unless of a physician).supervision All mast cell disease patients leukotriene inhibitors, and possibly aspirin (under direct with H1 and H2 antihistamines, mast cell stabilizers, anaphylaxis. Symptoms of mediator release are treated anxiety/depression; lightheadedness, syncope; and blood pressure instability; brain fog, cognitive dysfunction; osteosclerosis, osteopenia, osteoporosis; itching, +/- rash; macularis eruptiva perstans (TMEP); bone/muscle pain, including urticaria pigmentosa (UP), telangiectasia pain, bloating, GERD, diarrhea, vomiting; rashes, chest; headache; tachycardia and chest pain; abdominal Symptoms may include: flushing of the face, neck, and form of mastocytosis. activation can occur along with, or independent of, any antibiotics and NSAIDs. Use with caution. Mast cell certain medications, including but not limited to opiates, fatigue. Some patients may experience reactions to odors; viral/bacterial/fungal infections; venoms; and environmental, emotional, or physical stress; perfumes/ temperature change; foods; medications; alcohol; friction; Triggers of mediator release may include: heat; cold; experience during mast cell activation/degranulation. which result in the myriad symptoms patients can histamine, heparin, prostaglandins and leukotrienes, Mast cells release mediators, including tryptase, ADVANCED DISEASE CONSIDERATIONS MC MEDIATOR SYMPTOMS AND THERAPY MC ACTIVATION AND TRIGGERS 6 ). Imatinib is approved therapy for adult ASM

Pic. 13- Solitary mastocytoma, normal and inflamed Fold Copyright ©2014 The Mastocytosis Society, Inc. Society, Mastocytosis The ©2014 Copyright 68902-0129 NE Hastings, P.O. 129 Box 3 c 501 Inc. Society, Mastocytosis The [email protected] tmsforacure.org join. to encouraged is disorders cell mast about learning in interested or by affected Anyone ages. all of patients disorder cell mast welcomes TMS advocacy. and education research, through physicians and caregivers families, patients, to support provides TMS statement, mission the in defined As board. advisory medical expert an by guided and volunteers by lead organization a 501(c)3 is (TMS) Inc. Society, Mastocytosis The advocacy. and education research, through physicians and caregivers, families, their as well as Disorders Activation Cell Mast or Mastocytosis by affected patients supporting to dedicated organization a nonprofit is Inc. Society, Mastocytosis The 9. 8. 7. 6. 5. 4. 3. 2. 1. ORGANIZATION AND SUPPORT MISSION STATEMENT REFFERENCES morphological criteria, and immunohistochemical findings. Leuk Res. 2001 Jul;25(7):543-51. 2001 Res. Leuk findings. immunohistochemical and criteria, morphological aspects, histopathological general mastocytosis: of P. HP, Horny Valent Diagnosis mastocytosis. Leuk Res. 2011 Sep;35(9):1143-52. 2011 Res. Leuk mastocytosis. systemic of treatment the in inhibitors kinase Tyrosine C. Akin DL, DeRemer C, Ustun systemic mastocytosis. Blood. 2013 Mar 28;121(13):2393-401. Mar 2013 Blood. mastocytosis. systemic advanced in criteria response consensus (ECNM) Mastocytosis on Network Competence & European (IWG-MRT) Treatment and Research Neoplasms Group-Myeloproliferative Working International al. et O, T, Hermine George A, Reiter C, Akin A, Pardanani J, Gotlib Horny HP, Sotlar K, Valent P. Mastocytosis: state of the art. Pathobiology. 2007;74(2):121-32. Pathobiology. art. the of state P. Valent Mastocytosis: K, HP,Horny Sotlar 2009 Jun 4;113(23):5727-36. Jun 2009 Blood. factors. prognostic and studies survival adults: consecutive 342 in mastocytosis Systemic al. et JH, Butterfield M, Patnaik C, Finke TL, Lasho A, Tefferi KH, Lim activation syndromes: a consensus proposal. Int Arch Allergy Immunol. 2012;157(3):215-25. Immunol. Allergy Arch Int proposal. a consensus syndromes: activation cell mast to reference special with disorders cell mast of classification global and criteria Definitions, al. et MC, Carter JH, Butterfield K, Brockow M, P, Arock C, Valent Akin treatment, and progression. Eur J Haematol. 2013 Feb;90(2):89-98. 2013 J Haematol. Eur progression. and treatment, diagnosis, in mutations KIT of impact the mastocytosis: systemic Advanced S. Verstovsek malignancies. Blood. 2009 Oct 29;114(18):3769-72. Oct 2009 Blood. malignancies. myeloid other with associated mastocytosis systemic with patients 123 of breakdown relevant Prognostically al. RF, et CY, Li McClure C, Finke TL, Lasho KH, Lim A, Pardanani stratification, and management. Am J Hematol. 2012 Apr;87(4):401-11. 2012 J Hematol. Am management. and stratification, risk diagnosis, on Update 2012 adults: in mastocytosis Systemic A. Pardanani

Pic. 12- Adult female with urticaria pigmentosa during a flare

Pic. 15- Female with idiopathic anaphylaxis, and dermatagraphism Fold THE MASTOCYTOSIS SOCIETY, INC. Variants Aggressive Indolent & Including Mastocytosis Systemic RESEARCH + EDUCATION + ADVOCACY

Thank You!!! tmsforacure.org

TMS would like to thank all the people who sent in images of mast cell disease. Education is one of our primary goals. Sharing these images with our members and medical professionals will help doctors better recognize mast cell disease. Pic. 14- Female child with urticaria pigmentosa

20 | The Mastocytosis Chronicles Perf part. MCL requires a polychemotherapy approach. disease, which is commonly more aggressive than the SM therapy selection usually depends on the associated burden and control symptoms. In patients with SM-AHNMD, employed with antimediator therapy to reduce disease interferon and the chemotherapeutic agent cladribine, status is unknown. Standard therapies for ASM are patients lacking the KIT D816V mutation or if mutation midostaurin kinase inhibitors (TKIs) targeting the KIT kinase (e.g., being developed. Prominent among these are tyrosine for advanced SM, but promising new treatments are and early death. Therapies of limited effectiveness exist and lymph nodes, which ultimately lead to organ failure abnormalities, and enlargement of the liver, spleen, thrombocytopenia, ascites, bone fractures, gastrointestinal Advanced disease symptoms may include: anemia, administered for patients on beta-blockers). otherwise contraindicated (Glucagon may need to be should carry two doses of injectable epinephrine unless of a physician).supervision All mast cell disease patients leukotriene inhibitors, and possibly aspirin (under direct with H1 and H2 antihistamines, mast cell stabilizers, anaphylaxis. Symptoms of mediator release are treated anxiety/depression; lightheadedness, syncope; and blood pressure instability; brain fog, cognitive dysfunction; osteosclerosis, osteopenia, osteoporosis; itching, +/- rash; macularis eruptiva perstans (TMEP); bone/muscle pain, including urticaria pigmentosa (UP), telangiectasia pain, bloating, GERD, diarrhea, vomiting; rashes, chest; headache; tachycardia and chest pain; abdominal Symptoms may include: flushing of the face, neck, and form of mastocytosis. activation can occur along with, or independent of, any antibiotics and NSAIDs. Use with caution. Mast cell certain medications, including but not limited to opiates, fatigue. Some patients may experience reactions to odors; viral/bacterial/fungal infections; venoms; and environmental, emotional, or physical stress; perfumes/ temperature change; foods; medications; alcohol; friction; Triggers of mediator release may include: heat; cold; experience during mast cell activation/degranulation. which result in the myriad symptoms patients can histamine, heparin, prostaglandins and leukotrienes, Mast cells release mediators, including tryptase, ADVANCED DISEASE CONSIDERATIONS MC MEDIATOR SYMPTOMS AND THERAPY MC ACTIVATION AND TRIGGERS 6 ). Imatinib is approved therapy for adult ASM Fold Copyright ©2014 The Mastocytosis Society, Inc. Society, Mastocytosis The ©2014 Copyright 68902-0129 NE Hastings, P.O. 129 Box 3 c 501 Inc. Society, Mastocytosis The [email protected] tmsforacure.org join. to encouraged is disorders cell mast about learning in interested or by affected Anyone ages. all of patients disorder cell mast welcomes TMS advocacy. and education research, through physicians and caregivers families, patients, to support provides TMS statement, mission the in defined As board. advisory medical expert an by guided and volunteers by lead organization a 501(c)3 is (TMS) Inc. Society, Mastocytosis The advocacy. and education research, through physicians and caregivers, families, their as well as Disorders Activation Cell Mast or Mastocytosis by affected patients supporting to dedicated organization a nonprofit is Inc. Society, Mastocytosis The 9. 8. 7. 6. 5. 4. 3. 2. 1. ORGANIZATION AND SUPPORT MISSION STATEMENT REFFERENCES morphological criteria, and immunohistochemical findings. Leuk Res. 2001 Jul;25(7):543-51. 2001 Res. Leuk findings. immunohistochemical and criteria, morphological aspects, histopathological general mastocytosis: of P. HP, Horny Valent Diagnosis mastocytosis. Leuk Res. 2011 Sep;35(9):1143-52. 2011 Res. Leuk mastocytosis. systemic of treatment the in inhibitors kinase Tyrosine C. Akin DL, DeRemer C, Ustun systemic mastocytosis. Blood. 2013 Mar 28;121(13):2393-401. Mar 2013 Blood. mastocytosis. systemic advanced in criteria response consensus (ECNM) Mastocytosis on Network Competence & European (IWG-MRT) Treatment and Research Neoplasms Group-Myeloproliferative Working International al. et O, T, Hermine George A, Reiter C, Akin A, Pardanani J, Gotlib Horny HP, Sotlar K, Valent P. Mastocytosis: state of the art. Pathobiology. 2007;74(2):121-32. Pathobiology. art. the of state P. Valent Mastocytosis: K, HP,Horny Sotlar 2009 Jun 4;113(23):5727-36. Jun 2009 Blood. factors. prognostic and studies survival adults: consecutive 342 in mastocytosis Systemic al. et JH, Butterfield M, Patnaik C, Finke TL, Lasho A, Tefferi KH, Lim activation syndromes: a consensus proposal. Int Arch Allergy Immunol. 2012;157(3):215-25. Immunol. Allergy Arch Int proposal. a consensus syndromes: activation cell mast to reference special with disorders cell mast of classification global and criteria Definitions, al. et MC, Carter JH, Butterfield K, Brockow M, P, Arock C, Valent Akin treatment, and progression. Eur J Haematol. 2013 Feb;90(2):89-98. 2013 J Haematol. Eur progression. and treatment, diagnosis, in mutations KIT of impact the mastocytosis: systemic Advanced S. Verstovsek malignancies. Blood. 2009 Oct 29;114(18):3769-72. Oct 2009 Blood. malignancies. myeloid other with associated mastocytosis systemic with patients 123 of breakdown relevant Prognostically al. RF, et CY, Li McClure C, Finke TL, Lasho KH, Lim A, Pardanani stratification, and management. Am J Hematol. 2012 Apr;87(4):401-11. 2012 J Hematol. Am management. and stratification, risk diagnosis, on Update 2012 adults: in mastocytosis Systemic A. Pardanani

Fold THE MASTOCYTOSIS SOCIETY, INC. Variants Aggressive Indolent & Including Mastocytosis Systemic RESEARCH + EDUCATION + ADVOCACY tmsforacure.org Perf SM is ). In patients with Patients with 3 * Must be attributable to the MC infiltrate.

1 2 B and C Findings B FINDINGS B FINDINGS* C BM biopsy showing > 30% infiltration by MCs (focal, dense aggregates) and serum total tryptase level > 200 ng/mL Myeloproliferation or signs of dysplasia in non–MC lineage(s), no prominent cytopenias; criteria for AHNMD not met Hepatomegaly and/or splenomegaly on palpation without impairment of organ function and/or lymphadenopathy on palpation/imaging (> 2 cm) Cytopenia(s): ANC < 1 x 109/L, g/dL, Hb < 10 or platelets < 100 x 109/L Hepatomegaly on palpation with impairment of liver function, ascites, and/or portalhypertension Skeletal lesions: osteolyses and/or pathologic fractures Palpable splenomegaly with hypersplenism Malabsorption with weight loss from gastrointestinal tract MC infiltrates PROGNOSIS 3. TABLE Most patients with SM have ISM. ISM patients have preserved organ function and their survival is comparable to that of the general population. Patients with smoldering SM may have an increased risk of developing disease transformation to aggressive forms of SM. Survival of patients with more advanced significantly shorter than that of the overall population and is affected by disease subtype, with median survival monthsof 41 for patients with ASM, 24 months for SM-AHNMD, and 2 months for MCL. ASM suffer debilitating symptoms and have signs of organ dysfunction (C-findings; Table 3 SM-AHNMD, prognosis can differ depending on the subgroup: in one study of patients with SM-AHNMD, SM-chronic neoplasm, SM-myeloproliferative the myelomonocyticSM-myelodysplastic leukemia, syndrome, and SM-acute leukemia subgroups were associated with median survivals 13, 15, and of 31, 11 respectively.months, ). Pediatric Forms of mastocytosis 5 Table 2 1 Major Variants of Systemic Mastocytosis *A lymphoproliferative*A disorder or plasma cell dyscrasia may rarely be diagnosed with SM. ISM (INDOLENT SYSTEMIC MASTOCYTOSIS) SYSTEMIC (INDOLENT ISM CELL MAST NON HEMATOLOGIC CLONAL ASSOCIATED WITH (SM SM-AHNMD DISEASE)* LINEAGE MASTOCYTOSIS) SYSTEMIC (AGGRESSIVE ASM LEUKEMIA) CELL (MAST MCL WHO criteria for SM met, MC burden low, +/- skin lesions, no C findings, no evidence of AHNMD Bone marrow mastocytosis: ISM with BM involvement, but no skin lesions Smoldering SM: ISM, typically with skin lesions, with 2 or more B findings, but no C findings. Meets criteria for SM and also criteria for an AHNMD (MDS, MPN, MDS/MPN, AML), or other WHO-defined myeloid hematologic neoplasm, +/- skin lesions. Meets criteria for SM with one or more C findings. No evidence of MCL, +/- skin lesions. Meets criteria for SM. BM biopsy shows a diffuse infiltration, usually compact, by atypical, immature MCs. BM aspirate smears show 20% or more MCs. Typical MCL: MC comprise 10% or more of peripheral blood white cells. Aleukemic MCL: < 10% of peripheral blood white cells are MCs. Usually without skin lesions. Thank you to Srdan Verstosek, MD, PhD, MD Anderson Cancer Center and Jason Hornick,PhD,The Boston MD, Center of Excellence for Mastocytosis at Brigham and Women’s HospitalDana Farber and Cancer Institute for their contributions to this brochure.TMS Research Committee. TABLE 2. TABLE include, but are not limited to, cutaneous mastocytosis (CM) and variants of systemic mastocytosis ( mastocytosis is primarily a cutaneous disease (may include symptoms of mast cell activation), but 25-30% may go on to have some form of systemic disease in adulthood. Patients who exhibit symptoms of mast cell mediator release who do not fulfill criteria for SM may have mast cell activation non-clonal. or clonal syndrome(MCAS), 1

at least three minor

). Table 1 Table World Health Organization Diagnostic Criteria for Systemic Mastocytosis MAJORCRITERION CRITERIA MINOR SM diagnosis requires at least one major and one minor criteria OR Multifocal dense infiltrates of MCs MCs (> 15 in aggregates) are detected in sections of BM and/or other extracutaneous organ(s). > 25% of MCs in BM or other extracutaneous organ(s) display abnormal morphology (spindle shape typical). Activating KIT mutation at codon is 816 found in extracutaneous organ(s). MCs in BM, blood, or other extracutaneous organs express CD2 and/or CD25, plus normal MC markers. Serum total tryptase is persistently > 20 ng/mL (not valid if there is an associated clonal disorder).myeloid criteria be fulfilled. TABLE 1. TABLE Overview co-expression of CD25). Immunohistochemistry for KIT, Systemic Systemic Mastocytosis consists a group of (SM) mastocytosis Systemic involving disorders heterogeneous rare, of abnormal mast of accumulation and growth extracutaneous multiple or one in (MCs) cells systemsorgan ( Standard technique can be used to obtain an iliac crest bone marrow (BM) biopsy and aspirate smear for diagnosis. Aspirated BM should be allocated for flow cytometry to assess for the presence of mast cells with aberrant phenotype (i.e., MC tryptase, and CD25 should be performed on sections of biopsy. the

SM is ). In patients with

Patients with TMS DVD ORDER FORM 3 * Must be attributable to the MC infiltrate.

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1 2 Name: ______

B and C Findings Address: ______B FINDINGS B FINDINGS* C BM biopsy showing > 30% infiltration by MCs (focal, dense aggregates) and serum total tryptase level > 200 ng/mL Myeloproliferation or signs of dysplasia in non–MC lineage(s), no prominent cytopenias; criteria for AHNMD not met Hepatomegaly and/or splenomegaly on palpation without impairment of organ function and/or lymphadenopathy on palpation/imaging (> 2 cm) Cytopenia(s): ANC < 1 x 109/L, g/dL, Hb < 10 or platelets < 100 x 109/L Hepatomegaly on palpation with impairment of liver function, ascites, and/or portalhypertension Skeletal lesions: osteolyses and/or pathologic fractures Palpable splenomegaly with hypersplenism Malabsorption with weight loss from gastrointestinal tract MC infiltrates City: ______State: ______Zip: ______PROGNOSIS 3. TABLE Most patients with SM have ISM. ISM patients have preserved organ function and their survival is comparable to that of the general population. Patients with smoldering SM may have an increased risk of developing disease transformation to aggressive forms of SM. Survival of patients with more advanced significantly shorter than that of the overall population and is affected by disease subtype, with median survival monthsof 41 for patients with ASM, 24 months for SM-AHNMD, and 2 months for MCL. ASM suffer debilitating symptoms and have signs of organ dysfunction (C-findings; Table 3 SM-AHNMD, prognosis can differ depending on the subgroup: in one study of patients with SM-AHNMD, SM-chronic neoplasm, SM-myeloproliferative the myelomonocyticSM-myelodysplastic leukemia, syndrome, and SM-acute leukemia subgroups were associated with median survivals 13, 15, and of 31, 11 respectively.months, Country: ______Phone: ______Email: ______

Description Quantity Price Total 2014 - 5 DVD set 60.00 2013 – 5 DVD set ). Pediatric 20.00 Forms of mastocytosis 5

Table 2 2012 -- 3 DVD set 1 20.00 2011 -- 4 DVD set 20.00 2010 -- 4 DVD set 20.00 2009 -- 4 DVD set 20.00 Major Variants of Systemic Mastocytosis *A lymphoproliferative*A disorder or plasma cell dyscrasia may rarely be diagnosed with SM. 2008 – 4 DVD set 20.00 ISM (INDOLENT SYSTEMIC MASTOCYTOSIS) SYSTEMIC (INDOLENT ISM CELL MAST NON HEMATOLOGIC CLONAL ASSOCIATED WITH (SM SM-AHNMD DISEASE)* LINEAGE MASTOCYTOSIS) SYSTEMIC (AGGRESSIVE ASM LEUKEMIA) CELL (MAST MCL WHO criteria for SM met, MC burden low, +/- skin lesions, no C findings, no evidence of AHNMD Bone marrow mastocytosis: ISM with BM involvement, but no skin lesions Smoldering SM: ISM, typically with skin lesions, with 2 or more B findings, but no C findings. Meets criteria for SM and also criteria for an AHNMD (MDS, MPN, MDS/MPN, AML), or other WHO-defined myeloid hematologic neoplasm, +/- skin lesions. Meets criteria for SM with one or more C findings. No evidence of MCL, +/- skin lesions. Meets criteria for SM. BM biopsy shows a diffuse infiltration, usually compact, by atypical, immature MCs. BM aspirate smears show 20% or more MCs. Typical MCL: MC comprise 10% or more of peripheral blood white cells. Aleukemic MCL: < 10% of peripheral blood white cells are MCs. Usually without skin lesions. Thank you to Srdan Verstosek, MD, PhD, MD Anderson Cancer Center and Jason Hornick,PhD,The Boston MD, Center of Excellence for Mastocytosis at Brigham and Women’s HospitalDana Farber and Cancer Institute for their contributions to this brochure.TMS Research Committee. TABLE 2. TABLE include, but are not limited to, cutaneous mastocytosis (CM) and variants of systemic mastocytosis ( mastocytosis is primarily a cutaneous disease (may include symptoms of mast cell activation), but 25-30% may go on to have some form of systemic disease in adulthood. Patients who exhibit symptoms of mast cell mediator release who do not fulfill criteria for SM may have mast cell activation non-clonal. or clonal syndrome(MCAS), 2007 - 4 DVD set 20.00 2005-2007 3 years DVD set

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___ Check/money order ). ___Credit card or PayPal™

Table 1 Table Please make check or money order payable to The Mastocytosis Society or TMS, and mail to The Mastocytosis Society (or TMS), c/o Treasurer, P.O. Box 129 Hastings, NE 68902-0129. To pay online with credit card or PayPal™, go under Support TMS , then click TMS Store, click the appropriate “Add to Cart” button(s). The World Health Organization Diagnostic Criteria for Systemic Mastocytosis list of previous years’ conference DVD material can be found here as well.

Special Edition 2014 | 23 MAJORCRITERION CRITERIA MINOR SM diagnosis requires at least one major and one minor criteria OR Multifocal dense infiltrates of MCs MCs (> 15 in aggregates) are detected in sections of BM and/or other extracutaneous organ(s). > 25% of MCs in BM or other extracutaneous organ(s) display abnormal morphology (spindle shape typical). Activating KIT mutation at codon is 816 found in extracutaneous organ(s). MCs in BM, blood, or other extracutaneous organs express CD2 and/or CD25, plus normal MC markers. Serum total tryptase is persistently > 20 ng/mL (not valid if there is an associated clonal disorder).myeloid criteria be fulfilled. TABLE 1. TABLE Overview Systemic Systemic Mastocytosis consists a group of (SM) mastocytosis Systemic involving disorders heterogeneous rare, of abnormal mast of accumulation and growth extracutaneous multiple or one in (MCs) cells systemsorgan ( co-expression of CD25). Immunohistochemistry for KIT, MC tryptase, and CD25 should be performed on sections of biopsy. the Standard technique can be used to obtain an iliac crest bone marrow (BM) biopsy and aspirate smear for diagnosis. Aspirated BM should be allocated for flow cytometry to assess for the presence of mast cells with aberrant phenotype (i.e., Medical & Research Centers that Treat Patients with Mast Cell Diseases

Please note carefully any clarification of what each center specializes in. For example, some centers only treat patients with biopsy confirmed systemic mastocytosis, some centers only treat aggressive or malignant disease, some treat only adults or children, and many also treat mast cell activation syndromes/mast cell activation disorders (MCAS/MCAD). All centers listed can do the entire work-up including evaluation, physical exam, mediator testing and bone marrow biopsy with flow cytometry and appropriate stains for c-kit D816V mutation, tryptase, and expression of CD2 and CD25 antigen markers. Please be very clear when making your appointment to ask what you can expect to occur during your visit.

United States of America mastocytosis (SM) only, aggressive SM Adults and pediatric. Diagnostic, California and mast cell leukemia. Adults and treatment, and research. Can arrange Stanford Cancer Center pediatric. bone marrow biopsies. 875 Blake Wilbur Drive, Room 2327B Diagnostic, treatment, and research. ______Stanford, CA 94305-5821 Bone marrow biopsies. Also adult Contact: Jason Gotlib, MD, MS idiopathic anaphylaxis. Tufts University School of Medicine Associate Professor of Medicine ______136 Harrison Avenue (Hematology) Director, Stanford Boston, MA 02111 Hematology Fellowship Program Massachusetts Contact: Theoharis Theoharides, MD, Director, MPN Center Center of Excellence for Mastocytosis PhD, Professor of Pharm. and Internal Stanford Cancer Institute (and Mast Cell Activation Disorders) Medicine 875 Blake Wilbur Drive, Room 2324 at Brigham and Women’s Hospital and Email: [email protected] Stanford, CA 94305-5821 Dana Farber Cancer Institute Phone: 617-636-6866 Phone: 650-725-0744 Brigham and Women’s Hospital Fax: 617-636-2456 Fax: 650-724-5203 850 Boylston St., Suite 450 Does not see patients in clinic Email: [email protected] Chestnut Hill, MA 02467 ______Specialization: Biopsy proven only; Director: Cem Akin, MD, PhD including systemic mastocytosis Email: [email protected] Minnesota (SM) only, aggressive SM and mast Phone: 617-732-9850 Mayo Clinic Center of Excellence for cell leukemia. Adults. Diagnostic, Fax: 617-731-2748 Mast Cell and Eosinophil Disorders treatment, and research. Associate Director: Mariana Castells, Mayo Clinic – Allergy Department ______MD, PhD W15-B Mayo Clinic Email: [email protected] 200 SW 1st St. Maryland Phone: 617-732-9850 Rochester, MN 55905 National Institutes of Health: National Fax: 617-731-2748 Co-Director: Joseph Butterfield, MD Institute of Allergy and Infectious Contact: Norton J. Greenberger, MD, GI Email: [email protected] Diseases Email: [email protected] Co-Director: Catherine Weiler, MD, PhD NIH, NIAID Phone: 617-732-6389 Email: [email protected] Building 10, Room 11C207 Fax: 617-264-5277 Phone: 507-284-9077 10 Center Drive - MSC1881 Contact: Richard Horan, MD Fax: 507-284-0902 Bethesda, MD 20892-1881 Email: [email protected] Mayo Clinic – Hematology Department Contact: Dean D. Metcalfe, MD, Chief, Phone: 617-732-9850 Contact: Ayalew Tefferi, MD and Laboratory of Allergic Diseases Fax: 617-731-2748 Animesh Pardanani M.B.B.S., PhD Email: [email protected] Contact: Daniel DeAngelo, MD, PhD Phone: (507) 284-5363 Phone: 301-496-2165 Email: [email protected] Specialization: All mast cell related Fax: 301-480-8384 Phone: 617-632-6028 diseases including MCAS/MCAD. Adults Contact: Melody Carter, MD, Pediatrics Address: DFCI, 450 Brookline Ave., and pediatric. Diagnostic, bone marrow Email: [email protected] Dana D1B30 Boston, MA 02215 biopsy, treatment, and research. Specialization: Referrals only. Biopsy Specialization: All mast cell related ______proven only; including systemic diseases including MCAS/MCAD.

24 | The Mastocytosis Chronicles Ohio (SM) only, aggressive SM and mast ______Europe (Active Centers) University of Cincinnati and cell leukemia. Adults. Diagnostic, treatment, and research. Bernstein Allergy Group and Research Austria Center ______Medical University of Vienna 8444 Winton Rd. Denmark Utah Cincinnati, OH 45231 Odense University Hospital The University of Utah School of France Contact: Dr. Jonathan Bernstein, MD Medicine, Department of Internal Email: [email protected] Medicine, Hematology Division Association Française pour les Initiatives de Recherches sur le Phone: 513-931-0775 30 N 1900 E, Room 5C402 Mastocyte et les Mastocytoses Fax: 513-981-0779 Salt Lake City, UT 84132 (AFIRMM) Specialization: All mast cell related Contact: Michael Deininger, MD, PhD Germany diseases including MCAS/MCAD. Phone: 801-585-3229 University of Berlin Adults and pediatric. Diagnostic, Email: [email protected] University of Cologne treatment, and research. Can arrange Specialization: Bone marrow biopsy Technical University Munich Ludwig- bone marrow biopsies. Private family confirmed mastocytosis, aggressive Maximilians-University Munich practice. disease and mast cell leukemia. Greece ______University Hospital of Athens - Attikon Italy Oklahoma Virginia University of Naples University of Oklahoma, Virginia Commonwealth University The Netherlands College of Medicine, P.O. Box 980263 1000 North Lincoln Blvd., Suite 210, 1250 East Marshall St. University Hospital Groningen Oklahoma City, OK 73104 Richmond, VA 23298 Poland Contact: Philip B. Miner Jr., MD, Contact: Dr. Larry Schwartz, MD, PhD University of Gdansk Clinical Professor of Medicine, Internal Medicine: Rheumatology, Portugal President and Medical Director, Allergy, and Immunology University of Porto Oklahoma Foundation for Digestive Email: [email protected] Spain Research Phone: 804-828-9685 Centro de Estudios de Mastocitosis de Email: [email protected] Fax: 804-828-0283 Castilla a Mancha (CLMast) Specialization: All mast cell related Phone: 405-271-4602 Sweden diseases including MCAS/MCAD. Fax: 405-271-3116 Adults and pediatric. Diagnostic, Karolinska University Hospital, ______treatment, and research. Can arrange Stockholm bone marrow biopsies. Switzerland Texas Kantonsspital Aarau, Aarau MD Anderson Cancer Center Turkey 1515 Holcombe Blvd, Unit 428 Houston, TX 77030 University of Istanbul Contact: Srdan Verstovsek, MD, United Kingdom PhD, Associate Professor, Leukemia Guy's and St. Thomas' Trust - London Department Note: For additional current information on Email: [email protected] specialties and contacts within each European Phone: 713-792-7305 center visit: www.ecnm.net Fax: 713-794-4297 Specialization: Systemic mastocytosis

Special Edition 2014 | 25 Medical Advisory Board

Contact Information The Mastocytosis Society, Inc. is a nonprofit volunteer organization guided by a board of medical advisors who donate their time and expertise in support of the TMS mission. They have graciously agreed to act as a point of contact for other physicians and health care providers needing additional information about mastocytosis and mast cell activation disorders.

Lawrence B. Afrin, MD Philip Askenase, MD, Joseph Butterfield, MD Associate Professor of Medicine Chief Section of Allergy and Clinical Co-Director, Mayo Clinic Center Immunology Division of Hematology, Oncology & of Excellence for Mast Cell and Transplantation Department of Internal Medicine Eosinophil Disorders University of Minnesota Yale University School of Medicine W15-B Mayo Clinic 200 SW 1st Street Division of Hematology, Oncology & 333 Cedar Street Rochester, MN 55905 Transplantation New Haven CT 06520 Phone: 507-284-9077 University of Minnesota, MMC 480 Email: [email protected] Fax: 507-284-0902 420 Delaware Street SE Phone: 203-785-4143 Minneapolis, MN 55455 Fax: 203-785-3229 Mariana Castells, MD, PhD Clinical inquiries: Toll-free in the U.S. Associate Director, Mastocytosis and Canada: 855-4-UMP-CANCER; or K. Frank Austen, MD (Honorary) Center of Excellence 612-625-7637 Astra Zeneca Professor of Respiratory Brigham and Women’s Hospital Non-clinical inquiries: 612-624-0130 and Inflammatory Diseases Allergy and Clinical Immunology E-mail: [email protected] Department of Medicine Brigham and 850 Boylston Street, Suite 540 Women’s Hospital Chestnut Hill, MA 02467 Cem Akin, MD, PhD Smith Building, Room 638 Email: [email protected] Director, Mastocytosis Center of One Jimmy Fund Way Phone: 617-732-9850 Excellence Boston, MA 02115 Fax: 617-731-2748 Brigham and Women’s Hospital Email: [email protected] Allergy and Clinical Immunology Phone: 617-525-1300 Luis Escribano, MD, PhD, 850 Boylston Street, Suite 540 Fax: 617-525-1310 Coordinator, Spanish Network on Chestnut Hill, MA 02467 Mastocytosis (REMA) Associated Email: [email protected] Research, Servicio de Citometría, Phone: 617-732-9850 Centro de Investigación del Cáncer, Fax: 617-731-2748 Universidad de Salamanca Salamanca, Spain E-mail: [email protected]

Jason Gotlib, MD, MS Associate Professor of Medicine (Hematology), Director, Stanford Hematology Fellowship Program Director, MPN Center Stanford Cancer Institute 875 Blake Wilbur Drive, Room 2324 Stanford, CA 94305-5821 Email: [email protected] Phone: 650-725-0744 Fax: 650-724-5203

26 | The Mastocytosis Chronicles Norton J. Greenberger, MD Larry Schwartz, MD, PhD Srdan Verstovsek, MD, PhD Clinical Professor of Medicine/ Internal Medicine: Rheumatology, Associate Professor Gastroenterology Allergy, and Immunology Leukemia Department Harvard Medical School Virginia Commonwealth University MD Anderson Cancer Center 1515 Senior Physician P.O. Box 980263 Holcombe Blvd, Unit 428 Brigham and Women’s Hospital 1250 East Marshall Street Houston, TX 77030 75 Francis Street Richmond, VA 23298 Email: [email protected] Boston, MA 02115 Email: [email protected] Phone: 713-792-7305 Email: [email protected] Phone: 804-828-9685 Fax: 713-794-4297 Phone: 617-732-6389 Fax: 804-828-0283 Fax: 617-264-5277 Catherine Weiler, MD, PhD Theoharis Theoarides, MD, PhD Co-Director, Mayo Clinic Center Richard Horan, MD Professor of Pharmacology and of Excellence for Mast Cell and Brigham and Women’s Hospital Internal Medicine Eosinophil Disorders Allergy and Clinical Immunology Tufts University School of Medicine Assistant Professor of Medicine 850 Boylston Street, Suite 540 136 Harrison Avenue Division of Allergy, Department Chestnut Hill, MA 02467 Boston, MA 02111 of Medicine Email: [email protected] Phone: 617-636-6866 200 SW 1st Street Phone: 617-732-9850 Fax: 617-636-2456 Rochester, MN 55905 Fax: 617-731-2748 Email: [email protected] Email: [email protected] Phone: 507-284-9077 Nicholas Kounis, MD, PhD Ivan Alvarez-Twose, MD Fax: 507-284-0902 Patras Highest Institute of Education Staff Physician and Clinical and Technology Coordinator, Instituto de Estudios de Mastocitosis de Castilla La Mancha Professor of Medicine in Cardiology (CLMast) Department of Medical Sciences Toledo, Spain 7 Aratou St. Queen Olgas Square Phone: 0034-615-653-157 Patras 26221, Greece Email: [email protected] Email: [email protected] Phone: +302610279579 Peter Valent, MD Fax: +302610279579 Department of Internal Medicine I Division of Hematology and Philip B. Miner Jr., MD Hemostaseology President and Medical Director University of Vienna Oklahoma Foundation for Währinger Gürtel 18-20 Digestive Research A-1090 Vienna, Austria Clinical Professor of Medicine Email: [email protected] University of Oklahoma, College Phone:+43-1 40400-5488 or -6086 of Medicine Fax:+43 1 40400 4030 1000 North Lincoln Blvd., Suite 210 Oklahoma City, OK 73104 Phone: 405-271-4602 Fax: 405-271-3116 Email: [email protected]

Special Edition 2014 | 27 The Mastocytosis Society Printed Materials

Mastocytosis and mast cell activation disorders are complicated and not well-known diseases. To help educate and spread awareness, The Mastocytosis Society, Inc. (TMS) is pleased to offer informational material to physicians and patients.

Tri-fold Informational Brochures Symptoms, diagnosis and treatment of mast cell disorders.

Card and Brochure Dimensions: Spot Card, Generic Business...... 2" x 3.5" Mast Cell Patient and Emergency ...... 3" x 4" Informational Brochure, Tri-fold ...... 8.5" x 11"

Images not to scale

28 | The Mastocytosis Chronicles Mast Cell Patient Emergency Card Mast Cell Patient Card

Infant Card Generic Business Card

Ordering Information TMS printed material will be provided free of charge to medical personnel, members and non-members. Donations are gladly accepted. When requesting material, please include the following:

Name______Tri-fold Informational Brochures ❍ Emergency Care For Mast Cell Disorder Patients ❍ Systemic Mastocytosis Including Indolent & Address______Aggressive Variants ❍ Mastocytosis and Mast Cell Activation Disorders City ______

Cards State ______Zip______❍ Spot Card ❍ Generic Business Cards Phone ______❍ Mast Cell Patient Emergency Card ❍ Mast Cell Patient Card Email______

Special Edition 2014 | 29 MEDICAL RESOURCES: Mastocytosis and Mast Cell Activation Syndromes

International Consensus Statements and WHO 4. Valent P, Akin C, Escribano L, Fodinger M, Criteria1-6 Hartmann K, Brockow K, et al. Standards and standardization in mastocytosis: consensus Reviews and Expert Opinions7-21 statements on diagnostics, treatment recommendations and response criteria. Eur J Clin Laboratory Tests, Pathology, Immunohistology and Invest. 2007 Jun;37(6):435-53. Flow Cytometry11, 13, 14, 17, 22-25 5. Valent P, Horny H-P, Li CY, Longley JB, Metcalfe Pre-Medication Prior to Dental Work, Diagnostic DD, Parwaresch RM, et al. Mastocytosis. Jaffe Testing or Surgical Procedures10, 26, 27 ES, Harris NL, Stein H, Vardiman JW, editors. World Health Organization (WHO) Classification Therapy9, 10, 15-17, 28-30 of Tumours. Pathology and Genetics. Tumours of Haematopoietic and Lymphoid Tissues. Lyon: The Mastocytosis Society Survey on Mast Cell IARC Press; 2001. Disorders31 6. Valent P, Horny HP, Escribano L, Longley BJ, Li CY, Schwartz LB, et al. Diagnostic criteria and classification of mastocytosis: a consensus 1. Gotlib J, Pardanani A, Akin C, Reiter A, George proposal. Leuk Res. 2001 Jul;25(7):603-25. T, Hermine O, et al. International Working Group- Myeloproliferative Neoplasms Research and 7. Akin C, Valent P, Metcalfe DD. Mast cell activation Treatment (IWG-MRT) & European Competence syndrome: proposed diagnostic criteria. J Allergy Network on Mastocytosis (ECNM) consensus Clin Immunol. 2010 Dec;126(6):1099-104 e4. response criteria in advanced systemic mastocytosis. Blood. 2013 Mar 28;121(13):2393-401. 8. Valent P. Mastocytosis: a paradigmatic example of a rare disease with complex biology and pathology. 2. Valent P, Akin C, Arock M, Brockow K, Butterfield Am J Cancer Res. 2013;3(2):159-72. JH, Carter MC, et al. Definitions, criteria and global classification of mast cell disorders with special 9. Carter MC, Metcalfe DD, Komarow HD. reference to mast cell activation syndromes: a Mastocytosis. Immunol Allergy Clin North Am. consensus proposal. Int Arch Allergy Immunol. 2014 Feb;34(1):181-96. 2012;157(3):215-25. 10. Fried AJ, Akin C. Primary mast cell disorders 3. Horny HP, Akin C, Metcalfe DD, Escribano L, in children. Curr Allergy Asthma Rep. 2013 Bennett JM, Valent P, et al. Mastocytosis (mast Dec;13(6):693-701. cell disease) Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al., editors. 11. Torrelo A, Alvarez-Twose I, Escribano L. World Health Organization (WHO) Classification Childhood mastocytosis. Curr Opin Pediatr. 2012 of Tumours. Pathology and Genetics. Tumours Aug;24(4):480-6. of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2008. 12. Pardanani A. Systemic mastocytosis in adults: 2013 update on diagnosis, risk stratification, and management. Am J Hematol. 2013 May 30.

30 | The Mastocytosis Chronicles 13. Alvarez-Twose I, Morgado JM, Sanchez-Munoz 22. Horny HP, Sotlar K, Valent P. Evaluation of mast L, Garcia-Montero A, Mollejo M, Orfao A, et al. cell activation syndromes: impact of pathology Current state of biology and diagnosis of clonal and immunohistology. Int Arch Allergy Immunol. mast cell diseases in adults. Int J Lab Hematol. 2012;159(1):1-5. 2012 Oct;34(5):445-60. 23. Horny HP, Sotlar K, Valent P. Mastocytosis: state 14. Valent P. Mast cell activation syndromes: definition of the art. Pathobiology. 2007;74(2):121-32. and classification. Allergy. 2013 Apr;68(4):417-24. 24. Horny HP, Valent P. Diagnosis of mastocytosis: 15. Lee MJ, Akin C. Mast cell activation syndromes. general histopathological aspects, morphological Ann Allergy Asthma Immunol. 2013 Jul;111(1):5-8. criteria, and immunohistochemical findings. Leuk Res. [Review]. 2001 Jul;25(7):543-51. 16. Picard M, Giavina-Bianchi P, Mezzano V, Castells M. Expanding spectrum of mast cell 25. Escribano L, Garcia Montero AC, Nunez R, Orfao A. activation disorders: monoclonal and idiopathic Flow cytometric analysis of normal and neoplastic mast cell activation syndromes. Clin Ther. 2013 mast cells: role in diagnosis and follow-up of mast May;35(5):548-62. cell disease. Immunol Allergy Clin North Am. 2006 Aug;26(3):535-47. 17. Cardet JC, Castells MC, Hamilton MJ. Immunology and clinical manifestations of non-clonal mast cell 26. Dewachter P, Castells MC, Hepner DL, Mouton- activation syndrome. Curr Allergy Asthma Rep. Faivre C. Perioperative Management of Patients 2013 Feb;13(1):10-8. with Mastocytosis. Anesthesiology. 2013 Oct 16.

18. Afrin LB. Presentation, diagnosis and management 27. Carter MC, Uzzaman A, Scott LM, Metcalfe of mast cell activation syndrome. In: Murray DB, DD, Quezado Z. Pediatric mastocytosis: routine editor. Mast cells: phenotypic features, biological anesthetic management for a complex disease. functions and role in immunity. Hauppauge: Nova Anesth Analg. 2008 Aug;107(2):422-7. Science Publishers, Inc.; 2013. p. 155-232. 28. Cardet JC, Akin C, Lee MJ. Mastocytosis: update 19. Georgin-Lavialle S, Lhermitte L, Dubreuil P, on pharmacotherapy and future directions. Expert Chandesris MO, Hermine O, Damaj G. Mast cell Opin Pharmacother. 2013 Oct;14(15):2033-45. leukemia. Blood. 2013 Feb 21;121(8):1285-95. 29. Verstovsek S. Advanced systemic mastocytosis: 20. Georgin-Lavialle S, Aguilar C, Guieze R, Lhermitte the impact of KIT mutations in diagnosis, L, Bruneau J, Fraitag S, et al. Mast cell sarcoma: treatment, and progression. Eur J Haematol. 2013 a rare and aggressive entity--report of two cases Feb;90(2):89-98. and review of the literature. J Clin Oncol. 2013 Feb 20;31(6):e90-7. 30. Ustun C, DeRemer DL, Akin C. Tyrosine kinase inhibitors in the treatment of systemic mastocytosis. 21. Ryan RJ, Akin C, Castells M, Wills M, Selig MK, Leuk Res. 2011 Sep;35(9):1143-52. Nielsen GP, et al. Mast cell sarcoma: a rare and potentially under-recognized diagnostic entity with 31. Jennings S, Russell N, Jennings B, Slee V, Sterling specific therapeutic implications. Mod Pathol. L, Castells M, et al. The Mastocytosis Society 2013 Apr;26(4):533-43. Survey on Mast Cell Disorders: Patient Experiences and Perceptions. J Allergy Clin Immunol Pract. 2014;2(1):70-6.

Special Edition 2014 | 31 2014 Supporting Members*

Dr. Lawrence Afrin TITANIUM December 2012 Georgia S. Deifendorf COPPER June 2013 Rebekah Hines COPPER December 2012 Anne D. Ewart SILVER June 2013 Sandy Johnson COPPER January 2013 Cynthia Scott COPPER June 2013 Rita U. Kelly COPPER January 2013 Cary Wasinger COPPER June 2013 Stephanie King COPPER January 2013 Patricia Zarb TITANIUM June 2013 Stanley & Stephen Botticello COPPER July 2013 Penny Boney TITANIUM January 2013 Mishele & Janet Nordstrom COPPER February 2013 Casey Cunningham PLATINUM July 2013 Terry Lambert COPPER February 2013 Kristine Greer COPPER July 2013 S. Scott Roth PLATINUM March 2013 Erin Kolb COPPER July 2013 Steve Uebelhor GOLD March 2013 L. Dale Lincoln COPPER July 2013 Jerri Askling COPPER April 2013 Regina Rentz COPPER August 2013 Craig Ciarlelli GOLD April 2013 Mike & Velma Rinks PLATINUM August 2013 Martha W. Grant GOLD April 2013 Jill & Ken Shuck COPPER August 2013 Dee Klein COPPER April 2013 Dr. Janice Chiappone COPPER September 2013 D.K. Selover GOLD April 2013 Rick & Doris Hoopes TITANIUM September 2013 Andrew & Valerie Slee SILVER April 2013 Mark Humphrey COPPER September 2013 Stephen Walker PLATINUM April 2013 Gary & Dona Shockey COPPER September 2013 Susan Yadon COPPER April 2013 Beth Zinman COPPER September 2013 Dr. Michelle Burnett SILVER May 2013 Jean & Tom Hammen GOLD October 2013 Jim & Betty McKee GOLD May 2013 G.J. & Linda Leitch SILVER October 2013 Tara Notrica COPPER May 2013 Timothy Milicich, Sr. COPPER October 2013 Debra Schankweiler SILVER May 2013 *Members who have given beyond their annual $35 dues when renewing their membership or starting a membership are considered Supporting Members. Cynthia Bemis COPPER June 2013 (This does not include those who made major contributions to other initiatives/ Carolyn & funds such as the Walk-a-thon or the TMS Conference, but rather designates Nicholas Chingros GOLD June 2013 different levels of donations made at time of membership dues) Thank You!

32 | The Mastocytosis Chronicles Support Group Contacts United States Arkansas Southeast Northeast [email protected] Patty Smith Rita Barlow Arizona, Phoenix 413-862-4556 [email protected] Rachael Nathan [email protected] St. Louis Sean-Michael Gettys New Jersey Cheri Smith 952-905-6778 Marge Holtzman 618-444-6000 [email protected] [email protected] [email protected] Arizona, Tucson Southwest Northern California Kim Bonhoff [email protected] Michelle Lamanna [email protected] [email protected] Utah Chicago Tiffany McKibben Patti DalBello North Carolina [email protected] 847-767-4916 Sharon Renfroe [email protected] Celeste Thomason [email protected] Virginia Colorado Kay Butler Jan Marie Smith North Central 804-642-1542 719-221-9304 Mishele Cunningham [email protected] [email protected] [email protected] Washington DC Florida Ohio Patricia Beggiato Michele Kress/Sandy Johnson Allie Barnett/ Linda Buchheit [email protected] [email protected] [email protected]

Illinois/Missouri Oklahoma Cheri Smith Christal Boxberger 618-444-6000 405-255-2299 [email protected] [email protected]

Kansas City Pennsylvania Ann Kingman Kathie Murphy [email protected] [email protected] Michigan South Carolina Julia Stewart Celeste Thomason 248-545-7145 864-325-8840 [email protected] [email protected] Minnesota Southern California Mishele Cunningham Davita Greenwald and Janet Bender 952-905-6778 [email protected] [email protected] Nebraska Jim and Betty McKee [email protected] Navada, Las Vegas Jill Rosen-Zamir [email protected]

Special Edition 2014 | 33 The Mastocytosis Society PO Box 129 Hastings, NE 68902-0129

Membership Application Form

Applicant Information (please type or print): ! Name: ______Child Member’s Name:______! Address: ______! City: ______State:______Zip:______Country:______! Phone: ______E-Mail:______! Member: _____ Relative ______Spouse_____Child______Caregiver ______Friend ______! Membership Type: New ($35)______Renewal ($35) ______Supporting Member ______! Supporting Members are listed in The Mastocytosis Chronicles and will receive a thank you gift. Copper Member ( $75 ) ______Silver Member ( $150 ) ______Gold Member ( $250 ) ______Platinum Member ( $500 ) ______Titanium Member ( $1000 ) ______! Check Enclosed_____ Money Order Enclosed _____ Paid Online _____ Online Payment Option: http://www.tmsforacure.org/membership_form.php

Would you like to double your annual contribution! to include a donation to the Angel Fund for individuals with a mast cell disease who are unable to pay the annual membership fee of $35?

Yes _____ No ______Total amount to be paid :______(i.e., $35 dues plus one (1) Angel Fund donation of $35 is $70 total) Make check or money order payable to The Mastocytosis Society, and send to: The Mastocytosis Society, c/o Treasurer, P.O. Box 129, Hastings, NE 68902-0129 ! ANGEL FUND WAIVERS Patients who are unable to afford to pay dues at this time can have their dues waived through the “Angel Fund Program”. This Program was established to assist Patients with a Mast Cell Disorder to pay their dues. If you would like for your dues to be paid through the “Angel Program” due to financial hardship, please send a letter requesting an Angel Fund Waiver (to the address above) or an email to [email protected]. Those who are interested in learning more about the disease who are not patients, but would like their membership fee waived because of financial difficulties, may send a letter to the Board of Directors (to the address above) or an email to [email protected] requesting a waiver.

The Mastocytosis Society, Inc., PO Box 129, Hastings, NE 68902-0129 34 | The Mastocytosis Chronicles The Mastocytosis Society PO Box 129 Hastings, NE 68902-0129

Membership Application Form

Applicant Information (please type or print): ! Name: ______Child Member’s Name:______! Address: ______! City: ______State:______Zip:______Country:______! Phone: ______E-Mail:______! Member: _____ Relative ______Spouse_____Child______Caregiver ______Friend ______! Membership Type: New ($35)______Renewal ($35) ______Supporting Member ______! Supporting Members are listed in The Mastocytosis Chronicles and will receive a thank you gift. Copper Member ( $75 ) ______Silver Member ( $150 ) ______Gold Member ( $250 ) ______Platinum Member ( $500 ) ______Titanium Member ( $1000 ) ______! Check Enclosed_____ Money Order Enclosed _____ Paid Online _____ Online Payment Option: http://www.tmsforacure.org/membership_form.php

Would you like to double your annual contribution! to include a donation to the Angel Fund for individuals with a mast cell disease who are unable to pay the annual membership fee of $35?

Yes _____ No ______Total amount to be paid :______(i.e., $35 dues plus one (1) Angel Fund donation of $35 is $70 total) Make check or money order payable to The Mastocytosis Society, and send to: The Mastocytosis Society, c/o Treasurer, P.O. Box 129, Hastings, NE 68902-0129 ! ANGEL FUND WAIVERS Patients who are unable to afford to pay dues at this time can have their dues waived through the “Angel Fund Program”. This Program was established to assist Patients with a Mast Cell Disorder to pay their dues. If you would like for your dues to be paid through the “Angel Program” due to financial hardship, please send a letter requesting an Angel Fund Waiver (to the address above) or an email to [email protected]. Those who are interested in learning more about the disease who are not patients, but would like their membership fee waived because of financial difficulties, may send a letter to the Board of Directors (to the address above) or an email to [email protected] requesting a waiver.

The Mastocytosis Society, Inc., PO Box 129, Hastings, NE 68902-0129 Special Edition 2014 | 35 The Mastocytosis Chronicles P.O. Box 129 Hastings, NE 68902

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Visit the Mastocytosis Society website at www.tmsforacure.org

The Mastocytosis Society, Inc. would like to invite you to stop by our exhibitor booth at any of the following Medical Conferences.

American Academy of Pediatrics American Society of Hematology American College of Allergy Asthma and Immunology American Academy of Allergy Asthma and Immunology