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© 2020-2021 The Mastocytosis Society, Inc. All rights reserved Mast Cell Diseases

SPECIAL EDITION HEALTH CARE PROFESSIONALS EDITION

The Mastocytosis ChroniclesThe Mastocytosis Society, Inc. | 2020-2021, Volume 2

2 tmsforacure.org | Special Edition 2020-2021

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, with 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 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. Since then there have been many more champions who have served their fellow patients and families affected by Mastocytosis and Mast Cell Activation Diseases 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!

Our History

3tmsforacure.org | Special Edition 2020-2021

In this issue

5 Overview, Definitions, Diagnosis and Classification

9 Cytology of Mast Cells

10 Cutaneous Mastocytosis Variants

12 Systemic Mastocytosis Variants

16 Mast Cell Activation Syndrome Variants

17 Hereditary Alpha Tryptasemia

18 Signs, Symptoms And Triggers

21 Tests

25 Treatments For Mast Cell Diseases

27 Medications To Treat Mast Cell Diseases

29 Pediatric Mast Cell Diseases: Facts in Brief

34 Visual Guide to Diagnosing Mastocytosis

38 Medical & Research Centers that Treat Patients with Mast Cell Diseases

41 Medical Advisory Board

43 Support Group Contacts

44 Mast Cell Connect Patient Registry Brochure

The Mastocytosis ChroniclesThe Mastocytosis Society, Inc. | 2020-2021 - Volume 24

American Initiative in Mast Cell Diseases (AIM)

By Susan Jennings, PhD, and Valerie Slee, RN, BSN – September 2019

Since 2014, The Mastocytosis Society, Inc. (TMS) has hosted small ancillary Mast Cell Disorder Challenges meetings during specialty medical conferences. The objectives of these meetings have been to bring together specialist physicians, drug company representatives and members of the TMS Research Committee to identify primary challenges facing the mast cell disease community in the United States and to explore possible actions to address those challenges. A key conclusion from our initial meetings was that the establishment of a US network for mast cell diseases would be extremely helpful in overcoming many of the challenges faced by our disease community. During these meetings, our US physicians have received significant support from many international mast cell disease specialists, who have shared their experiences of forming networks in their own countries and more broadly in Europe. TMS has collaborated with a committee established for the formation of an American network, under the direction of Jason Gotlib, MD, MS, and Cem Akin, MD, PhD, as Co-Chairs. In May 2019, the TMS Patient/Caregiver Conference was paired with the inaugural investigator meeting of the American Initiative in Mast Cell Diseases (AIM). AIM will be a network of centers established across North, Central and South America, with a goal of excellence in patient diagnosis and treatment, and collaboration on research initiatives. AIM will collaborate closely with the European Competence Network on Mastocytosis (ECNM), which has centers established throughout Europe.

Please see www.aimcd.net for more information on the American Initiative in Mast Cell Diseases.

tmsforacure.org | Special Edition 2020-20214

Committees

Advanced Systemic Mastocytosis Variants([email protected])Valerie M. Slee, RN, BSN, ChairMichele Q. Kress, Smoldering SM Liaison

Drug Shortage([email protected])Valerie M. Slee, RN, BSN, Co-ChairEmily A. Menard, Co-ChairCarlene Bartolotta RN, BSN

Education([email protected])Gail Barbera, Chair

Fundraising([email protected])Counrtney Rabb, Chair

International Mastocytosis & Mast Cell Diseases CommitteeGail Barbera, USA RepresentativeJodylynn Bachiman, Website Design Committee

Media Relations([email protected])Ariella Cohen, JD, Chair

Medical Conference Planning([email protected])Kathy TomasicChantelle Bosco, Materials Management

Patient Care Coordination([email protected])Jan Hempstead, RN, Chair

Pediatric([email protected])Wendy Garr Ringer, Chair

Political and Patient Advocacy([email protected])Jennifer Lockhart, Chair

Research([email protected])Susan Jennings, PhD, Chair

Support Groups([email protected])Gail Barbera, Interim Support Group ChairJan Hempstead, RN Patient Care Coordination ChairEmily Bolden, Interim Support Group Coordinator

Website Content([email protected])Gail Barbera, Co-ChairSusan Jennings, PhD, Co-Chair

SUPPORTING CONTRACTORS

Graphic DesignersRachael ZinmanJohn Gilligan

Webmaster([email protected])Ben Rabb

TMS Medical Advisory Board

TMS is proud to be a Lay Organization member of The AmericanAcademy of Allergy Asthma and Immunology (AAAAI)

TMS is a long-standing member of the National Organization for Rare Disorders (NORD)

We thank each of these doctors for their time, caring, and expertise.

Ivan Alvarez-Twose, MDK. Frank Austen, MD (Honorary)Patrizia Bonadonna, MDJoseph Butterfield, MDMariana Castells, MD, PhD Madeleine Duvic, MDLuis Escribano, MD, PhD,

Tracy I. George, MD Jason Gotlib, MD, MSNorton J. Greenberger, MD (Honorary)Matthew J. Hamilton, MDOlivier Hermine, MD, PhDNicholas Kounis, MD, PhD

Anne Maitland, MD, PhDLarry Schwartz, MD, PhD Theoharis Theoharides, MD, PhD Megha Tollefson, MDCelalettin Ustun, M.D.Peter Valent, MDSrdan Verstovsek, MD, PhD

Special Edition For Health Care Professionals

The special edition of The Mastocytosis Chronicles has been published specifically for physicians and health care professionals since 2007. This edtion contains diagnostic and treatment information for mastocytosis and mast cell activation diseases, locations of mast cell disease treatment centers, physician contact information, documentation of research articles, and other pertinent information. For additional information visit www.tmsforacure.org.

Board of DirectorsExecutive Board/Officers Valerie M. Slee RN, BSN: Chair Medical Advisory Board Liaison [email protected]

Jan Hempstead, RN: Interim Vice Chair Patient Care Coordination Chair [email protected]

Gail Barbera: Secretary Education Chair [email protected] [email protected]

Rosemary Schultz: Interim Treasurer [email protected]

Other Board Members/Directors

Courtney Rabb: Fundraising Chair [email protected]

Jennifer Lockhart: Advocacy Chair [email protected]

Rita Barlow: Retired, Director Emeritus

Our MissionThe Mastocytosis Society, Inc. is dedicated to providing multi-faceted support to patients, families and medical professionals in our community and to leading the advancement of knowledge and research in mast cell diseases through education, advocacy and collaboration.


What are Mast Cells?

Mast cells (MC) are immune system cells that live in the bone marrow and in body tissues, internal and external, such as the gastrointestinal tract, the lining of the airway, and the skin. Everyone has mast cells in their body, and they play many complex and critical roles in keeping us healthy. The positive roles that they play include protecting us from infection, and helping our body by participating in the inflammatory process. However, mast cells are also involved in allergic reactions, from the tiny swelling that appears after a mosquito bite to a life threatening, full-blown anaphylaxis.

Mast cells have within them small sacs, or granules, surrounded by membranes (Figure 1). The sacs contain many different kinds of substances called mediators, which participate in all of the roles above, including allergic response and anaphylaxis. The mediators are selectively released when there is an allergic or mast cell based reaction.1

There is a difference between someone who is healthy, with mast cells that are functioning normally, and someone with a mast cell disease, whose mast cells may be activating inappropriately, sometimes in response to triggers, or may also be proliferating and accumulating in organ tissues.

What are Mast Cell Diseases?

Mast cell diseases are caused by the proliferation and accumulation of genetically altered mast cells and/or the inappropriate release of mast cell mediators, creating

symptoms in multiple organ systems.2 The three major forms of mast cell diseases are mastocytosis,

mast cell activation syndromes (MCAS), and hereditary alpha tryptasemia (HaT). HaT

is caused by a duplication or triplication of the alpha-tryptase gene.2a Mast

cell diseases can cause tremendous suffering and disability due to symptomatology from recurrent mast cell mediator release, and/or symptoms arising from infiltration and accumulation of mast cells in

major organ systems. In addition, those suffering from HaT may

experience additional symptoms from

Mast cell granule (sac) which contains mediators

Figure 1. Mast cell (electron micrograph)

MAST CELLS AND MAST CELL DISEASES

Overview, Definitions, Diagnosis and Classification

Continued on page 6


Overview, Definitions, Diagnosis and ClassificationContinued from page 5

dysautonomia and connective tissue disease. Although systemic mastocytosis is a rare disease,3 those suffering with MCAS and/or HaT have recently been increasingly recognized and diagnosed. As a result, patients with MCAS and/or HaT appear to represent a growing proportion of the mast cell disease patient population.4, 5

It is important to note that the process of mast cell activation can occur in anyone, even without a mast cell disease, as well as in patients with mastocytosis, MCAS, and HaT.6

MASTOCYTOSIS

Definition

Mastocytosis has been defined in the literature as an abnormal accumulation

of mast cells in one or more organ systems. Previously classified by the

World Health Organization (WHO) as a myeloproliferative neoplasm, mastocytosis is now classified in its own category under myeloid neoplasms.7 Broadly separated into three categories – cutaneous mastocytosis (CM), systemic mastocytosis (SM) and mast cell

sarcoma – these diseases occur 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 in

early adulthood.8-10 In pediatric mastocytosis, symptoms of mast cell mediator release may

occur systemically as a result of mast cell mediators released from skin lesions.10 This, however, does not necessarily indicate systemic disease. The incidence of systemic pediatric disease was previously unknown, but systemic forms have now been proven to exist in some children.8-10 The majority of adult patients are diagnosed with systemic disease. Skin involvement,

typically maculopapular cutaneous mastocytosis/urticaria pigmentosa, is common in adult patients and can provide an important clue to accurate diagnosis.11, 12

Diagnosis and Classification13-17

CM is diagnosed by the presence of typical skin lesions and a positive skin biopsy demonstrating characteristic clusters of mast cells. The preferred method of diagnosing SM is via bone marrow (BM) biopsy. The WHO has established criteria for diagnosing SM, summarized18 as follows:

Major ª: Multifocal dense infiltrates of mast cells (MCs) (> 15 MCs in aggregate) in tryptase stained biopsy sections of the bone marrow or other extracutaneous organ

Minorª: • More than 25% of MCs in bone marrow or

other extracutaneous organ(s) show abnormal morphology (i.e. are atypical MC type 1 or are spindle–shaped MCs) in multifocal lesions in histologic examination

• KIT mutation at codon 816V in extracutaneous organ(s) (in most cases bone marrow cells are examined)

• KIT+MCs in bone marrow show aberrant expression of CD2 and/or CD25

• Serum total tryptase > 20 ng/mL (does not count in patients who have SM-AHN-type disease.)

Abbreviation Key: KIT: Mast cell growth receptor/tyrosine kinase receptor MC(s): Mast cells; SM-AHN: Systemic mastocytosis with associatiated hematologic neoplasm.

ª If at least one major criterion and one minor criterion OR at least three minor criteria are fulfilled, the diagnosis of systemic mastocytosis can be established. b Activating mutations at codon 816, in most cases, KIT D816V.


MAST CELL ACTIVATION SYNDROMES

Definition

Existence of a subset of mast cell disease patients who experience episodes of mast cell activation without detectable evidence of a proliferative mast cell disease was postulated over 20 years ago.19, 20 Over the last two decades, with development of improved methodology for identification of abnormal mast cells,21-24 it became apparent that there were patients who exhibited symptoms of mast cell mediator release who did not fulfill the criteria for SM.25, 26 Thus began the evolution of discussions about other forms of mast cell diseases, both clonal and nonclonal, which became known as Mast Cell Activation Syndromes (MCAS).6, 27, 28

Diagnosis and Proposed Classification

Recognition by specialist physicians of the importance of mast cell activation in disease led to an international Mast Cell Disorders Working Conference emphasizing this topic in September of 2010. Consensus statements were published regarding classification of and diagnostic criteria for mast cell diseases,6 where mast cell activation plays a prominent role.

Mediators produced by mast cells have a considerable effect on specific symptomatology. Symptoms, including, but not limited to flushing, pruritis (itching), urticaria (hives), headache, gastrointestinal symptoms (including diarrhea, nausea, vomiting, abdominal pain, bloating, gastroesophageal reflux), and hypotension (low blood pressure), allow a patient to meet the first of three required co-criterion for systemic mast cell activation when the patient exhibits symptoms involving two or more organ systems in parallel, which recur, or are chronic, are found not to be caused by any other condition or disorder other than mast cell activation, and require treatment or therapy.6, 28

The second required co-criterion for systemic mast cell activation depends on documentation that mast cells are directly involved in the symptomatology. An increase in the serum level of tryptase, above baseline and within a narrow (generally accepted as one to two hour) window of time after a symptomatic episode, is proposed as the preferred method for providing evidence of mast cell involvement according to these criteria.6, 28-30 The consensus article provides a method for calculating the required minimum rise in serum tryptase.6 After a reaction, a level of serum tryptase that is a minimum of 20% above the basal serum tryptase level, plus 2 ng/ml, will meet the second criterion listed above for a mast cell activation event. Consensus members also agreed that when serum tryptase evaluation is not available or when the tryptase level does not rise sufficiently to meet the required increase for the co-criterion, other mediator tests could suffice. A rise in urinary n-methyl histamine, prostaglandin-D2, or its metabolite, 11β-prostaglandin-F2α (24-hour or spot urine test for any of the three), is considered an alternative for the co-criterion related to a requirement for a mast cell mediator level rise during a systemic mast cell activation event.6

Finally, the third co-criterion requires a response (based on response criteria15) to medications that inhibit the action of histamine.6 In addition, in those with typical mast cell activation symptoms, a “complete or major” response to drugs that inhibit other mediators produced by mast cells or block mast cell mediator release can be regarded as fulfillment of the third co-criterion for MCAS.6, 28

Continued on page 8


Mast cell types Morphology Types of disease

Normal/reactive Round, well-granulated, with granules that fill the cytoplasm and obscure the nucleus; round to oval nucleus

Normal marrow, mast cell hyperplasia, well differentiated SM

Atypical type I

(spindle shaped)

Hypogranular, enlarged, with cytoplasmic projections

Indolent SM, ASM, SM-AHN

Atypical type II

(promastocyte)

Enlarged and round, hypogranular; indented bilobed nuclei

Mast cell leukemia, myelomastocytic leukemia

Metachromatic blast

(immature)

Hypogranular with a few large metachromatic granules; high nuclear-to-cytoplasm ratio; smooth chromatin in nuclei


References

1. Gilfillan AM, Austin SJ, Metcalfe DD. Mast cell biology: introduction and overview. Adv Exp Med Biol. 2011;716:2-12.

2. Theoharides TC, Valent P, Akin C. Mast Cells, Mastocytosis, and Related Disorders. N Engl J Med. 2015 Jul 9;373(2):163-72.

2a. Lyons JJ, Yu X, Hughes JD, Le QT, Jamil A, Bai Y, et al. Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number. Nat Genet. 2016 Dec;48(12):1564-9.

3. Horny HP, Sotlar K, Valent P, Hartmann K. Mastocytosis: a disease of the hematopoietic stem cell. Dtsch Arztebl Int. 2008 Oct;105(40):686-92.

4. Akin C, Valent P, Metcalfe DD. Mast cell activation syndrome: proposed diagnostic criteria. J Allergy Clin Immunol. 2010 Dec;126(6):1099-104 e4.

5. Afrin LB. Presentation, diagnosis and management of mast cell activation syndrome. In: Murray DB, editor. Mast cells: phenotypic features, biological functions and role in immunity. Hauppauge: Nova Science Publishers, Inc.; 2013. p. 155-232.

6. Valent P, Akin C, Arock M, Brockow K, Butterfield JH, Carter MC, et al. Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal. Int Arch Allergy Immunol. 2012;157(3):215-25.

7. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016 May 19;127(20):2391-405.

8. Torrelo A, Alvarez-Twose I, Escribano L. Childhood mastocytosis. Curr Opin Pediatr. 2012 Aug;24(4):480-6.

9. Fried AJ, Akin C. Primary mast cell disorders in children. Curr Allergy Asthma Rep. 2013 Dec;13(6):693-701.

10. Meni C, Bruneau J, Georgin-Lavialle S, Le Sache de Peufeilhoux L, Damaj G, Hadj-Rabia S, et al. Paediatric mastocytosis: a systematic review of 1747 cases. Br J Dermatol. 2015 Mar;172(3):642-51.

11. Berezowska S, Flaig MJ, Rueff F, Walz C, Haferlach T, Krokowski M, et al. Adult-onset mastocytosis in the skin is highly suggestive of systemic mastocytosis. Mod Pathol. 2014 Jan;27(1):19-29.

12. Hartmann K, Escribano L, Grattan C, Brockow K, Carter MC, Alvarez-Twose I, et al. Cutaneous manifestations in patients with mastocytosis: Consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology. J Allergy Clin Immunol. 2016 Jan;137(1):35-45.

13. Valent P, Horny HP, Escribano L, Longley BJ, Li CY, Schwartz LB, et al. Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res. 2001 Jul;25(7):603-25.

14. Valent P, Horny H-P, Li CY, Longley JB, Metcalfe DD, Parwaresch RM, et al. Mastocytosis. Jaffe ES, Harris NL, Stein H, Vardiman JW, editors. World Health Organization (WHO) Classification of Tumours. Pathology and Genetics. Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2001.

15. Valent P, Akin C, Escribano L, Fodinger M, Hartmann K, Brockow K, et al. Standards and standardization in mastocytosis: consensus

statements on diagnostics, treatment recommendations and response criteria. Eur J Clin Invest. 2007 Jun;37(6):435-53.

16. Horny HP, Akin C, Metcalfe DD, Escribano L, Bennett JM, Valent P, et al. Mastocytosis (mast cell disease) Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al., editors. World Health Organization (WHO) Classification of Tumours. Pathology and Genetics. Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2008.

17. Valent P, Escribano L, Broesby-Olsen S, Hartmann K, Grattan C, Brockow K, et al. Proposed diagnostic algorithm for patients with suspected mastocytosis: a proposal of the European Competence Network on Mastocytosis. Allergy. 2014 Oct;69(10):1267-74.

18. Valent P. Diagnostic evaluation and classification of mastocytosis. Immunol Allergy Clin North Am. 2006 Aug;26(3):515-34.

19. Roberts LJ, 2nd, Oates JA. Biochemical diagnosis of systemic mast cell disorders. J Invest Dermatol. 1991 Mar;96(3):19S-24S; discussion S-5S.

20. Metcalfe DD. Classification and diagnosis of mastocytosis: current status. J Invest Dermatol. 1991 Mar;96(3):2S-4S.

21. 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 protooncogene c-kit in peripheral blood mononuclear cells of patients who have mastocytosis with an associated hematologic disorder. Proc Natl Acad Sci U S A. 1995 Nov 7;92(23):10560-4.

22. Longley BJ, Tyrrell L, Lu SZ, Ma YS, Langley K, Ding TG, et al. Somatic c-KIT activating mutation in urticaria pigmentosa and aggressive mastocytosis: establishment of clonality in a human mast cell neoplasm. Nat Genet. 1996 Mar;12(3):312-4.

23. Escribano L, Orfao A, Diaz-Agustin B, Villarrubia J, Cervero C, Lopez A, et al. Indolent systemic mast cell disease in adults: immunophenotypic characterization of bone marrow mast cells and its diagnostic implications. Blood. 1998 Apr 15;91(8):2731-6.

24. Horny HP. Mastocytosis: an unusual clonal disorder of bone marrow-derived hematopoietic progenitor cells. Am J Clin Pathol. 2009 Sep;132(3):438-47.

25. Sonneck K, Florian S, Mullauer L, Wimazal F, Fodinger M, Sperr WR, et al. Diagnostic and subdiagnostic accumulation of mast cells in the bone marrow of patients with anaphylaxis: monoclonal mast cell activation syndrome. Int Arch Allergy Immunol. 2007;142(2):158-64.

26. Akin C, Scott LM, Kocabas CN, Kushnir-Sukhov N, Brittain E, Noel P, et al. Demonstration of an aberrant mast-cell population with clonal markers in a subset of patients with “idiopathic” anaphylaxis. Blood. 2007 Oct 1;110(7):2331-3.

27. Horny HP, Sotlar K, Valent P. Evaluation of mast cell activation syndromes: impact of pathology and immunohistology. Int Arch Allergy Immunol. 2012;159(1):1-5.

28. Valent P. Mast cell activation syndromes: definition and classification. Allergy. 2013 Apr;68(4):417-24.

29. Schwartz LB, Sakai K, Bradford TR, Ren S, Zweiman B, Worobec AS, et al. The alpha form of human tryptase is the predominant type present in blood at baseline in normal subjects and is elevated in those with systemic mastocytosis. J Clin Invest. 1995 Dec;96(6):2702-10.

30. Schwartz LB, Irani AM. Serum tryptase and the laboratory diagnosis of systemic mastocytosis. Hematol Oncol Clin North Am. 2000 Jun;14(3):641-57.

Overview, Definitions, Diagnosis and ClassificationContinued from page 7

Mast cell types Morphology Types of disease

Normal/reactive Round, well-granulated, with granules that fill the cytoplasm and obscure the nucleus; round to oval nucleus

Normal marrow, mast cell hyperplasia, well differentiated SM

Atypical type I

(spindle shaped)

Hypogranular, enlarged, with cytoplasmic projections

Indolent SM, ASM, SM-AHN

Atypical type II

(promastocyte)

Enlarged and round, hypogranular; indented bilobed nuclei


Metachromatic blast

(immature)

Hypogranular with a few large metachromatic granules; high nuclear-to-cytoplasm ratio; smooth chromatin in nuclei


SM: Systemic mastocytosis

ASM: Aggressive systemic mastocytosis

SM-AHN: Systemic mastocytosis with an associated hematologic neoplasm [previously referred to as SM-AHNMD (systemic mastocytosis with an associated (clonal) hematologic non-mast cell lineage disease]

Reference

1. George TI, Horny HP. Systemic mastocytosis. Hematol Oncol Clin North Am. 2011 Oct;25(5):1067-83, vii.

Cytology of Mast Cells1 By Tracy I. George, MD

tmsforacure.org | Special Edition 2019-2020 9


An international consensus task force of mast cell disease specialists has recently proposed updates to the diagnostic criteria and classification for cutaneous disease.1 Typical skin lesions found in mastocytosis, along with a positive Darier’s sign (see below), is the major criterion for diagnosing skin involvement in patients with mastocytosis. The two minor criteria are identified via skin lesion biopsy: increased mast cell numbers and the presence of an (activating) KIT mutation.1,

2 Cutaneous mastocytosis (CM) includes three variants: maculopapular cutaneous mastocytosis (MPCM), which includes urticaria pigmentosa (UP) and telangiectasia macularis eruptiva perstans (TMEP), diffuse cutaneous mastocytosis (DCM), and cutaneous mastocytoma.1 The taskforce recommends that telangiectasia macularis eruptiva perstans (TMEP) be removed as a separate category because, although some adult patients may have telangiectatic lesions on their chest, shoulders, neck and back, they may also demonstrate maculopapular lesions in other places, therefore fulfilling criteria for MPCM.

Most cases of pediatric mastocytosis fall into one of the above categories and may or may not include symptoms of systemic mast cell activation, including anaphylaxis, as a result of mediators released from the skin.3, 4 Pediatric CM encompasses a variety of clinical manifestations. In children, some forms of CM will spontaneously resolve, some will go on to be diagnosed as indolent systemic mastocytosis (ISM), with a smaller percentage identified as well-differentiated systemic mastocytosis (WDSM).5

In most adults with skin lesions typical for mastocytosis (in particular, the maculopapular type), systemic disease will ultimately be found, leading to a diagnosis of systemic mastocytosis, usually in an indolent form (indolent systemic mastocytosis).1, 6

Definitions1, 7

Darier’s sign is an important diagnostic finding of patients with mastocytosis. It can be elicited by stroking

an existing CM lesion with a wooden tongue depressor, approximately 5 times with moderate pressure. Within a few minutes, a wheal and flare reaction of the lesion will be seen. A positive Darier’s sign is usually seen in pediatric patients, but not always in adults. It may be decreased by treatment with antihistamines. If the testing procedure for Darier’s sign is not done properly, false positives or false negatives may result. Darier’s sign is to be applied to the evaluation of fixed cutaneous lesions except in the case of a pediatric patient with cutaneous mastocytoma or nodular lesions. Testing for Darier’s sign may provoke a systemic reaction and should either be performed with the greatest of caution or avoided.

Dermatographism is a skin reaction characterized by a wheal and flare response when normal skin, not affected by skin lesions, is stroked with a tongue depressor, finger nails or other instrument. The nick-name for dermatographism is skin writing disease.

A macule is a lesion that is flat and even with the surrounding skin, identified by a change in color compared to the surrounding skin.

A papule is a small bump or elevated lesion, up to 1 cm in diameter, containing no visible fluid.

A nodule is a growth of abnormal tissue just below the skin.

A bulla is a large blister filled with fluid.

Telangiectasia is a vascular lesion formed by dilatation of a group of small blood vessels.

VARIANTS OF CUTANEOUS MASTOCYTOSIS

Maculopapular Cutaneous Mastocytosis (MPCM)/Urticaria Pigmentosa (UP)1

• May be seen in infants, children or adults• Adults presenting with maculopapular lesions have

a very high likelihood of systemic disease, most frequently indolent systemic mastocytosis (ISM)

• Rarely, an adult presents with maculopapular lesions who does not have systemic disease, and has a diagnosis of MPCM

• Red maculopapular lesions tend to wheal when scratched (positive Darier’s sign)

• Blister formation can occur with rubbing or stroking of lesion and is associated with pruritis8

Cutaneous Mastocytosis Variants


• Encompasses several clinical entities with different outcomes, including: pitted melanotic macules, reddish brown telangiectatic macules, lightly pigmented papules, brownish papules, and small nodules

• This group is divided into two sub-variants

° Monomorphic variant - Mostly seen in adults and in a small subgroup

of children - Small maculopapular lesions, similar in shape,

size and color - Adults most typically express the KIT D816V

mutation in exon 17 of the KIT gene - In adults, thigh, axilla, trunk, extremities and

neck may be involved - 95% of adults diagnosed with ISM, 50% with

advanced systemic mastocytosis [systemic mastocytosis with an associated hematologic neoplasm (SM-AHN, formerly SM-AHMND) or aggressive systemic mastocytosis (ASM)] and less than 50 % of mast cell leukemia patients exhibit this variant

- Children presenting with this form may have increased serum tryptase and a tendency toward systemic disease that persists into adulthood

- The type of lesions can vary during the course of the disease, i.e., nodules during infancy may turn into plaques at age 6

° Polymorphic variant - Mostly seen in children - Can be macular, plaque or nodular, with lesions

of variable shape, color and size - Although children typically express mutations

in exon 8, 9, 11 or 17 of the KIT gene, KIT mutations may be negative

- Usually involving head, neck and extremities - May involve blistering upon irritation until 3

years of age - Prognosis is favorable with regression of

disease in adolescence or young adulthood

Diffuse Cutaneous Mastocytosis (DCM)1

• Skin thickened, hyperpigmented and diffusely infiltrated• Can involve up to 100% of the skin with the trunk,

head and scalp heavily affected

• Can appear at birth or early infancy; may persist into adulthood, possibly as well differentiated systemic mastocytosis (WDSM)5

• Blisters, some of which are hemorrhagic, and bullae may be present and dermatographism may be prominent

• Flushing is a common symptom• Tryptase may be elevated due to increased mast cell

burden in the skin and can be indicative of WDSM5

Cutaneous Mastocytoma1

• Usually present at birth• Elevated lesion(s) (up to a total of three lesions)

which usually resolves during childhood• Four cutaneous mastocytomas or more become a

diagnosis of MPCM• Multiple mastocytomas may evolve into adult WDSM5

References

1. Hartmann K, Escribano L, Grattan C, Brockow K, Carter MC, Alvarez-Twose I, et al. Cutaneous manifestations in patients with mastocytosis: Consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology. J Allergy Clin Immunol. 2016 Jan;137(1): 35-45.

2. Valent P, Akin C, Escribano L, Fodinger M, Hartmann K, Brockow K, et al. Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. Eur J Clin Invest. 2007 Jun;37(6):435-53.

3. Matito A, Carter M. Cutaneous and systemic mastocytosis in children: a risk factor for anaphylaxis? Curr Allergy Asthma Rep. 2015 May;15(5):22.



6. Berezowska S, Flaig MJ, Rueff F, Walz C, Haferlach T, Krokowski M, et al. Adult-onset mastocytosis in the skin is highly suggestive of systemic mastocytosis. Mod Pathol. 2014 Jan;27(1):19-29.

7. Venes D, Thomas CL. Taber’s cyclopedic medical dictionary. 19 ed. Philadelphia: F.A. Davis Co.; 2001.

8. Castells M, Metcalfe DD, Escribano L. Diagnosis and treatment of cutaneous mastocytosis in children: practical recommendations. Am J Clin Dermatol. 2011 Aug 1;12(4):259-70.


Systemic mastocytosis (SM) consists of a group of rare, heterogeneous diseases involving growth and accumulation of abnormal mast cells (MC) in one or multiple extracutaneous (non-skin) organ systems (Table 1). 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., co-expression of CD25). Immunohistochemistry for KIT, mast cell

tryptase, and CD25 should be performed on sections of the biopsy.1-5

Recent Updates in Diagnosis

A new diagnostic algorithm has been proposed by the European Competence Network on Mastocytosis for evaluating patients with suspected mastocytosis.6 Recommendations for KIT mutation analysis, including in peripheral blood, have also been recently published.7

Systemic Mastocytosis Variants

Table 1. Major Variants of Systemic Mastocytosis8

ISM (Indolent systemic mastocytosis) WHO criteria for SM met, MC burden low, +/- skin lesions, no C findings, no evidence of AHN• Bone marrow mastocytosis: ISM variant with BM involvement, but no skin lesionsSSM (Smoldering systemic mastocytosis)WHO criteria for SM met, typically with skin lesions, with 2 or more B findings, but no C findings.

Advanced Disease VariantsSM-AHN (SM with an associated hematologic neoplasm, formerly SM-AHNMD)Meets criteria for SM and also criteria for an AHN (MDS, MPN, MDS/MPN, AML), or other WHO-defined myeloid hematologic neoplasm, +/- skin lesions.ASM (Aggressive systemic mastocytosis)Meets criteria for SM with one or more C findings. No evidence of MCL, +/- skin lesions.MCL (Mast cell leukemia)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: MCs comprise 10% or more of peripheral blood white cells. Aleukemic MCL: < 10% of peripheral blood white cells are MCs. Usually without skin lesions.

* SM-AHN is the recently updated term from the 2016 WHO classification of mastocytosis;9 a lymphoproliferative disorder or plasma cell

dyscrasia may rarely be diagnosed with SM.

WHO: World Health Organization; BM: bone marrow; MC: mast cell; MDS: myelodysplastic syndrome; MPN: myeloproliferative neoplasm; MDS/MPN: myelodysplastic syndrome/ myeloproliferative neoplasm overlap disorders; AML: acute myeloid leukemia.


INDOLENT SYSTEMIC MASTOCYTOSIS

The majority of adult patients fit into this category, fulfilling the criteria for indolent systemic mastocytosis (ISM).2, 10-12 The bone marrow, gastrointestinal tract, skeletal system, nervous system and skin may be affected. Some patients may have enlarged livers and spleens and lymphadenopathy. Mediator-related symptoms are common, but the grade of bone marrow infiltration is low (usually less than 5 percent) with the bone marrow fulfilling the criteria for SM and 80-90% of the patients exhibiting a positive D816V KIT mutation. In most patients the serum tryptase concentration exceeds 20 ng/mL, but a normal level of tryptase does not rule out either mastocytosis or another mast cell activation disease. Treatment usually includes mediator-targeting drugs, including antihistamines, but does not usually require cytoreductive agents, although there are exceptions.

Isolated bone marrow mastocytosis (BMM) is a variant of indolent SM.12 BMM is characterized by the absence of skin lesions, lack of multi-organ involvement, and an increased incidence of anaphylaxis.13

Well differentiated SM (WDSM) first described in 200414, is reported in the literature as a rare variant that fulfills the major criterion for SM and continues to be studied by researchers.15-17 WDSM is distinguished from pediatric cutaneous mastocytosis by its inclusion in

the systemic category, despite that 91% of patients with WDSM have childhood onset of disease, with familial involvement in 39%. There is a heterogeneous presentation of lesions, maculopapular, nodular and diffuse cutaneous, that may involve a large percentage of the skin.17 Severe mast cell symptoms can occur and the variant may persist into adulthood in a low percentage of cases. The mast cells often do not express CD25 or CD2 that are part of the minor World Health Organization (WHO) criterion for SM, but may have CD30. Also, roughly 90% of WDSM patients don’t have the KIT D816V or other exon 17 KIT mutations.17 Bone marrow analysis identifies mast cells in WDSM patients as notably large, round, mature-appearing mast cells with the absence of the spindle-shaped mast cells typically seen in SM.15 Baseline serum tryptase levels

Table 2. B and C Findings8

B FindingsBM biopsy showing > 30% infiltration by MCs (focal, dense aggregates) and serum total tryptase level > 200 ng/mLMyeloproliferation or signs of dysplasia in non–MC lineage(s), no prominent cytopenias; criteria for AHN not metHepatomegaly and/or splenomegaly on palpation without impairment of organ function and/or lymphadenopathy on palpation/imaging (> 2 cm)

C Findings*Cytopenia(s): ANC < 1 x 109/L, Hb < 10 g/dL, or platelets < 100 x 109/LHepatomegaly on palpation with impairment of liver function, ascites, and/or portal hypertensionSkeletal lesions: osteolyses and/or pathologic fracturesPalpable splenomegaly with hypersplenismMalabsorption with weight loss from gastrointestinal tract MC infiltrates

*Must be attributable to the MC infiltrate.

91% of patients with WDSM have childhood onset of disease, with familial involvement in 39%

Continued on page 14


Systemic Mastocytosis VariantsContinued from page 13

in these patients are usually lower than what is frequently detected in SM, except in a variable percentage of children at onset. Imatinib mesylate has been used in some patients with severe cases of WDSM, since these patients do not usually carry the KIT D816V mutation, which causes resistance to imatinib.18

SMOLDERING SYSTEMIC MASTOCYTOSIS

Smoldering systemic mastocytosis (SSM) was recently moved out of the WHO ISM category and into its own category under SM.9 In SSM, two or more B findings, but no C findings (Table 2) are found and there is a greater possibility that the disease will progress to a more aggressive variant.

Advanced Systemic Mastocytosis Variants8

SM WITH AN ASSOCIATED HEMATOLOGIC NEOPLASM (SM-AHN)

SM-AHN is the recently updated term for SM-AHNMD from the 2016 WHO classification of mastocytosis.9 These patients fit the criteria for SM and they fit the WHO criteria for myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), MDS/MPN overlap disorder, or acute myeloid leukemia (AML), with or without skin lesions.8, 19, 20 Patients are treated for both the SM component and for the associated hematologic neoplasm.

AGGRESSIVE SYSTEMIC MASTOCYTOSIS

In this rare variant, aggressive systemic mastocytosis (ASM) patients fit the criteria for SM, with or without skin lesions, and also meet criteria for one or more C findings (Table 2).8 Patients with ASM often require chemotherapy.

MAST CELL LEUKEMIA21

In this extremely rare variant, mast cell leukemia (MCL) patients fit the criteria for SM, and a bone marrow aspirate smear shows that 20% or more of the cells are mast cells, or 10% or more mast cells are seen in circulating blood.8, 21, 22 The mast cells have malignant features. A 2014 international consensus proposal recommends that MCL be separated into acute and chronic23 subvariants based on whether or not C findings (Table 2) are present.21 In addition, it recommends a distinction between a primary form of MCL and a secondary form that evolves from an existing mast cell neoplasm, such as ASM or mast cell sarcoma. There is a prognostic pre-phase identified in patients with ASM with 5-19% mast cells in bone marrow smears, associated with rapid progression. It has been proposed that this condition be called “ASM in transformation to MCL” (ASM-t). Prognosis can be variable based on the form of disease; life expectancy has been extended, in some cases, due to advances in cytoreductive therapy.24 It is important to note that myelomastocytic leukemia (MML), which is a differential diagnosis, is not regarded by mast cell disease specialists as a subvariant of MCL or SM and should be considered a secondary condition.21

References


2. Alvarez-Twose I, Morgado JM, Sanchez-Munoz L, Garcia-Montero A, Mollejo M, Orfao A, et al. Current state of biology and diagnosis of clonal mast cell diseases in adults. Int J Lab Hematol. 2012 Oct;34(5):445-60.

3. Horny HP, Sotlar K, Valent P. Mastocytosis: state of the art. Pathobiology. 2007;74(2):121-32.

4. Horny HP, Valent P. Diagnosis of mastocytosis: general histopathological aspects, morphological criteria, and immunohistochemical findings. Leuk Res. 2001 Jul;25(7):543-51.

5. Escribano L, Garcia Montero AC, Nunez R, Orfao A. Flow cytometric analysis of normal and neoplastic mast cells: role in diagnosis and follow-up of mast cell disease. Immunol Allergy Clin North Am. 2006 Aug;26(3):535-47.


6. Valent P, Escribano L, Broesby-Olsen S, Hartmann K, Grattan C, Brockow K, et al. Proposed diagnostic algorithm for patients with suspected mastocytosis: a proposal of the European Competence Network on Mastocytosis. Allergy. 2014 Oct;69(10):1267-74.

7. Arock M, Sotlar K, Akin C, Broesby-Olsen S, Hoermann G, Escribano L, et al. KIT mutation analysis in mast cell neoplasms: recommendations of the European Competence Network on Mastocytosis. Leukemia. 2015 Jun;29(6):1223-32.

8. Gotlib J, Pardanani A, Akin C, Reiter A, George T, Hermine O, et al. International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) & European Competence Network on Mastocytosis (ECNM) consensus response criteria in advanced systemic mastocytosis. Blood. 2013 Mar 28;121(13):2393-401.


10. Carter MC, Metcalfe DD, Komarow HD. Mastocytosis. Immunol Allergy Clin North Am. 2014 Feb;34(1):181-96.

11. Valent P. Mastocytosis: a paradigmatic example of a rare disease with complex biology and pathology. Am J Cancer Res. 2013;3(2):159-72.

12. Pardanani A. Systemic mastocytosis in adults: 2013 update on diagnosis, risk stratification, and management. Am J Hematol. 2013 May 30.

13. Zanotti R, Bonadonna P, Bonifacio M, Artuso A, Schena D, Rossini M, et al. Isolated bone marrow mastocytosis: an underestimated subvariant of indolent systemic mastocytosis. Haematologica. 2011 Mar;96(3):482-4.

14. Akin C, Fumo G, Yavuz AS, Lipsky PE, Neckers L, Metcalfe DD. A novel form of mastocytosis associated with a transmembrane c-kit mutation and response to imatinib. Blood. 2004 Apr 15;103(8):3222-5.



17. Alvarez-Twose I, Jara-Acevedo M, Morgado JM, Garcia-Montero A, Sanchez-Munoz L, Teodosio C, et al. Clinical, immunophenotypic, and molecular characteristics of well-differentiated systemic mastocytosis. J Allergy Clin Immunol. 2016 Jan;137(1):168-78 e1.

18. Alvarez-Twose I, Gonzalez P, Morgado JM, Jara-Acevedo M, Sanchez-Munoz L, Matito A, et al. Complete response after imatinib mesylate therapy in a patient with well-differentiated systemic mastocytosis. J Clin Oncol. 2012 Apr 20;30(12):e126-9.

19. Stoecker MM, Wang E. Systemic mastocytosis with associated clonal hematologic nonmast cell lineage disease: a clinicopathologic review. Arch Pathol Lab Med. 2012 Jul;136(7):832-8.

20. Wang SA, Hutchinson L, Tang G, Chen SS, Miron PM, Huh YO, et al. Systemic mastocytosis with associated clonal hematological non-mast cell lineage disease: clinical significance and comparison of chomosomal abnormalities in SM and AHNMD components. Am J Hematol. 2013 Mar;88(3):219-24.

21. Valent P, Sotlar K, Sperr WR, Escribano L, Yavuz S, Reiter A, et al. Refined diagnostic criteria and classification of mast cell leukemia (MCL) and myelomastocytic leukemia (MML): a consensus proposal. Ann Oncol. 2014 Sep;25(9):1691-700.

22. Georgin-Lavialle S, Lhermitte L, Dubreuil P, Chandesris MO, Hermine O, Damaj G. Mast cell leukemia. Blood. 2013 Feb 21;121(8):1285-95.

23. Valent P, Sotlar K, Sperr WR, Reiter A, Arock M, Horny HP. Chronic mast cell leukemia: a novel leukemia-variant with distinct morphological and clinical features. Leuk Res. 2015 Jan;39(1):1-5.

24. Gotlib J, Kluin-Nelemans HC, George TI, Akin C, Sotlar K, Hermine O, et al. Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis. N Engl J Med. 2016 Jun 30;374(26):2530-41.

Mast cell sarcoma is a rare tumor that may present in many different anatomic locations and age groups, and prognosis is generally poor. Mast cell sarcoma is often misdiagnosed because the presenting cells bear little resemblance to normal mast cells and spindle-shaped mast cells frequently seen in systemic mastocytosis.3 The cells of mast cell sarcoma more closely resemble “atypical type II mast cells” or “promastocytes” that are associated with some cases of aggressive systemic mastocytosis.1, 3 Pathological examination of the tumor has shown it to be highly malignant with an aggressive growth pattern.3, 4 Patients with this tumor do not fulfill the criteria for SM.1 The imatinib mesylate-resistant KIT D816V mutation has not been found in reported mast cell sarcomas, such that use of imatinib has been attempted in some patients.3

References

1. Valent P, Horny HP, Escribano L, Longley BJ, Li CY, Schwartz LB, et al. Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res. 2001 Jul;25(7):603-25.

2. Horny HP, Akin C, Metcalfe DD, Escribano L, Bennett JM, Valent P, et al. Mastocytosis (mast cell disease) Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al., editors. World Health Organization (WHO) Classification of Tumours. Pathology and Genetics. Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2008.

3. Ryan RJ, Akin C, Castells M, Wills M, Selig MK, Nielsen GP, et al. Mast cell sarcoma: a rare and potentially under-recognized diagnostic entity with specific therapeutic implications. Mod Pathol. 2013 Apr;26(4):533-43.

4. Georgin-Lavialle S, Aguilar C, Guieze R, Lhermitte L, Bruneau J, Fraitag S, et al. Mast cell sarcoma: a rare and aggressive entity--report of two cases and review of the literature. J Clin Oncol. 2013 Feb 20;31(6):e90-7.

Mast Cell Sarcoma1, 2


PRIMARY MCAS

Primary MCAS results from a clonal population of mast cells, where a genetic alteration in the cells exists, and may be due to mastocytosis or to monoclonal Mast Cell Activation Syndrome (MMAS). Primary MCAS with mastocytosis can be diagnosed if the patient fulfils criteria for MCAS and fulfills the WHO criteria for mastocytosis. MMAS is a distinct disease characterized by the presence of abnormal mast cells and fulfillment of criteria for MCAS, but where sufficient criteria for a diagnosis of mastocytosis are not identified.1-10

SECONDARY MCAS

Secondary MCAS is diagnosed when mast cell activation occurs as an indirect result of another disease or condition.1-3, 9, 11 Physician awareness of the presence of secondary MCAS will allow for more appropriate mast cell activation-targeted treatments, in addition to primary disease-related medications, to be provided. In addition to the widespread example of IgE-dependent allergy as a cause of secondary MCAS, other diseases that can cause secondary MCAS have been reviewed in the literature.1-3, 11

IDIOPATHIC MCAS

Idiopathic MCAS is proposed as a final diagnosis after proposed MCAS criteria have been fulfilled and a thorough evaluation has excluded the possibility of another known underlying cause for this activation.2,

12 Idiopathic MCAS is therefore nonclonal, with regard to current diagnostic capabilities related to mast cell analyses, and has been presented and discussed in the literature by a variety of mast cell disease specialists.1-3,

9-13 Review of other causes of MCAS to aid physicians in evaluation for the exclusionary diagnosis of idiopathic MCAS have also been provided.1-3, 10

Additional Considerations for MCAS

It is recognized by researchers that current diagnostic methods for capturing a rise in mast cell mediators after a symptomatic episode are not ideal.12, 14, 15 Some patients who

present with typical and recurrent signs and symptoms of mast cell activation do not present with elevated levels of mediators for which we are currently able to test. Non-specialist physicians may most commonly use serum tryptase levels to exclude a mast cell disease. However, some MCAS specialists have indicated that tryptase rises are not seen as often in patients with certain forms of MCAS, and that other changes in bloodwork and urine tests can sometimes be more reliable.13, 14 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,2 such that obtaining laboratory evidence of the event can prove difficult in many circumstances. Some specialists suggest that despite lack of proof of elevated mast cell mediators, a response to mast cell or mast cell mediator blockers should be determined in such patients.12 If a patient responds well to anti-mediator treatment and fulfills the other proposed criteria,2 with the exception of displaying a rise in mediators, then a diagnosis of idiopathic MCAS remains open for consideration, as long as other diagnoses continue to be considered (please see Valent article noted below for more information on differential diagnoses). The patient should be periodically monitored to try to capture a rise in any of the mediators for which commercial testing is both available and recognized as a widely accepted diagnostic standard.12

Even the co-criterion requiring a response to mast cell targeted therapy can be difficult to obtain in some patients. Sometimes multiple mast cell (or mast cell mediator) blocking therapies must be tried before successful symptom resolution is attained.3, 16 Also, it is reported in another study, that only one third of MCAS patients experience a complete resolution with treatment; one third have a major response and another third have a minor response, and a combination of drugs is usually required to achieve control of symptoms.10

Please see the following article for more information on mast cell activation syndromes, including potential causes, symptoms, variants, effects of comorbidities and other possible diagnoses to exclude:

Mast Cell Activation Syndrome Variants1-3


Valent P. Mast cell activation syndromes: definition and classification. Allergy. 2013 Apr;68(4):417-24.

References




4. Akin C, Scott LM, Kocabas CN, Kushnir-Sukhov N, Brittain E, Noel P, et al. Demonstration of an aberrant mast-cell population with clonal markers in a subset of patients with “idiopathic” anaphylaxis. Blood. 2007 Oct 1;110(7):2331-3.


6. Sonneck K, Florian S, Mullauer L, Wimazal F, Fodinger M, Sperr WR, et al. Diagnostic and subdiagnostic accumulation of mast cells in the bone marrow of patients with anaphylaxis: monoclonal mast cell activation syndrome. Int Arch Allergy Immunol. 2007;142(2):158-64.

7. Bonadonna P, Perbellini O, Passalacqua G, Caruso B, Colarossi S, Dal Fior D, et al. Clonal mast cell disorders in patients with systemic reactions to hymenoptera stings and increased serum tryptase levels. J Allergy Clin Immunol Pract. 2009 Mar;123(3):680-6.

8. Alvarez-Twose I, Gonzalez de Olano D, Sanchez-Munoz L, Matito A, Esteban-Lopez MI, Vega A, et al. Clinical, biological, and molecular characteristics of clonal mast cell disorders presenting with systemic mast cell activation symptoms. J Allergy Clin Immunol. 2010 Jun;125(6):1269-78 e2.

9. Akin C, Metcalfe DD. Mastocytosis and mast cell activation syndromes presenting as anaphylaxis. In: Castells MC, editor. Anaphylaxis and hypersensitivity reactions. New York: Humana Press; 2011. p. 245-56.

10. Picard M, Giavina-Bianchi P, Mezzano V, Castells M. Expanding spectrum of mast cell activation disorders: monoclonal and idiopathic mast cell activation syndromes. Clin Ther. 2013 May;35(5):548-62.

11. Valent P, Horny HP, Triggiani M, Arock M. Clinical and laboratory parameters of mast cell activation as basis for the formulation of diagnostic criteria. Int Arch Allergy Immunol. 2011;156(2):119-27.

12. Cardet JC, Castells MC, Hamilton MJ. Immunology and clinical manifestations of non-clonal mast cell activation syndrome. Curr Allergy Asthma Rep. 2013 Feb;13(1):10-8.

13. Hamilton MJ, Hornick JL, Akin C, Castells MC, Greenberger NJ. Mast cell activation syndrome: a newly recognized disorder with systemic clinical manifestations. J Allergy Clin Immunol. 2011 Jul;128(1):147-52 e2.

14. Molderings GJ, Brettner S, Homann J, Afrin LB. Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. J Hematol Oncol. 2011;4:10.

15. Afrin LB. Polycythemia from mast cell activation syndrome: lessons learned. Am J Med Sci. 2011 Jul;342(1):44-9.


Hereditary Alpha Tryptasemia (HaT)Tryptase is a protein made primarily by mast cells and can be used as a marker for mast cell activation. Hereditary alpha tryptasemia is an inherited genetic mutation causing extra copies of the alpha tryptase gene (TPSAB1), leading to increased levels of tryptase in the blood. There is a great variability from person to person with duplications or triplications in terms of symptoms. If a patient’s blood tryptase level is above 10 ng/ml and he or she has another relative who has an elevated level, the patient is more likely to have hereditary alpha tryptasemia. Some patients with hereditary alpha tryptasemia may manifest the following symptoms: allergic-like symptoms such as skin itching, flushing, hives, and even anaphylaxis; gastrointestinal (GI) symptoms such as bloating, abdominal pain, diarrhea and/or constipation (frequently diagnosed as irritable bowel syndrome or IBS), heartburn, reflux, and difficulty swallowing; connective tissue symptoms such as hypermobile joints and scoliosis; cardiac symptoms such as a racing or pounding heartbeat or blood pressure swings, sometimes with fainting; as well as anxiety, depression, chronic pain or panic attacks. It is not clear the extent to which activated mast cells contribute to this disease, nor whether mast cell activation plays any role in symptoms, but this is an area of ongoing research. Many patients do respond to mast cell mediator targeted medications. If your serum tryptase is 8 ng/ml or greater, there is a commercial test offered by Gene by Gene labs. Symptoms are treated individually and definitive treatments have yet to be identified for hereditary alpha tryptasemia. https://www.niaid.nih.gov/research/hereditary-alpha-tryptasemia-faq


Mast cells can be activated through both IgE and non-IgE-related mechanisms, resulting in the release of mediators, such as tryptase, histamine, heparin, leukotrienes and prostaglandins.1 This activation can occur in a healthy person, for example in response to a mosquito bite, and in patients with both mastocytosis and mast cell activation syndrome (MCAS). Patients with mastocytosis have extra mast cells that can activate and release their mediators, in addition to the possibility of mast cells that may more readily release mediators, resulting in increased mediator-induced symptoms. Patients with MCAS may also have mast cells that are signaled to release their mediators more easily; this may depend on genetics, tissue location of the reacting mast cells, the trigger that initiates the response, or even coexisting conditions.2, 3 Symptomatology can arise from both mediator release and/or from mast cell proliferation, accumulation and infiltration in tissues, depending on the form of mast cell disease. Individuals with HaT may have higher blood tryptase levels associated with more alpha tryptase copies and they may report symptoms in multiple organ systems similar to those affected by SM and MCAS but also including symptoms of dysautonomia and connective tissue disease.3a Triggers can be common to patients with mastocytosis, MCAS, and HaT, but may be different for each patient.

SYMPTOMS AND TRIGGERS OF MAST CELL ACTIVATION (MASTOCYTOSIS AND MCAS)

Mast Cell Activation and Triggers

Mast cells can be activated to release mediators by multiple triggers. Possible triggers of mediator release are shown below in Figure 1. Please note that any patient with a mast cell disease can potentially react to any trigger, and triggers can change over the course of the disease. In addition, patients may experience reactions to virtually any medications, including medications that they have tolerated previously. Common medication reactions in mast cell disease patients include, but are not limited to: opioids, antibiotics, NSAIDs, alcohol-containing medicines and intravenous vancomycin. Use with caution. More information related to drug hypersensitivity in mast cell diseases is available in a position paper by European specialists (http://onlinelibrary.wiley.com/doi/10.1111/all.12617/full).4

Signs, Symptoms And Triggers

Figure 1. Some Potential Mast Cell Triggers5-8

Heat, cold or sudden temperature changes,

Sun/sunlight

Stress: emotional, physical, including pain,

or environmental (i.e., weather changes, pollution, pollen, pet

dander, etc.)

Drugs (opioids, NSAIDs, antibiotics and some

local anesthetics) and contrast dyes

Natural odors, chemical odors,

perfumes and scents

Venoms (bee, wasp, mixed vespids, spiders, fire ants,

jelly fish, snakes, biting insects, such as flies,

mosquitos and fleas, etc.)

Exercise Fatigue Food or beverages, including alcohol

Mechanical irritation, friction, vibration

Infections (viral, bacterial or fungal)


Mast Cell Mediator Symptoms

The myriad symptoms patients with mast cell diseases experience during mast cell activation can wreak havoc on patients on a daily basis, and multiple organ systems, including pulmonary, cardiovascular, dermatologic, gastrointestinal, musculoskeletal, and neurologic can be involved. Table 1 lists some potential effects linked to specific mediators.1, 8-15 Symptoms (Table 2) may include, but are not limited to: flushing of the face, neck, and chest; headache; tachycardia and chest pain; abdominal pain, bloating, gastroesophageal reflux disease (GERD), diarrhea, vomiting; uterine cramps or bleeding; rashes, including maculopapular cutaneous mastocytosis (MPCM)/urticaria pigmentosa (UP), telangiectatic lesions; bone/muscle pain, osteosclerosis, osteopenia, osteoporosis; itching, +/- rash; blood pressure instability; brain fog, cognitive dysfunction; anxiety/depression; lightheadedness, syncope; and the most life-threatening symptom, anaphylaxis. Please note that it is not yet clear if the process of mast cell activation plays a roll in the presentation of these symptoms in HaT. These symptoms may appear as acute (as in anaphylaxis, see Table 3) or as chronic conditions. It should be noted that the manifestation of anaphylaxis or similar symptoms among infants and preschoolers may be more difficult to identify.

Table 1. Possible Effects of Some Mast Cell Mediators15, 16

MEDIATOR POSSIBLE EFFECTSHistamine Flushing, itching, diarrhea, hypotension

Leukotrienes Shortness of breath

Prostaglandins Flushing, bone pain, brain fog, cramping

Tryptase Osteoporosis, skin lesions

Interleukins Fatigue, weight loss, enlarged lymph nodes

Heparin Osteoporosis, problems with clotting/bleeding

Tumor Necrosis Factor-α

Fatigue, headaches, body aches

This mediator list is by no means complete and serves as an example. Mast cells secrete many mediators responsible for numerous symptoms within different organ systems.

Table 2. Mast Cell Mediator Symptoms14, 15

MAST CELL MEDIATOR SYMPTOMSANAPHYLAXISFlushing of the face, neck, and chest

Itching, +/- rash

Hives, skin rashes

Angioedema (swelling)

Nasal itching and congestion

Wheezing and shortness of breath

Throat itching and swelling

Headache and/or brain fog, cognitive dysfunction, anxiety, depression

Diarrhea, nausea, vomiting, abdominal pain, bloating, gastroesophageal reflux disease (GERD)

Bone/muscle pain, osteosclerosis, osteopenia, osteoporosis

Light-headedness, syncope/fainting

Tachycardia (rapid heart rate), chest pain

Low blood pressure, high blood pressure at the start of a reaction, blood pressure instability

Uterine cramps or bleeding

Table 3. When Does this Become Anaphylaxis?

Anaphylaxis is an acute life-threatening systemic reaction that results from the sudden, rapid, systemic release of mediators.

MOUTH Itching, swelling of lips and/or tongue

THROAT* Itching, tightness/closure, hoarseness

SKIN Itching, hives, redness, swelling

GUT Vomiting, diarrhea, cramps

LUNG* Shortness of breath, cough, wheeze

HEART* Weak pulse, dizziness, passing out

Only a few symptoms may be present. Severity of symptoms can change quickly. *Some symptoms can be life-threatening. ACT FAST! Use your anaphylaxis action plan!17

Information from Table 3 taken from the American Academy of Allergy, Asthma and Immunology (AAAAI) Anaphylaxis Emergency Action Plan17 and the Anaphylaxis Guidelines Pocketcard.18

An AAAAI Anaphylaxis Card (http://www.aaaai.org/Aaaai/media/MediaLibrary/PDF%20Documents/Libraries/Anaphylaxis-Card.pdf) in English and Spanish is also available.



Signs, Symptoms And Triggers

Continued from page 19

SIGNS AND SYMPTOMS OF MAST CELL PROLIFERATION, ACCUMULATION AND INFILTRATION (MASTOCYTOSIS)

Advanced disease symptoms may include the following signs of mast cell proliferation, accumulation and infiltration: anemia, thrombocytopenia, ascites, bone fractures, gastrointestinal abnormalities, and enlargement of the liver, spleen, and lymph nodes.19, 20 Mast cell proliferation, accumulation and infiltration can occur in systemic mastocytosis (SM), smoldering SM (SSM), aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN) [previously called “SM with associated clonal hematologic non mast cell lineage disease” (SM-AHNMD)],21 or mast cell leukemia (MCL). B and C findings (see Systemic Mastocytosis Variants section), in addition to meeting the criteria for SM (see Overview section), clearly define these signs and assist physicians with the diagnosis.

References

1. Castells M. Mast cell mediators in allergic inflammation and mastocytosis. Immunol Allergy Clin North Am. 2006 Aug;26(3):465-85.

2. Akin C. Mast cell activation disorders. J Allergy Clin Immunol Pract. 2014 May-Jun;2(3):252-7 e1; quiz 8.


3a. Lyons JJ, Yu X, Hughes JD, Le QT, Jamil A, Bai Y, et al. Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number. Nat Genet. 2016 Dec;48(12):1564-9.

4. Bonadonna P, Pagani M, Aberer W, Bilo MB, Brockow K, Oude Elberink H, et al. Drug hypersensitivity in clonal mast cell disorders: ENDA/EAACI position paper. Allergy. 2015 Jul;70(7):755-63.

5. Silva I, Carvalho S, Pinto PL, Machado S, Rosado Pinto J. Mastocytosis: a rare case of anaphylaxis in paediatric age and literature review. Allergol Immunopathol (Madr). 2008 May-Jun;36(3):154-63.

6. Jennings S, Russell N, Jennings B, Slee V, Sterling L, Castells M, et al. The Mastocytosis Society survey on mast cell disorders: patient experiences and perceptions. J Allergy Clin Immunol Pract. 2014 Jan-Feb;2(1):70-6.

7. Boyden SE, Desai A, Cruse G, Young ML, Bolan HC, Scott LM, et al. Vibratory Urticaria Associated with a Missense Variant in ADGRE2. N Engl J Med. 2016 Feb 18;374(7):656-63.

8. Akin C, Metcalfe DD. Mastocytosis and mast cell activation syndromes presenting as anaphylaxis. In: Castells MC, editor. Anaphylaxis and hypersensitivity reactions. New York: Humana Press; 2011. p. 245-56.

9. Escribano L, Akin C, Castells M, Orfao A, Metcalfe DD. Mastocytosis: current concepts in diagnosis and treatment. Ann Hematol. 2002 Dec;81(12):677-90.

10. Castells M, Austen KF. Mastocytosis: mediator-related signs and symptoms. Int Arch Allergy Immunol. 2002 Feb;127(2):147-52.

11. Butterfield JH, Weiler CR. Prevention of mast cell activation disorder-associated clinical sequelae of excessive prostaglandin D(2) production. Int Arch Allergy Immunol. 2008;147(4):338-43.






17. American Academy of Allergy Asthma and Immunology Anaphylaxis Emergency Action Plan. 2016 [9/9/16]; Available from: https://www.aaaai.org/aaaai/media/medialibrary/pdf%20documents/libraries/anaphylaxis-emergency-action-plan.pdf.

18. Lieberman P, American College of Allergy, Asthma and Immunology and American Academy of Allergy, Asthma and Immunology. Anaphylaxis Guidelines Pocketcard. Baltimore, MD: International Guidelines Center; 2011; Available from: http://eguideline.guidelinecentral.com/i/55265-anaphylaxis.


20. Lim KH, Tefferi A, Lasho TL, Finke C, Patnaik M, Butterfield JH, et al. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood. 2009 Jun 4;113(23):5727-36.



Tests

First and foremost, a careful examination of the skin should be undertaken, looking for characteristic lesions of mastocytosis. If lesions are found, the physician should stroke the lesion firmly with a tongue depressor 5 or 6 times to see if it urticates (Darier’s sign). However, flushing and systemic low blood pressure can result from attempts to identify Darier’s sign in young children who have cutaneous mastocytoma or a polymorphic variant of maculopapular cutaneous mastocytosis with nodular lesions, such that this test should be avoided in these patients.1, 2 Darier’s sign is positive in almost all children and most of the adults who have skin involvement in mastocytosis. An international consensus task force of mast cell disease specialists has recently proposed that Darier’s sign be included as part of the major criterion for diagnosing skin involvement in mastocytosis patients.2 Clear areas of skin can be stroked in the same way noted above to check for dermatographism, or skin writing, in which the area stroked becomes inflamed. Darier’s sign and dermatographism are characteristic cutaneous symptoms in mast cell diseases.

Tests for Mast Cell Activation and/or Mast Cell Activation Syndrome (MCAS) Diagnostic Workup

An increase in the serum level of tryptase, above baseline and within a narrow (generally accepted as one to two hour) window of time after a symptomatic episode, is proposed as the preferred method for providing evidence of mast cell involvement.3-5 An international consensus article provides a method for calculating the required minimum rise in serum tryptase:5

After a reaction, a level of serum tryptase that is a minimum of 20% above the basal serum tryptase level, plus 2 ng/ml, will meet the second criterion for a mast cell activation event. For example, if a patient had a basal (baseline level, at least 24 hours after a reaction) serum tryptase level of 8 ng/ml, a 20% rise, plus 2 ng/ml, would be 11.6 ng/ml. To meet the above criterion for serum tryptase, the patient would need a post-reaction serum tryptase level above 11.6 ng/ml. The calculation would be conducted as follows:

(basal level, plus 20%) + additional 2 ng/ml = the serum tryptase level, after a reaction, that must be met or exceeded in order to meet a rise in serum tryptase considered a mast cell activation event.

Consensus members also agreed that when serum tryptase evaluation is not available or when the tryptase level does not rise sufficiently to meet the required increase for the co-criterion, other mediator tests could suffice. A rise in urinary n-methyl histamine, prostaglandin-D2, or its metabolite, 11β-prostaglandin-F2α (24-hour or spot urine test for any of the three), is considered an alternative for the co-criterion related to a requirement for a mast cell mediator level rise during a systemic mast cell activation event.5, 6 Some practitioners currently utilize other tests to make a diagnosis of mast cell activation. While we strongly recognize that we are limited in that there are many mast cell mediators, and yet we have commercial tests available for less than five of them here in the US, The Mastocytosis Society, Inc. (TMS) cannot endorse the use of other mediator markers as diagnostic tools until they have been adequately evaluated and proven as valid for mast cell diseases in sound, scientific research. TMS strongly supports and currently funds research to identify better markers for mast cell activation.

TMS does recognize, however, that capturing a mediator rise is not always easy, and depends on many factors, internal and environmental. We have seen 24-hour urine samples test negative simply because the lab technician did not refrigerate the sample in a timely manner (when the test was repeated and handled properly, the result was positive). Therefore, we support the use of a clinical diagnosis and advise that the patient continues to be treated when the following criteria have been met:7


TMS strongly supports and currently funds research to identify better markers for mast cell activation.


• An exhaustive work-up has ruled out other medical conditions with similar symptoms and presentations

• The patient has exhibited consistent symptoms of mast cell activation in 2 or more organ systems during the same period of time, such as skin, gastrointestinal tract, central nervous system, etc.

• The patient responds to antimediator therapy• The patient is monitored on a regular basis, with

testing for mediator rises performed periodically, by a mast cell or other specialist and/or in conjunction with an established local allergist or other physician

• The patient is evaluated for other disease processes on an ongoing basis in order to be inclusive of any new changes in the patient’s condition

Routine and Follow-up Testing for MCAS

In patients who demonstrate a mediator rise, mediator testing should be repeated periodically. In addition, a complete blood count (CBC) with differential, blood chemistries, immunoglobulin levels, liver function tests, DEXA scans for bone density, and other testing may all be done as part of the routine exam, depending on the patient’s age, presenting symptoms, coexisting conditions and medication profile.8

Tests for Clonal Mast Cell Diseases Such as Systemic Mastocytosis or Monoclonal MCAS

Bone Marrow Biopsy

Standard technique can be used to obtain an iliac crest bone marrow biopsy and aspirate smear for diagnosis. Aspirated bone marrow should be allocated for flow cytometry to assess for the presence of mast cells with aberrant phenotype (i.e., co-expression of CD25). KIT mutation testing (see below) can also be performed on bone marrow aspirate. Immunohistochemistry for KIT, mast cell tryptase, and CD25 should be performed on sections of the biopsy.1, 9-12

KIT Mutation Testing13

To understand why KIT testing is necessary, one must first understand the difference between clonal and non-clonal mast cell diseases. Clonal means that there is a defect in a person’s mast cell DNA, which results in their mast cells having abnormal characteristics. Although the most common defect seen in mast cell disease is KIT D816V, it is not the only one that can result in an abnormal disease process. Numerous other mutations in KIT have been associated with mastocytosis, and in the absence of a KIT D816V mutation, other testing can be performed to identify them, including KIT sequencing. If there is no change (no mutation, such as a KIT mutation) identified in the mast cell DNA, but the patient experiences mast cell activation, this may be non-clonal disease, such as idiopathic mast cell activation syndrome.

There has been a peptide nucleic acid mediated PCR based test available for years that can identify the KIT D816V mutation in peripheral blood, and it has been able to detect the mutation in 44% of systemic mastocytosis patients tested.14 A newer test, an allele-specific oligonucleotide qPCR test, has proven to be much more sensitive and reliable. Patients with indolent systemic mastocytosis with skin involvement, for example, were

TestsContinued from page 21

In patients who demonstrate a mediator rise, mediator testing should be repeated periodically.


found to have the KIT D816V mutation 92% of the time using the newer allele-specific qPCR blood test.14

Although the more sensitive test for the KIT D816V mutation (the allele-specific qPCR, with a sensitivity of 0.01%) that can be performed in peripheral blood samples has been developed, is not yet widely available here in the US. However, Mayo Clinic in Rochester, MN can perform the allele-specific oligonucleotide PCR (ASO-PCR) test for KIT D816V and the test may be available through several other labs in the US. Currently in the US, the result is often reported as either positive or negative, although in a research setting, results can be presented in more detail as an “allelic frequency”, which is essentially a measure of the extent to which the mutation is present versus KIT without that mutation (the allelic frequency can help in determining disease prognosis). It is important to note that receiving a negative test does not rule out a mast cell disease.13, 15 If an adult with systemic mastocytosis does not test positive for the KIT D816V mutation using sensitive testing methods, then sequencing of KIT might be considered.

Knowing the KIT mutation status can be very important when considering therapeutic options such as new medications and chemotherapy. The development of the allele-specific qPCR test will make peripheral blood KIT testing more widely available in the near future. More information on the use of KIT mutation testing in mast cell diseases (including potential use in prognosis) is available in published recommendations from the European Competence Network on Mastocytosis.

Routine and Follow-up Testing for Systemic Mastocytosis (SM) and Smoldering SM

Examinations should occur periodically and include:13

• Dermatological exam (with stroking for Darier’s sign)• Careful palpation of the liver, spleen and lymph nodes• A full neuropsychological evaluation• CBC with differential

• Serum tryptase and 24-hour or spot urines for N-methyl histamine, prostaglandin D2 (PGD2), 11β-prostaglandin F2α

• Liver function tests, serum albumin, serum LDH, and serum alkaline phosphatase

• Blood chemistries• Total immunoglobulins or total IgE, if indicated by

previous testing• DEXA scans for bone density; nuclear medicine bone

scan, if indicated• Bone marrow biopsy with flow cytometry and

cytology, when indicated• Allele-specific qPCR for KIT D816V mutation in

peripheral blood/bone marrow, if not already performed; KIT sequencing, if indicated13

• CT scan/ultrasound, if indicated• Other tests may be performed, as indicated, if there

is a suspected hematologic disorder or to evaluate the individual patient’s symptoms.

Diagnostic Workup for Advanced Systemic Mastocytosis Variants or Associated Hematological Disorders1, 13, 16, 17

When advanced disease or an associated hematological disorder is suspected, further evaluation of the patient beyond a bone marrow biopsy and aspirate with flow cytometry may include:

• Comprehensive bloodwork• X-ray or CT scan of the chest, looking for evidence

of significantly enlarged lymph nodes (greater than 2 cm in diameter)

• X-ray, nuclear medicine bone scan of the skeletal system, or bone density scan looking for osteoporosis, osteosclerosis, or areas where calcium has been completely lost from bone

• CT scan or ultrasound of the abdomen, looking for enlarged liver or spleen, enlarged lymph nodes, or the collection of fluid



TestsContinued from page 23

• Endoscopy/colonoscopy and biopsy of the gastrointestinal tract, looking for evidence of mast cell infiltration, ulcers, or areas of bleeding. Mast cell infiltration can be identified by aggregates of 15 or more abnormal mast cells, or sheets of mast cells. Abnormal mast cells can be identified by the presence of CD25 on these cells.18

• Other tests may include next-generation sequencing and myeloid gene panels for additional genetic lesions.

References



3. Schwartz LB, Sakai K, Bradford TR, Ren S, Zweiman B, Worobec AS, et al. The alpha form of human tryptase is the predominant type present in blood at baseline in normal subjects and is elevated in those with systemic mastocytosis. J Clin Invest. 1995 Dec;96(6):2702-10.

4. Schwartz LB, Irani AM. Serum tryptase and the laboratory diagnosis of systemic mastocytosis. Hematol Oncol Clin North Am. 2000 Jun;14(3):641-57.


6. Hamilton MJ, Hornick JL, Akin C, Castells MC, Greenberger NJ. Mast cell activation syndrome: a newly recognized disorder with systemic clinical manifestations. J Allergy Clin Immunol. 2011 Jul;128(1):147-52 e2.



9. Alvarez-Twose I, Morgado JM, Sanchez-Munoz L, Garcia-Montero A, Mollejo M, Orfao A, et al. Current state of biology and diagnosis of clonal mast cell diseases in adults. Int J Lab Hematol. 2012 Oct;34(5):445-60.

10. Horny HP, Sotlar K, Valent P. Mastocytosis: state of the art. Pathobiology. 2007;74(2):121-32.

11. Horny HP, Valent P. Diagnosis of mastocytosis: general histopathological aspects, morphological criteria, and immunohistochemical findings. Leuk Res. 2001 Jul;25(7):543-51.

12. Escribano L, Garcia Montero AC, Nunez R, Orfao A. Flow cytometric analysis of normal and neoplastic mast cells: role in diagnosis and follow-up of mast cell disease. Immunol Allergy Clin North Am. 2006 Aug;26(3):535-47.

13. Arock M, Sotlar K, Akin C, Broesby-Olsen S, Hoermann G, Escribano L, et al. KIT mutation analysis in mast cell neoplasms: recommendations of the European Competence Network on Mastocytosis. Leukemia. 2015 Jun;29(6):1223-32.

14. Jara-Acevedo M, Teodosio C, Sanchez-Munoz L, Alvarez-Twose I, Mayado A, Caldas C, et al. Detection of the KIT D816V mutation in peripheral blood of systemic mastocytosis: diagnostic implications. Mod Pathol. 2015 Aug;28(8):1138-49.

15. Kristensen T, Vestergaard H, Bindslev-Jensen C, Moller MB, Broesby-Olsen S, Mastocytosis Centre OUH. Sensitive KIT D816V mutation analysis of blood as a diagnostic test in mastocytosis. Am J Hematol. 2014 May;89(5):493-8.


17. Lim KH, Tefferi A, Lasho TL, Finke C, Patnaik M, Butterfield JH, et al. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood. 2009 Jun 4;113(23):5727-36.

18. Hahn HP, Hornick JL. Immunoreactivity for CD25 in gastrointestinal mucosal mast cells is specific for systemic mastocytosis. Am J Surg Pathol. 2007 Nov;31(11):1669-76.


Mast Cell Activation/Mediator Release Symptoms

Controlling symptoms of mast cell activation/mediator release starts with avoiding the triggers which will initiate mast cell activation, and the triggers can be very individual. Avoiding heat, cold, abrupt changes in temperature, sunlight, strong odors/perfumes and chemical smells can help many patients. Caution must be taken around venomous creatures such as bees, wasps, hornets, spiders, jellyfish and snakes, etc. Stress and fatigue can be major triggers for many patients, as can viruses, bacterial and fungal infections. Sometimes a simple change in routine can be a trigger.

Many foods can trigger mast cells to activate and release their mediators; shellfish, peanuts, tree nuts, citrus, and high histamine foods are high on the list of potential triggers known to bother some people, but not others. Medications to be taken with caution include NSAIDs such as ibuprofen, toradol, aspirin (this can be confusing, because aspirin can also be used as a treatment for those with high prostaglandin levels; when used as a treatment it must be started under the supervision of a physician!), opioid narcotics, alcohol, the intravenous form of vancomycin (the oral form is usually fine), some anesthetics, some antibiotics, and topical agents, like benzocaine. However, everyone is different. Anyone can react to anything, and a patient can even react to something that he or she has never reacted to before. Encourage your patients to always have someone with them when taking a new medication, starting a new treatment, or traveling to a new place.

Patients are often frustrated by their inability to determine what trigger activated their mast cells. In that situation, treat the symptoms, advise rest, tell the patient to be watchful for any recurrence of symptoms (bi-phasic reaction) and advise the patient to keep a diary of foods, medications, symptoms and possible triggers.

In addition to avoiding triggers, futher treatment of mastocytosis depends on the symptoms and the classification of disease.1-3 Symptoms of mast cell activation/mediator release are treated with H1 and H2 antihistamines, mast cell stabilizers, leukotriene inhibitors, and possibly aspirin (under direct supervision of a physician). All mast cell disease patients should carry two doses of self-injectable epinephrine, unless otherwise contraindicated (glucagon may need to be administered for patients on beta-blockers). Patients should also be instructed on how to self-administer the epinephrine while lying down, to maximize rapid absorption of the drug. Every patient should carry a physician-signed American Academy of Allergy, Asthma and Immunology Anaphylaxis Action Plan at all times. http://www.aaaai.org/Aaaai/media/MediaLibrary/PDF%20Documents/Libraries/Anaphylaxis-Emergency-Action-Plan.pdf

Treatment of mast cell mediator-related symptoms are the same for mastocytosis, MCAS and HaT.4-6

Treatments For Mast Cell Diseases

TMS recommends keeping a food, medicine and symptom diary to help the physician and patient to connect the dots!



Treatments For Mast Cell DiseasesContinued from page 25

There has been growing recognition of the detrimental effects on cognition (mental clouding and other cognitive impairments) caused by long term use of antihistamines.7 A high risk group of patients 65 years and older (defined as patients taking 50 mg per day for 3 years diphenhydramine or doxepin or 25 mg for 6 years), were found to have a significant association between diphenhydramine use and cognitive impairment.8 Similarly, high doses of sedating antihistamines such as diphenhydramine can cause increased seizure activity, seen mostly in children. In addition, a tolerance to or a dependence upon diphenhydramine may result in a need for even higher doses.7 Caution and restraint must be used when taking antihistamines long term in order to help preserve neurological function. While these drugs are crucial for their antimediator effects, they should be titrated to the lowest dose necessary to achieve control of mast cell activation symptoms.

Additional Symptoms of Indolent Systemic Mastocytosis

A suggested order of treatment options for adult patients with indolent systemic mastocytosis, aimed at symptom control, and including suggested therapies for osteoporosis, can be found in table 3 of this article: http://onlinelibrary.wiley.com/doi/10.1002/ajh.23931/full from the American Journal of Hematology.9

Advanced Disease

Therapies exist for smoldering systemic mastocytosis (SSM) and advanced systemic mastocytosis, and promising new treatments are being developed. Prominent among these newer treatments are tyrosine kinase inhibitors (TKIs) targeting the KIT kinase10, 11 (e.g., midostaurin10, 12). Imatinib is approved therapy for adult aggressive systemic mastocytosis (ASM) patients lacking the KIT D816V mutation or if mutation status is unknown. Additional standard therapies for advanced variants are interferon, the chemotherapeutic agent cladribine, and

tyrosine kinase inhibitors such as midostaurin.9, 12 These chemotherapeutic agents are used in combination with antimediator therapy to control symptoms and reduce the overall mast cell burden. In patients with systemic mastocytosis with associated clonal hematologic non-mast cell lineage disease (SM-AHNMD)/systemic mastocytosis with an associated hematologic neoplasm (SM-AHN), therapy selection usually depends on the associated disease, which is commonly more aggressive than the SM part. Mast cell leukemia and sarcoma require a polychemotherapy approach.

References



3. Cardet JC, Akin C, Lee MJ. Mastocytosis: update on pharmacotherapy and future directions. Expert Opin Pharmacother. 2013 Oct;14(15):2033-45.

4. Lee MJ, Akin C. Mast cell activation syndromes. Ann Allergy Asthma Immunol. 2013 Jul;111(1):5-8.



7. Theoharides TC, Stewart JM. Antihistamines and Mental Status. J Clin Psychopharmacol. 2016 Jun;36(3):195-7.

8. Gray SL, Anderson ML, Dublin S, Hanlon JT, Hubbard R, Walker R, et al. Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Intern Med. 2015 Mar;175(3):401-7.

9. Pardanani A. Systemic mastocytosis in adults: 2015 update on diagnosis, risk stratification, and management. Am J Hematol. 2015 Mar;90(3):250-62.

10. Verstovsek S. Advanced systemic mastocytosis: the impact of KIT mutations in diagnosis, treatment, and progression. Eur J Haematol. 2013 Feb;90(2):89-98.

11. Ustun C, DeRemer DL, Akin C. Tyrosine kinase inhibitors in the treatment of systemic mastocytosis. Leuk Res. 2011 Sep;35(9):1143-52.

12. Gotlib J, Kluin-Nelemans HC, George TI, Akin C, Sotlar K, Hermine O, et al. Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis. N Engl J Med. 2016 Jun 30;374(26):2530-41.mastocytosis. Am J Surg Pathol. 2007 Nov;31(11):1669-76.


ALL PATIENTS:

Self-Injectable Epinephrine (two doses; e.g., EpiPen®/EpiPen Jr®) should be carried by all patients with a mast cell disease at all times, even if previous anaphylaxis has not occurred. Both the patient and family members/caregivers should be trained on administering the epinephrine!

Please visit the American Academy of Allergy, Asthma and Immunology (AAAAI) website for more information on anaphylaxis.

http://www.aaaai.org/conditions-and-treatments/allergies/anaphylaxis

Basic Medications for Symptomatic Patients with Mast Cell Diseases1-4

• H1 antihistamines: help with itching, abdominal pain, flushing, headaches, brain fog

• H2 antihistamines: help with gastrointestinal symptoms and overall mast cell stability (all mast cell activation symptoms)

• Mast cell stabilizers: help with stomach and intestinal symptoms and brain fog

• Leukotriene inhibitors: help with respiratory symptoms and overall mast cell stability (all mast cell activation symptoms)

• Aspirin therapy (under direct supervision of a physician): if tolerated and if prostaglandins are elevated, helps with flushing, brain fog and bone pain

• Other medications may include: omalizumab (Xolair®, anti-IgE therapy), steroids, and proton pump therapy [for additional control of gastroesophageal reflux (GERD), but proton pump therapy may not replace the H2 antihistamine necessary to stabilize mast cells]

Please see Table 1- Table 6 for lists of some specific drugs in these different categories.

Please see Table 7 for a list of some specific drugs for advanced systemic mastocytosis.

Table 1. Some First Generation H1 Antihistamines

Brand Name Generic Name

Atarax® Hydroxyzine hydrochlorideBenadryl® DiphenhydramineChlor-trimeton® ChlorpheniramineDoxepin®, Sinequan® Doxepin hydrochlorideTavist® Clemastine

Table 2. Some Second Generation H1 Antihistamines (may tend to cause less drowsiness)

Brand Name Generic NameAllegra® FexofenadineClaritin® LoratidineClarinex® DesloratidineZaditor®/Zaditen® (in Europe)*

Ketotifen

Xyzal® LevocetirizineZyrtec® Cetirizine

*Zaditor® is only available in the US as eye drops; Zaditen® is available by prescription, but it must be obtained from a compounding pharmacy or from abroad.

Table 3. Some H2 Antihistamines

Brand Name Generic NameAxid® NizatidinePepcid® FamotidineTagamet® CimetidineZantac® Ranitidine

Medications To Treat Mast Cell Diseases



Medications To Treat Mast Cell DiseasesContinued from page 27

Table 4. Mast Cell Stabilizers and Others

Brand Name Generic NameGastrocrom® Oral cromolyn sodiumZaditor®/Zaditen® (in Europe)*

Ketotifen

Algonot, Neuroprotect, etc.

Food supplements containing bioflavonoids such as quercetin and luteolin

Aspirin; ASA Aspirin, acetylsalicylic acid (for those with high prostaglandin levels; aspirin therapy must be initiated under the direct supervision of a physician!)

Xolair® Omalizumab * Zaditor® is only available in the US as eye drops; Zaditen® is available by prescription, but it must be obtained from a compounding pharmacy or from abroad.

Table 5. Some Leukotriene Inhibitors


Singulair® MontelukastAccolate® ZafirlukastZyflo®/Zyflo CR® Zileuton

Table 6. Proton Pump Inhibitors to Help with GERD (Gastroesophageal Reflux)


Aciphex® RabeprazoleDexilant® DexlansoprazoleNexium® EsomeprazolePrevacid® LansoprazolePrilosec® OmeprazoleProtonix® Pantoprazole

Table 7. Some Chemotherapy Drugs for Selected Patients with Smoldering and Advanced Variants of Systemic Mastocytosis1, 5


Gleevec® ImatinibMasivet® MasitinibSprycel® DasatinibTasigna® NilotinibRydapt® MidostaurinHydrea® HydroxyureaLeustatin®, Leustat®, Litak®

Cladribine, 2-CDA

Intron® Interferon Alfa-2b

There are several more therapies in the pipeline, including additional tyrosine kinase inhibitors and other targeted therapies.

Sometimes symptoms change, and it becomes necessary to increase or decrease doses of medications, or to add additional medications to a patient’s prescribed protocol. Sometimes a simple adjustment made by a mast cell specialist can make a significant difference in a patient’s symptoms. Please reinforce with your patients that while it is tempting to change dosing regimens on their own, it is important that they work closely with their physician to achieive the safest most effective outcome.

References

1. Pardanani A. Systemic mastocytosis in adults: 2015 update on diagnosis, risk stratification, and management. Am J Hematol. 2015 Mar;90(3):250-62.


3. Akin C. Mast cell activation disorders. J Allergy Clin Immunol Pract. 2014 May-Jun;2(3):252-7 e1; quiz 8.


5. C, DeRemer DL, Akin C. Tyrosine kinase inhibitors in the treatment of systemic mastocytosis. Leuk Res. 2011 Sep;35(9):1143-52.


Pediatric Mast Cell DiseasesBy Valerie M. Slee, RN, and Susan Jennings, PhD


Pediatric mast cell diseases, a group of rare diseases, are characterized by either the presence of too many mast cells in the skin or other tissues (pediatric mastocytosis),1 or recurrent symptoms arising from release of mast cell mediators in two or more organ systems, in parallel (mast cell activation syndrome, MCAS).2 A fairly common genetic trait, hereditary alpha-tryptasemia (HaT), is caused by an increase in the copy number of the gene encoding alpha-tryptase. HaT causes elevated basal serum tryptase and has been associated with mast cell disease.3 Mast cells are instrumental in mediating anaphylaxis, and children with mast cell diseases may be at higher risk to develop both provoked and unprovoked episodes of anaphylaxis. A child with mastocytosis whose disease appears to be confined to the skin may still exhibit systemic symptoms due to mast cell mediator release.4 Symptoms common to pediatric mast cell diseases may include flushing of the face and neck, dermatographism, gastrointestinal complaints [such as diarrhea, abdominal pain, nausea, gastroesophageal reflux (GERD) and bloating], pruritis, dyspnea, headache, lethargy, fatigue, and neuropsychiatric symptoms. In addition, patients affected by HaT may also demonstrate symptoms of a connective tissue disorder and dysautonomia/postural orthostatic tachycardia syndrome (POTS). Many children with mast cell diseases may complain of generally feeling unwell, may have difficulty identifying or localizing specific symptoms, or may seem to present with several symptoms of mast cell activation, while others may seem to have very few or none.

Pediatric cutaneous mastocytosis (CM) encompasses a variety of clinical manifestations. In children, some of these varieties will spontaneously resolve before young adulthood, some will persist into adulthood as cutaneous disease only, some will be diagnosed in childhood or later as systemic mastocytosis (SM), mostly indolent, and some will evolve into well-differentiated systemic mastocytosis (WDSM).4

DEFINITIONS1, 3

Darier’s sign is an important diagnostic finding of patients with mastocytosis. It can be elicited by stroking an existing CM lesion with a wooden tongue depressor, approximately 5 times with moderate pressure. Within a few minutes, a wheal and flare reaction of the lesion will be seen. A positive Darier’s sign is usually seen in pediatric patients, but not always in adults. It may be decreased by treatment with antihistamines. If the testing procedure for Darier’s sign is not done properly, false positives or false negatives may result. Darier’s sign is to be applied to the evaluation of fixed cutaneous lesions except in the case of a pediatric patient with cutaneous mastocytoma or nodular lesions. Testing for Darier’s sign may provoke a systemic reaction and should either be performed with the greatest of caution or avoided.

Dermatographism is a skin reaction characterized by a wheal and flare response when normal skin, not affected by skin lesions, is stroked with a tongue depressor, finger nails or other instrument. The nick-name for dermatographism is skin writing disease.

A macule is a lesion that is flat and even with the surrounding skin, identified by a change in color compared to the surrounding skin.


Pediatric Mast Cell DiseasesContinued from page 29

A papule is a small bump or elevated lesion, up to 1 cm in diameter, containing no visible fluid.

A nodule is a growth of abnormal tissue just below the skin.

A bulla is a large blister filled with fluid.

Telangiectasia is a vascular lesion formed by dilatation of a group of small blood vessels.

AGE OF ONSET

• Pediatric CM is commonly diagnosed prior to age two.- Pediatric disease is seen at a ratio of 1.4 males:1 female.6

- No race has been found to be predominant.7

• Pediatric mast cell activation syndrome (MCAS) can be diagnosed at any age.

PEDIATRIC CUTANEOUS MASTOCYTOSIS VARIANTS

Presentation: In 90% of the cases, the typical presentation involves cutaneous manifestations (skin lesions). These may include: Cutaneous Mastocytoma1

• Usually present at birth• Elevated lesion(s) (up to a total of three lesions)

which usually resolves during childhood• Four cutaneous mastocytomas or more become

a diagnosis of MPCM (see below)• Multiple mastocytomas may evolve into adult

WDSM4

Maculopapular Cutaneous Mastocytosis (MPCM)/Urticaria Pigmentosa (UP)1

• Red maculopapular lesions tend to wheal when scratched (positive Darier’s sign)

• Blister formation can occur with rubbing or stroking of lesion and is associated with pruritis7

• Encompasses several clinical entities with different outcomes, including: pitted melanotic macules, reddish brown telangiectatic macules, lightly pigmented papules, brownish papules, and small nodules

• This group is divided into two sub-variants■ Monomorphic variant (Monomorphic means one

basic shape/size)- Mostly seen in adults and in a small subgroup of

children- Small maculopapular lesions, similar in shape,

size and color- Children presenting with this form may have

increased serum tryptase and a tendency toward systemic disease that persists into adulthood

- The type of lesions can vary during the course of the disease, i.e., nodules during infancy may turn into plaques at age 6

■ Polymorphic variant (Polymorphic means different shapes/sizes)

- Mostly seen in children- Can be macular, plaque or nodular, with lesions

of variable shape, color and size- Although, children typically express mutations

in exon 8, 9, 11 or 17 of the KIT gene, KIT mutations may be negative

- Usually involving head, neck and extremities- May involve blistering upon irritation until 3

years of age- Prognosis is favorable with regression of

disease in adolescence or young adulthood



Diffuse Cutaneous Mastocytosis (DCM)1

• Skin thickened, hyperpigmented and diffusely infiltrated

• Can involve up to 100% of the skin with the trunk, head and scalp heavily affected

• Can appear at birth or early infancy; may persist into adulthood, possibly as WDSM4

• Blisters, some of which are hemorrhagic; bullae may be present and dermatographism may be prominent

• Flushing is a common symptom• Tryptase may be elevated due to increased mast

cell burden in the skin, as most patients do not have systemic organ involvement; however, this elevation may also be indicative of WDSM4

PEDIATRIC SYSTEMIC MASTOCYTOSISApproximately 15% of children with who are diagnosed with mastocytosis have disease that is actually systemic mastocytosis (SM), which will then persist into adulthood. As recently as 13 years ago, it was not recognized that pediatric patients could even have systemic disease. We are learning more each day about patients with pediatric SM and will add more to this section as more articles are published.

SYMPTOMS OF MAST CELL ACTIVATION Which May be Seen in Both Pediatric CM and MCAS8

• Itching• Flushing• Darier’s sign and dermatographism• Abdominal pain, nausea, diarrhea, bloating,

colic in infants, GERD• Bone and muscle pain• Headache• Fatigue• Neuropsychiatric symptoms, such as: brain fog,

ADD/ADHD, irritability, behavioral issues, seizures• Anaphylaxis

GUIDELINES FOR DIAGNOSIS

Pediatric Mastocytosis• Completion of a thorough patient history• Careful skin examination and biopsy of lesions with

mast cell stains (hematoxylin, eosin, giemsa stains) and immunohistochemistry for tryptase and KIT (CD117)

• Acquisition of labs, including complete blood count, peripheral smear, serum chemistry, serum tryptase and liver function tests

• Exam of liver and spleen for hepatosplenomegaly by ultrasound or scan

• Any other exam relevant to individual symptoms (endoscopy, colonoscopy, bone scan, etc.)

• Bone marrow biopsy and aspirate with flow cytometry only if clinical suspicion of systemic or progressive disease, indicated by:■ abnormal peripheral blood counts, organomegaly,

significant lymphadenopathy, severe recurrent systemic mast cell mediator-related symptoms, persistent high tryptase, persistence of disease into adulthood7, 9



Pediatric MCAS• Although specific guidelines do not exist for

diagnosing pediatric MCAS, proposed consensus criteria for diagnosing MCAS have been utilized by specialists2, 10, 11

• Three criteria must be met:■ The patient exhibits symptoms of mast cell

activation involving two or more organ systems at the same time, which recur or are always present, cannot be attributed to any other disease or condition and require treatment.2

■ The patient demonstrates a rise in either total serum tryptase (above baseline and within one to two hours of a symptomatic episode; see below for calculation method to determine if the rise indicates mast cell activation has occurred) or one or more of the three urinary mediators, n-methyl histamine, prostaglandin-D2, or its metabolite, 11β-prostaglandin-F2α. Additionally, another mediator test, leukotriene E4 (LTE4), collected as a spot or 24 hour urine after an acute, symptomatic episode is available through the Mayo Clinic.2, 10 Further study is needed to determine if all patients being evaluated for MCAS will demonstrate a rise in one of the five known mast cell mediators (see above) for which validated tests are currently available.8

- The consensus article provides a method for calculating the required minimum rise in serum tryptase.2 After a reaction, a level of serum tryptase that is a minimum of 20% above the basal serum tryptase level, plus 2 ng/ml, will meet the second criterion listed above for a mast cell activation event. For example, if a patient had a basal (baseline level, at least 24 hours after a reaction) serum tryptase level of 8 ng/ml, a 20% rise, plus 2 ng/ml, would be 11.6 ng/ml.

To meet the above criterion for serum tryptase, the patient would need a post-reaction serum tryptase level above 11.6 ng/ml. The calculation would be conducted as follows:(8 ng/ml x 1.2) + 2 ng/ml = 9.6 ng/ml + 2 ng/ml = 11.6 ng/ml(basal level plus 20%) + additional 2 ng/ml = the serum tryptase level, after a reaction, that must be exceeded in order to meet a rise in serum tryptase considered a mast cell activation event

- The patient must display a response (based on response criteria12) to antimediator therapy.2, 10

Pediatric Hereditary Alpha-Tryptasemia (HaT)• Patients who suspect they may have HaT should

have a baseline (not after a major reaction) serum tryptase blood test drawn. This will have to be ordered by their physician. A serum level greater than 10 ng/ml may be suggestive of HaT, especially in children who have not been diagnosed with mastocytosis. Additionally, a clinical assay to identify an increase in the number of copies of the alpha-tryptase gene is available through by Gene By Gene (Tryptase CNV test).

SOME POTENTIAL TRIGGERS TO AVOID (VARIES BY PATIENT)

• Heat and/or cold; abrupt changes in temperature; sun/sunlight

• Friction or pressure on the skin; vibration• Specific foods: very individualized but may include

shellfish, high histamine foods such as left-overs, salicylate-containing foods, nuts, peanuts and other potential allergens


• Contrast dyes and medications, including: opioid narcotics, alcohol as an additive or in any form, IV vancomycin, neomycin, benzocaine, and certain anesthetics.13 See TMS Emergency Protocol at https://tmsforacure.org/wp-content/uploads/2019-TMS-ER-Protocol.pdf

• Venoms (bee, wasp, mixed vespids, spiders, fire ants, jelly fish, snakes, biting insects, such as flies, mosquitos and fleas, etc.)

• Bacterial, viral and fungal infections• Stress: physical, including pain, emotional

or environmental• Fatigue• Exercise• Perfumes, odors, natural odors and

chemical exposures TREATMENT GUIDELINES FOR PEDIATRIC MAST CELL DISEASES11, 14

• Identification and avoidance of triggers• H1 and H2 antihistamines

- H1: loratadine, cetirizine, desloratadine, diphenhydramine, hydroxyzine, fexofenadine, chlorpheniramine maleate, doxepin

- H2: ranitidine, cimetidine, famotidine• Leukotriene inhibitors

- Montelukast, zileuton, zafirlukast• UVA/UVB Photolight therapy (treatment option

for skin lesions in some pediatric mastocytosis patients only)

• Mast cell stabilizers- Oral cromolyn sodium- Ketotifen

• Omalizumab• Injectable epinephrine (to be safe, TMS recommends

that 2 doses of injectable epinephrine be prescribed and available at all times (or carried by the child if older) for children with mast cell diseases; this is especially critical for children with SM)- EpiPen®/EpiPen Jr® auto injector

• Topical treatments- Steroid creams- Cromolyn sodium cream 1%-5%

• In children with HaT, treatment for connective tissue disease and autonomic dysfunction, as indicated

• No chemotherapy is indicated in cutaneous or indolent systemic mastocytosis in children, unless clear evidence of progression to aggressive disease is identified

PROGNOSIS

Pediatric Mastocytosis• Benign course will be seen in approximately 70%

of patients.4

• In approximately 30% of pediatric mastocytosis cases, disease persists into adulthood, with 15% as disease confined only to the skin, and 15% as disease that starts out as pediatric SM and remains SM.4

• Children with extensive bullous lesions appear to be at increased risk of shock or sudden death from anaphylaxis.15

• Children with widespread skin lesions (MPCM/UP & DCM) are at increased risk for severe systemic reaction due to potential mast cell mediator release from affected skin.15

Pediatric MCAS• There is no data on prognosis for pediatric patients

with MCAS; however all patients with MCAS may be at increased risk for anaphylaxis and a potentially poor outcome. Therefore, these children need to be followed by an allergist familiar with pediatric MCAS, be treated with antimediator therapy when indicated and always carry two doses of injectable epinephrine.




Pediatric HaT • There has not been sufficient time to study the

natural history of HaT. Presently there is no reason to suspect that those with multiple copies of the alpha-tryptase gene will have a shortened lifespan.

SUPPORT SERVICES

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

• The Mastocytosis Society, Inc. coordinates support groups across the United States. Please visit https://tmsforacure.org/resources/support-groups-2/

• Mastokids.org is a site where parents and caregivers of children with mastocytosis can come to learn, find support, and discover a safe environment to interact with other families.

TMS thanks Mishele Cunningham, RN, BSN, PHN, for her contributions to previous issues of this text. REFERENCES:



3. Lyons JJ, Yu X, Hughes JD, Le QT, Jamil A, Bai Y, et al. Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number. Nat Genet. 2016 Dec;48(12):1564-9.


5. Venes D, Thomas CL. Taber’s cyclopedic medical dictionary. 19 ed. Philadelphia: F.A. Davis Co.; 2001.


7. Castells M, Metcalfe DD, Escribano L. Diagnosis and treatment of cutaneous mastocytosis in children: practical recommendations. Am J Clin Dermatol. 2011 Aug 1;12(4):259-70.

8. Butterfield J, et al., American Academy of Allergy, Asthma and Immunology Mast Cell Disorder Committee and The Mastocytosis Society, Inc. Mastocytosis and Mast Cell Activation Syndrome (MCAS). Laminated sheet, 2012.


10. Valent P, Akin C, Bonadonna P, Hartmann K, Brockow K, Niedoszytko M, et al. Proposed Diagnostic Algorithm for Patients with Suspected Mast Cell Activation Syndrome. J Allergy Clin Immunol Pract. 2019 Apr;7(4):1125-33 e1.

11. Weiler CR, Austen KF, Akin C, Barkoff MS, Bernstein JA, Bonadonna P, et al. AAAAI Mast Cell Disorders Committee Work Group Report: Mast Cell Activation Syndrome (MCAS) Diagnosis and Management. J Allergy Clin Immunol. 2019 Aug 30.


13. Bonadonna P, Pagani M, Aberer W, Bilo MB, Brockow K, Oude Elberink H, et al. Drug hypersensitivity in clonal mast cell disorders: ENDA/EAACI position paper. Allergy. 2015 Jul;70(7):755-63.


15. Alvarez-Twose I, Vano-Galvan S, Sanchez-Munoz L, Morgado JM, Matito A, Torrelo A, et al. 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.

Pediatric Mast Cell Diseases Copyright © 2019 The Mastocytosis Society, Inc. All rights reserved.


SYMPTOMSof MAST CELL DISEASE

hives, skin rashesitching with or without rash

nasal itching and congestion

wheezingshortness of breath

throat itching and swelling

headache, brain fog, cognitive dysfunction,

anxiety, depression

bone/muscle pain, osteopenia, osteoporosis

diarrhea, nausea, vomiting, abdominal pain, bloating, gastroesophageal reflux

disease (GERD)

flushing of the face/neck/chest

light-headednesssyncope (fainting)

rapid heart rate, chest painlow blood pressure

blood pressure instability

uterine cramps

bladder irritabilityfrequent voiding

high blood pressure at the start of a reaction

Ear/Nose/Throat/respiratory

neurological

cardiovascular

gynecological

systemic and/or organ specific

urinary

cutaneous (skin)

Gastrointestinal

skeletal

that are caused by mast cell mediator release

Symptoms can be

Sudden and

in onsetunpredictable

Patients may have a fewor symptomsmany

tmsforacure.orgLEARN MORE AT

anaphylaxis

bleeding

angioedema (swelling)and more...

Some common

Symptoms of Mast Cell Disease InfographicView more inforgraphics at https://tmsforacure.org/printable-resources-infographics/


Visual Guide to Diagnosing MastocytosisThe following pages are a photo journal of examples of how mast cell diseases can present. A majority of the pictures are of skin manifestations of mastocytosis. While cutaneous mastocytosis can include maculopapular cutaneous mastocytosis (MPCM), including urticaria pigmentosa (UP) and telangiectasia macularis eruptiva perstans (TMEP), diffuse cutaneous mastocytosis (DCM), and cutaneous mastocytoma, skin manifestations can also occur in systemic mastocytosis (SM), mast cell activation syndrome (MCAS) and idiopathic anaphylaxis patients.

Most cases of childhood-onset mastocytosis fall into one of the cutaneous mastocytosis categories listed above and may or may not include symptoms of systemic mast cell activation as a result of mediators released from the skin. It should be noted that the formerly used term “UP” encompasses a variety of clinical manifestations. In children, some of these varieties will fade away, some will develop into indolent systemic mastocytosis and some will evolve into a newly described entity called well-differentiated systemic mastocytosis.

Pic. 3- Female child with cutaneous mastocytosis and characteristic maculopapular, polymorphic skin lesions (formerly known as urticaria pigmentosa or UP)

Pic. 1- Female adult athlete with maculopapular cutaneous lesions, monomorphic type (formerly known as urticaria pigmentosa or UP), during a flare when the lesions are swelling

Pic. 4- Female child with cutaneous mastocytoma on shoulder, which can present with an elevated lesion which is red or tannish brown

Pic.2- Female adult with smoldering systemic mastocytosis (SSM), and typical maculopapular, cutaneous lesions, monomorphic type (formerly called urticaria pigmentosa or UP) during a flare


Pic. 6- Male child with cutaneous mastocytosis with polymorphic lesions and other rashes

Pic. 5- Male child with cutaneous mastocytosis, characterized by maculopapular cutaneous lesions, polymorphic type (formerly known as urticaria pigmentosa or UP). Note that in some children, during a flare in response to a trigger, lesions may become bullous or blistered.


Pic. 7- Male child with cutaneous mastocytosis during flare causing blisters in his maculopapular cutaneous lesions

Pic. 8- Male child with mast cell activation syndrome, during flushing episode

Pic. 9- Male child with the maculopapular cutaneous lesions, polymorphic type, consistent with cutaneous mastocytosis (formerly called urticaria pigmentosa or UP)


Pic. 12- Cutaneous mastocytoma, normal and inflamed

Pic. 13- Female with idiopathic anaphylaxis, hives (urticaria) and dermatographism

Pic. 10- Adult female with maculopapular, cutaneous lesions, monomorphic type during a flare

Pic. 11- Female child with maculopapular, polymorphic lesions of cutaneous mastocytosis

For more information on skin manifestations in mastocytosis (including a large selection of photos) and to review the source of our publication’s descriptions of cutaneous mastocytosis variants, please see the following full-text article, which is freely available online:

Hartmann K, Escribano L, Grattan C, Brockow K, Carter MC, Alvarez-Twose I, et al. Cutaneous manifestations in patients with mastocytosis: Consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology. J Allergy Clin Immunol. 2016 Jan;137(1):35-45


Please note carefully what each center specializes in. For example, some centers only treat patients with biopsy-confirmed systemic mastocytosis, while others only treat advanced variants. It is indicated below if a center will treat patients for mast cell activation syndrome and whether or not they will treat adults and/or children. Comprehensive centers can do the entire work-up, including evaluation, physical exam, KIT mutation analysis, mediator testing and bone marrow biopsy with flow cytometry, using appropriate stains for tryptase and expression of CD2 and CD25.

Abbreviations used below:MCAS: Mast Cell Activation SyndromeCM: Cutaneous MastocytosisSM: Systemic MastocytosisISM: Indolent Systemic MastocytosisSSM: Smoldering Systemic MastocytosisSM-AHN: Systemic Mastocytosis with an Associated Hematologic NeoplasmASM: Aggressive Systemic MastocytosisMCL: Mast Cell LeukemiaMCS: Mast Cell SarcomaMPN: Myeloproliferative Neoplasm

UNITED STATES OF AMERICAAlabamaUniversity of Alabama at Birmingham UAB Comprehensive Cancer Center 1720 2nd Avenue, South North Pavilion, Room 2540C Birmingham, AL 35294

Contact: Pankit Vachhani, MD Email: [email protected] Phone: 205-934-6770

Specialization: Adults with SM, SSM, ASM, SM-AHN and MCL.

CaliforniaStanford Cancer Center 875 Blake Wilbur Drive, Room 2327B Stanford, CA 94305-5821

Contact: Jason Gotlib, MD, MS Professor of Medicine (Hematology) Stanford University Medical Center Email: [email protected] Phone: 650-498-6000 Fax: 650-724-5203

Specialization: Adults. Biopsy-proven, advanced variants of SM only, including SSM, SM-AHN, ASM and MCL. Diagnosis, treatment, and research.

ColoradoUniversity of Colorado Hospital Blood Cancer/Bone Marrow Transplant Program 1665 Aurora Ct, Rm 2257 Aurora, CO 80045

Contact: William A. Robinson, MD, PhD Professor, Division of Medical Oncology Email: [email protected] Phone: 720-848-2869 Fax: 720-848-0704

Specialization: Adults. ISM, SSM, SM-AHN, ASM and MCL. Diagnosis (bone marrow biopsy can be arranged), treatment, and research.

IllnoisRush University Department of Medicine Division of Hematology, Oncology and Cell Therapy 1725 West Harrison St., Suite 836 Chicago, IL 60612 888-352-7874 (appointment line)

Contact: Celalettin Ustun, MD Email: [email protected]

Specialization: Adults with advanced variants: SSM, ASM, SM-AHN, and MCL. Diagnosis, treatment, and research. Stem cell transplant program.

MarylandNational Institutes of Health/ National Institute of Allergy and Infectious Diseases (NIH/NIAID)Building 10, Room 11C207 10 Center Drive - MSC1881 Bethesda, MD 20814-1881

Contact: Dean D. Metcalfe, MD Chief, Mast Cell Biology Section Email: [email protected] Phone: 301-496-2165 Fax: 301-480-8384

Contact: Melody Carter, MD Pediatrics Email: [email protected] Phone: 301-496-8772

Contact: Joshua Milner, MD Chief, Laboratory of Allergic Diseases Chief, Genetics and Pathogenesis of Allergy Section Email: [email protected] Phone: 301-827-3662 Fax: 301-480-8384

Specialization: Adults and pediatric. Physician referrals only for CM, biopsy-proven SM, and adult idiopathic anaphylaxis. Diagnosis (bone marrow biopsies), treatment, and research.

MassachusettsBrigham and Women’s Hospital (BWH) and Dana Farber Cancer Institute (DFCI): Boston Center of Excellence for Mastocytosis

Brigham and Women’s Hospital Division of Rheumatology, Immunology and Allergy

60 Fenwood Rd., Brookline, MA 02115 Phone: 617-732-9850 Fax: 617-525-1310

Contact: Mariana Castells, MD, PhD Director, Center of Excellence for Mastocytosis Professor of Medicine Harvard Medical School Email: [email protected] Phone: 617-732-9850 Fax: 617-525-1310

Contact: Richard Horan, MD Assistant Professor of Medicine Harvard Medical School Email: [email protected] Phone: 617-732-9850 Fax: 617-525-1310

Medical & Research Specialty Centers for Mast Cell Disease


Contact: Matthew P. Giannetti, MD Phone: 617-525-1272 Fax: 617-732-5766

Brigham and Women’s Hospital Division of Gastroenterology 75 Francis St., Boston, MA 02115

Contact: Matthew J. Hamilton, MD Instructor of Medicine Harvard Medical School Email: [email protected] Phone: 617-732-6389 Fax: 617-264-5277

Dana Farber Cancer Institute Hematologic Oncology Program 450 Brookline Ave., Dana D1B30 Boston, MA 02215

Contact: Daniel DeAngelo, MD, PhD Associate Professor of Medicine Harvard Medical School Email: [email protected] Phone: 617-632-6028 Fax: 617-632-6771

Specialization: Adults. Pediatric (outpatient only at BWH; more complex pediatric cases may be seen in conjunction with Children’s Hospital Boston). Physician referral required. All mastocytosis and MCAS; only SM and variants for DFCI. Diagnosis (can arrange bone marrow biopsies), treatment, and research.

Tufts University School of Medicine 136 Harrison Avenue Boston, MA 02111

Contact: Theoharis Theoharides, MD, PhD Professor of Pharm. and Internal Medicine Email: [email protected] Phone: 617-636-6866 Fax: 617-636-2456

Does not see patients in clinic. Available for consultation with physicians.

MichiganUniversity of Michigan Comprehensive Cancer Center Myeloproliferative Neoplasms and Systemic Mastocytosis Clinic 1500 East Medical Center Drive, Ann Arbor, MI 48109

Contact: Cem Akin, MD, PhD Professor of Medicine Department of Internal Medicine

Division of Allergy and Clinical Immunology 24 Frank Lloyd Wright Drive PO Box 442, Suite H-2100, Ann Arbor, MI 48106-0422

Email: [email protected] Phone: 734-936-5634 Phone (new patient coordinator): 734-232-2071 Fax: 734-647-6263

Specialization: Adults. Biopsy-proven only. ISM, SSM, ASM, SM-AHN, and MCL. Will perform diagnostic bone marrow biopsies for patients with elevated tryptase or biopsy-proven cutaneous disease. Diagnosis, treatment, and research.

MinnesotaMayo Clinic Program for Mast Cell and Eosinophil Disorders 200 First St. SW, Rochester, MN 55905 Mayo Clinic – Allergy Department

Contact: Joseph Butterfield, MD, Director Email: [email protected]

Contact: Anupama Ravi, MD Email: [email protected]

Pediatric Mastocytosis and MCAS

Contact: Thanai Pongdee, MD Email: [email protected] Phone: 507-284-9077 Fax: 507-284-0902

Specialization: Adults and pediatric. All mast cell related diseases including MCAS. Diagnosis, bone marrow biopsy, treatment, and research.

Mayo Clinic – Hematology Department

Contact: Animesh Pardanani, MBBS, PhD Email: [email protected]

Specialization: Adults. ISM, SSM, ASM, SM-AHN, and MCL. Will perform diagnostic bone marrow biopsies for patients with elevated tryptase or biopsy-proven cutaneous disease. Diagnosis, treatment, and research.

New YorkColumbia University Medical Center New York Presbyterian Hospital Herbert Irving Pavilion 161 Fort Washington Avenue Garden Level New York, NY 10032

Contact: Mark Heaney, MD, PhD Director, Hematology and Medical Oncology Fellowship Program Email: [email protected] Phone: 202-305-0566 Fax: (212) 305-8112

Specialization: Adults with advanced variants: SSM, ASM, SM-AHN, and MCL. Diagnosis, treatment, and research. Specialty area-MPNs.

OhioUniversity of Cincinnati College of Medicine 231 Albert Sabin Way, ML#563 Cincinnati, Ohio 45267-0563

Contact: Jonathan Bernstein, MD Professor of Clinical Medicine Department of Internal Medicine Division of Immunology/Allergy Email: [email protected] Phone: 513-558-5533 Fax: 513-558-3799

Specialization: All mast cell related diseases including mastocytosis and MCAS. Adults and pediatric. Diagnosis, treatment, and research. Can arrange bone marrow biopsies. Private family practice.

Ohio State University Wexner Medical Center 410 West 10th Avenue, Columbus, OH 43210

Contact: Charity Fox, MD Associate Professor Internal Medicine Pulmonary, Allergy, Critical Care and Sleep Medicine [email protected] 614-366-3687



Medical & Research Centers that Treat Patients with Mast Cell DiseasesContinued from page 41

TexasMD Anderson Cancer Center 1515 Holcombe Blvd, Unit 428 Houston, TX 77030

Contact: Srdan Verstovsek, MD, PhD Associate Professor, Leukemia Department Email: [email protected] Phone: 713-792-7305 Fax: 713-794-4297

Specialization: Adults. Advanced variants of SM only: SSM, SM-AHN, ASM and MCL. Diagnosis, treatment, and research.

UtahThe University of Utah School of Medicine Department of Internal Medicine, Hematology Division 30 N 1900 E, Room 5C402, Salt Lake City, UT 84132

Contact: Michael Deininger, MD, PhD Professor of Internal Medicine Adjunct Professor of Oncological Sciences Email: [email protected] Phone: 801-585-3229

Specialization: Adults. Advanced variants of systemic mastocytosis (SM) only: SSM, SM-AHN, ASM and MCL. Diagnosis, treatment, and research.

VirginiaVirginia Commonwealth University P.O. Box 980263 1250 East Marshall St., Richmond, VA 23298

Contact: Dr. Larry Schwartz, MD, PhD Professor of Medicine Chair, Division of Rheumatology, Allergy, and Immunology Email: [email protected] Phone: 804-828-9685 Fax: 804-828-0283

Specialization: All mast cell related diseases including mastocytosis and MCAS. Adults and pediatric. Diagnosis, treatment, and research. Can arrange bone marrow biopsies

Virginia Commonwealth University Health System Mc Guire Hall Annex, Rm 4-421 1112 East Clay Street Richmond, Virginia 23298-0225

Contact: Anne-Marie Irani, MD Professor of Pediatrics & Internal Medicine Division of Pediatric Allergy & Immunology Email: [email protected] Phone: 804-828-9620 Fax: 804-828-1751

Specialization: Asthma, food allergy, eosinophilic esophagitis, atopic dermatitis, urticaria, drug and insect allergy, immunodeficiency disorders, human mast cells and basophils

INTERNATIONAL (Active Centers)EuropeEuropean Competence Network on Mastocytosis (ECNM) www.ecnm.net

North, Central and South AmericaAmerican Initiative in Mast Cell Diseases (AIM) www.aimcd.net Email: [email protected]

Latin AmericaAliança Latino-Americana em MAstocitose (ALMA) President : Ana Mósca de Cequeira, MD Associate Clinical Professor of Pediatric Dermatology Hospital Municipal Jesus, Rio de Janeiro, RJ, BRAZIL Email: [email protected]

Hospital das Clinicas, University of São Paulo, São Paulo, BRAZIL Contact: Pedro Giavina-Bianchi Jr. , MD, PhD Head of Allergy and Immunology Service Associate Professor Email: [email protected]

IsraelTechnion - Israel Institute of Technology, Haifa Emek Medical Center, Afula

Contact: Menachem Rottem, MD, PhD Head of the Allergy, Asthma and Immunology Service Clinical Associate Professor Email: [email protected] Phone: 972-52-8617823

Meir Medical Center, Kfar Saba Contact: Alon Hershko, MD, PhD Email: [email protected]

Australia and AsiaEmail: [email protected]

Please note that the names of these centers and specialists are listed for informational purposes only. The Mastocytosis Society, Inc. is not responsible for any diagnostic evaluations, treatment or information provided as a result of visits or interactions with these medical professionals.


Ivan Alvarez-Twose, MDStaff Physician and Clinical Coordinator, Instituto de Estudios de Mastocitosis de Castilla La Mancha (CLMast) Toledo, Spain

Email: [email protected] Phone: 0034-615-653-157

K. Frank Austen, MD (Honorary)Astra Zeneca Professor of Respiratory and Inflammatory Diseases Department of Medicine Brigham and Women’s Hospital Smith Building, Room 638 One Jimmy Fund Way Boston, MA 02115

Email: [email protected] Phone: 617-525-1300 Fax: 617-525-1310

Patrizia Bonadonna, MDAllergy and Immunology Clinic Multidisciplinary Outpatient Clinic of Mastocytosis (also hymenoptera venom allergy,drug allergy and other allergic diseases) Verona General and University Hospital Piazzale Stefani 1 Verona, Italy

Email: [email protected] Phone: +390458122556 Fax: +390458122048

Joseph Butterfield, MDCo-Director, Mayo Clinic Program for Mast Cell and Eosinophil Disorders W15-B Mayo Clinic 200 SW 1st Street Rochester, MN 55905


Mariana Castells, MD, PhD Professor of Medicine Harvard Medical School Director, Mastocytosis Center of Excellence Brigham and Women’s Hospital Allergy and Clinical Immunology 60 Fenwood Rd., Brookline, MA 02115


Madeleine Duvic, MDProfessor and Deputy Chair, Dermatology, Univ. of Texas MD Anderson Cancer Center 1515 Holcombe Blvd, Unit 1452 Houston, TX 77030

Email: [email protected] Phone: 713 745-4615 Fax: 713 745-3597

Luis Escribano, MD, PhD Coordinator, Spanish Network on Mastocytosis (REMA) Associated Research, Servicio de Citometría, Centro de Investigación del Cáncer, Universidad de Salamanca Salamanca, Spain

Email: [email protected]

Tracy I. George, MD Professor of Pathology University of Utah Executive Director, Clinical Trials and PharmaDx Medical Director, Hematopathology ARUP Laboratories 500 Chipeta Way Salt Lake City, UT 84108Email: [email protected] Phone: 801-583-2787 Fax: 801-584-5124

Jason Gotlib, MD, MSAssociate 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


Norton J. Greenberger, MD (Honorary)Clinical Professor of Medicine/Gastroenterology Harvard Medical School

Email: [email protected]

Medical Advisory BoardContact 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 diseases. We thank them for their dedication and volunteerism.



Matthew J. Hamilton, MDAssistant Professor of Medicine Harvard Medical School Division of Gastroenterology Brigham and Women’s Hospital 75 Francis St. Boston, MA 02115


Olivier Hermine, MD, PhDUniversité Sorbonne Paris Cité Department of Clinical Hematology National Center of Mastocytosis Hôpital Necker 149-161 Rue de Sèvres, 75015 Paris, France

Email: [email protected] Tel: 33-1-44-49-52-82 (office)

Nicholas Kounis, MD, PhDPatras Highest Institute of Education and Technology Professor of Medicine in Cardiology Department of Medical Sciences 7 Aratou St. Queen Olgas Square Patras 26221, Greece

Email: [email protected] Phone: +302610279579 Fax: +302610279579

Anne Maitland, MD, PhDAnne Maitland, MD, PhD Asst. Professor, Dept. of Medicine - Allergy & Clinical Immunology Icahn School of Medicine at Mount Sinai New York, NY 10029

Medical Director, Comprehensive Allergy & Asthma Care, PLLC 200 South Broadway, Suite 104 Tarrytown, NY 10591


Larry Schwartz, MD, PhD Professor of Medicine Chair, Division of Rheumatology, Allergy, and Immunology Virginia Commonwealth University P.O. Box 980263 1250 East Marshall St., Richmond, VA 23298


Theoharis Theoharides, MD, PhDProfessor of Pharmacology and Internal Medicine Tufts University School of Medicine 136 Harrison Avenue Boston, MA 02111


Megha M. Tollefson, MDAssistant Professor of Dermatology and Pediatrics Mayo Clinic 200 First Street SW Rochester, MN 55905

Email: [email protected] Phone: (507) 284-3579 Fax: (507) 284-2072

Celalettin Ustun, MDRush University Department of Medicine Division of Hematology, Oncology and Cell Therapy 1725 West Harrison St., Suite 836 Chicago, IL 60612 Phone: 888-352-7874 (appointment line)Email: [email protected] Peter Valent, MDDepartment of Internal Medicine I Division of Hematology and Hemostaseology University of Vienna Währinger Gürtel 18-20 A-1090 Vienna, Austria

Email: [email protected] Phone: +43-1 40400-5488 or -6086 Fax: +43 1 40400 4030

Srdan Verstovsek, MD, PhD Professor Leukemia Department MD Anderson Cancer Center 1515 Holcombe Blvd, Unit 428 Houston, TX 77030


Medical Advisory BoardContinued from page 43


Selected references, listed by topic, that might be of interest to mast cell disease patients, their caregivers, physicians or others may be found at www.tmsforacure.org/research/research-resources.

MASTOCYTOSIS, MAST CELL ACTIVATION SYNDROMES, AND HEREDITARY ALPHA TRYPTASEMIA

Medical References

Support Group Contacts

WWW.MASTOCYTOSIS-MCAS.ORG

The International Mastocytosis and Mast Cell Diseases website is an online global platform uniting Mastocytosis and Mast Cell Disease patients, caregivers and health care practitioners from around the world. Here you will find the individual links and contact information for country-specific support groups.

TMSFORACURE.ORG/RESOURCES/SUPPORT-GROUPS-2

Support groups provide a way for individuals suffering from Mast Cell Diseases, and their caregivers and families, to communicate with each other, support each other, provide comfort and often share information that makes their daily lives better. TMS offers a variety of support opportunities which are described on the link listed above.

International

United States

What Is M

ast Cell C

onnect?

Mast Cell Connect is an electronic patient registry

created to advance the understanding of mastocytosis

as a disease. It is a voluntary online registry to collect inform

ation from patients w

ith mastocytosis on their

experiences with the disease. The ultim

ate goal of M

ast Cell Connect is to help speed the development of

new treatm

ents for people with m

astocytosis.

The registry allows m

astocytosis patients and caregivers to enter inform

ation about their experience living w

ith the disease directly into a secure, web-based

data collection tool. Those who participate in M

ast Cell Connect w

ill be able to view the de-identified sum

mary

of responses from other patients, and can choose to

receive information about ongoing clinical trials and

other related research studies.

You are invited to learn more and to consider

participating in this important effort. By providing

researchers with a database of detailed m

edical inform

ation about people with a specific disease,

registries have proven to be a valuable tool in better understanding rare diseases like m

astocytosis. Q

uestions?

For questions about the goals of the Mast Cell

Connect registry, contact the study doctor at m

astcellregistry@blueprintm

edicines.com or at

617-714-6678.

For all other questions, contact the Mast Cell

Connect registry coordinator at coordinator@

mastcellconnect.org.

MastC

ellConnect.org

MastC

ellConnect.org

Together, we can advance

mastocytosis research

Mast Cell Connect

Patient Registry

About M

astocytosis

Mastocytosis is a rare disease in w

hich imm

une cells know

n as mast cells abnorm

ally build up in the skin, bone m

arrow and other parts of the body. In healthy

people, mast cells produce so-called m

ediators, like histam

ine, that help activate the imm

une system and

appropriately direct disease-fighting blood cells. In m

astocytosis, however, the abnorm

al build-up of mast

cells leads to high levels of these mediators, and can

cause symptom

s that resemble allergies, including hives,

flushing, shortness of breath and anaphylactic shock. The signs, sym

ptoms and severity of m

astocytosis vary w

idely, but in more severe cases, m

ast-cell accumulation

in the organs results in organ function impairm

ent.

In patients with m

astocytosis, mast cells can accum

ulate in the skin (know

n as cutaneous mastocytosis, or CM

) and/or in tissues including bone, bone m

arrow, liver,

spleen and the gastrointestinal tract (known as system

ic m

astocytosis, or SM).

In almost all patients w

ith SM, a genetic m

utation known

as KIT D816V is believed to be the root cause of the

disease. The genetic mutation is not hereditary, and it is

highly unusual for SM to run in fam

ilies. Today, most

treatments for SM

are used to provide symptom

relief due to lim

ited treatment options, and there is no cure

for the disease.

What Is M

ast Cell C

onnect?







ate goal of M


new treatm


astocytosis.






ast Cell Connect w


mary







edical inform



astocytosis. Q

uestions?




edicines.com or at

617-714-6678.




MastC

ellConnect.org

MastC

ellConnect.org



Mast Cell Connect

Patient Registry

About M

astocytosis


hich imm

une cells know







une system and



al build-up of mast


cause symptom




astocytosis vary w




ent.

In patients with m





arrow, liver,


ic m



ith SM, a genetic m

utation known




ilies. Today, most

treatments for SM


relief due to lim


for the disease.

What Is Mast Cell Connect?

Mast Cell Connect is an electronic patient registry created to advance the understanding of mastocytosis as a disease. It is a voluntary online registry to collect information from patients with mastocytosis on their experiences with the disease. The ultimate goal of Mast Cell Connect is to help speed the development of new treatments for people with mastocytosis.

The registry allows mastocytosis patients and caregivers to enter information about their experience living with the disease directly into a secure, web-based data collection tool. Those who participate in Mast Cell Connect will be able to view the de-identified summary of responses from other patients, and can choose to receive information about ongoing clinical trials and other related research studies.

You are invited to learn more and to consider participating in this important effort. By providing researchers with a database of detailed medical information about people with a specific disease, registries have proven to be a valuable tool in better understanding rare diseases like mastocytosis. Questions?

For questions about the goals of the Mast Cell Connect registry, contact the study doctor at [email protected] or at 617-714-6678.

For all other questions, contact the Mast Cell Connect registry coordinator at [email protected].

MastCellConnect.orgMastCellConnect.org

Together, we can advance mastocytosis research

Mast Cell Connect Patient Registry

About Mastocytosis

Mastocytosis is a rare disease in which immune cells known as mast cells abnormally build up in the skin, bone marrow and other parts of the body. In healthy people, mast cells produce so-called mediators, like histamine, that help activate the immune system and appropriately direct disease-fighting blood cells. In mastocytosis, however, the abnormal build-up of mast cells leads to high levels of these mediators, and can cause symptoms that resemble allergies, including hives, flushing, shortness of breath and anaphylactic shock. The signs, symptoms and severity of mastocytosis vary widely, but in more severe cases, mast-cell accumulation in the organs results in organ function impairment.

In patients with mastocytosis, mast cells can accumulate in the skin (known as cutaneous mastocytosis, or CM) and/or in tissues including bone, bone marrow, liver, spleen and the gastrointestinal tract (known as systemic mastocytosis, or SM).

In almost all patients with SM, a genetic mutation known as KIT D816V is believed to be the root cause of the disease. The genetic mutation is not hereditary, and it is highly unusual for SM to run in families. Today, most treatments for SM are used to provide symptom relief due to limited treatment options, and there is no cure for the disease.

What Is M

ast Cell C

onnect?







ate goal of M


new treatm


astocytosis.






ast Cell Connect w


mary







edical inform



astocytosis. Q

uestions?




edicines.com or at

617-714-6678.




MastC

ellConnect.org

MastC

ellConnect.org



Mast Cell Connect

Patient Registry

About M

astocytosis


hich imm

une cells know







une system and



al build-up of mast


cause symptom




astocytosis vary w




ent.

In patients with m





arrow, liver,


ic m



ith SM, a genetic m

utation known




ilies. Today, most

treatments for SM


relief due to lim


for the disease.

What Is M

ast Cell C

onnect?







ate goal of M


new treatm


astocytosis.






ast Cell Connect w


mary







edical inform



astocytosis. Q

uestions?




edicines.com or at

617-714-6678.




MastC

ellConnect.org

MastC

ellConnect.org



Mast Cell Connect

Patient Registry

About M

astocytosis


hich imm

une cells know







une system and



al build-up of mast


cause symptom




astocytosis vary w




ent.

In patients with m





arrow, liver,


ic m



ith SM, a genetic m

utation known




ilies. Today, most

treatments for SM


relief due to lim


for the disease.

Get

ting

Invo

lved

Who

can

join

?Pe

ople

with

a d

iagn

osis

of m

asto

cyto

sis,

incl

udin

g sy

stem

ic m

asto

cyto

sis

(SM

), cu

tane

ous

mas

tocy

tosi

s (C

M) a

nd th

eir v

aria

nts,

are

invi

ted

to jo

in M

ast C

ell

Conn

ect.

To jo

in, y

ou m

ust b

e ab

le to

pro

vide

info

rmed

co

nsen

t. An

yone

und

er 1

8, o

r adu

lts w

ho c

anno

t mak

e th

eir o

wn

med

ical

dec

isio

ns o

r wou

ld p

refe

r to

have

so

meo

ne e

lse

ente

r the

ir in

form

atio

n, m

ust h

ave

a fa

mily

mem

ber,

med

ical

car

egiv

er, l

egal

gua

rdia

n or

ot

her d

esig

nee

to re

gist

er o

n th

eir b

ehal

f.

Wha

t do

es p

artic

ipat

ing

in t

he r

egis

try

invo

lve?

If yo

u jo

in M

ast C

ell C

onne

ct, y

ou w

ill be

ask

ed to

co

mpl

ete

a qu

estio

nnai

re a

bout

you

r exp

erie

nce

livin

g w

ith m

asto

cyto

sis,

as

wel

l as

to s

hare

med

ical

reco

rds

that

des

crib

e yo

ur d

iagn

osis

, tre

atm

ents

, sym

ptom

s an

d ch

ange

s in

the

dise

ase

over

tim

e. Y

ou m

ay o

ccas

iona

lly

be a

sked

add

ition

al s

urve

y qu

estio

ns, a

nd to

ens

ure

the

regi

stry

’s ac

cura

cy, y

ou w

ill be

ask

ed to

upd

ate

your

in

form

atio

n a

few

tim

es a

yea

r.

Who

has

acc

ess

to M

ast

Cel

l Con

nect

? Th

e br

oade

r med

ical

com

mun

ity, i

nclu

ding

rese

arch

ers,

phys

icia

ns, p

atie

nt a

dvoc

acy

grou

ps a

nd c

ompa

nies

en

gage

d in

mas

tocy

tosi

s re

sear

ch, c

an re

ques

t acc

ess

to

the

regi

stry

. All

info

rmat

ion

in th

e re

gist

ry is

de-

iden

tified

, m

eani

ng it

has

bee

n st

rippe

d of

info

rmat

ion

that

co

uld

be u

sed

to id

entif

y yo

u. A

s a

part

icip

ant,

you

have

imm

edia

te a

cces

s to

the

pool

of d

e-id

entifi

ed

surv

ey a

nsw

ers.

Add

ition

al R

esou

rces

Her

e ar

e m

ore

reso

urce

s th

at y

ou m

ay fi

nd u

sefu

l if y

ou

have

mas

tocy

tosis

, car

e fo

r som

eone

with

mas

tocy

tosis

, or

wou

ld lik

e to

lear

n m

ore

abou

t par

ticip

atin

g in

clin

ical t

rials:

ww

w.s

yste

mic

mas

tocy

tosi

s.co

m

The

Mas

tocy

tosi

s So

ciet

yw

ww

.tmsf

orac

ure.

org

Nat

iona

l Org

aniz

atio

n fo

r R

are

Dis

ease

s (N

OR

D):

M

asto

cyto

sis

ww

w.ra

redi

seas

es.o

rg/r

are-

dise

ases

/mas

tocy

tosi

s

Euro

pean

Com

pete

nce

Net

wor

k on

Mas

tocy

tosi

sw

ww

.mas

tocy

tosi

s.eu

Abo

ut t

he S

pons

or

Abo

ut B

luep

rint

Med

icin

es

Blue

prin

t Med

icin

es is

a b

iote

chno

logy

com

pany

dev

elop

ing

a ne

w

inve

stig

atio

nal t

reat

men

t for

sys

tem

ic m

asto

cyto

sis

(SM

). At

Blu

eprin

t M

edic

ines

, we

are

mot

ivat

ed b

y on

e go

al: t

o dr

amat

ical

ly im

prov

e th

e liv

es o

f peo

ple

with

deb

ilita

ting

dise

ases

. Our

inve

stig

atio

nal t

hera

pies

ar

e cu

rren

tly in

clin

ical

stu

dies

for S

M, g

astr

oint

estin

al s

trom

al tu

mor

s an

d he

pato

cellu

lar c

arci

nom

a. F

or m

ore

info

rmat

ion,

ple

ase

visi

t w

ww

.blu

epri

ntm

edic

ines

.com

.

Abo

ut P

atie

ntC

ross

road

s Pa

tient

Cros

sroa

ds is

a le

ader

in b

uild

ing

web

-bas

ed p

atie

nt re

gist

ries

desi

gned

to a

dvan

ce re

sear

ch a

nd c

onne

ct p

atie

nts

with

rese

arch

ers,

ad

voca

tes

and

indu

stry

org

aniz

atio

ns w

orki

ng to

und

erst

and

or tr

eat

spec

ific

dise

ases

and

con

ditio

ns. F

or m

ore

info

rmat

ion,

vis

it w

ww

.pat

ient

cros

sroa

ds.c

om.

Spon

sore

d by

P

ower

ed b

y

The

mor

e w

e un

ders

tand

abo

ut

mas

tocy

tosi

s an

d th

e m

ore

peop

le

part

icip

ate

in re

sear

ch a

nd c

linic

al

tria

ls, t

he m

ore

we

can

help

adv

ance

re

sear

ch a

nd s

peed

dev

elop

men

t of

new

trea

tmen

ts fo

r mas

tocy

tosi

s.

Lear

n fr

om o

ther

pat

ient

s’ e

xper

ienc

es.

By p

artic

ipat

ing,

you

will

gain

acc

ess

to d

ata

and

insi

ghts

gl

eane

d fro

m o

ther

pat

ient

s’ re

spon

ses

that

may

be

usef

ul in

bet

ter u

nder

stan

ding

you

r ow

n di

seas

e.

Find

out

abo

ut c

linic

al t

rial

s an

d ot

her

rese

arch

stu

dies

. You

can

sig

n up

to b

e no

tified

ab

out c

linic

al tr

ials

and

oth

er re

sear

ch s

tudi

es th

at y

ou

may

be

elig

ible

for b

ased

on

the

info

rmat

ion

you

ente

r in

to th

e re

gist

ry.

Adv

ance

res

earc

h an

d sp

eed

deve

lopm

ent

of

new

tre

atm

ents

. By

impr

ovin

g ou

r und

erst

andi

ng o

f m

asto

cyto

sis a

nd it

s im

pact

on

patie

nts

over

tim

e, y

ou c

an

help

spu

r the

dev

elop

men

t of n

ew p

oten

tial t

reat

men

ts.

Why

Join

?

Patie

nt C

ross

road

s™

Get

ting

Invo

lved

Who

can

join

?Pe

ople

with

a d

iagn

osis

of m

asto

cyto

sis,

incl

udin

g sy

stem

ic m

asto

cyto

sis

(SM

), cu

tane

ous

mas

tocy

tosi

s (C

M) a

nd th

eir v

aria

nts,

are

invi

ted

to jo

in M

ast C

ell

Conn

ect.

To jo

in, y

ou m

ust b

e ab

le to

pro

vide

info

rmed

co

nsen

t. An

yone

und

er 1

8, o

r adu

lts w

ho c

anno

t mak

e th

eir o

wn

med

ical

dec

isio

ns o

r wou

ld p

refe

r to

have

so

meo

ne e

lse

ente

r the

ir in

form

atio

n, m

ust h

ave

a fa

mily

mem

ber,

med

ical

car

egiv

er, l

egal

gua

rdia

n or

ot

her d

esig

nee

to re

gist

er o

n th

eir b

ehal

f.

Wha

t do

es p

artic

ipat

ing

in t

he r

egis

try

invo

lve?

If yo

u jo

in M

ast C

ell C

onne

ct, y

ou w

ill be

ask

ed to

co

mpl

ete

a qu

estio

nnai

re a

bout

you

r exp

erie

nce

livin

g w

ith m

asto

cyto

sis,

as

wel

l as

to s

hare

med

ical

reco

rds

that

des

crib

e yo

ur d

iagn

osis

, tre

atm

ents

, sym

ptom

s an

d ch

ange

s in

the

dise

ase

over

tim

e. Y

ou m

ay o

ccas

iona

lly

be a

sked

add

ition

al s

urve

y qu

estio

ns, a

nd to

ens

ure

the

regi

stry

’s ac

cura

cy, y

ou w

ill be

ask

ed to

upd

ate

your

in

form

atio

n a

few

tim

es a

yea

r.

Who

has

acc

ess

to M

ast

Cel

l Con

nect

? Th

e br

oade

r med

ical

com

mun

ity, i

nclu

ding

rese

arch

ers,

phys

icia

ns, p

atie

nt a

dvoc

acy

grou

ps a

nd c

ompa

nies

en

gage

d in

mas

tocy

tosi

s re

sear

ch, c

an re

ques

t acc

ess

to

the

regi

stry

. All

info

rmat

ion

in th

e re

gist

ry is

de-

iden

tified

, m

eani

ng it

has

bee

n st

rippe

d of

info

rmat

ion

that

co

uld

be u

sed

to id

entif

y yo

u. A

s a

part

icip

ant,

you

have

imm

edia

te a

cces

s to

the

pool

of d

e-id

entifi

ed

surv

ey a

nsw

ers.

Add

ition

al R

esou

rces

Her

e ar

e m

ore

reso

urce

s th

at y

ou m

ay fi

nd u

sefu

l if y

ou

have

mas

tocy

tosis

, car

e fo

r som

eone

with

mas

tocy

tosis

, or

wou

ld lik

e to

lear

n m

ore

abou

t par

ticip

atin

g in

clin

ical t

rials:

ww

w.s

yste

mic

mas

tocy

tosi

s.co

m

The

Mas

tocy

tosi

s So

ciet

yw

ww

.tmsf

orac

ure.

org

Nat

iona

l Org

aniz

atio

n fo

r R

are

Dis

ease

s (N

OR

D):

M

asto

cyto

sis

ww

w.ra

redi

seas

es.o

rg/r

are-

dise

ases

/mas

tocy

tosi

s

Euro

pean

Com

pete

nce

Net

wor

k on

Mas

tocy

tosi

sw

ww

.mas

tocy

tosi

s.eu

Abo

ut t

he S

pons

or

Abo

ut B

luep

rint

Med

icin

es

Blue

prin

t Med

icin

es is

a b

iote

chno

logy

com

pany

dev

elop

ing

a ne

w

inve

stig

atio

nal t

reat

men

t for

sys

tem

ic m

asto

cyto

sis

(SM

). At

Blu

eprin

t M

edic

ines

, we

are

mot

ivat

ed b

y on

e go

al: t

o dr

amat

ical

ly im

prov

e th

e liv

es o

f peo

ple

with

deb

ilita

ting

dise

ases

. Our

inve

stig

atio

nal t

hera

pies

ar

e cu

rren

tly in

clin

ical

stu

dies

for S

M, g

astr

oint

estin

al s

trom

al tu

mor

s an

d he

pato

cellu

lar c

arci

nom

a. F

or m

ore

info

rmat

ion,

ple

ase

visi

t w

ww

.blu

epri

ntm

edic

ines

.com

.

Abo

ut P

atie

ntC

ross

road

s Pa

tient

Cros

sroa

ds is

a le

ader

in b

uild

ing

web

-bas

ed p

atie

nt re

gist

ries

desi

gned

to a

dvan

ce re

sear

ch a

nd c

onne

ct p

atie

nts

with

rese

arch

ers,

ad

voca

tes

and

indu

stry

org

aniz

atio

ns w

orki

ng to

und

erst

and

or tr

eat

spec

ific

dise

ases

and

con

ditio

ns. F

or m

ore

info

rmat

ion,

vis

it w

ww

.pat

ient

cros

sroa

ds.c

om.

Spon

sore

d by

P

ower

ed b

y

The

mor

e w

e un

ders

tand

abo

ut

mas

tocy

tosi

s an

d th

e m

ore

peop

le

part

icip

ate

in re

sear

ch a

nd c

linic

al

tria

ls, t

he m

ore

we

can

help

adv

ance

re

sear

ch a

nd s

peed

dev

elop

men

t of

new

trea

tmen

ts fo

r mas

tocy

tosi

s.

Lear

n fr

om o

ther

pat

ient

s’ e

xper

ienc

es.

By p

artic

ipat

ing,

you

will

gain

acc

ess

to d

ata

and

insi

ghts

gl

eane

d fro

m o

ther

pat

ient

s’ re

spon

ses

that

may

be

usef

ul in

bet

ter u

nder

stan

ding

you

r ow

n di

seas

e.

Find

out

abo

ut c

linic

al t

rial

s an

d ot

her

rese

arch

stu

dies

. You

can

sig

n up

to b

e no

tified

ab

out c

linic

al tr

ials

and

oth

er re

sear

ch s

tudi

es th

at y

ou

may

be

elig

ible

for b

ased

on

the

info

rmat

ion

you

ente

r in

to th

e re

gist

ry.

Adv

ance

res

earc

h an

d sp

eed

deve

lopm

ent

of

new

tre

atm

ents

. By

impr

ovin

g ou

r und

erst

andi

ng o

f m

asto

cyto

sis a

nd it

s im

pact

on

patie

nts

over

tim

e, y

ou c

an

help

spu

r the

dev

elop

men

t of n

ew p

oten

tial t

reat

men

ts.

Why

Join

?

Patie

nt C

ross

road

s™

Get

ting

Invo

lved

Who

can

join

?Pe

ople

with

a d

iagn

osis

of m

asto

cyto

sis,

incl

udin

g sy

stem

ic m

asto

cyto

sis

(SM

), cu

tane

ous

mas

tocy

tosi

s (C

M) a

nd th

eir v

aria

nts,

are

invi

ted

to jo

in M

ast C

ell

Conn

ect.

To jo

in, y

ou m

ust b

e ab

le to

pro

vide

info

rmed

co

nsen

t. An

yone

und

er 1

8, o

r adu

lts w

ho c

anno

t mak

e th

eir o

wn

med

ical

dec

isio

ns o

r wou

ld p

refe

r to

have

so

meo

ne e

lse

ente

r the

ir in

form

atio

n, m

ust h

ave

a fa

mily

mem

ber,

med

ical

car

egiv

er, l

egal

gua

rdia

n or

ot

her d

esig

nee

to re

gist

er o

n th

eir b

ehal

f.

Wha

t do

es p

artic

ipat

ing

in t

he r

egis

try

invo

lve?

If yo

u jo

in M

ast C

ell C

onne

ct, y

ou w

ill be

ask

ed to

co

mpl

ete

a qu

estio

nnai

re a

bout

you

r exp

erie

nce

livin

g w

ith m

asto

cyto

sis,

as

wel

l as

to s

hare

med

ical

reco

rds

that

des

crib

e yo

ur d

iagn

osis

, tre

atm

ents

, sym

ptom

s an

d ch

ange

s in

the

dise

ase

over

tim

e. Y

ou m

ay o

ccas

iona

lly

be a

sked

add

ition

al s

urve

y qu

estio

ns, a

nd to

ens

ure

the

regi

stry

’s ac

cura

cy, y

ou w

ill be

ask

ed to

upd

ate

your

in

form

atio

n a

few

tim

es a

yea

r.

Who

has

acc

ess

to M

ast

Cel

l Con

nect

? Th

e br

oade

r med

ical

com

mun

ity, i

nclu

ding

rese

arch

ers,

phys

icia

ns, p

atie

nt a

dvoc

acy

grou

ps a

nd c

ompa

nies

en

gage

d in

mas

tocy

tosi

s re

sear

ch, c

an re

ques

t acc

ess

to

the

regi

stry

. All

info

rmat

ion

in th

e re

gist

ry is

de-

iden

tified

, m

eani

ng it

has

bee

n st

rippe

d of

info

rmat

ion

that

co

uld

be u

sed

to id

entif

y yo

u. A

s a

part

icip

ant,

you

have

imm

edia

te a

cces

s to

the

pool

of d

e-id

entifi

ed

surv

ey a

nsw

ers.

Add

ition

al R

esou

rces

Her

e ar

e m

ore

reso

urce

s th

at y

ou m

ay fi

nd u

sefu

l if y

ou

have

mas

tocy

tosis

, car

e fo

r som

eone

with

mas

tocy

tosis

, or

wou

ld lik

e to

lear

n m

ore

abou

t par

ticip

atin

g in

clin

ical t

rials:

ww

w.s

yste

mic

mas

tocy

tosi

s.co

m

The

Mas

tocy

tosi

s So

ciet

yw

ww

.tmsf

orac

ure.

org

Nat

iona

l Org

aniz

atio

n fo

r R

are

Dis

ease

s (N

OR

D):

M

asto

cyto

sis

ww

w.ra

redi

seas

es.o

rg/r

are-

dise

ases

/mas

tocy

tosi

s

Euro

pean

Com

pete

nce

Net

wor

k on

Mas

tocy

tosi

sw

ww

.mas

tocy

tosi

s.eu

Abo

ut t

he S

pons

or

Abo

ut B

luep

rint

Med

icin

es

Blue

prin

t Med

icin

es is

a b

iote

chno

logy

com

pany

dev

elop

ing

a ne

w

inve

stig

atio

nal t

reat

men

t for

sys

tem

ic m

asto

cyto

sis

(SM

). At

Blu

eprin

t M

edic

ines

, we

are

mot

ivat

ed b

y on

e go

al: t

o dr

amat

ical

ly im

prov

e th

e liv

es o

f peo

ple

with

deb

ilita

ting

dise

ases

. Our

inve

stig

atio

nal t

hera

pies

ar

e cu

rren

tly in

clin

ical

stu

dies

for S

M, g

astr

oint

estin

al s

trom

al tu

mor

s an

d he

pato

cellu

lar c

arci

nom

a. F

or m

ore

info

rmat

ion,

ple

ase

visi

t w

ww

.blu

epri

ntm

edic

ines

.com

.

Abo

ut P

atie

ntC

ross

road

s Pa

tient

Cros

sroa

ds is

a le

ader

in b

uild

ing

web

-bas

ed p

atie

nt re

gist

ries

desi

gned

to a

dvan

ce re

sear

ch a

nd c

onne

ct p

atie

nts

with

rese

arch

ers,

ad

voca

tes

and

indu

stry

org

aniz

atio

ns w

orki

ng to

und

erst

and

or tr

eat

spec

ific

dise

ases

and

con

ditio

ns. F

or m

ore

info

rmat

ion,

vis

it w

ww

.pat

ient

cros

sroa

ds.c

om.

Spon

sore

d by

P

ower

ed b

y

The

mor

e w

e un

ders

tand

abo

ut

mas

tocy

tosi

s an

d th

e m

ore

peop

le

part

icip

ate

in re

sear

ch a

nd c

linic

al

tria

ls, t

he m

ore

we

can

help

adv

ance

re

sear

ch a

nd s

peed

dev

elop

men

t of

new

trea

tmen

ts fo

r mas

tocy

tosi

s.

Lear

n fr

om o

ther

pat

ient

s’ e

xper

ienc

es.

By p

artic

ipat

ing,

you

will

gain

acc

ess

to d

ata

and

insi

ghts

gl

eane

d fro

m o

ther

pat

ient

s’ re

spon

ses

that

may

be

usef

ul in

bet

ter u

nder

stan

ding

you

r ow

n di

seas

e.

Find

out

abo

ut c

linic

al t

rial

s an

d ot

her

rese

arch

stu

dies

. You

can

sig

n up

to b

e no

tified

ab

out c

linic

al tr

ials

and

oth

er re

sear

ch s

tudi

es th

at y

ou

may

be

elig

ible

for b

ased

on

the

info

rmat

ion

you

ente

r in

to th

e re

gist

ry.

Adv

ance

res

earc

h an

d sp

eed

deve

lopm

ent

of

new

tre

atm

ents

. By

impr

ovin

g ou

r und

erst

andi

ng o

f m

asto

cyto

sis a

nd it

s im

pact

on

patie

nts

over

tim

e, y

ou c

an

help

spu

r the

dev

elop

men

t of n

ew p

oten

tial t

reat

men

ts.

Why

Join

?

Patie

nt C

ross

road

s™

Get

ting

Invo

lved

Who

can

join

?Pe

ople

with

a d

iagn

osis

of m

asto

cyto

sis,

incl

udin

g sy

stem

ic m

asto

cyto

sis

(SM

), cu

tane

ous

mas

tocy

tosi

s (C

M) a

nd th

eir v

aria

nts,

are

invi

ted

to jo

in M

ast C

ell

Conn

ect.

To jo

in, y

ou m

ust b

e ab

le to

pro

vide

info

rmed

co

nsen

t. An

yone

und

er 1

8, o

r adu

lts w

ho c

anno

t mak

e th

eir o

wn

med

ical

dec

isio

ns o

r wou

ld p

refe

r to

have

so

meo

ne e

lse

ente

r the

ir in

form

atio

n, m

ust h

ave

a fa

mily

mem

ber,

med

ical

car

egiv

er, l

egal

gua

rdia

n or

ot

her d

esig

nee

to re

gist

er o

n th

eir b

ehal

f.

Wha

t do

es p

artic

ipat

ing

in t

he r

egis

try

invo

lve?

If yo

u jo

in M

ast C

ell C

onne

ct, y

ou w

ill be

ask

ed to

co

mpl

ete

a qu

estio

nnai

re a

bout

you

r exp

erie

nce

livin

g w

ith m

asto

cyto

sis,

as

wel

l as

to s

hare

med

ical

reco

rds

that

des

crib

e yo

ur d

iagn

osis

, tre

atm

ents

, sym

ptom

s an

d ch

ange

s in

the

dise

ase

over

tim

e. Y

ou m

ay o

ccas

iona

lly

be a

sked

add

ition

al s

urve

y qu

estio

ns, a

nd to

ens

ure

the

regi

stry

’s ac

cura

cy, y

ou w

ill be

ask

ed to

upd

ate

your

in

form

atio

n a

few

tim

es a

yea

r.

Who

has

acc

ess

to M

ast

Cel

l Con

nect

? Th

e br

oade

r med

ical

com

mun

ity, i

nclu

ding

rese

arch

ers,

phys

icia

ns, p

atie

nt a

dvoc

acy

grou

ps a

nd c

ompa

nies

en

gage

d in

mas

tocy

tosi

s re

sear

ch, c

an re

ques

t acc

ess

to

the

regi

stry

. All

info

rmat

ion

in th

e re

gist

ry is

de-

iden

tified

, m

eani

ng it

has

bee

n st

rippe

d of

info

rmat

ion

that

co

uld

be u

sed

to id

entif

y yo

u. A

s a

part

icip

ant,

you

have

imm

edia

te a

cces

s to

the

pool

of d

e-id

entifi

ed

surv

ey a

nsw

ers.

Add

ition

al R

esou

rces

Her

e ar

e m

ore

reso

urce

s th

at y

ou m

ay fi

nd u

sefu

l if y

ou

have

mas

tocy

tosis

, car

e fo

r som

eone

with

mas

tocy

tosis

, or

wou

ld lik

e to

lear

n m

ore

abou

t par

ticip

atin

g in

clin

ical t

rials:

ww

w.s

yste

mic

mas

tocy

tosi

s.co

m

The

Mas

tocy

tosi

s So

ciet

yw

ww

.tmsf

orac

ure.

org

Nat

iona

l Org

aniz

atio

n fo

r R

are

Dis

ease

s (N

OR

D):

M

asto

cyto

sis

ww

w.ra

redi

seas

es.o

rg/r

are-

dise

ases

/mas

tocy

tosi

s

Euro

pean

Com

pete

nce

Net

wor

k on

Mas

tocy

tosi

sw

ww

.mas

tocy

tosi

s.eu

Abo

ut t

he S

pons

or

Abo

ut B

luep

rint

Med

icin

es

Blue

prin

t Med

icin

es is

a b

iote

chno

logy

com

pany

dev

elop

ing

a ne

w

inve

stig

atio

nal t

reat

men

t for

sys

tem

ic m

asto

cyto

sis

(SM

). At

Blu

eprin

t M

edic

ines

, we

are

mot

ivat

ed b

y on

e go

al: t

o dr

amat

ical

ly im

prov

e th

e liv

es o

f peo

ple

with

deb

ilita

ting

dise

ases

. Our

inve

stig

atio

nal t

hera

pies

ar

e cu

rren

tly in

clin

ical

stu

dies

for S

M, g

astr

oint

estin

al s

trom

al tu

mor

s an

d he

pato

cellu

lar c

arci

nom

a. F

or m

ore

info

rmat

ion,

ple

ase

visi

t w

ww

.blu

epri

ntm

edic

ines

.com

.

Abo

ut P

atie

ntC

ross

road

s Pa

tient

Cros

sroa

ds is

a le

ader

in b

uild

ing

web

-bas

ed p

atie

nt re

gist

ries

desi

gned

to a

dvan

ce re

sear

ch a

nd c

onne

ct p

atie

nts

with

rese

arch

ers,

ad

voca

tes

and

indu

stry

org

aniz

atio

ns w

orki

ng to

und

erst

and

or tr

eat

spec

ific

dise

ases

and

con

ditio

ns. F

or m

ore

info

rmat

ion,

vis

it w

ww

.pat

ient

cros

sroa

ds.c

om.

Spon

sore

d by

P

ower

ed b

y

The

mor

e w

e un

ders

tand

abo

ut

mas

tocy

tosi

s an

d th

e m

ore

peop

le

part

icip

ate

in re

sear

ch a

nd c

linic

al

tria

ls, t

he m

ore

we

can

help

adv

ance

re

sear

ch a

nd s

peed

dev

elop

men

t of

new

trea

tmen

ts fo

r mas

tocy

tosi

s.

Lear

n fr

om o

ther

pat

ient

s’ e

xper

ienc

es.

By p

artic

ipat

ing,

you

will

gain

acc

ess

to d

ata

and

insi

ghts

gl

eane

d fro

m o

ther

pat

ient

s’ re

spon

ses

that

may

be

usef

ul in

bet

ter u

nder

stan

ding

you

r ow

n di

seas

e.

Find

out

abo

ut c

linic

al t

rial

s an

d ot

her

rese

arch

stu

dies

. You

can

sig

n up

to b

e no

tified

ab

out c

linic

al tr

ials

and

oth

er re

sear

ch s

tudi

es th

at y

ou

may

be

elig

ible

for b

ased

on

the

info

rmat

ion

you

ente

r in

to th

e re

gist

ry.

Adv

ance

res

earc

h an

d sp

eed

deve

lopm

ent

of

new

tre

atm

ents

. By

impr

ovin

g ou

r und

erst

andi

ng o

f m

asto

cyto

sis a

nd it

s im

pact

on

patie

nts

over

tim

e, y

ou c

an

help

spu

r the

dev

elop

men

t of n

ew p

oten

tial t

reat

men

ts.

Why

Join

?

Patie

nt C

ross

road

s™

The Mastocytosis ChroniclesP.O. Box 416 Sterling, MA 01564

Return Service Requested

The Mastocytosis Society, Inc. invites you to visit our exhibitor booths at the following Medical Conferences:American Academy of PediatricsAmerican Society of HematologyAmerican Academy of DermatologyAmerican Academy of Allergy, Asthma and Immunology Physicians treating patients with mast cell disease, please self-enroll in our TMS physicians’ database: https://tmsforacure.org/physician-database/

TMS Needs Your Help!

If you find the information and support provided by TMS helpful for you or your patients, please consider making a monetary contribution to our organization. Donations, easily made through our website, www.tmsforacure.org, help us fulfill our mission of Research, Education, Advocacy and Support for Mast Cell Diseases. TMS is an all-volunteer organization that receives funding directly from people affected by mast cell diseases. Any donation is appreciated!

After Years of Planning...

The American Initiative in Mast Cell Diseases (AIM) is finally being launched! In collaboration with The Mastocytosis Society, Inc., a partnered Patient/Caregiver Conference was followed by an inaugural meeting of physicians and investigators in May 2019 at Stanford University School of Medicine. AIM will be a network of diagnosis, treatment and research centers established first across the United States and ultimately planned to encompass all of North, Central and South America. Please join us in celebrating this giant step toward improved care for our patient population and exciting new research initiatives in mast cell diseases. Visit www.aimcd.net for more information on AIM!

Mast Cell Diseases