ANXIETY PROVOKING CONSULTATIONS: MAST CELLS AND EOSINOPHILS

How to evaluate the patient with a suspected

mast cell disorder and how/when to manage
symptoms

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Cem Akin
Division of Allergy and Clinical Immunology, Department of Medicine, University of Michigan, Ann Arbor, MI

Mast cell disorders include mastocytosis and mast cell activation syndromes. Mastocytosis is a rare clonal disorder of
the mast cell, driven by KIT D816V mutation in most cases. Mastocytosis is diagnosed and classified according to World
Health Organization criteria. Mast cell activation syndromes encompass a diverse group of disorders and may have clonal
or nonclonal etiologies. Hematologists may be consulted to assist in the diagnostic workup and/or management of mast
cell disorders. A consult to the hematologist for mast cell disorders may provoke anxiety due to the rare nature of these
diseases and the management of nonhematologic mast cell activation symptoms. This article presents recommendations
on how to approach the diagnosis and management of patients referred for common clinical scenarios.

LEARNING OBJECTIVES
• Review the diagnostic criteria and classification of mastocytosis
• Identify which patients with mast cell activation symptoms and elevated tryptase levels need further workup for
a mast cell disorder

choose the right tests, and interpret them correctly. Sec­

CLINICAL CASE
A 35­year­old man is referred for evaluation of a mast cell
disorder. He was admitted to the hospital for hypoten­
sive syncope after sustaining a wasp sting while biking.
He felt flushed and light­headed and collapsed within
10 minutes of the sting. When emergency medical ser­
vices arrived, his systolic blood pressure was noted to
be 50 mmHg, with a heart rate of 120/min. There were no
hives or angioedema, and the skin exam otherwise was
unremarkable. His past medical history is significant for
occasional flushing and lightheadedness with vigorous
exercise. A serum tryptase level obtained 1 hour after the
episode in the emergency department was 120 ng/mL.
Another tryptase level 1 week later when he is at his base­
line was 28 ng/mL.
Introduction
Consults with a hematologist for a “mast cell disorder” can
provoke anxiety for a number of different reasons. First,
these disorders are rare, and the provider may not have
enough practical experience to direct a diagnostic workup,
ond, treatment guidelines for many disease categories are
evolving. Third, many patients with mast cell disorders
have no abnormalities in other hematologic lineages, and
therefore the hematologist may feel the treatment options
to be out of their range of expertise. Likewise, there may
be questions about when and how to initiate a workup for
a patient referred to rule out a mast cell disorder due to
symptoms of mast cell activation or elevated tryptase.
The hematologist may receive consultations or referrals
for mast cell disorders due to a number of different clinical
scenarios:
1. Patient has an established diagnosis of advanced systemic
mastocytosis (advSM) and is in need of cytoreductive ther­
apy of the mast cell disease and any associated non–mast
cell neoplastic component such as a myelodysplastic syn­
drome (MDS) or myeloproliferative neoplasm (MPN).
2. Patient has skin lesions of maculopapular mastocytosis,
and a bone marrow biopsy is needed to confirm or rule
out systemic mastocytosis and categorize the disease.
3. Patient has a diagnosis of cutaneous or nonadvanced
(indolent) systemic mastocytosis, and recommendations
for management and follow­up are needed.

Mast cell disorders | 55

Figure 1. Mast cell disorders can be separated into those involving proliferation and activation. Mastocytosis is a clonal proliferative
disorder of the mast cell and its progenitor. Reactive mast cell hyperplasia can be seen in a number of inflammatory and neoplastic
conditions. Mast cell activation disorders (MCADs) include a broad range of conditions stemming from primary (mastocytosis/mono­
clonal MCAS), secondary (IgE and non–IgE-mediated mast cell activation due to allergic and nonallergic inflammatory and neoplastic
diseases), and idiopathic origins. MCAS is a subgroup of MCADs usually presenting with severe episodic symptoms, which may be
similar to anaphylaxis (see text for explanation). There may be overlap in patients with mastocytosis presenting with recurrent ana­
phylaxis symptoms or in patients with monoclonal MCAS.
4. Patient has an ele­vated tryptase level.
5. Patient has symp­toms of mast cell acti­va­tion, and an opin­ion
is needed regard­ing whether the patient is in need of fur­ther
hema­to­logic workup.
Before discussing each of these sce­nar­ios, a primer on the
diag­no­sis and clas­si­fi­ca­tion of mastocytosis and mast cell acti­va­
tion dis­or­ders would be help­ful.
Mast cell dis­or­ders
Mast cell dis­or­ders can be broadly cat­e­go­rized into those involv­
ing mast cell acti­va­tion and those involv­ing pro­lif­er­a­tion, with a
sig­nif­i­cant over­lap between the 2 categories (Figure 1).1 One can
also encoun­ter the ter­mi­nol­ogy of “clonal” and “nonclonal” mast
cell dis­or­ders in the lit­er­a­ture, the for­mer refer­ring to mastocyto­
sis and the lat­ter refer­ring to patients presenting with r­ecur­rent
idi­o­pathic ana­phy­laxis or other mast cell acti­va­tion dis­or­ders
with­out evi­dence of mastocytosis.2 The pro­to­typ­i­cal pro­lif­er­a­tive
mast cell dis­or­der is mastocytosis.3,4 Although patients with rare
myelomastocytic leu­ke­mia or reac­tive mast cell hyper­pla­sia pres­
ent with increased mast cells in bone mar­row biop­sies, these are
not “dis­or­ders of the mast cell” and are not discussed here.5
Diagnosis and clas­si­fi­ca­tion of mastocytosis
Mastocytosis is a clonal dis­ ease of the mast cell pro­ gen­i­
tor,
most often driven by a somatic gain-of-func­tion muta­tion in KIT,
resulting in the path­o­logic accu­mu­la­tion and acti­va­tion of mast
cells in tis­sues. It can be diag­nosed in chil­dren and adults. The
driver muta­tion is KIT D816V in more than 90% of adults and in
about 30% of chil­dren.6
Pediatric-onset dis­ease
Pediatric-onset mastocytosis usu­ally pres­ents in the first year of
life with typ­i­cal maculopapular skin lesions, also known as urti­caria
pigmentosa. Pediatric mastocytosis gen­er­ally has a self-lim­ited
course, with spon­ta­ne­ous res­o­lu­tion or sig­nif­i­cant regres­sion by
ado­les­cence.7 Systemic involve­ment can be diag­nosed in about
10% of cases. These chil­dren pres­ent with pro­gres­sively increas­
ing tryptase lev­els, liver or spleen enlarge­ment, lymph­ade­nop­
a­thy, or unex­plained abnor­mal­i­ties in the com­plete blood count
with dif­fer­en­tial. The periph­eral blood KIT D816V muta­tion may
56 | Hematology 2022 | ASH Education Program
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be pos­i­tive. Children with typ­i­cal self-lim­ited pedi­at­ric mastocy­
tosis have poly­mor­phic skin lesions, while chil­dren with sys­temic
dis­ease have mono­mor­phic, smaller lesions resem­bling adult-
onset skin lesions. Other rare types of skin involve­ ment in
­chil­dren include mastocytomas and dif­fuse cuta­ne­ous masto­
cytosis (CM).8 A bone mar­row biopsy is usu­ally not nec­es­sary
in chil­dren with typ­i­cal poly­mor­phic skin lesions and a tryptase
level within nor­mal range unless the child pres­ents with increas­
ing tryptase lev­els or one of the red flags men­tioned above, or
the skin lesions fail to improve by ado­les­cence. It is very unusual
for pedi­at­ric patients with mastocytosis to pres­ent with symp­
toms of mast cell acti­va­tion with­out skin lesions (as opposed to
some adult patients). Therefore, in a pedi­at­ric patient referred
for mast cell acti­va­tion symp­toms with­out skin lesions, a bone
mar­row biopsy is usu­ally not nec­es­sary unless there is another
indi­ca­tion. If such a patient has an ele­vated base­line tryptase
(nor­ mal range is con­ sid­ered <11.5 ng/mL in most com­ mer­cial
assays), hered­i­tary alpha tryptasemia (HaT) should be con­sid­
ered first (see below for more detailed dis­cus­sion). If HaT is not
found, a bone mar­row biopsy can be con­sid­ered.
Adult-onset dis­ease
Adult-onset mastocytosis can be diag­nosed in the third decade
of life or later.9 Patients may pres­ent with maculopapular CM
lesions, symp­toms of mast cell acti­va­tion such as recur­rent ana­
phy­laxis, signs and symp­toms of a hema­to­logic dis­or­der, or skel­
e­tal abnor­mal­i­ties on imag­ing rais­ing sus­pi­cion for a met­a­static
dis­ease or mye­loma. Adult-onset mastocytosis is almost always
sys­temic, and a bone mar­row biopsy is needed to estab­lish the
diag­no­sis. Systemic dis­ease refers to the pres­ence of neo­plas­tic
mast cells in extracutaneous tis­sue.
The World Health Organization (WHO) diag­nos­tic cri­te­ria for
sys­temic mastocytosis are shown in Table 1.10,11 A major cri­te­rion
plus 1 minor cri­te­ria or 3 minor cri­te­ria are required to estab­lish
the diag­no­sis.
Patients fulfilling only 1 or 2 minor clonality cri­ te­
ria (KIT
muta­tion and/or CD25 expres­sion) with symp­toms of mast cell
acti­va­tion are termed to have mono­clo­nal mast cell acti­va­tion
syn­drome (MMAS).11 MMAS rep­re­sents a low-bur­den clonal mast
cell dis­ease and is man­aged sim­i­larly to sys­temic mastocytosis.
Table 1. WHO diag­nos­tic cri­te­ria for sys­temic mastocytosis
Major cri­te­rion
Multifocal com­pact infil­trates of mast cells (>15 cells per infil­trate) in a
tis­sue biopsy other than skin (such as bone mar­row).
Minor cri­te­ria
Mast cells co-express CD25, CD2, and CD30.
Morphological abnor­mal­i­ties in mast cells, such as spin­dle-shaped,
elon­gated mast cells with hypogranulation, cyto­plas­mic pro­jec­tion,
and an off-cen­tric or multilobated nucleus.
Detection of KIT D816V muta­tion or another gain of func­tion KIT
muta­tion in blood, bone mar­row, or another noncutaneous tis­sue.
Baseline serum or plasma tryptase level of >20 ng/ml.
An impor­tant point has to be made about KIT D816V muta­tion
detec­tion: next gen­er­a­tion sequenc­ing (NGS) or sequenc­ing-
based muta­tion detec­tion meth­ods are often not ade­quate, and
KIT D816V allele-spe­cific poly­mer­ase chain reac­tion (PCR) or dig­
i­tal drop­let PCR are required, espe­cially if periph­eral blood is
used for screen­ing (see sce­nario 4 below). However, NGS would
be use­ful for eval­u­at­ing for addi­tional muta­tions that one would
typ­i­cally see in advSM, espe­cially hema­to­logic non–mast cell
neo­plasm (SM-AHN), as these muta­tions may have fur­ther prog­
nos­tic sig­nif­i­cance.
Bone mar­row biopsy and aspi­rate is the gold stan­dard to
estab­lish the diag­no­sis by checking for the molec­u­lar and his­
to­ path­ o­
logic mark­ ers below, as the bone mar­ row is almost
uni­formly involved in SM. However, work­ing with a gas­tro­en­ter­
ol­o­gist may often be required in the fur­ther workup of symp­toms
such as abdom­i­nal pain and diar­rhea. In this regard, immu­no­
his­to­chem­ i­
cal stains for tryptase, CD117, and CD25 should
be employed on endo­ scopic biop­sies to deter­ mine whether
abdom­i­nal symp­toms may be due to mast cell infil­tra­tion or
medi­at­or release or both. Some mast cells in gas­tro­in­tes­ti­nal
(GI) tract biop­sies may be neg­a­tive for tryptase and pos­i­tive for
CD117. It should be noted that an increased num­ber of mast cells
alone in the GI tract are not diag­nos­tic of mastocytosis and that
bands or clus­ters of aber­rant mast cells fulfilling WHO pathol­ogy
cri­te­ria are required to prove GI involve­ment.12
Well-dif­fer­en­ti­ated sys­temic mastocytosis (WDSM) is a rare
his­to­logic sub­type in which mast cells have a mature, round mor­
phol­ogy, do not express aber­rant CD25 or CD2, and u ­ su­ally lack
Comments
Mast cells are best visu­al­ized by tryptase or CD117 immu­no­his­to­chem­i­cal
stains in biopsy sec­tions. These infil­trates are gen­er­ally found in
perivascular and paratrabecular loca­tions.
CD25 is the most spe­cific neo­plas­tic mast cell marker. CD2 may be
absent in some advanced SM cases. CD30 has been recently added as
a marker in the lat­est WHO doc­um ­ ent. These mark­ers can be assessed
by serial sec­tions by immu­no­his­to­chem­is­try or by flow cytom­e­try.
However, mast cell flow cytom­e­try should be treated as a rare event
anal­y­sis with acqui­si­tion of ide­ally 1 mil­lion or more events. Typical
leu­ke­mia/lym­phoma FC pan­els do not con­tain enough cells to gate on
mast cells.
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More than 25% of mast cells in the infil­trate should be mor­pho­log­i­cally
aber­rant. A bone mar­row aspi­rate smear is the best sam­ple to eval­u­ate
for these aber­rant mast cell forms. Mast cells are usu­ally found
embed­ded in or in close prox­im­ity to spic­ules. There is insuf­fi­cient data
on other tis­sue biop­sies to assess mast cell mor­phol­ogy. A detailed
pho­to­graphic guide to these abnor­mal­i­ties is presented in Sperr et al.42
Mutation detec­tion should be done by a high-sen­si­tiv­ity test such as
allele spe­cific PCR or drop­let dig­i­tal PCR with a sen­si­tiv­ity to detect
mutated allele fre­quency of <0.1%. NGS pan­els or sequenc­ing-based
assays lack this sen­si­tiv­ity and are often falsely neg­a­tive.
Tryptase is a highly spe­cific marker for mast cell bur­den and acti­va­tion.
It should be mea­sured when the patient is at base­line and not after
an ana­phy­lac­tic or mast cell acti­va­tion event, dur­ing which it may be
found ele­vated regard­less of mastocytosis. This cri­te­rion is not valid if
the patient has another mye­loid neo­plasm as tryptase can be found in
smaller quan­ti­ties in mye­loid pro­gen­i­tor cells.
the typ­i­cal KIT D816V muta­tion, mak­ing it a chal­leng­ing diag­no­
sis.13,14 Patients with WDSM can have a his­tory of pedi­at­ric-onset
cuta­ne­ous dis­ease that may have resolved or been per­sis­tent.
Mast cells in WDSM express CD30, which should not be pres­ent
in nor­mal mast cells.
Classification of mastocytosis
The most recent WHO clas­si­fi­ca­tion of mastocytosis is shown in
Table 2.
CM is the most com­mon cat­e­gory in chil­dren with involve­
ment lim­ited to the skin. Patients with CM most often pres­ent
with poly­mor­phic skin lesions in the first year of life. Other less
com­mon skin man­i­fes­ta­tions of CM include mastocytomas and
dif­fuse CM. These chil­dren do not require a bone mar­row biopsy
unless one of the red flag signs discussed above is pres­ent. In
con­ trast, adult patients with skin lesions almost always have
bone mar­row involve­ment. If an adult patient with skin lesions
does not have a bone mar­row biopsy, that patient should be
clas­si­fied as “mastocytosis in the skin” rather than CM, as the
prob­a­bil­ity of sys­temic dis­ease is high.
Systemic mastocytosis means the pres­ ence of neo­plas­tic
mast cells meet­ing WHO diag­nos­tic cri­te­ria in noncutaneous
tis­sue, char­ac­ter­is­ti­cally bone mar­row. Systemic mastocytosis
can be fur­ ther subdivided into nonadvanced SM (bone mar­
row mastocytosis [BMM], indo­lent SM [ISM], and smol­der­ing SM
[SSM]) and advanced SM (SM-AHN, aggres­sive SM [ASM], and
mast cell leu­ke­mia [MCL]) based on his­to­path­o­logic cri­te­ria,
end organ dys­func­tion, and the pres­ence of another asso­ci­ated
Mast cell dis­or­ders | 57
Table 2. WHO clas­si­fi­ca­tion of mastocytosis
Category
Cutaneous mastocytosis
Systemic mastocytosis
Indolent sys­temic mastocytosis (ISM)
Bone mar­row mastocytosis (BMM)
Smoldering sys­temic mastocytosis (SSM)
 Systemic mastocytosis with asso­ci­ated hema­to­logic non–mast cell
neo­plasm (SM-AHN)
Aggressive sys­temic mastocytosis (ASM)
Mast cell leu­ke­mia (MCL)
Mast cell sar­coma
non–mast cell clonal dis­ease).11 Patients with advanced SM usu­
ally have other mye­loid muta­tions detected in NGS, in addi­tion
to KIT D816V.15
As men­tioned in Table 2, oste­o­po­ro­sis or scle­rotic lesions
should not be misinterpreted as advanced dis­ease as they are
com­mon find­ings in ISM. To that end, a rou­tine dual-energy x-ray
absorptiometry bone den­sity scan is recommended for each
patient diag­nosed with SM. Furthermore, radio­graphic imag­ing
of areas with bone pain may be con­sid­ered in indi­vid­ual patients.
A bone scan may show increased uptake focally or appear as a
58 | Hematology 2022 | ASH Education Program
Comment
Most com­mon cat­e­gory in chil­dren. Subtypes include MPCM,
mastocytoma, and dif­fuse CM.
Presence of neo­plas­tic mast cell infil­trates in extracutanous tis­sues. Most
com­mon in adults.
The most com­mon cat­e­gory of SM, representing >80% of patients with
SM. Patients in this cat­e­gory have mast cell col­lec­tions meet­ing WHO
cri­te­ria for sys­temic dis­ease in the bone mar­row but do not have an
asso­ci­ated hema­to­logic neo­plasm or advanced dis­ease find­ings or 2 or
more B find­ings of SSM. Patients with ISM have a life expec­tancy that is
com­pa­ra­ble to the gen­eral age-matched pop­u­la­tion with less than 5%
risk of pro­gres­sion to advanced dis­ease.
This cat­e­gory was added in the most recent WHO doc­um ­ ent and was
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for­merly included in ISM. BMM is diag­nosed in a patient with­out skin
lesions, tryptase level <125, no mast cell infil­trates in extramedullary
tis­sue, and oth­er­wise fits the cri­te­ria for ISM. This cat­e­gory is believed
to have a lower risk of pro­gres­sion than ISM and SSM.
This is a rare cat­e­gory of nonadvanced SM with higher mast cell bur­den
as evidenced by 2 or more B find­ings: i. tryptase level ≥200 ng/mL or
bone mar­row biopsy infil­tra­tion by mast cells of ≥30% or KIT D816V var­i­
ant allele frac­tion of ≥10% in bone mar­row or periph­eral blood;
ii. spleno­meg­aly with­out hypersplenism and/or hepa­to­meg­aly with­out
liver dys­func­tion and/or lymph­ade­nop­a­thy >2 cm; iii. myeloproliferation
or sub­tle mor­pho­logic abnor­mal­i­ties in mye­loid cells with­out meet­ing
the cri­te­ria for a WHO-clas­si­fied neo­plasm. Patients with SSM may have
a higher rate of pro­gres­sion to advSM, which still remains <10%.
These patients have an AHN (usu­ally an MPN or MDS) meet­ing the WHO
cri­te­ria in addi­tion to SM. Prognosis is deter­mined by the AHN but is
gen­er­ally poor, with a median sur­vival time of about 2 years after
diag­no­sis.
Patients with ASM have high-level mast cell bur­den and tis­sue ­­
dys­func­tion due to infil­trat­ing mast cells (also known as C find­ings).
One or more C find­ings attrib­ut­­able to MC infil­tra­tion are required for
diag­no­sis: cytopenias (hemo­glo­bin <10 g/dL, plate­lets <100 000, and
neutropenia <1000), liver dys­func­tion with por­tal hyper­ten­sion, ele­vated
liver func­tion tests, asci­tes, mal­ab­sorp­tion, and diar­rhea with exten­sive
GI infil­trates, spleno­meg­aly with hypersplenism, large (≥2 cm) lytic bone
lesions with path­o­log­i­cal bone frac­tures. It should be noted that
oste­o­po­ro­sis and smaller lytic and scle­rotic bone lesions are com­mon
in all­categories of SM and are not con­sid­ered a C find­ing. Patients with
ASM have a reduced life expec­tancy, with <3 years of aver­age sur­vival
after diag­no­sis.
MCL is diag­nosed when ≥10% mast cells are found in periph­eral
cir­cu­la­tion or ≥20% in bone mar­row aspi­rate smears in a nonspicular
area. It should be noted that 20% infil­tra­tion grade refers to bone
mar­row aspi­rate and not to bone mar­row biopsy. Patients with­out
cir­cu­lat­ing mast cells are referred to as aleukemic MCL. Patients with
typ­i­cal MCL also have C find­ings sim­i­lar to ASM and carry a very poor
prog­no­sis. A chronic form of MCL with­out C-find­ings or cytopenias have
recently been rec­og­nized with more favor­able sur­vival rates.
Rare inva­sive solid mast cell tumor with poor prog­no­sis.
superscan, although it is not rou­tinely recommended. We would
rec­om­mend treat­ment of oste­o­po­ro­sis in col­lab­o­ra­tion with an
endo­cri­nol­og
­ ist. Bisphosphonates or denosumab has been suc­
cess­fully used in these patients.16
Mast cell sar­coma is an exceed­ingly rare sub­type that does not
meet the diag­nos­tic cri­te­ria for SM but is char­ac­ter­ized by a high-
grade inva­sive solid MC tumor that car­ries a poor prog­no­sis.17
Categories of sys­temic mastocytosis include ISM (most com­
mon), BMM, SSM, SM-AHN, ASM, and MCL. See Table 2 for impor­
tant com­ments about these categories.
Mast cell acti­va­tion syn­dromes
Mast cell acti­va­tion syn­dromes (MCASs) rep­re­sent a het­ero­ge­
neous group of dis­or­ders char­ac­ter­ized by (1) the epi­sodic pres­
ence of mast cell acti­va­tion symp­toms in more than 2 organ
sys­tems, such as cuta­ne­ous, car­dio­vas­cu­lar, GI, pul­mo­nary, and
naso-ocu­lar; (2) response of symp­toms to mast cell medi­a­tor–
targeting drugs; and (3) the detec­tion of a val­i­dated marker of
mast cell acti­va­tion dur­ing the symp­tom­atic phase.2,18 The best
val­i­dated sur­ro­gate marker of mast cell acti­va­tion is tryptase.19
Tryptase should be checked at base­line and within 4 hours of a
suspected mast cell acti­va­tion event. A for­mula of 20% of base­line
plus 2ng/mL is used to cal­cu­late the min­i­mal increase required to
diag­nose mast cell acti­va­tion.20 Urinary metab­o­lites of other mast
cell medi­a­tors such as his­ta­mine, pros­ta­glan­din D2, and leu­ko­tri­
ene C4 mea­sured in a 24-hour or spot col­lec­tion can also be used
to doc­u­ment mast cell acti­va­tion if tryptase lev­els are not avail­­
able; how­ever, the sen­si­tiv­ity and spec­i­fic­ity of these mark­ers as
well as the min­im ­ al increases and cut­off lev­els diag­nos­tic for mast
cell acti­va­tion have not been established.21 A patient with recur­
rent ana­phy­laxis is a pro­to­typ­i­cal pre­sen­ta­tion of MCAS; how­ever,
less severe man­i­fes­ta­tions can meet the above cri­te­ria.
MCAS can be pri­mary or clonal when it is asso­ci­ated with
mastocytosis or MMAS, sec­ond­ary when asso­ci­ated with immu­
no­glob­u­lin (Ig) E or non–IgE-medi­ated mast cell acti­va­tion trig­
gers, or idi­o­pathic when no under­ly­ing cause has been found.
There is quite an exten­sive con­tro­versy surrounding the diag­
no­sis of MCAS, and alter­na­tive diag­nos­tic schemes with broader
inclu­sion cri­te­ria may result in diag­nos­ing nearly 17% of the gen­eral
pop­u­la­tion with MCAS.22 However, this can become prob­lem­atic
for patients whose symp­toms may be caused by another entity
that may sim­ply be asso­ci­ated with reac­tive mast cell acti­va­tion
because focus­ing on mast cell acti­va­tion may leave the under­ly­ing
entity undi­ag­nosed. Contributing to this con­tro­versy some­what
is the International Classification of Diseases ICD-10-CM clas­si­fi­
ca­tion of diag­nos­tic codes that cur­rently includes addi­tional cat­
egories of mast cell acti­va­tion, includ­ing “Mast cell acti­va­tion, not
oth­er­wise spec­ifi ­ ed,” which until recently did not have diag­nos­tic
guid­ance.23 A detailed dis­cus­sion of mast cell acti­va­tion dis­or­ders
is out­side the scope of this arti­cle, as hema­tol­o­gists are gen­er­ally
not expected to diag­nose and treat these dis­or­ders.
With this back­ground infor­ma­tion in mind, let us exam­ine
spe­cific con­sul­ta­tion sce­nar­ios men­tioned at the begin­ning of
the text.
1. Patients with advSM. This group of patients rep­re­sents a
clas­si­cal indi­ca­tion for refer­ral to a hema­tol­o­gist. Patients with
advanced SM are in need of cytoreductive ther­apy and treat­
ment of non–mast cell hema­to­logic neo­pla­sias such as MPNs and
MDSs.4,24 The recent approval of KIT D816V–targeting tyro­sine
kinase inhib­i­tors (TKIs) rev­o­lu­tion­ized the treat­ment of patients
with advSM, who typ­ic ­ ally have a reduced life expec­tancy.25-27
Since most of these patients pres­ent with muta­tions in addi­tion
to KIT D816V, addi­tional ther­a­pies in those who do not respond
or lose their response to TKIs may be needed, and targeted or
pal­li­a­tive treat­ment options for the asso­ci­ated AHN regard­less of
mastocytosis should be con­sid­ered. These options are discussed
in a sep­a­rate arti­cle by Gotlib in this edu­ca­tional pro­gram.43
2. The patient has skin lesions of maculopapular mastocytosis,
and a bone mar­row biopsy is needed to con­firm or rule out sys­
temic mastocytosis and cat­e­go­rize the dis­ease. This is another
com­mon sce­nario for refer­ral to the hema­tol­o­gist. The approach
in this sce­nario is fairly straight­for­ward. If the patient is an adult
with skin lesions, the like­li­hood of sys­temic dis­ease is high, and a
bone mar­row biopsy and aspi­ra­tion is indi­cated to estab­lish the
diag­no­sis and cat­e­go­rize the dis­ease. In pedi­at­ric patients pre­
senting with typ­i­cal CM, a bone mar­row biopsy is gen­er­ally not
indi­cated due to the low risk of sys­temic dis­ease unless the child
has liver or spleen enlarge­ment, has unex­plained per­sis­tent or
pro­gres­sive lymph­ade­nop­a­thy, has periph­eral blood abnor­mal­
i­ties not explain­able by another pro­cess, dem­on­strates con­sis­
tently increas­ing tryptase lev­els in repeated mea­sure­ments, has
a pos­i­tive periph­eral blood KIT D816V muta­tion, or has per­sis­tent
or pro­gres­sive skin dis­ease after ado­les­cence.
3. The patient has a diag­no­sis of cuta­ne­ous or nonadvanced
(indo­lent) sys­temic mastocytosis, and rec­om­men­da­tions for
man­age­ment and fol­low-up are needed. In this sce­nario, patients
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do not have a hema­to­logic abnor­mal­ity but pres­ent for man­age­
ment of var­i­ous mast cell acti­va­tion symp­toms, such as flushing,
abdom­i­nal pain, diar­rhea, pep­tic symp­toms, tachy­car­dia, hypo­
ten­sive recur­rent ana­phy­laxis, neurocognitive prob­lems such
as brain fog, mus­cu­lo­skel­e­tal pain, and fatigue. Symptoms vary
greatly from patient to patient; while some have min­i­mal or no
symp­toms, oth­ers may have severe and dis­abling pre­sen­ta­tions.
Symptom bur­den does not cor­re­late with the extent of bone
mar­row infil­tra­tion by mast cells. Up to 50% of adult patients
may expe­ri­ence ana­phy­laxis dur­ing the course of their dis­ease.28
A pre­scrip­tion of mul­ti­ple doses of self-inject­able epi­neph­rine
is there­fore recommended for all­patients diag­nosed with SM.
Approximately 1 of 3 patients have clin­i­cally sig­nif­i­cant oste­o­
po­ro­sis,16 and about 10% may have an asso­ci­ated IgE-medi­ated
hyme­nop­tera (bee or ves­pid) venom allergy, which can be life
threat­en­ing.29 In this sce­nario, hema­tol­o­gists may feel they lack
the expe­ri­ence or exper­tise to man­age these symp­toms, and it
is rea­son­able to refer these patients to an aller­gist with spe­cial
exper­tise in treating mast cell acti­va­tion symp­toms.
Common man­age­ment strat­e­gies include the avoid­ance of
trig­gers known to cause symp­toms for each spe­cific patient and
the use of anti–mast cell medi­a­tor–targeting ther­a­pies such as
H1 and H2 anti­his­ta­mines, antileukotriene drugs, and mast cell
sta­bi­liz­ers such as cromolyn.30,31 The anti-IgE mono­clo­nal anti­
body omalizumab has been shown to reduce recur­rent ana­phy­
lac­tic symp­toms in patients who do not respond to first-line
antimediator ther­a­pies.32
Patients with SM may be more sus­cep­ti­ble to perioperative
MC acti­va­tion events and ana­phy­laxis, although most patients
undergo suc­ cess­
ful sur­ ger­ ies with premedication and the
selec­tion of agents less likely to cause mast cell acti­va­tion and
the avoid­ance of those known to cause symp­toms in indi­vid­ual
patients.33 Multidisciplinary man­age­ment involv­ing sur­geons,
aller­gists, and anes­the­si­­ol­o­gists is cru­cial to mit­i­gate MC acti­
va­tion in patients need­ing sur­gery. Pregnancy is gen­er­ally well
tol­er­ated in SM, and the man­age­ment of SM in preg­nancy is
discussed else­where.34
KIT D816V–targeting TKIs are cur­ rently approved for the
treat­ment of advanced SM and are in the clin­i­cal trial stage for
patients with nonadvanced SM who do not respond to opti­mized
antimediator man­age­ment.35 Hematological exper­tise may be
required for the treat­ment and mon­i­tor­ing of these patients with
TKIs in the future if they are approved for nonadvanced SM indi­
ca­tions. Avapritinib, cur­rently approved for advSM, was eval­u­
ated in a mul­ti­cen­ter pla­cebo-con­trolled clin­i­cal trial. According
Mast cell dis­or­ders | 59
to part 1 data avail­­able from the PIONEER study (clinicaltrials​­.gov,
NCT03731260), a dose of 25 mg/d was selected to move for­ward
in an expanded part 2 cohort based on safety and effi­cacy data
show­ing an approx­i­ma­tely 30% reduc­tion in patient-reported
symp­ tom scores and no seri­ ous adverse events.36 Avapritinib
has also been shown to be highly effec­tive in improv­ing skin
lesions in SM, and these improve­ments were asso­ci­ated with
objec­tive reduc­tions in mast cell dis­ease bur­den. The PIONEER
trial is cur­rently closed to new patient enroll­ment. Other clin­i­cal
tri­als cur­rently open for enroll­ment to eval­u­ate D816V-­­selec­tive
KIT inhib­i­tors in patients with ISM involve BLU-263 (HARBOR,
NCT04910685) and bezuclastinib (SUMMIT, NCT05186753).
4. The patient has an ele­vated tryptase level. In this sce­nario
a patient with or with­out mast cell acti­va­tion symp­toms and no
skin lesions is referred due to an ele­vated tryptase level to rule
out mastocytosis. The most com­mon cause of an ele­vated trypt­
ase level in the gen­eral pop­u­la­tion is HaT, which is seen in up
to 7% of the pop­u­la­tion in the US (Figure 2).37 HaT is an auto­
so­mal dom­i­nantly trans­mit­ted genetic poly­mor­phism of uncer­
tain clin­i­cal sig­nif­i­cance due to copy num­ber var­i­a­tions of the
TPSAB1 gene encoding the alpha tryptase gene. Alpha tryptase,
a pro­en­zyme with no pro­teo­lytic activ­ity, accounts for the bulk
of mea­sur­able serum tryptase in base­line con­di­tions. A median
nor­mal tryptase level is around 4.5 to 5 ng/mL. Patients with
HaT are gen­er­ally mea­sured to have tryptase lev­els higher than
8 ng/mL. The ele­va­tion in tryptase level is pro­por­tion­ate to the
num­ber of alpha-encoding TPSAB1 genes. Due to the auto­so­mal-
dom­i­nant mode of trans­mis­sion, patients with HaT are expected
to have at least 1 par­ent with an ele­vated tryptase level and
have a 50% chance of pass­ing it on to their chil­dren. The ini­tial
descrip­tion of HaT asso­ci­ated this genetic event with a num­ber
of seem­ingly unre­lated phe­no­typic fea­tures, such as irri­ta­ble
bowel ­syn­drome, skel­e­tal abnor­mal­i­ties, retained pri­mary den­
Figure 2. Hereditary alpha tryptasemia.
60 | Hematology 2022 | ASH Education Program
ti­tion, skin rashes, and venom aller­gies.37 Subsequent stud­ies,
how­ever, failed to con­sis­tently con­firm many of the non­al­ler­gic
phe­no­types.38 HaT alone is not a mast cell acti­va­tion dis­or­der;
how­ ever, some reports indi­ cate that HaT may be a dis­ ease-
mod­i­fy­ing ­fac­tor in those with con­cur­rent hyme­nop­tera venom
allergy, idi­o­pathic ana­phy­laxis and mastocytosis account­ing
for more severe mast cell acti­va­tion symp­toms in HaT car­ri­ers,
although pro­spec­tive stud­ies with no refer­ral bias are needed
to con­firm these asso­ci­a­tions.39 Interestingly, HaT is 2 to 3 times
more prev­a­lent in patients with sys­temic mastocytosis than in
the gen­eral pop­u­la­tion.37 Patients with SM and con­cur­rent HaT
tend to pres­ent more often with mast cell acti­va­tion symp­toms
rather than skin lesions or hema­to­logic abnor­mal­i­ties.40 Whether
this asso­ci­a­tion is due to a mech­a­nis­tic link between HaT and
SM or selec­tion bias needs to be inves­ti­gated in future stud­ies.
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There is no spe­cific treat­ment avail­­able (or needed) for HaT,
other than the treat­ment of under­ly­ing mastocytosis symp­toms
or man­age­ment of ana­phy­laxis.
Testing for HaT (TPSAB1 gene copy num­ber) is cur­rently com­
mer­cially avail­­able in the US. In this test, copy num­bers of alpha
and beta alleles are reported, and their sum should be 4 in most
indi­vid­u­als. Possible com­bi­na­tions include 4 beta and 0 alpha,
3 beta and 1 alpha, and 2 beta and 2 alpha. A quick inter­pre­ta­
tion would be to con­sider any num­ber above 4 to be an extra
alpha allele, pro­vided there are at least 2 alpha alleles. For exam­
ple, in a patient with 3 beta and 2 alpha alleles, there is 1 extra
alpha allele. However, as stated above, a pos­i­tive test for HaT
does not rule out con­cur­rent mastocytosis. Patients with HaT
and mastocytosis tend to have higher tryptase lev­els than what
might be expected for HaT alone. A cor­rec­tion of tryptase level
according to HaT geno­type has been pro­posed as tryptase level
divided by the extra alpha allele num­ber plus 1. For exam­ple, if
the serum tryptase is 15 ng/mL and the patient has an extra copy
of the alpha tryptase allele, the corrected tryptase level would
be 7.5 ng/mL.
Our approach to a patient with an ele­vated tryptase level
higher than 8 ng/mL with­out skin lesions of mastocytosis or
any other rea­son to explain ele­vated tryptase (such as mye­
loid neo­pla­sia, chronic renal fail­ure, etc) is as fol­lows: If the
patient has a his­tory of severe hypo­ten­sive ana­phy­laxis and a
score of 2 points or greater in REMA score (see below),41 or if
the corrected tryptase is greater than 8 ng/mL, we con­sider
a bone mar­row biopsy and aspi­ra­tion to rule out mastocyto­
sis. Some experts also pro­pose a high-sen­si­tiv­ity periph­eral
blood KIT D816V test in patients reluc­tant to have a bone mar­
row biopsy; how­ever, a neg­a­tive result in this test would not
nec­es­sar­ily rule out mastocytosis. If the patient, how­ever, is
asymp­tom­atic or has non­spe­cific symp­toms such as fatigue,
mus­cu­lo­skel­e­tal pain, abdom­i­nal pain, or mul­ti­ple food intol­
er­ances, HaT test­ing is done. If this test shows pos­i­tive results
and the corrected tryptase is lower than 8 ng/mL, a bone mar­
row biopsy is optional, and the patient can be followed yearly
with symp­tom­atic assess­ment and a com­plete blood count
with dif­fer­en­tial and tryptase lev­els. If the patient shows an
increas­ing trend in tryptase lev­els or devel­ops new symp­toms
such as hypo­ten­sive ana­phy­laxis, a bone mar­row biopsy is
con­sid­ered. If HaT test­ing is neg­a­tive in a patient with an ele­
vated tryptase level, a bone mar­row biopsy is recommended
regard­less of symp­tom­atic sta­tus.
Figure 3. REMA score to predict clonal mast cell disease (mastocytosis) in patients presenting with mast cell activation symptoms
and/or anaphylaxis. Reproduced with permission from Alvarez-Twose et al.41
The clin­i­cal case presented at the begin­ning of this arti­cle
is an exam­ple of a patient with an ele­vated base­line tryptase
and severe hypo­ten­sive ana­phy­laxis. Even though he is fairly
asymp­tom­atic other than the ana­phy­laxis epi­sode, his ele­vated
base­line tryptase and high REMA score indi­cate the need for
a bone mar­row biopsy. While one can also check HaT sta­tus, a
pos­i­tive HaT test does not nec­es­sar­ily rule out mastocytosis in
this case. The patient should also be referred to an aller­gist for
venom allergy test­ing and con­sid­er­ation for venom immu­no­
ther­apy and should be pre­scribed self-inject­able epi­neph­rine
for as-needed use.
5. The patient has symp­ toms of mast cell acti­ va­
tion with
a nor­ mal base­ line tryptase level, and an opin­ ion is needed
regard­ ing whether the patient is in need of fur­ ther hema­ to­
logic workup. This sce­nario is prob­a­bly the most con­fus­ing for
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the hema­tol­o­gist, as most of these patients pres­ent with­out an
obvi­ous hema­to­logic abnor­mal­ity, and hema­tol­o­gists may feel
they lack suf­fi­cient exper­tise to eval­ua
­ te and treat mast cell acti­
va­tion or ana­phy­laxis. While a nor­mal tryptase level does not
­nec­es­sar­ily rule out sys­temic mastocytosis, SM is exceed­ingly
rare in patients with a base­line tryptase lower than 4 ng/mL.
Further guid­ance can be obtained by assessing the patient for
REMA cri­te­ria (Figure 3).41 These cri­te­ria were devel­oped by the
Span­ ish Network of Mastocytosis and have a high pre­ dic­
tive
value for deter­min­ing under­ly­ing mastocytosis in patients pre­
senting with ana­phy­lac­tic symp­toms. Patients with hypo­ten­sive
Mast cell dis­or­ders | 61
ana­phy­laxis epi­sodes (par­tic­u­larly after bee/wasp stings or idi­o­
pathic) with­out urti­caria or angioedema are at par­tic­u­lar risk. It
should be noted that while patients with sev­eral unex­plain­able
symp­toms such as chronic fatigue; fibromyalgia; head­aches; irri­
ta­ble bowel syn­drome-like symp­toms; dysautonomia, includ­ing
pos­tural ortho­static tachy­car­dia syn­drome; Ehlers-Danlos syn­
drome; and mul­ti­ple food, drug, and envi­ron­men­tal intol­er­ances
are con­sid­ered for a diag­no­sis of mast cell dis­or­der, there are
no mech­a­nis­tic stud­ies prov­ing a causal link between a pri­mary
mast cell dis­or­der, such as mastocytosis or MCAS, and these enti­
ties, and such patients, espe­cially those with nor­mal tryptase
lev­els, are not can­di­dates for a hema­to­logic workup. Some of
these patients may have other local­ized man­i­fes­ta­tions of mast
cell acti­va­tion com­mon to the gen­eral pop­u­la­tion, such aller­gic
rhi­ni­tis, urti­caria, and even flushing, and these patients could be
eval­u­ated for MCAS with the help of an aller­gist for these spe­cific
enti­ties. Patients with a his­tory of ana­phy­laxis should be eval­u­
ated and man­aged by an aller­gist.
Conclusions
Mast cell dis­or­ders encom­pass mastocytosis and MCASs. Due to
their rar­ity and var­i­ous forms of pre­sen­ta­tion with­out a hema­to­
logic dis­ease, hema­tol­o­gists may feel they lack suf­fic ­ ient exper­
tise to diag­nose and treat these dis­or­ders. However, using the
approach outlined above for dif­fer­ent sce­nar­ios, most of these
patients can be triaged to an appro­pri­ate diag­nos­tic workup. A
hematopathologist with expe­ri­ence in reviewing bone mar­row
and other tis­sue biopsy sam­ples as well as an aller­gist knowl­
edge­able about the symp­tom­atic man­age­ment of these patients
can be help­ful resources dur­ing this pro­cess. A refer­ral to a cen­
ter with more exper­tise can be con­sid­ered for man­age­ment rec­
om­men­da­tions and eval­u­a­tion for clin­i­cal tri­als. A list of these
aca­demic cen­ters is avail­­able through the Amer­i­can Initiative
on Mastocytosis (www​­.aimcd​­.net). Finally, the patient sup­port
group the Mast Cell Disease Society (www​­.tmsforacure​­.org) has
many use­ful infor­ma­tional mate­ri­als for patients diag­nosed with
a mast cell dis­or­der.
Conflict-of-inter­est dis­clo­sure
Cem Akin: con­sul­tancy: Blueprint Medicines, Cogent; research
funding: Blueprint Medicines, Cogent.
Off-label drug use
Cem Akin: omalizumab is discussed. In addition, avapritinib,
BLU-263, and bezuclastinib are in clinical trials for ISM.
Correspondence
Cem Akin, Division of Allergy and Clinical Immunology, Depart­
ment of Medicine, University of Michigan, 24 Frank Lloyd Wright Dr,
Lobby H-2100, Ann Arbor, MI 48106; e-mail: cemakin@umich​­.edu.
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DOI 10.1182/hema­tol­ogy.2022000366
Mast cell dis­or­ders | 63