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Blood Res 2023; 58(S1):

Published online April 30, 2023

https://doi.org/10.5045/br.2023.2023024

© The Korean Society of Hematology

Recent advances in diagnosis and therapy in systemic mastocytosis

Hyun Jung Lee

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Division of Hematology and Medical Oncology, Department of Internal Medicine, Kyung Hee University Hospital, Kyung Hee University College of Medicine, Seoul, Korea

Correspondence to : Hyun Jung Lee, M.D., Ph.D.
Division of Hematology and Medical Oncology, Department of Internal Medicine, Kyung Hee University Hospital, Kyung Hee University College of Medicine, 23 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea
E-mail: hyunjung.lee.md@gmail.com

Received: January 27, 2023; Accepted: April 17, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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Mastocytosis is a heterogeneous neoplasm characterized by accumulation of neoplastic mast cells in various organs. There are three main types: cutaneous mastocytosis (CM), systemic mastocytosis (SM), and mast cell sarcoma. CM mainly affects children and is confined to the skin, whereas SM affects adults and is characterized by extracutaneous involvement, with or without cutaneous involvement. Most cases of SM have an indolent clinical course; however, some types of SM have aggressive behavior and a poor prognosis. Recent advances in the understanding of the molecular changes in SM have changed the diagnosis and treatment of aggressive and advanced SM subtypes. The International Consensus Classification and World Health Organization refined the diagnostic criteria and classification of SM as a result of accumulation of clinical experience and advances in molecular diagnostics. Somatic mutations in the KIT gene, most frequently KIT D816V, are detected in 90% of patients with SM. Expression of CD30 and any KIT mutation were introduced as minor diagnostic criteria after the introduction of highly sensitive screening methods. SM has a wide spectrum of clinical features, and only a few drugs are effective at treating advanced SM. Currently, the mainstay of SM treatment is limited to the management of chronic symptoms related to release of mast cell mediators. Small-molecule kinase inhibitors targeting the KIT-downstream and KIT-independent pathways were recently approved for treating advanced SM. I describe recent advances in diagnosis of SM, and review the currently available and emerging therapeutic options for SM management.

Keywords Systemic mastocytosis, Diagnosis, Treatment, Review

Article

Review Article

Blood Res 2023; 58(S1): S96-S108

Published online April 30, 2023 https://doi.org/10.5045/br.2023.2023024

Copyright © The Korean Society of Hematology.

Recent advances in diagnosis and therapy in systemic mastocytosis

Hyun Jung Lee

Division of Hematology and Medical Oncology, Department of Internal Medicine, Kyung Hee University Hospital, Kyung Hee University College of Medicine, Seoul, Korea

Correspondence to:Hyun Jung Lee, M.D., Ph.D.
Division of Hematology and Medical Oncology, Department of Internal Medicine, Kyung Hee University Hospital, Kyung Hee University College of Medicine, 23 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea
E-mail: hyunjung.lee.md@gmail.com

Received: January 27, 2023; Accepted: April 17, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Mastocytosis is a heterogeneous neoplasm characterized by accumulation of neoplastic mast cells in various organs. There are three main types: cutaneous mastocytosis (CM), systemic mastocytosis (SM), and mast cell sarcoma. CM mainly affects children and is confined to the skin, whereas SM affects adults and is characterized by extracutaneous involvement, with or without cutaneous involvement. Most cases of SM have an indolent clinical course; however, some types of SM have aggressive behavior and a poor prognosis. Recent advances in the understanding of the molecular changes in SM have changed the diagnosis and treatment of aggressive and advanced SM subtypes. The International Consensus Classification and World Health Organization refined the diagnostic criteria and classification of SM as a result of accumulation of clinical experience and advances in molecular diagnostics. Somatic mutations in the KIT gene, most frequently KIT D816V, are detected in 90% of patients with SM. Expression of CD30 and any KIT mutation were introduced as minor diagnostic criteria after the introduction of highly sensitive screening methods. SM has a wide spectrum of clinical features, and only a few drugs are effective at treating advanced SM. Currently, the mainstay of SM treatment is limited to the management of chronic symptoms related to release of mast cell mediators. Small-molecule kinase inhibitors targeting the KIT-downstream and KIT-independent pathways were recently approved for treating advanced SM. I describe recent advances in diagnosis of SM, and review the currently available and emerging therapeutic options for SM management.

Keywords: Systemic mastocytosis, Diagnosis, Treatment, Review

Fig 1.

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Figure 1.Diagnostic algorithm for patients with suspected systemic mastocytosis. In all adult patients with documented mastocytosis in the skin (MIS), a complete staging, including a bone marrow (BM) examination, is required. a)Independent of the serum tryptase level; b)Basal tryptase levels at least 48 hours after resolution of all MC-MRSs; c)in ICC, a core biopsy specimen may be used to diagnose MCL if the aspirate is a dry tap.
Abbreviations: MC-MRS, mast cell-mediator related symptoms; MCAS, mast cell activation syndrome; MIS, mastocytosis in the skin; M/LN-Eo, myeloid/lymphoid neoplasm with eosinophilia.
Blood Research 2023; 58: S96-S108https://doi.org/10.5045/br.2023.2023024

Table 1 . 2022 WHO/ICC classification of mastocytosis..

WHOICC
Cutaneous mastocytosisCutaneous mastocytosis
Urticaria pigmentosa/maculopapular cutaneous mastocytosisUrticaria pigmentosa/maculopapular cutaneous mastocytosis
Monomorphic
Polymorphic
Diffuse cutaneous mastocytosisDiffuse cutaneous mastocytosis
Cutaneous mastocytomaMastocytoma of skin
Isolated mastocytoma
Multilocalized mastocytoma
Systemic mastocytosisSystemic mastocytosis
Bone marrow mastocytosis (BMM)
Indolent systemic mastocytosis (ISM)Indolent systemic mastocytosis (ISM) include bone marrow mastocytosis (BMM)
Smoldering systemic mastocytosis (SSM)Smoldering systemic mastocytosis (SSM)
Aggressive systemic mastocytosis (ASM)Aggressive systemic mastocytosis (ASM)
Systemic mastocytosis with an associated hematologic neoplasm (SM-AHN)Systemic mastocytosis with an associated myeloid neoplasm (SM-AMN)
Mast cell leukemiaMast cell leukemia
Mast cell sarcomaMast cell sarcoma

Bone marrow mastocytosis (BMM) as a clinicopathologic variant in ICC classification became a new SM subtype in WHO classification..

Table 2 . Molecular abnormalities in patients with CM and SM..

Molecular abnormalityReported in patients withEstimated frequency in patients with SM
KIT D816VAll SM variants>90%
Also in CM15–20%
KIT D816YCM, ISM, SM-AHNMD<5%
KIT D816FCM<5%
KIT D816HMCL, ASM, SM-AHNMD<5%
KIT D820GASM<5%
KIT V560GISM<5%
KIT F522CISM<5%
KIT E839KCM<5%
KIT V530ISM-AHNMD<5%
KIT K509ICM, SM (including familial variant)<5%
Other KIT mutationsCM and/or SM variants<5%
FIP1L1/PDGFRASM-CEL<5%
AML1/ETOSM-AML with t(8;21)<5%
JAK2 V617FSM-PMF<5%
TET2 mutationsSM-AHNMD, ISM, ASM<5%∼
SRSF2 mutationsa)ASM, SM-AHNMD<5%∼
DNMT3A mutationsISM, SM-AHNMD<5%∼
ASXL1 mutationsa)ASM, SM-AHNMD<5%∼
RUNX1 mutationa)ASM, SM-AHNMD<5%∼
CBL mutationsSM-AHNMD<5%∼
U2AF1 mutationsSM-AHNMD<5%∼
EZH2 mutationsSM-AHNMD<5%∼
RAS mutationsASM, SM-AHNMD<5%∼

Modified from Valent [26]..

a)Indicates the high molecular risk gene mutations frequently used in multiparameter prognostic scoring systems for advanced SM..

Abbreviations: AHNMD, associated hematologic non-mast cell-lineage disease; AML, acute myeloid leukemia; CEL, chronic eosinophilic leukemia; PMF, primary myelofibrosis..

Table 3 . Clinical manifestations of systemic mastocytosis..

SymptomsFlushing, prutirus, blistering
Anaphylaxis
Hypotension, tachycardia
Fever, night sweats
Fatigue
Abdominal clamping
Nausea, vomiting
Diarrhea
Peptic ulcer disease/GERD
Weight lossa), malabsorption
Headache, cognitive impairment, depression
Organ involvement/damageSplenomegalya)
Hepatomegaly
Portal hypertension, ascitesa)
Lymphadenopathy
Osteoporosis/osteosclerosis, pathologic fracturea)
Laboratory findingsAnemia, thrombocytopeniaa)
Monocytosis
Eosinophilia
Circulating mast cells
Elevated serum tryptase
Elevated alkaline phosphatasea)
Hypoalbuminemiaa)

a)Indicates C-findings..

Table 4 . Refined diagnostic criteria for systemic mastocytosis..

WHOICC
Major criterionMultifocal dense infiltrates of mast cells (≥15 mast cells in aggregates) in bone marrow biopsies and/or in sections of other extracutaneous organ(s)Multifocal dense infiltrates of tryptase- and/or CD117 positive mast cells (≥15 mast cells in aggregates) detected in sections of bone marrow and/or other extracutaneous organ(s)d)
Minor criteria≥25% of all mast cells are atypical cells (type I or type II) on bone marrow smears or are spindle-shaped in mast cell infiltrates detected in sections of bone marrow or other extracutaneous organsa)In bone marrow biopsy or in section of other extracutaneous organs >25% of mast cells are spindle shaped or have an atypical immature morphologye)
KIT-activating KIT point mutation(s) at codon 816 or in other critical regions of KITb) in bone marrow or another extracutaneous organKIT D816V mutation or other activating KIT mutation detected in bone marrow, peripheral blood, or other extracutaneous organsd,f)
Mast cells in bone marrow, blood, or another extracutaneous organ express one or more of: CD2 and/or CD25 and/or CD30c)Mast cells in bone marrow, peripheral blood or other extracutaneous organs express CD25, CD2, and/or CD30, in addition to mast cell markers
Baseline serum tryptase concentration >20 ng/mL (in the case of an unrelated myeloid neoplasm, an elevated tryptase does not count as an SM criterion. In the case of a known HαT, the tryptase level should be adjusted)Elevated serum tryptase level, persistently >20 ng/mL. In cases of SM-AMN an elevated tryptase does not count as a SM minor criterion.
At least 1 major and 1 minorThe presence of the major criterion
In the absence of the major criterion, 3 minor criteriaIn the absence of the major criterion, at least 3 of the following 4 minor criteria must be present

a)In tissue sections, an abnormal mast cell morphology counts in both a compact infiltrate and a diffuse (or mixed diffuse+compact) mast cell infiltrate. However, the spindle-shaped form does not count as an SM criterion when mast cells are lining vascular cells, fat cells, nerve cells, or the endosteal-lining cell layer. In the bone marrow smear, an atypical morphology of mast cells does not count as SM criterion when mast cells are located in or adjacent to bone marrow particles. Morphologic criteria of atypical mast cells have been described previously..

b)Any type of KIT mutation counts as minor SM criterion when published solid evidence for its transforming behavior is available..

c)All 3 markers fulfill this minor SM criterion when expression in mast cells can be confirmed by either flow cytometry or by immunohistochemistry or by both techniques..

d)In the absence of a KIT mutation particularly in cases with eosinophilia, the presence of tyrosine kinase gene fusions associated with myeloid/lymphoid neoplasm with eosinophilia (M/LN-Eo) must be excluded..

e)Round-cell well-differentiated morphology can occur in a small subset of cases. In these cases, the mast cells are often negative for CD25 and CD2 but positive for CD30..

f)To avoid “false-negative” results, use of a high sensitivity PCR assay for detection of KIT D816V mutation is recommended. If negative, exclusion of KIT mutation variants is strongly recommended in suspected SM..

Table 5 . “B” findings and “C” findings in WHO and ICC diagnostic criteria..

WHOICC
B findingsInfiltration grade (MC) in BM ≥30% in histology (IHC) and/or serum tryptase ≥200 ng/mLa) and/or KIT D816V VAF ≥10% in BM or PB leukocytesHigh mast cell burden, >30% of BM cellularity by mast cell aggregates (assessed on BM biopsy) and serum tryptase >200 ng/mL
Signs of myeloproliferation and/or myelodysplasia without a frank AHN; normal or mildly abnormal CBCsCytopenia (not meeting criteria for C findings) or -cytosis. Reactive causes are excluded, and criteria for other myeloid neoplasms are not met
Organomegaly without dysfunction; hepatomegaly, splenomegaly or lymphadenopathy (>2 cm)Hepatomegaly without impairment of liver function, or splenomegaly without features of hypersplenism including thrombocytopenia, and/or lymphadenopathy (>1 cm size) on palpation or imaging
C findingsBM dysfunction: HB <10 g/dL, and/or PLT <100 G/L, and/or neutrophils <1 G/L
Hepatomegaly with liver dysfunction
Splenomegaly with hypersplenism
Large osterolysis (≥2 cm) with pathologic fracture±bone pain
Malabsorption with weight loss due to GI MC infiltrates

a)In the case of a known hereditary α tryptasemia (HαT), the basal serum tryptase level should be adjusted..

The diagnosis of variants of systemic mastocytosis require correlation with B and C findings. “B” findings represent burden of disease. “C”-findings represent SM induced organ damage..

Table 6 . Refined diagnostic criteria for systemic mastocytosis with associated hematologic/myeloid neoplasms..

SM-AHNSM-AMNa)
Meets the diagnostic criteria for systemic mastocytosisMeets the diagnostic criteria for systemic mastocytosis
Meets the WHO criteria for myeloid AHN type, lymphoid AHN typeMeets the criteria for an associated myeloid neoplasm, e.g., CMML or other MDS/MPN, MDS, MPN, AML, or other myeloid neoplasm
The associated myeloid neoplasm should be fully classified according to established criteria

a)SM-AHN is modified to SM-AMN in new ICC criteria because SM-AHN is limited to the presence of an associated myeloid neoplasm, with which it often also shares a KIT mutations and/or clonal genetic abnormalities..

Table 7 . Summary of prognostic factors in multiparameter prognostic scoring systems applicable to SM..

Non-advanced SMAdvanced SM
REMA [38]IPSM [41]IPSMMARS [42]GPS [43]MAPS [44]
Age >60 year✔✔✔✔
Hb, g/dL
>10✔
>11✔✔
Platelet×109/L
<100✔✔✔a)
<150✔
WBC >16×109/L
Increased serum level
Baseline tryptase✔✔a)
β2-microglobulin✔a)✔a)
Alkaline phosphatase✔✔✔
Mutational profile
BM KIT D816V VAF>1%✔a)
Additional somatic mutationsASXL1a),b)
RUNX1a)
DNMT3Aa)		SRSF2
ASXL1
RUNX1		SRSF2
ASXL1
RUNX1
DNMT3A		ASXL1
RUNX1
NRAS

a)Prognostic factor only for PFS. b)A/R/D gene pathogenic VAF ≥30%, independent predictors for OS in REMA..

Table 8 . Therapeutic considerations for mast cell mediator related symptoms..

Pruritis, flushing
H1 and H2 antagonist
Leukotriene antagonist
Topical glucocorticoids
Nonsteroidal anti-inflammatory drug (aspirin)
Psoralen plus UVA (PUVA) for refractory symptoms
Omalizumab
Hypotension/anaphylaxis
Intramuscular epinephrine
For attempted prophylaxis in patients with frequent life-threatening episodes consider scheduled H1 and H2 antagonists +/- glucocorticoids
Cytoreductive therapy (IFN-α or cladribine)
Headache, cognitive impairment, depression
H1 and H2 antagonist
Sodium cromolyn
Abdominal pain, cramping
H2 antagonists +/- proton pump inhibitor
Leukotriene antagonists
Sodium cromolyn
Peptic ulcer disease/GERD, nausea, vomiting
H2 antagonists +/- proton pump inhibitor
Glucocorticoids
Diarrhea
Proton pump inhibitor +/- leukotriene antagonist +/- anticholinergics
Glucocorticoids
Ascites
Glucocorticoids
Portocaval shunt or cytoreductive therapy (INFα or cladribine)
Osteopenia/osteoporosis
Calcium supplementation +/- vitamin D
Bisphosphonates
Cytoreductive therapy (IFN-α or cladribine) in severe osteoporosis at risk for pathologic fracture or severe localized bone pain

Abbreviations: H1, histamine receptor 1; H2, histamine receptor 2; IFN-α, interferon-α..
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