Systemic Mastocytosis in Adults: 2026 Update on Diagnosis, Risk Stratification and Management

ABSTRACT

Overview

Systemic mastocytosis (SM) results from clonal proliferation of mast cells (MC) in extra‐cutaneous organs.

Diagnosis

The major criterion is the presence of multifocal MC clusters in the bone marrow and/or extracutaneous organs. Minor diagnostic criteria include elevated serum tryptase level, MC CD25/CD2/CD30 expression, and the presence of activating KIT mutations.

Risk Stratification

Establishing SM subtype as per the International Consensus Classification/World Health Organization classification systems is an important first step. Patients either have indolent/smoldering SM (ISM/SSM) or advanced SM, including aggressive SM (ASM), SM with associated myeloid neoplasm (SM‐AMN), or mast cell leukemia. Identification of poor‐risk mutations (i.e., ASXL1, RUNX1, SRSF2, NRAS) further refines the risk stratification. Several risk models are available to help assign prognosis in SM patients.

Management

Treatment goals for ISM patients are primarily directed towards anaphylaxis prevention/symptom control/osteoporosis treatment. Patients with advanced SM frequently need MC cytoreductive therapy to reverse disease‐related organ dysfunction. Tyrosine kinase inhibitors (TKI) (midostaurin, avapritinib) have changed the treatment landscape in SM. While deep biochemical, histological, and molecular responses have been documented with avapritinib treatment, its efficacy as monotherapy against a multimutated AMN disease component in SM‐AMN patients remains unclear. Cladribine continues to have a role for MC debulking, whereas interferon‐α has a diminishing role in the TKI era. Treatment of SM‐AMN primarily targets the AMN component, particularly if an aggressive disease such as acute leukemia is present. Allogeneic stem cell transplant has a role in such patients. Imatinib has a therapeutic role only in the rare patient with an imatinib‐sensitive KIT mutation.

1. Disease Overview and Pathogenesis

Systemic mastocytosis (SM) results from a clonal proliferation of morphologically and immunophenotypically abnormal mast cells (MC) that accumulate in one or more organ systems [1, 2]. The sine qua non of mastocytosis is the presence of multifocal clusters of abnormal MC, which in contrast to normal MC are variable in appearance, ranging from round to fusiform variants with long, polar cytoplasmic processes, and may display cytoplasmic hypogranularity with uneven distribution of fine granules, as well as atypical nuclei with monocytoid appearance [3, 4, 5].

The clinical presentation of mastocytosis is heterogeneous, ranging from skin‐limited disease (cutaneous mastocytosis, CM), particularly in pediatric cases where the majority have disease‐onset within the first 2 years of life and commonly experience spontaneous regression of skin lesions at puberty [6, 7, 8, 9], to a more aggressive variant with extra‐cutaneous involvement (SM) that may be associated with multiorgan dysfunction/failure and shortened survival, that is generally seen in adult patients (Figure 1) [11]. SM is distinct from non‐clonal mast cell activation syndrome (MCAS), in which patients display recurrent symptoms of systemic MC activation of varying severity, with concurrent increase in MC mediator release [12]. Further, there is increased frequency (2–3×) of hereditary α‐tryptasemia, a condition associated with increased copy number of the TPSAB1 gene and increased baseline serum tryptase level, in both MCAS and SM patients [13, 14].

FIGURE 1.

Clinical spectrum of patients with clonal mast cell disorders. Please refer to Tables 1A and 1B for the International Consensus Classification and World Health Organization classification of mastocytosis, respectively. “Pre‐diagnostic” systemic mastocytosis (SM) refers to an abnormal clonal bone marrow mast cell infiltrate that falls short of the diagnostic threshold for SM (generally satisfies 1–2 minor criteria only).

In 2022, two independent updates to the previous 2016 World Health Organization (WHO) classification and diagnostic criteria (revised 4th edition) [15, 16] for mastocytosis were published, namely the International Consensus Classification (ICC) of Myeloid Neoplasms and Acute Leukemias [1] and the 5th edition of the WHO Classification of Haematolymphoid Tumours (Table 1A/Table 1B and Table 2A/Table 2B) [2].

TABLE 1A.

International consensus classification (ICC) mastocytosis subtypes (variants) (reproduced from Arber et al. [1]).

Cutaneous mastocytosis

Urticaria pigmentosa/Maculopapular cutaneous mastocytosis

Diffuse cutaneous mastocytosis

Mastocytoma of skin

Systemic mastocyosis

Indolent systemic mastocytosis (includes bone marrow mastocytosis) a

Smoldering systemic mastocytosis a

Aggressive systemic mastocytosis a

Systemic mastocytosis with an associated myeloid neoplasm

Mast cell leukemia b

Mast cell sarcoma

^a The diagnosis of these variants of systemic mastocytosis require correlation with B and C findings.

^b Mast cell leukemia: (i) Meets diagnostic criteria for systemic mastocytosis. (ii) Bone marrow aspirate shows ≥ 20% atypical immature mast cells (include promastocytes, metachromatic blast‐like forms, multinucleated or highly pleomorphic mast cells).

TABLE 1B.

World Health Organization 5th edition classification of mastocytosis (reproduced from Khoury et al. [2, 10]).

Cutaneous mastocytosis

Urticaria pigmentosa/Maculopapular cutaneous mastocytosis ○ Monomorphic ○ Polymorphic

Diffuse cutaneous mastocytosis

Cutaneous mastocytoma ○ Isolated mastocytoma ○ Multilocalized mastocytoma

Systemic mastocyosis

Bone marrow mastocytosis

Indolent systemic mastocytosis

Smoldering systemic mastocytosis

Aggressive systemic mastocytosis

Systemic mastocytosis with an associated hematologic neoplasm

Mast cell leukemia

Mast cell sarcoma

Note: Well‐differentiated systemic mastocytosis (WDSM) represents a morphologic variant that may occur in any SM type/subtype, including mast cell leukemia.

TABLE 2A.

International consensus classification (ICC) systemic mastocytosis (SM): Diagnostic criteria (reproduced from Arber et al.). Cit.

Major criterion 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) a

In the absence of the major criterion, at least 3 of the following 4 minor criteria must be present In bone marrow biopsy or in section of other extracutaneous organs > 25% of mast cells are spindle shaped or have an atypical immature morphology b Mast cells in bone marrow, peripheral blood or other extracutaneous organs express CD25, CD2, and/or CD30, in addition to mast cell markers KIT D816V mutation or other activating KIT mutation detected in bone marrow, peripheral blood, or other extracutaneous organs a , c Elevated serum tryptase level, persistently > 20 ng/mL. In cases of SM‐AMN an elevated tryptase does not count as a SM minor criterion.

Note: SM‐AMN indicates systemic mastocytosis with an associated myeloid neoplasm.

^a In the absence of a KIT mutation particularly in cases with eosinophilia, the presence of tyrosine kinase gene fusions associated with Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions must be excluded.

^b 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.

^c 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 2B.

World Health Organization 5th edition refined major and minor systemic mastocytosis criteria (adapted from Valent et al. [10]).

Major criterion: Multifocal dense infiltrates of mast cells (≥ 15 mast cells in aggregates) in bone marrow biopsies and/or in sections of other extracutaneous organ(s)

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 extracutanous organs a KIT‐activating KIT point mutation(s) at codon 816 or in other critical regions of KIT b in bone marrow or another extracutaneous organ Mast cells in bone marrow, blood, or another extracutaneous organ express one or more of: CD2 and/or CD25 and/or CD30 c 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 d

If at least 1 major and 1 minor or 3 minor criteria are fulfilled → the diagnosis is SM

Abbreviations: HαT, hereditary alpha‐tryptasemia; SM, systemic mastocytosis.

^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 [17].

^b Any type of KIT mutation counts as minor SM criterion when published solid evidence for its transforming behavior is available. A list of such KIT mutations (including variants in KIT codons 417, 501–509, 522, 557–560, 642, 654, 799, 816, 820, 822) is provided in Supplemental Digital Content, http://links.lww.com/HS/A201 (KIT‐activating mutations are labeled in bold).

^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 Although the optimal way of adjustment may still need to be defined, one way is to divide the basal tryptase level by 1 plus the extra copy numbers of the alpha tryptase gene. Example, when the tryptase level is 30 and 2 extra copies of the alpha tryptase gene are found in a patient with HαT, the HαT‐corrected tryptase level is 10 (30/3 = 10) and thus is not a minor SM criterion.

Mastocytosis is frequently associated with somatic gain‐of‐function point mutations within KIT. KIT (CD117) is a Type III receptor tyrosine kinase that is expressed by MC, hematopoietic progenitor cells, germ cells, melanocytes, and interstitial cells of Cajal in the gastrointestinal tract and is therefore functionally relevant for normal mast cell development, hematopoiesis, gametogenesis, melanogenesis, and regulation of slow gastric waves [18]. KIT expression is downregulated upon differentiation of hematopoietic progenitors into mature cells of all lineages, except mast cells, which retain high levels of cell surface KIT expression. The interaction between KIT and its ligand, stem cell factor (SCF), plays a key role in regulating mast cell proliferation, maturation, adhesion, chemotaxis, and survival [19].

Gain‐of‐function somatic mutations in the KIT tyrosine kinase domain, particularly the D816V mutation, have been found to occur in a majority of cases of adult SM, irrespective of WHO SM subtype [11, 20]. Other less common (< 5%) somatic KIT mutations identified in adult SM include V560G [21, 22], D815K [23], D816Y [20, 23, 24, 25], insVI815‐816 [20], D816F [23, 25], D816H [26], and D820G [27]. Recent studies have confirmed that childhood‐onset mastocytosis is also clearly clonal in nature and is associated with germline or acquired activating KIT mutations [28, 29, 30]. In one study of pediatric CM that screened the entire KIT coding sequence for mutations using skin lesional DNA, only 42% of cases harbored missense mutations targeting KITD816; in 44% of cases, genetic alterations (insertions (insFF419), deletions (Δ419), deletion‐insertions (Δ417‐419insY), internal tandem duplications (ITD SA501‐502, ITD AY502‐503, ITD NFAF505‐508) and missense mutations (D816V, D816Y, D816I, C443Y, S476I, K509I, D572A, M541L)) were found to mainly involve exons 8 and 9, which encode the fifth Ig (D5) domain and the extracellular region near the transmembrane domain. The aforementioned mutations in exons 8 and 9 have been reported in core binding factor—acute myeloid leukemia (AML) (Δ417‐419insY) [31, 32], kindreds with familial gastrointestinal stromal tumors (GISTs) and mastocytosis (Δ 419) [33], familial mastocytosis (K509I) [34], and GISTs (ITD AY502‐503) [35]. As with KITD816V, every mutation in exons 8 and 9 that was tested was found to constitutively activate KIT kinase activity. Other rare germline KIT mutations that target the transmembrane domain and that are associated with familial mastocytosis include F522C and A533D [36, 37].

While activating KIT mutations are frequently associated with human mastocytosis, they do not occur universally, and the question as to whether individual mutations are necessary and sufficient to cause mast cell transformation and whether such mutations alone explain the diverse clinical presentations of mastocytosis remains currently unsettled. Furthermore, while childhood‐ and adult‐onset mastocytosis are both associated with activating KIT mutations, the natural history of the two conditions is quite different, with the former often exhibiting skin‐limited disease that spontaneously regresses with age; in contrast, the latter is characterized by persistent multi‐organ involvement, often with a concurrent non‐MC hematologic neoplasm.

Experimental data with regard to this issue have not been conclusive; in transgenic mice expressing human KITD816V in mature MC (under the control of the chymase promoter), only a subset (30%) of mice developed a limited form of mastocytosis (some with cutaneous‐limited disease) at an old age (12–18 months) [38]. Although BM‐derived MC from the transgenic animals eventually became growth factor independent and could be maintained in long‐term cultures, the incomplete disease penetrance in this model suggested that additional somatic mutations are necessary for full MC transformation. In another transgenic mouse model that allowed conditional expression of murine KITD814V (the homolog of human KITD816V) driven by the KIT promoter, expression of mutant KIT in adult mice including in hematopoietic precursors caused severe mastocytosis with 100% penetrance at a young age [39]. Approximately half of the mice developed a non‐MC lineage hematologic neoplasm, most frequently a leukemic disease derived from an immature B‐cell precursor. The mice also developed a severe focal inflammatory colitis associated with a massive increase in mucosal mast cell numbers. In contrast, when mutant KIT expression in this model was limited to more mature MC, disease expression was significantly attenuated; while half of the mice developed MC tumors and erosive skin lesions and all developed severe colitis, the disease occurred significantly later and progressed much slower. While both the aforementioned transgenic murine models are imperfect (abnormal intracellular processing/trafficking of human KITD816V resulting in low oncogenicity in the former, and low transgene expression in the latter), they cumulatively suggest that the effects of constitutive KIT signaling depend on the developmental stage of the cell targeted by the gain‐of‐function mutation. As has been noted in mastocytosis patients [20], mutations targeting undifferentiated progenitors result in multi‐lineage involvement and expression of a severe systemic disease phenotype; in contrast, mutations that target committed MC progenitors or mature MC result in milder forms of the disease.

One paper demonstrated canonical and non‐canonical hedgehog (Hh) pathway activation in neoplastic cells, but not in primary MC, through a study of patients with Greig cephalopolysyndactyly syndrome and congenital mastocytosis, who have haploinsufficiency of GLI3, a major repressor of Hh pathway [40]. GLI3 and KIT mutations were found to have a synergistic role in mastocytosis development in a murine model, and Hh inhibitors inhibited neoplastic MC proliferation both in vivo and in vitro.

2. Diagnosis

The diagnosis and classification of mastocytosis is based on criteria outlined in the 2022 ICC and WHO 5th edition documents (Classification: Table 1A/Table 1B; Diagnosis Table 2A/Table 2B; Figure 2) [1, 2]. Biopsy of organs other than bone marrow (BM), such as liver or spleen, is infrequently pursued, either for diagnostic purposes or to demonstrate MC infiltration as the cause of impaired organ dysfunction. The diagnosis of SM in the absence of skin involvement is considerably more challenging, particularly in those patients with the low disease burden entity termed bone marrow mastocytosis (BMM) where B‐findings are absent and the serum tryptase is often normal or near normal [15, 41, 42]; the WHO recognizes BMM as an independent SM subcategory [2], while the ICC considers BMM as a variant of indolent SM (ISM) [1]. Consequently, a high index of suspicion is required in the setting of recurrent unexplained anaphylaxis, flushing, osteoporosis, gastrointestinal ulcerative disease, or chronic abdominal cramping. A BM aspirate and biopsy are essential for diagnosing mast cell leukemia.

FIGURE 2.

Diagnostic algorithm for systemic mastocytosis. AMN, associated myeloid neoplasm; ASM, aggressive SM; ICC, International Consensus Classification; ISM, indolent SM; MC, mast cells; MCL, mast cell leukemia; SM, systemic mastocytosis; SSM, smoldering SM; WHO, World Health Organization.

2.1. Bone Marrow Histology

In practice, the current diagnostic approach for SM starts with a BM examination since this site is almost universally involved in adult mastocytosis, and histological diagnostic criteria for non‐BM, extra‐cutaneous organ involvement in SM are not standardized. Further, BM examination also allows detection of a second hematologic neoplasm, if present [43, 44].

In general, the pathognomonic multifocal dense MC aggregates, frequently in perivascular and/or paratrabecular BM locations (major diagnostic criterion), may not be readily recognized by standard dyes such as Giemsa, particularly when MC exhibit significant hypogranulation or abnormal nuclear morphology, or in cases with extensive BM involvement by a second hematological neoplasm (e.g., AML), or when significant reticulin fibrosis is present. Among the immunohistochemical markers, tryptase is the most sensitive, given that virtually all MC, irrespective of their stage of maturation, or activation statusexpress this marker, and consequently allows for detection of even small and/or immature MC infiltrates [45, 46, 47]. Notably, gastrointestinal neoplastic MC infiltrates can frequently be tryptase‐negative [48]. The use of tryptase and KIT/CD117 immunostaining is encouraged in the ICC diagnostic criteria to ensure proper identification of MC [1], but neither immunostain is able to distinguish between normal and neoplastic MC [49]. Also, abnormal basophils seen in some cases of acute and chronic basophilic leukemia, as well as in chronic myeloid leukemia (CML), and blasts in some AML cases may be tryptase positive, and may prove difficult to distinguish from MC [44].

In contrast, immunohistochemical detection of aberrant CD25 expression on BM MC appears to be a reliable diagnostic tool in SM, given its ability to detect abnormal MC in virtually all SM subtypes, including the rare cases with a loosely scattered, interstitial pattern of MC involvement [47].

2.2. Mast Cell Immunophenotyping

Neoplastic MC generally express CD25 and/or CD2, and the abnormal expression of CD25 with or without CD2 counts as a minor criterion towards the diagnosis of SM per the ICC and WHO systems [1, 2, 15]. Expression of CD2 has been noted to be variable in SM, and consequently, CD25 expression is considered the more reliable marker for neoplastic MC [50, 51]. The aforementioned immunostaining and immunophenotyping studies enhance the morphological and immunophenotypic distinction between normal (round and CD25‐negative) and abnormal (spindle‐shaped and CD25‐positive) mast cells, respectively [46, 51].

CD30 (Ki‐1 antigen) was initially reported to be preferentially expressed in neoplastic MC from patients with advanced or high‐grade SM; that is, aggressive SM (ASM) or mast cell leukemia (MCL) [52, 53]. Other studies however identified MC CD30 expression in a majority of SM patients, including those with ISM and well differentiated SM (WDSM), a variant where MC exhibit a well differentiated morphology and lack the characteristic CD25 and CD2 expression seen on neoplastic MC [51, 54, 55]. Further, there was no association between level of CD30 expression and any clinical or biological disease features [54]. Based on these data, both ICC and WHO have included MC CD30 expression as a minor criterion (in addition to CD25 and CD2) towards diagnosing SM in the 2022 updates [1, 2].

2.3. Serum Tryptase Level

Normal MC display a spectrum of “activation levels” in vivo, and the mechanisms governing the secretory phenotype and mediator release patterns are not completely understood [56]. Further, the prevalence of hereditary α‐tryptasemia (HAT), a relatively common genetic trait associated with increased basal serum tryptase level and increased predilection for mast cell activation, has been shown to be significantly higher in mastocytosis patients (17.2%) as compared to normal controls (4.4%) [14]. In SM, a persistently elevated basal serum tryptase level (> 20 ng/mL) counts as a minor diagnostic criterion per the ICC and WHO frameworks [1, 2]; while the levels vary widely, serum tryptase is elevated in the vast majority of SM patients across all subgroups; a significantly greater proportion of ASM and SM with associated myeloid neoplasm (SM‐AMN) patients exhibit a markedly elevated serum tryptase level (> 200 ng/mL) compared to those with ISM [11]. Serum tryptase levels are also elevated in a significant proportion of cases with AML, CML, and MDS [57]; consequently, elevated serum tryptase does not qualify as a diagnostic criterion in the presence of an associated myeloid neoplasm [1, 2]. Further, the WHO recommends adjustment of the serum tryptase level in cases of known HAT [2, 10]. The correlation between MC mediator levels and presence of MC mediator‐release symptoms (MCMRS) or systemic MC burden remains incompletely understood; in one study of indolent mastocytosis patients, MC mediator levels were significantly correlated with BM MC burden, but not MCMRS [42]. In contrast, mastocytosis patients with HAT demonstrate significantly higher serum tryptase level and frequency of Hymenoptera venom reactions/anaphylaxis, independent of BM MC burden [14].

2.4. Molecular Studies

In the 2022 update, identification of KITD816V or “other KIT activating mutations at codon 816, or other critical regions of KIT” count as a minor diagnostic criterion per the ICC and WHO systems [1, 2]. A list of transforming KIT mutations in SM is available online (http://links.lww.com/HS/A201) [10]. Of note, there is a high correlation between KIT mutation detection and the proportion of lesional cells in the sample, as well as the sensitivity of the screening method employed [58]. Sensitivity of detection may be enhanced by enriching lesional MC by laser capture microdissection, or magnetic bead‐ or FACS‐based cell sorting, respectively [20, 59, 60], or through the use of highly sensitive PCR techniques [23]. While it has not been standard clinical practice to screen for KIT mutations other than those involving D816, this may change in light of the 2022 updates. The frequency of KITD816V‐mutated non‐MC lineages (generally myeloid, but occasionally lymphoid lineages) appears to be greater in ASM or MCL, as compared to ISM [20]. For SM‐AMN patients, KITD816V is variably identified in non‐MC lineage cells, depending upon the particular AMN subtype (chronic myelomonocytic leukemia [CMML] > myeloproliferative neoplasm [MPN], AML > lymphoid neoplasms) [61].

Attempts at validating the older WHO diagnostic criteria [62] reveal that approximately 20% of ISM patients lack mast cell clusters in the BM and approximately 30% exhibit a serum tryptase level lower than 20 ng/mL [63]. In contrast, the sensitivity for detecting morphologic atypia, aberrant CD25 and/or CD2 expression, or KITD816V in BM mast cells exceeds 90% when sensitive assays are used, thereby illustrating the increasing importance of these specific minor criteria in diagnosing SM [63, 64]. Patients who have mast cell degranulation symptoms with clonal/neoplastic mast cells (i.e., mutated KIT gene and/or CD25 expression), but who do not meet criteria for SM (only 1 or 2 minor criteria satisfied, and no skin involvement), may have “pre‐diagnostic ISM” or “monoclonal mast cell activation syndrome”; these patients generally have normal or slightly elevated baseline serum tryptase level [10, 65, 66]. While the clinical characteristics of this entity may be indistinguishable from ISM, its true natural history remains to be defined.

Rare SM cases may exhibit a well‐differentiated phenotype (i.e., WDSM, characterized by round and well granulated MC; absence of aberrant CD25/CD2 expression); these cases are associated with non‐D816V KIT mutations (e.g., germline F522C or somatic I817V) and, in the case of KITF522C‐associated SM, has been shown to be sensitive to imatinib therapy [20, 36]. These cases frequently have childhood onset, exhibit familial aggregation and MC CD30 expression [55]. WDSM is recognized as a distinct rare variant of SM by both ICC and WHO classifications [1, 2].

In the presence of blood eosinophilia and BM MC proliferation, screening for FIP1L1‐PDGFRA, using either FISH or RT‐PCR, is warranted [67]. In contrast, conventional cytogenetics analysis generally permits identification of cases with a PDGFRB rearrangement (i.e., chromosomal translocations involving 5q31‐32), to be confirmed by fluorescence in situ hybridization (FISH) [68]. These cases with PDGFRA/PDGFRB‐rearranged neoplasms with BM MC proliferation/blood eosinophilia are distinct from SM, and are appropriately classified as “Myeloid or lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions” by both ICC and WHO classifications [1, 2]. The clinical presentation is diverse, frequently involves both myeloid and lymphoid lineages, as well as extramedullary involvement, and presence of eosinophilia is not universal [69].

3. Risk Stratification

This section focuses on adult SM patients; their life expectancy, when considered as a group, appears to be shorter as compared to age‐ and gender‐matched controls, with the excess deaths in this group occurring within the first 3–5 years after diagnosis (Figure 3A) [11, 70].

FIGURE 3.

Adapted from Reference [11]. Panel a) The observed Kaplan–Meier survival for 342 systemic mastocytosis patients (red) compared with the expected age and gender matched US population's survival (blue). Panel b) The observed Kaplan–Meier survival for systemic mastocytosis patients classified by disease type ISM (red), ASM (green), AMN/AHN (yellow), and MCL (purple) compared with the expected age and gender matched US population's survival (blue) for the entire cohort.

Historically, patient categorization per the WHO classification was a practical first step in risk stratifying newly diagnosed adult SM patients [15, 16]. The 2022 WHO classification recognizes six SM subtypes: BMM, ISM, smoldering SM (SSM), ASM, SM‐AMN, and MCL (Table 1B) [2]; BMM is included as a variant of ISM in the ICC classification (Table 1A) [1].

The Mayo study of 342 adult patients has validated the prognostic value of the WHO classification for SM [11]. An important caveat is that these data reflect patient outcomes in the pre‐tyrosine kinase inhibitor (TKI) era at a tertiary medical center.

3.1. Indolent SM

Comprised the largest subgroup (n = 159; 46%) [11]. Compared to patients with ASM and SM‐AMN, ISM patients were significantly younger at presentation (median age 49 years) and had a higher prevalence (66%–75%) of urticaria pigmentosa (UP)‐like skin lesions, MCMRS, and gastrointestinal symptoms; ISM patients were significantly less likely, however, to exhibit constitutional symptoms or hepatosplenomegaly (< 20%).

In the 2022 ICC and WHO iterations [1, 2], SSM is recognized as a distinct variant of SM. SSM is distinguished from ISM by a high burden of MC, defined by the presence of ≥ 2 “B‐findings” (Table 3; Figure 2). BMM is typically characterized by absence of skin involvement and B‐findings and a low basal serum tryptase level (< 125 ng/mL) [2, 10]. The definition of B‐findings has been revised in both classifications (Table 3); of note, the presence of KITD816V mutation at variant allele frequency ≥ 10% now counts as a B‐finding in the WHO system [2].

TABLE 3.

World Health Organization 5th edition refined B‐findings and C‐findings (adapted from Valent et al. [10]).

B‐findings: High MC burden: Infiltration grade (MC) in BM ≥ 30% in histology (IHC) and/or serum tryptase ≥ 200 ng/mL a and/or KIT D816V VAF ≥ 10% in BM or PB leukocytes Signs of myeloproliferation and/or myelodysplasia b : Hypercellular BM with loss of fat cells and prominent myelopoiesis ± left shift and eosinophilia ± leukocytosis and eosinophilia and/or discrete signs of myelodysplasia (< 10% neutrophils, erythrocytes, and megakaryocytes) Organomegaly: Palpable hepatomegaly without ascites or other signs of organ damage or/and palpable splenomegaly without hypersplenism and without weight loss or/and lymphadenopathy palpable or visceral LN‐enlargement found in ULS or CT (> 2 cm)

C‐findings: Cytopenia/s: ANC < 1 × 109/L, Hb < 10 g/dL, PLT < 100 × 109/L (one or more found) Hepatopathy: Ascites and elevated liver enzymes c ± hepatomegaly or cirrhotic liver ± portal hypertension Spleen: Palpable splenomegaly with hypersplenism ± weight loss ± hypalbuminemia GI tract: Malabsorption with hypoalbuminemia ± weight loss Bone: Large‐sized osteolysis (≥ 2 cm) with pathologic fracture ± bone pain

Note: International Consensus Classification: Systemic mastocytosis: B‐findings [1]. (1) High mast cell burden, > 30% of BM cellularity by mast cell aggregates (assessed on BM biopsy) and serum tryptase > 200 ng/mL. (2) Cytopenia (not meeting criteria for C findings) or ‐cytosis. Reactive causes are excluded, and criteria for other myeloid neoplasms are not met. (3) Hepatomegaly without impairment of liver function, or splenomegaly without features of hypersplenism including thrombocytopenia, and/or lymphadenopathy (> 1 cm size) on palpation or imaging.

Abbreviations: AHN, associated hematologic neoplasm; ANC, absolute neutrophil count; BM, bone marrow; CT, computed tomography; GI, gastrointestinal; Hb, hemoglobin; HαT, hereditary alpha‐tryptasemia; IHC, immunohistochemistry; LN, lymph node; MC, mast cells; MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasm; PB, peripheral blood; PLT, platelet count; SM, systemic mastocytosis; SSM, smoldering systemic mastocytosis; ULS, ultrasound; VAF, variant allele frequency.

^a In the case of a known HαT, the basal serum tryptase level should be adjusted. Although the optimal way of adjustment still needs to be defined, one way is to divide the basal tryptase level by 1 plus the extra copy numbers of the alpha tryptase gene. Example, when the tryptase level is 300 and 2 extra copies of the alpha tryptase gene are found in a patient with HαT, the HαT‐corrected tryptase level is 100 (300/3 = 100) and would thus not qualify as a B‐finding.

^b Signs of myeloproliferation and/or myelodysplasia must be discrete and stable (neither disappear nor progress) and must not reach diagnostic criteria of an MPN, MDS, or MPN/MDS in which case the diagnosis changes to SM‐AHN. The presence of a myeloid AHN excludes B‐findings and SSM by definition.

^c Alkaline phosphatase levels are typically elevated in patients with advanced SM and SM‐induced liver damage. In some of these patients, only elevated liver enzymes but no (clinically relevant) ascites is found.

Of the 159 ISM patients in the aforementioned series, 22 (14%) had SSM, 36 (23%) BMM, and the remaining 101 (63%) did not fit in with either category (ISM‐other) [42]. In an updated report, the median overall survival (OS) of 17 SSM patients was found to be significantly inferior when compared to 274 ISM patients (HR 5.5, 95% CI 2.8–10.2). This difference was accounted for by a higher prevalence of poor‐risk features in SSM patients, including, in particular, older age and hemoglobin below the lower limit of the sex‐adjusted reference range [71]. In contrast, BMM patients more frequently presented with MCMRS (86%), including anaphylaxis (78%), but had a more favorable survival outcome [42]. The median OS of ISM patients was 198 months, which was not significantly different than that of the age‐ and sex‐matched U.S. control population (Figure 3B, red curve) [11]. In contrast, in a recent Danish population‐based matched cohort study, the mortality risk of ISM patients was found to be significantly higher (HR 1.9 [95% CI 1.4–2.5]) as compared to the general population [72]. In the European Competence Network on Mastocytosis (ECNM) cohort, 22 (3.4%) of 655 ISM patients died during a median follow up of 4.3 years (median OS = 28.4 years) [73]. There was no significant difference in survival between ISM, SSM, and BMM groups in this study.

The overall risk of transformation to acute leukemia or ASM is low (< 1% and 3%, respectively) but was significantly higher in SSM (18%) [11]. Another study confirmed the low rate of disease progression in ISM; after a median follow up of 147 months (range 61–329), the progression rate was 3%; predictors of disease progression were serum β2‐microglobulin level and multilineage presence of KITD816V [74]. In the ECNM cohort, transformation rates to ASM, SM‐AMN and MC sarcoma were 1.2%, 1.8% and 0.1%, respectively [73]. There was no significant difference in the rate of transformation between ISM, SSM and BMM groups in this study. Age ≥ 60 years and serum alkaline phosphatase ≥ 100 U/L were found to be predictive of disease transformation and OS, and formed the basis for the International Prognostic Scoring System for Mastocytosis (IPSM) model.

3.2. Systemic Mastocytosis With an Associated Myeloid Neoplasm

In the ICC classification, SM with an associated hematological neoplasm (SM‐AHN) is now modified to “SM‐AMN,” given evidence of a shared clonal origin with associated myeloid but not lymphoid neoplasms [1]. SM‐AMN was the second most common SM subgroup (n = 138; 40%) in the Mayo series [11, 75]. Of the associated hematological neoplasms, 123 (89%) had an associated myeloid neoplasm, while the remainder had lymphoma (n = 7), myeloma (n = 5), chronic lymphocytic leukemia (n = 2), or primary amyloidosis (n = 1). Of the patients with an associated myeloid malignancy, 55 (45%) had SM‐MPN, 36 (29%) SM‐chronic myelomonocytic leukemia (SM‐CMML), and 28 (23%) SM‐MDS. A significant proportion (n = 42; 34%) exhibited prominent eosinophilia (≥ 1.5 × 10⁹/L), especially those with SM‐MPN (n = 31; 56%); of the latter, 12 (39%) harbored the FIP1L1‐PDGFRA fusion. This latter group would currently be classified as “Myeloid or lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions.”

Overall median survival in SM‐AMN was 24 months (Figure 3B, gold curve). SM‐MPN patients had a significantly longer median survival (31 months) as compared to patients with SM‐CMML (15 months), SM‐MDS (13 months), or SM‐AL (11 months). Leukemic transformation (13% overall) was seen significantly more frequently in SM‐MDS (29%), as compared to SM‐MPN (11%) or SM‐CMML (6%). Clinical outcome was similar between SM‐MPN patients with or without eosinophilia. In the ECNM registry data, median OS for 174 SM‐AMN patients was 2.9 years (10‐year OS 11.2%) [76].

3.3. Aggressive Systemic Mastocytosis

ASM is characterized by one or more C‐findings (Table 3); of note, the definition of C‐findings has undergone revision in the 2022 WHO classification [2]. ASM was the third most common subgroup (n = 41; 12%) in the Mayo series [11]. ASM patients frequently displayed constitutional symptoms (60%), hepatosplenomegaly (50%), lymphadenopathy (30%), severe anemia (Hgb < 10 g/dL; 24%) or thrombocytopenia (platelets < 100 × 10⁹/L; 27%), leukocytosis (41%), and markedly elevated serum tryptase levels (> 200 ng/mL; 40%). Overall median survival in ASM was 41 months (Figure 3B, green curve) and leukemic transformation occurred in 2 patients (5%). In the ECNM registry data, median OS for 62 ASM patients was 5.7 years (10‐year OS 44%) [76].

3.4. Mast Cell Leukemia

MCL was relatively rare (n = 4; 1%) in the Mayo series [11]; the prognosis in these cases was dismal with median survival of only 2 months (Figure 3B, violet curve). In the ECNM registry data, median OS for 23 MCL patients was 1.9 years (10‐year OS 29.9%) [76]. A recent series of 92 MCL patients (defined by MC ≥ 20% in BM aspirate), not surprisingly, identified a heterogenous population of patients—34% had an associated hematological neoplasm (AHN), 14% had “chronic” MCL (i.e., absent C‐findings) and 5% had “leukemic” MCL (i.e., ≥ 10% circulating MC) [77]. The median OS was 1.6 years; presence of AHN and abnormal karyotype in contrast to KITD816V positivity and midostaurin treatment were associated with significantly inferior and superior OS, respectively. A weakness of this study was the lack of consideration of MC morphology—in a single institution study of 16 MCL patients with independent central review of BM slides by at least 2 hematopathologists, immature MC morphology was the only predictor of inferior OS on multivariate analysis [78]. Correspondingly, the 2022 ICC classification requires the presence of atypical immature MC (i.e., promastocytes, metachromatic blast‐like forms, and multinucleated or highly pleomorphic MC) to account for ≥ 20% of BM cellularity (aspirate and/or trephine biopsy) in MCL [1]. While presence of circulating MC is to be noted, the terms “leukemic” or “aleukemic” have been removed, and the poorly characterized entity “chronic MCL” is not recognized by ICC.

A more recent study of 910 SM patients from the Mayo clinic, median overall survival/5‐year survival for patients subclassified by the ICC classification was: ISM/SSM 24.3 years/92%, ASM 5.8 years/50%, SM‐AMN 2 years/28%, and MCL 0.08 years/14% [79].

3.5. Additional Prognostic Variables

Recent data suggests that the broader mutational profile of SM patients provides useful prognostic information, including in decision making for allogeneic stem cell transplantation. For example, ASXL1, RUNX1, NRAS, and SRSF2 mutations that are frequently observed in other myeloid malignancies have been identified as being prognostically detrimental in advanced SM patients [80, 81, 82]. Further, one study showed inferior clinical outcomes (i.e., response rates, survival and disease progression) in advanced SM patients receiving midostaurin treatment, for those harboring poor‐risk mutations as compared to those without such mutations [83].

Several prognostic models have been developed to allow for risk stratification of SM patients; these include the Mutation‐adjusted risk score (MARS) [84], Mayo Alliance Prognostic System (MAPS) [85], and the Global Prognostic score for Mastocytosis (GPSM) [86]. A caveat, however, is that the performance of these risk models in SM patients in the TKI era has not been studied in detail. At our institution, two complementary risk models for SM were initially developed for SM (MAPS); one model (clinical) was based on clinical variables alone while the other (hybrid clinical‐molecular) included presence of adverse mutations (ASXL1/RUNX1/NRAS) as an independent risk factor [85]. Risk stratification of SM patients based on these 2 risk models is shown in Figure 4. The utility of the MAPS models (both clinical and hybrid clinical‐molecular) was recently confirmed in an expanded cohort of 910 SM patients [79]. In this analysis, classification of patients as “advanced SM” per ICC defined SM‐subcategories was found to be prognostically superior as compared to WHO 5th edition based subclassification. This analysis also identified serum tryptase > 125 μg/L to adversely affect OS in multivariable analysis (HR 4.2, p < 0.01).

FIGURE 4.

Panel A: Depicts a “clinical” risk model for systemic mastocytosis (SM) that is based on number of risk factors: (i) advanced SM versus ISM/SSM (HR 2.7), (ii) age > 60 years (HR 2.5), (iii) platelets < 150 × 10⁹/L (HR 2.5), (iv) anemia below sex‐adjusted normal (HR 2.2), and (v) serum alkaline phosphatase above normal range (HR 2.1). HR (95% CI) values listed are calculated against the next lower risk level. Panel B: Depicts a “clinical‐molecular” risk model for systemic mastocytosis that is based on HR‐weighted risk points: (i) advanced SM versus ISM/SSM (HR 4.0; 2 points), (ii) age > 60 years (HR 2.2; one point), (iii) platelets < 150 × 10⁹/L (HR 2.8; one point), (iv) serum alkaline phosphatase above normal range (HR 2.1; one point), and (v) adverse mutations (HR 2.6; one point). HR (95% CI) values listed are calculated against the next lower risk level.

The aforementioned models rely on initial stratification of patients as per the WHO/ICC classification systems, which can be challenging in practice, given the paucity of data regarding inter observer reproducibility of BM morphological findings. Consequently, in a follow up study, a WHO class‐independent risk model for mastocytosis (WHO‐independent MAPS) was developed based on the following clinical/laboratory variables that represent widely available objective criteria: age > 60 years (2 points), platelets < 100 × 10⁹/L (2 points), Hgb < sex‐adjusted lower normal range (2 points), increased serum alkaline phosphatase (1 point) and serum albumin < 3.5 g/dL (1 point) [87]. The 580 SM patients were stratified into 5 risk groups: low‐risk (0 points, median OS not reached), intermediate‐1‐risk (1–2 points; median OS = 291 months), intermediate‐2‐risk (3 points, median OS = 99 months), high‐risk (4–6 points, median OS = 38 months) and very high‐risk (7–8 points, median OS = 8 months).

The German registry derived mutation‐adjusted risk score for advanced mastocytosis (MARS) model integrates age > 60 years, hemoglobin < 10 g/dL, platelets < 100 × 10⁹/L, and presence of 1 or ≥ 2 high‐risk mutations (ASXL1/SRSF2/RUNX1), to identify low (median OS not reached), intermediate (median OS = 3.9 years), and high risk (median OS = 1.9 years) patient groups [84].

Increased plasma IL‐2Rα/CD25 levels have also been associated with inferior overall survival in advanced and indolent SM patients, independent of conventional risk factors [88]. KITD816V, which is the hallmark of adult SM, has been shown to occur in BM hematopoietic cell compartments other than MC, particularly in cases of SM‐AMN, ASM, and MCL, but less frequently in ISM, thereby indicating involvement of a pluripotent stem cell in such cases [20]. Further, comprehensive immunophenotyping has shown that an immature BM MC phenotype (CD25⁺/FcεRI^lo/FSC^lo/SSC^lo/CD45^lo), in the absence of coexisting normal MC in the BM, correlated with multilineage hematopoietic involvement by KITD816V, regardless of the WHO SM subtype [89]. In contrast, BM MC from patients with ISM subtypes displayed a mature activated MC phenotype (e.g., increased expression of MC activation markers CD63, CD69, and CD203c in patients with BMM) [90]. While such assays require considerable technical expertise and are not routinely available, these data indicate the potential prognostic value of these observations; in one study, multilineage KITD816V involvement was the most important prognostic criterion for progression of ISM to more aggressive SM subtypes [74].

4. Treatment

The treatment of adult SM is highly individualized (Figure 5). Treatment options in SM range from observation alone (supplemented by preventative measures to avoid precipitating MC degranulation), to symptom management (e.g., treating pruritus or diarrhea) (Table 4), to supportive measures (e.g., red blood cell transfusion or osteoporosis treatment), to cytoreductive therapy for MC debulking in the setting of aggressive, advanced, or treatment‐refractory disease. Historically, patients with advanced SM have been treated off label with cladribine, (PEG)‐interferon α, or chemotherapy drugs, particularly for the AMN component in SM‐AMN, or for MCL. Recent data with potent tyrosine kinase inhibitors (TKI) that selectively target mutant‐KIT have shown reversion of organ damage with marked decrease in BM MC burden, as well as the potential for KITD816V molecular remissions, suggesting the possibility of disease modifying therapeutic effect in patients with advanced SM [91, 92]. Data also shows significant improvement in symptoms and quality of life measures associated with decreased MC burden and decreased KITD816V variant allele frequency (VAF) in ISM patients treated with TKI's [93, 94]. For the rare SM patient with a transmembrane KIT mutation (e.g., F522C or K509I), dramatic clinical responses to imatinib therapy can be observed [34, 36]. Although not FDA approved for the indication, a systematic review suggested that omalizumab, a recombinant humanized monoclonal antibody that inhibits binding of IgE to the high‐affinity IgE receptor (RI) on the surface of MCs, ameliorates symptoms in mastocytosis patients, particularly those with severe recurrent anaphylaxis episodes [95]. Recently published consensus criteria have facilitated objective and standardized assessment of treatment response in SM patients in the era of novel, molecularly targeted drugs [96, 97].

FIGURE 5.

Algorithm for the treatment of systemic mastocytosis.

TABLE 4.

Supportive therapies for symptom control in adult patients with indolent systemic mastocytosis (adapted from Reference [41]).

Symptoms	Treatment ladder a , b	Drug class	Specific drugs/doses	Common side effects (> 5%–10%)/precautions c
Pruritus/flushing	1st‐line	H1‐antagonist	Cetirizine 5–10 mg/d* Fexofenadine 60 mg BID or 180 mg/d* Hydroxyzine 25 mg q 6 h* *Doses can be increased with supervision if indicated	Headache, somnolence, confusion, asthenia, xerostomia Precautions: Hydroxyzine—anti‐cholinergic effects: use with caution in older patients, those with glaucoma, BPH, asthma, etc.
	2nd‐line	Leukotriene antagonist	Montelukast 10 mg/d Zafirlukast 20 mg BID	Headache Precautions: liver function impairment, neuropsychiatric conditions
	3rd‐line	Non‐steroidal anti‐inflammatory drug	Aspirin (see text)	Gastrointestinal bleeding, peptic ulcer disease Precautions: may precipitate anaphylactic reaction (see text), aspirin hypersensitivity, children/adolescents with flu (Reye's syndrome), hepatic or renal dysfunction, bleeding disorders
	3rd‐line	Psolaren plus ultraviolet A (PUVA) photochemotherapy	See specialized texts	Nausea, pruritus, erythema of varying degree, increased risk of non‐melanoma skin cancers. Contraindications: Pregnancy, xeroderma pigmentosa, lupus erythematosus with photosensitivity
Abdominal pain, cramping, diarrhea, heartburn, nausea, vomiting	1st‐line	H2‐antagonist	Ranitidine 150 mg BID Famotidine 10 mg BID Cimetidine 400 mg BID	Headache, abdominal pain, dizziness, constipation, diarrhea Cimetidine: gynecomastia
	2nd‐line	Proton pump inhibitor	Omeprazole 20 mg/d Pantoprazole 40 mg/d Rabeprazole 20 mg/d	Headache, abdominal pain, nausea, vomiting, diarrhea, flatulence
	3rd‐line	Sodium cromolyn	100–200 mg QID 30 min before meals and bedtime	Dysgeusia, cough, osmotic diarrhea
	4th‐line	Corticosteroid	Prednisone 0.5–1 mg/kg/d starting dose; taper as feasible based on response/tolerance	Dose/duration dependent (consult comprehensive drug reference resource)
Headache, cognitive impairment, depression	1st‐line	H1‐ and H2‐antagonist	As above	As above
	2nd‐line	Sodium cromolyn	As above	As above
Recurrent hypotension a	1st‐line	Epinephrine	See text	See text
	2nd‐line	H1‐ and H2‐antagonists	As above	As above
	3rd‐line	Corticosteroid	Prednisone (as above)	As above
	4th‐line	Cytoreductive therapy (Interferon‐α or 2‐chlorodeoxyadenosine)	See text/below	See text/below
Osteoporosis	1st‐line	Bisphosphonate	Alendronate 70 mg q week Risedronate 35 mg q week Pamidronic acid 90 mg IV q 4 weeks Zolendronic acid 4 mg IV q 4 weeks	Flu‐like symptoms, abdominal pain, nausea, vomiting, diarrhea, asthenia, hypocalcemia, rash musculoskeletal pain, headache, osteonecrosis of the jaw, nephrotoxicity. Follow established guidelines for bisphosphonate use (see text) Precautions: esophageal/upper GI disease (oral bisphosphonates), renal disease, poor oral hygiene or dental procedures
	2nd‐line	Cytokine/Immunomodulatory drug	Interferon‐α Starting dose: 1–3 MU SQ three times per week Target dose: 3–5 MU SQ 3–5 times per week	Dose dependent (consult comprehensive drug reference resource) Comment: pegylated interferon may be better tolerated
	3rd‐line	Purine nucleoside analogue	2‐Chlorodeoxyadenosine (Cladribine/2‐CdA) Dose: 5 mg/m2 IV × 5 days every 4–8 weeks	Myelosuppression, immunosuppression

Abbreviations: BID, twice a day; BPH, benign prostatic hypertrophy; d, day; GI, gastrointestinal; H1, histamine receptor 1; H2, histamine receptor 2; IV, intravenously; kg, kilogram; mg, milligram; MU, million units; q, every; QD, once daily; QID, four times a day; SQ, subcutaneously.

^a Avoidance of symptom trigger(s) applies to all patients. Those at risk of anaphylaxis should carry an emergency kit with self‐injected epinephrine (EpiPen) (see text). Immunotherapy can be considered in those with IgE‐mediated allergic reactions (see text).

^b Treatments can be combined in a stepwise manner for inadequate symptom control at prior step if clinically indicated/feasible.

^c Basic overview provided. Consult a comprehensive drug reference manual for detailed information regarding feasibility of use during pregnancy, black box warnings, specific contraindications/precautions, drug‐drug interactions, dose reduction for hepatic/renal dysfunction, and so forth.

Allogeneic stem cell transplant (ASCT) can prolong overall and progression‐free survival in select SM patients, although the overall experience is heavily skewed towards SM‐AMN patients, and the utility of ASCT in the modern KIT inhibitor era remains to be fully defined [98, 99]. Results from a retrospective study of SM patients who underwent ASCT described 57 patients (median age 46 years), of which 38 had SM‐AMN (20 with AML), 12 MCL and 7 ASM [100]. The primary assessment of treatment response was at day +100 post‐ASCT; responses were seen in 40 patients (70%), of which 16 patients (28%) achieved complete remission of the mastocytosis component with 2 patients becoming KITD816V‐negative. Another 24 (42%), 12 (21%), and 5 (9%) patients had partial response, stable disease, and primary refractory disease, respectively; primary refractoriness was chiefly observed in MCL patients. The AMN was more treatment sensitive, with complete remission of this component being noted in all 38 SM‐AMN patients. Overall survival at 3 years was 57% for the entire cohort, and 74% for SM‐AMN, 43% of ASM, and 17% of MCL subgroups. Predictors of poor overall survival were presence of MCL (vs. ASM or SM‐AMN), reduced‐intensity (vs. myeloablative) conditioning and disease‐progression (vs. response or stable disease). Another recent report concluded that ASCT outcomes in advanced SM were primarily influenced by disease phenotype (e.g., KITD816V mutation‐negative, presence of complex karyotype) and treatment response prior to ASCT (both SM and AMN components in SM‐AMN patients), rather than transplant characteristics [101]. Use of midostaurin or avapritinib pre‐transplant was associated with significantly improved progression‐free survival. Recent consensus guidelines on ASCT in advanced SM include recommendations on how KIT inhibitors might fit into the transplant algorithm, both prior to and post‐transplant [99].

Currently used agents for SM therapy are presented below. Our current algorithm for SM treatment is illustrated in Figure 5.

1. Avapritinib: is approved for treatment of SM patients; approval for advanced SM patients was based on data from EXPLORER (NCT02561988) and PATHFINDER (NCT03580655), two multi‐center, single‐arm, open‐label clinical trials (https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/212608s007lbl.pdf).

   Avapritinib is a small molecule kinase inhibitor that selectively inhibits activation‐loop mutants of KIT, including KITD816V, at subnanomolar concentrations [102, 103, 104]. Avapritinib also inhibits the analogous mutation in PDGFRA, namely D842V, seen in imatinib‐refractory gastrointestinal stromal tumors (GIST). The drug appears highly selective, with limited inhibitory activity outside of KIT and PDGFRA kinases, and has shown therapeutic activity in murine models of mastocytosis.

   In the phase 1 EXPLORER trial, avapritinib was evaluated at doses of 30–400 mg daily; MTD was not reached; 200 and 300 mg daily were studied in the dose expansion phase [91]. At data cutoff, 51% of 69 advanced SM patients had discontinued treatment, 20% for disease progression and 10% for related adverse events. Fifty (72%) patients had at least one dose reduction for adverse events, most commonly for cytopenias. The most frequent adverse events were periorbital edema (69%), anemia (55%), diarrhea (45%), and thrombocytopenia (44%). Intracranial bleeding was observed in 13% of patients. Cognitive adverse events, largely grades 1–2, were seen in 30% of patients. Responses were assessed per modified International Working Group‐Myeloproliferative Neoplasm Research and Treatment‐European Competence Network on Mastocytosis (mIWG‐MRT‐ECNM) criteria [97], in 53 of 86 response evaluable patients. The overall (ORR) and complete remission (CR) rates were 75% and 36%, respectively. Greater than 50% reduction in BM MC and serum tryptase level was seen in 92% and 99% of patients, respectively. The KITD816V VAF was reduced from baseline by ≥ 50% and became undetectable in 80% and 30% of patients, respectively. Estimated progression‐free survival (PFS) rates at 12 and 24 months were 84% and 63%, respectively. Median overall survival (OS) was not reached after median follow up of 23 months.

   Interim and 3‐year follow up results from the PATHFINDER study, the registrational Phase 2 trial of avapritinib in adult patients with advanced SM, have been published [92, 105]. The latter reported on 107 patients (ASM 21, SM‐AHN 71, MCL 15) who received avapritinib 200 mg (n = 105) or 100 mg (n = 2). ORR/composite CR rate in 83 response evaluable patients was 73%/29%, with higher response rates in treatment‐naïve (87%/43%) versus previously treated patients (66%/21%). Median treatment duration was 33.2 months; median duration of response, PFS and OS were not reached. Clearance of BM MC aggregates was seen in 71%, KITD816V VAF < 1% in 63% and serum tryptase < 20 ng/mL in 65%. The most frequent treatment‐related adverse events (TRAE; any grade) were periorbital edema 41%, thrombocytopenia 40%, peripheral edema 38% and anemia 32%. TRAE related dose reductions, interruptions and discontinuation occurred in 76%, 63%, and 13%, respectively.

   Avapritinib was approved for treatment of ISM based on PIONEER (NCT03731260) which was a phase 2, randomized, placebo‐controlled, double‐blind clinical trial comparing avapritinib (25 mg daily) plus best supportive care (BSC) versus placebo plus BSC (2:1) in patients with moderate–severe symptomatic ISM [94]. At week 24, avapritinib treated patients had a mean decrease in total symptom score points of 15.6 versus 9.2 in the placebo group (p < 0.003). Key secondary endpoints also favored avapritinib: ≥ 50% reduction in BM MC burden (53% vs. 23%), serum tryptase (54% vs. 0%) and KITD816V VAF (68% vs. 6%). Overall avapritinib was well tolerated; TRAE's leading to dose interruption/reduction were 8.5%/1.4% for avapritinib versus 12.7%/1.4% for placebo. TRAE's more frequently associated with avapritinib included flushing, edema (peripheral, periorbital, facial), and increased serum alkaline phosphatase.

   At a median 2‐year follow up, avapritinib at the 25 mg once daily dose showed durable improvement in disease symptoms and quality of life, without any new safety concerns being identified [93].

   Summary: Treatment with avapritinib in advanced SM has yielded promising results, with clinically meaningful responses associated with deep biochemical, histopathology and molecular responses, that suggest possible disease modifying activity in SM. Caveats include need for longer follow up data and limited data availability regarding response of the AMN component in patients with SM‐AMN, who comprise the largest subset of adult patients with advanced SM. Intracranial bleeding initially emerged as a major concern; subsequent measures to mitigate this risk include exclusion of patients with platelet count < 50 × 10 ⁹ /L, closer monitoring of platelet counts during treatment, dose hold and reduction guidelines for new/progressive thrombocytopenia, and use of platelet transfusions and growth factors to maintain platelet count ≥ 50 × 10 ⁹ /L. Adverse effects on cognition (e.g., confusion, memory impairment, dizziness) remain a concern with regards to tolerability of long term treatment., The development of a new generation of mutant‐KIT targeting TKI's with low CSF penetration may allow for reduced risk of CNS adverse events [106]. It is not clear whether avapritinib treatment decreases the rate of disease progression/transformation, particularly in the SM‐AMN subgroup, where the disease is multimutated, with frequent presence of non‐KITD816V pathogenic mutations.

   While avapritinib is effective at decreasing disease symptoms and MC burden in ISM patients who remain highly symptomatic despite standard of care therapies, follow‐up is limited, and additional data regarding potential toxicities with longer‐term use are needed.

2. Midostaurin: is a multikinase inhibitor with in vitro activity against kinase domain KIT mutants (D816Y and D816V) [107, 108]. In the global registrational trial, 116 patients with advanced SM were enrolled; the primary efficacy population comprised 89 patients (16 with ASM, 57 with SM‐AMN, and 16 with MCL); patients were treated with midostaurin at 100 mg BID [109]. The ORR (per modified Valent and Cheson criteria) [97] was 60% with 45% having a major response and 15% having a partial response. The response rate was 75% in ASM patients, 58% in SM‐AMN patients, and 50% in MCL patients. A post hoc exploratory analysis of responses by the FDA using mIWG‐MRT‐ECNM criteria yielded a response rate of 17% (https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/207997s000lbl.pdf). After a median follow‐up of 26 months (range 12–54), the median duration of response was not reached in ASM or MCL patients and was 12.7 months in SM‐AMN patients. Responses occurred regardless of KITD816V status. Reversal of organ damage (major or partial responses) was reflected by normalization of hypoalbuminemia (58%), achieving red blood cell transfusion independence (40%) or platelet transfusion independence (100%), improvement in liver function test abnormalities (44%–58%), and/or reversion of weight loss (25%). Patients reported improvement of disease‐related symptoms with treatment. The median overall survival for ASM, SM‐AMN, and MCL subgroups was not reached, 20.7 and 9.4 months, respectively. The corresponding progression‐free survival for the 3 groups was 28.7, 11, and 11.3 months, respectively. Outcomes that were associated with longer overall survival were response versus nonresponse (hazard ratio, 0.44; p = 0.03), decrease in BM MC burden of 50% or more versus less than 50% (hazard ratio, 0.33; p = 0.01), and SM subtype other than MCL (hazard ratio, 0.37; p = 0.04). Exposure to prior therapy was associated with shortened survival (hazard ratio, 2.33; p = 0.02). Of 72 evaluable patients, 41 (57%) had a decrease in BM MC burden of ≥ 50%. The median best percentage change in BM MC burden was −59% (range, −96 to 160). The median best percentage change in serum tryptase level was −58% (range, −99 to 185); 53 of 89 patients (60%) had a decrease of more than 50%.

   Of the 116 patients in the intention‐to‐treat population, 72% had discontinued treatment (33% and 22% due to disease progression and adverse events, respectively). The most common drug side effects (all grades/grades 3–4) were nausea (79%/6%), vomiting (66%/6%), diarrhea (54%/3%), and fatigue (28%/9%). New or worsening grade 3 or 4 neutropenia, anemia, and thrombocytopenia occurred in 24%, 41%, and 29% of patients, respectively; many of these patients had preexisting cytopenias. The dose of midostaurin was reduced in 65 patients (56%), mostly due to adverse events (in 48 patients). Re‐escalation to the initial dose level was accomplished in 21 of the 65 patients (32%).

   In an earlier Phase 2 study of midostaurin in 26 patients with advanced SM, similar responses were seen: overall 69% (major/partial response 50%/19%) during the first 12 cycles [110]. Data after a 10‐year median follow up have been reported; 2 patients achieved a complete remission of SM and ≥ 50% reduction in BM MC burden and serum tryptase level was seen in 68% and 46% of patients, respectively. The median OS for the overall cohort and MCL patients was 40 and 18.5 months, respectively. No unexpected toxicities emerged during the longer follow up.

   In the retrospective Mayo Clinic study of 33 patients with advanced SM (11 pretreated—including cladribine 4, imatinib 3), the ORR using modified Valent criteria was 44% (all major responses) [111]. Responses included ≥ 50% reduction in BM MC in 40% and normalization of serum tryptase in 29% of evaluable cases. Responses were not predicted by KITD816V mutation status or prior cytoreductive therapy. After a median follow up of 14.6 months, 7 deaths and 1 leukemic transformation were documented. Eighteen patients (55%) discontinued treatment (median duration of midostaurin treatment 7.9 months). Gastrointestinal adverse events were seen in 51%, and grade 3/4 neutropenia/thrombocytopenia in 12% of patients. Median OS was longer in midostaurin responders (26.5 vs. 16 months; p = 0.15).

   A German registry (GREM) retrospective study showed that high‐risk mutations (SRSF2, ASXL1, RUNX1) were associated with significantly lower ORR (39% vs. 75%) and OS (27 months vs. not reached) [83]. In a French compassionate‐use study of 28 patients with advanced SM (2 had “progressive SSM”), the overall response rate was 71% (major/partial 57%/14%), with median response duration of 17 months [112]. This cohort was compared to 44 control patients matched for age at diagnosis and SM subtype. After a similar median follow up, the risk of death in the control group was more than twice that of the midostaurin group (hazard ratio, 2.2; p = 0.02).

   Summary: Midostaurin was approved by the U.S. Food and Drug Administration (FDA) for treatment of adult patients with advanced SM in April 2017. Although avapritinib inhibits KITD816V 10‐fold more potently in vitro as compared to midostaurin, there is no head‐to‐head trial data comparing the 2 drugs, and no clear consensus regarding sequencing of therapies, particularly with respect to multimutated SM‐AMN patients. Avapritinib is clinically effective in patients previously treated with midostaurin, although response rates were numerically higher in midostaurin‐naïve as compared to previously treated patients [105]. Midostaurin is appropriate both as first‐line treatment, particularly in MCL patients, as well as salvage treatment in patients progressing after interferon‐α or cladribine therapy. Treatment with midostaurin can be challenging because of frequent gastrointestinal adverse events, with many patients requiring antiemetic prophylaxis. Patients need monitoring of blood counts, liver function tests, EKG (QTc interval) and amylase/lipase levels during treatment. Other possible roles for midostaurin include maintenance therapy after ASCT or for control of severe MCMRS in ISM/SSM patients who fail conventional antimediator therapy [113, 114, 115].

3. 2‐Chlorodeoxyadenosine (cladribine or 2‐CdA) has demonstrated in vitro and in vivo activity against neoplastic MC; the published experience suggests that 2‐CdA has therapeutic activity in all SM subtypes including in MCL [108, 116, 117, 118, 119, 120].

   In a Mayo Clinic study, 2‐CdA was administered to 26 patients (8 as first‐line); the dose was 5 mg/m² per day or 0.13–0.17 mg/kg per day for 5 days as a 2‐h intravenous (IV) infusion, and the median number of treatment cycles was 3 (range 1–9) [121]. Treatment response was evaluable in 22 patients and the ORR was 55% (ORR in ISM, ASM, and SM‐AMN was 56%, 50%, and 55%, respectively). Median duration of response was 11 months (range, 3–74 months). Presence of circulating immature myeloid cells was significantly associated with inferior response to 2‐CdA (0% vs. 75%). Major toxicities were myelosuppression and infection.

   Tefferi et al. [122] updated the Mayo Clinic experience of 42 SM patients (13 patients had SM‐AMN, 8 ASM, 1 MCL, 13 ISM, and 3 SSM) treated with cladribine. Responses were adjudicated based on modified Valent criteria for advanced SM patients [97]; for ISM/SSM patients, major response (MR) was assigned for > 50% decrease in MC mediator release symptoms or UP skin lesions, whereas PR represented a 10%–50% regression. Overall/major response rates were 77%/45% in advanced‐SM and 70%/60% in ISM/SSM, with a median duration of response of 10 and 46 months, respectively. A > 50% reduction in BM mast cell burden and serum tryptase level were observed in 63%/67% and 50%/46% of patients with advanced SM and ISM/SSM, respectively. The presence of KITD816V was associated with a significantly higher probability of response in advanced SM patients: 17 (90%) of 19 responders, while none of three without the mutation responded (p < 0.01). Grade 3/4 neutropenia, thrombocytopenia, or lymphopenia occurred in 27%, 27%, and 27% of patients with advanced SM, and 5%, 5%, and 30% with ISM/SSM, respectively.

   In a French study, 68 adult SM patients (28 ISM, 2 SSM, 14 ASM, 17 SM‐AMN, 1 MCL, and 6 cutaneous mastocytosis [CM]) were treated with cladribine (0.14 mg/kg via infusion or subcutaneously for 5 days) every 4–12 weeks up to 9 cycles [123]. The median number of cycles administered was 3.7, with overall response rate of 72% (major/partial 47%/25%). Corresponding responses in indolent and advanced SM patients were 92% (56%/36%) and 50% (38%/13%). Response rates by SM subtype were: ISM/SSM/CM 100%, ASM 43%, and AMN 59%. After a median follow‐up of > 10 years, the median durations of response for indolent and advanced SM patients were 3.71 (range 0.1–8) and 2.47 (range 0.5–8.6) years, respectively. The most frequent grade 3/4 toxicities were cytopenias and opportunistic infections.

   Summary: 2‐CdA has activity in all SM subtypes, with response rates roughly comparable to midostaurin, although there are no head‐to‐head studies, and the analysis is limited by small patient numbers. While a registry study suggested that midostaurin therapy was associated with superior overall‐ and leukemia‐free survival as compared to cladribine treated advanced SM patients, such analyses are compromised by potential patient selection bias, variable treatment schedules and incomplete clinical data [124]. The major weakness of cladribine as compared to avapritinib is lack of a selective potent anti‐clonal effect. Advantages of cladribine over TKI's include the potential for time‐limited therapy (3–6 cycles), broad efficacy in myeloid malignancies with non‐KIT driver mutations (particularly relevant for the SM‐AMN subgroup), and a well understood side effect profile. We favor 2‐CdA as first‐line treatment in cases where rapid MC debulking is indicated, or as salvage treatment in patients progressing after interferon‐α, TKI, or other cytoreductive therapy. There may be a future role for cladribine in combination with TKI's, for high‐risk advanced SM patients with rapidly progressive or relapsed/refractory disease [125]. Potential toxicities of 2‐CdA include myelosuppression and lymphopenia with increased risk of opportunistic infections; this risk can be mitigated with use of appropriate prophylactic antibiotic/antiviral therapies.

4. Interferon (IFN)‐α: IFN‐α has clinical activity in symptomatic SM; since the initial report in 1992 [126], several case reports or small series have shown IFN‐α (IFN‐α2b in most instances) to improve symptoms of MC degranulation, decrease BM MC infiltration, and ameliorate mastocytosis‐related ascites/hepatosplenomegaly, cytopenias, skin findings, and osteoporosis [127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139]. IFN‐α treatment is not uniformly effective [140], and the frequency of major response (i.e., complete resolution of one or more baseline “C” findings) is approximately 20%–30%; the optimal dose and duration of IFN‐α therapy for SM remain unclear, however concurrent administration of corticosteroids (prednisone) may improve its efficacy (up to 40% major response rate) and tolerability [134, 141]. The time to best response may be a year or longer [134] and delayed responses to therapy have been described [142]. IFN‐α treatment is frequently (up to 50%) complicated by toxicities, including flu‐like symptoms, bone pain, fever, cytopenias, depression, and hypothyroidism; consequently, the adverse dropout rate with IFN‐α treatment is not trivial [121, 134, 143]. Finally, a significant proportion of patients will relapse within a short period of IFN‐α treatment being discontinued, illustrating the cytostatic rather than cytolytic effects of the drug [143].

   In a French study, 20 SM patients (16 ASM and 4 ISM) were treated with IFN‐α starting at 1 MU/day with progressive increase to 5 MU/m²/day; 13 patients were treated for at least 6 months (median dose 3.2 MU/day) [143]. All 13 patients exhibited responses (non were complete) in systemic and cutaneous disease manifestations that were associated with decrease in circulating MC mediator levels, but not in BM MC burden. Adverse effects were frequent (cytopenias and depression in 9 and 7 patients, respectively); there were 2 deaths during the treatment phase. Four responding patients experienced prompt relapse of symptoms after treatment cessation.

   In the Mayo Clinic study, 47 patients received IFN‐α with or without prednisone [121]; the median weekly dose was 15 MU per week (range 3.5–30 MU per week) and the initial dose of prednisone ranged from 20 to 60 mg per day with a slow tapering over weeks or months in some patients. In 40 evaluable patients, the overall response rate (ORR) was 53% (ISM and ASM 60%; SM‐AMN 45%). Overall median duration of response was 12 months (range, 1–67 months). Responses were not significantly different when comparing patients who did and did not receive prednisone. Absence of systemic mediator‐related symptoms was significantly associated with inferior response to IFN‐α; 41% versus 77%, respectively. Major toxicities included fatigue, depression, and thrombocytopenia.

   Summary: We see diminishing utility of IFN‐α for SM treatment in the TKI era, but may have a role in resource limited settings. Historically, IFN‐α has shown activity in all SM subtypes and has been shown to improve dermatological, hematological, gastrointestinal, and systemic symptoms associated with histamine release. IFN‐α also has a role in treating skeletal symptoms because of its ability to increase bone density. Use of higher doses of IFN‐α has the potential to decrease the BM MC burden in some patients. The pegylated form of IFN‐α is preferred due to less frequent dosing and possibly better tolerability. We start treatment at a low dose and gradually escalate to target dose; time on IFN‐α treatment may be more important for its anti‐clonal effect than the dose level per se. Prednisone (30–60 mg/day) can be added at the start of treatment to improve tolerability and response, and is tapered over a 2–3 months period. IFN‐α treatment is generally continued as long as a response is observed and there are no intolerable adverse effects.

5. Imatinib mesylate (IM): demonstrates in vitro efficacy against wild‐type KIT and certain trans‐membrane (F522C) and juxta‐membrane (V560G) KIT mutants, but not the common kinase (D816V) domain mutants [36, 144, 145, 146]. Similarly, not all juxta‐membrane mutations may be sensitive to IM (e.g., V559I) [147].

   In the Mayo Clinic study that excluded FIP1L1‐PDGFRA‐positive cases, IM was administered to 27 SM patients; the median starting dose was 400 mg/day (range 100–400 mg/day), and the maintenance dose in responding patients ranged from 200 to 400 mg/day [121]. In 22 evaluable patients, the ORR was 18% (ORR in ISM, ASM, and SM‐AMN was 14%, 50%, and 9%, respectively), and median duration of response was 19.6 months (range, 9–69 months). Responses included improvement in UP and decrease in the BM MC burden. The majority (86%) of IM treated patients were KITD816V positive—ORR in mutation‐positive and ‐negative patients was 17% and 33%, respectively. None of the 6 patients with SM and associated eosinophilia (all KITD816V‐positive) responded to IM treatment. Major toxicities included diarrhea and peripheral edema; two patients developed interstitial pneumonitis.

   Data from another study however suggested an ORR of 36% in KITD816V‐positive SM patients [148]. In yet another study of 20 SM patients treated with IM, only one KITD816V‐negative patient responded while 6 other patients reported symptomatic improvement [149]. Finally, in another study wherein 17 SM patients received IM treatment, the response rate was 29% (1 complete and 4 partial remissions), all in KITD816V‐negative patients [150].

   Summary: While IM is currently approved by the FDA (specific indication is treatment of adult patients with ASM without the KITD816V mutation or with unknown KIT mutational status), it has a limited role in the treatment of unselected adult SM patients, the majority of whom likely harbor KITD816V. Patients with the rare “well differentiated SM” subtype exhibit round mature‐appearing MC that are commonly CD25‐/CD2‐, CD30+, and harbor non‐D816V imatinib‐sensitive KIT mutations, such as F522C [36]. Such rare SM cases that harbor an IM‐sensitive KIT mutation, or those that are KITD816‐unmutated may be appropriate candidates for IM treatment.

6. Hydroxyurea (HU): In the Mayo Clinic study, HU was given to 30 SM patients (28 with SM‐AMN) [121]. The drug was used as first‐line therapy in 24 patients. The dose ranged from 500 mg every other day to 2000 mg per day. Treatment response was evaluable in 26 patients; control of thrombocytosis, leukocytosis, and/or hepatosplenomegaly was observed in 5 SM‐AMN patients (ORR = 19%). Median duration of response was 31.5 months (range, 5–50 months), and the major toxicity was myelosuppression.

   Summary: The utility of HU in treating SM‐AMN stems from its myelosuppressive activity. HU does not, however, exhibit any selective anti‐MC activity.

4.1. Investigational KIT Inhibitors (Partial List)

1. Bezuclastinib: is an oral, potent TKI that specifically targets mutations in KIT exons 9, 11, 17, and 18, including D816V, while avoiding targeting related kinases (e.g., PDGFRα, PDGFRβ, and CSF1R). Of note, the drug shows minimal penetration of the blood–brain barrier. APEX (NCT04996875) is a Phase 2 open label multicenter study of bezuclastinib treatment in patients with advanced SM. In Part 1, 32 patients were enrolled (ASM 7, SM‐AHN 23, MCL 2) and were randomized to 50 mg BID (n = 8), 100 mg BID (n = 7), 200 mg BID (n = 8), or 400 mg QD (n = 9) [151]. Of these, 31% had received prior midostaurin only and 16% both avapritinib and midostaurin. At median treatment duration of 60 weeks, 94%, 93%, and 100% of patients across all dose levels achieved a ≥ 50% reduction in serum tryptase, KITD816V VAF and BM mast cell burden, respectively. Top‐line results for APEX were recently announced, wherein 81 advanced SM patients (SM‐AHN 57, ASM 11, and MCL 13) were treated with bezuclastinib 150 mg QD. For the 68 patients who were evaluable for response by mIWG‐MRT‐ECNM criteria, OR was 57%, with median time to response of 2 months. 89%, 91%, and 89% of patients achieved a ≥ 50% reduction in serum tryptase, KITD816V VAF and BM mast cell burden, respectively. The most frequent TEAE's were hair color change 30.9%, neutropenia 29.6%, altered taste 28.4%, thrombocytopenia 24.7%, and ALT/AST elevations 20.9%. Dose reductions were required and 14.8%, but no discontinuation were needed for TEAE's. SUMMIT (NCT05186753) is a pivotal phase 2 multicenter, double‐blind, placebo‐controlled study in patients with ISM/BMM/SSM with inadequate symptom control despite 2 lines of anti‐mediator therapies. Recently, data were presented for 179 patients (bezuclastinib 119, placebo 60); SM subgroups were ISM 147, SSM 12, and BMM 20, of whom 22 patients had previously received KIT inhibitor therapy [152]. The primary endpoint was met; mean change in total symptom score (TSS) at week 24 was −24.32 for bezuclastinib versus −15.41 for placebo arm (p < 0.001). Symptom relief was observed across all domains assessed. A significantly greater proportion receiving bezuclastinib achieved ≥ 50% reduction of serum tryptase (87.4% vs. 0%), BMMC burden (75.6% vs. 21.7%), and KITD816V VAF (85.7% vs. 0%) as compared to placebo at week 24. TEAE's ≥ 10% that occurred with greater frequency in the bezuclastinib arm included: hair color changes (69.5% vs. 5%), altered taste (23.7% vs. 0%), nausea (22% vs. 13.3%), AST/ALT increased (22% vs. 6.6%), headache (17.8% vs. 11.7%), alopecia (11.9% vs. 3.3%) and alkaline phosphatase increased (10.2% vs. 3.3%).

2. Elenestenib: is an orally administered selective KITD816V inhibitor, that is distinguishable from avapritinib by its limited central nervous system penetration potential. HARBOR (NCT04910685) is a randomized, double blind, placebo controlled, Phase‐2/3 trial comparing the efficacy and safety of elenestinib + best supportive care (BSC) versus placebo + BSC in ISM patients whose symptoms are inadequately controlled by BSC [153]. In Part 1, 122 patients were treated; 39 were blinded and randomized to elenestinib or placebo, and 83 were treated with open‐label elenestinib in the PK groups (21 patients at 50 mg, 34 patients at 75 mg, and 28 patients at 100 mg). After a median treatment duration of 35.3 weeks, elenestinib was well‐tolerated at all dose levels. There were no treatment related serious adverse events and no TEAE's that led to drug discontinuation. Symptom improvement was observed for all dose cohorts and TSS score reduction was greater for patients on elenestinib versus placebo in the blinded population. Patients receiving elenestinib at 25, 50, and 100 mg doses showed mean reduction from baseline for tryptase (−15.4%, −50.9%, and −68.4% vs. 3.3%, respectively) and KITD816V VAF (−37.5%, −70.3%, and −77.0% vs. −2.5%, respectively) as compared to placebo.

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Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.