Advanced systemic mastocytosis: Management and prognosis

INTRODUCTION — 

Mastocytosis refers to a diverse category of neoplasms in which clonal mast cells infiltrate the skin, bone marrow, liver, spleen, gastrointestinal tract, and/or other tissues. These disorders manifest a broad spectrum of clinical features and prognoses. Mastocytosis is driven by constitutive activation of the KIT receptor, which is associated with KIT D816V mutation in >90 percent of cases.

There are two major categories of mastocytosis.

●Cutaneous mastocytosis – Cutaneous forms of mastocytosis primarily affect children, are generally confined to skin, and have a good prognosis.

●Systemic mastocytosis – Systemic mastocytosis (SM) is characterized by an accumulation of mast cells in the bone marrow and other extracutaneous sites, with or without skin involvement. There are five subtypes of SM:

•Indolent SM

•Smoldering SM

•Aggressive SM (ASM)

•Mast cell leukemia (MCL)

•SM with an associated hematologic/myeloid neoplasm (SM-AHN)

Collectively, ASM, MCL, and SM-AHN are referred to as advanced SM (advSM). These disorders require systemic treatment and have an inferior prognosis compared with other categories of SM.

This topic discusses the management and prognosis of advSM.

Related topics include:

●(See "Systemic mastocytosis: Determining the subtype of disease".)

●(See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)

●(See "Mastocytosis (cutaneous and systemic) in children: Epidemiology, clinical manifestations, evaluation, and diagnosis".)

●(See "Indolent and smoldering systemic mastocytosis: Management and prognosis".)

PRETREATMENT EVALUATION — 

Pretreatment evaluation of patients with advSM includes clinical, laboratory, and cytogenetic evaluation to assess symptom burden, comorbid conditions, and disease classification.

We encourage enrollment in a clinical trial and referral to a specialized center for evaluation by a multidisciplinary team that is experienced with advSM.

Evaluation should include the following:

Clinical and laboratory

●Clinical – Evaluation of symptom burden, comorbidities, higher burden of disease/organ enlargement ("B findings"), and mast cell-related organ damage ("C findings"). B findings and C findings are described below. (See 'B findings and C findings' below.)

•History – Symptoms of mast cell activation and/or anaphylaxis and their potential triggers; comorbid illnesses, medications; transfusion history; and constitutional symptoms.

It is important to assess symptoms and quality of life at baseline to accurately evaluate response to treatment. Validated tools for such assessments include the Mastocytosis Quality of Life Questionnaire (MQLQ) and the Mastocytosis Symptom Assessment Form (MSAF) [1].

•Physical examination – Skin, lymph nodes, and size of liver and spleen.

●Laboratory

•Hematology – Complete blood count with leukocyte differential count and review of blood smear.

•Chemistries – Comprehensive metabolic panel, liver function tests, lactate dehydrogenase (LDH), uric acid, and serum tryptase.

●Imaging – A dual x-ray absorptiometry (DEXA) scan should be performed to evaluate for osteopenia/osteoporosis.

Imaging to assess B and C findings is discussed below. (See 'B findings and C findings' below.)

Pathology — Criteria for the classification of advSM subtypes are presented separately. (See "Systemic mastocytosis: Determining the subtype of disease".)

●Bone marrow – A bone marrow examination should be performed at diagnosis and at the initiation of therapy. Analysis should include:

•Flow cytometry – CD34, CD117, CD25, CD30, CD2.

•Immunohistochemistry – CD117, CD25, CD30, tryptase.

•Cytogenetics – Karyotype by metaphase chromosomal banding. Fluorescence in situ hybridization (FISH) should be performed for patients with suspected SM with an associated hematologic/myeloid neoplasm (AHN).

•Molecular

-KIT mutation – KIT D816V mutation testing should be performed using a highly sensitive assay, such as digital droplet polymerase chain reaction (PCR) or KIT D816V allele-specific PCR. If KIT D816V is present, the variant allele frequency (VAF) should be determined so that it can be monitored during treatment for an assessment of the molecular response.

If the assay is negative for KIT D816V and eosinophilia is present, the specimen should be screened for FIP1L1::PDGFRA gene fusion by PCR or FISH (for CHIC2 deletion).

-Other mutations – Multigene next-generation sequencing (NGS) panel, including SRSF2, ASXL1, and RUNX1, which are considered high-risk mutations.

●Organ-directed biopsy – If needed to assess involvement by mast cells as a cause for organ damage (eg, C findings).

B findings and C findings — Descriptions of B findings ("burden of disease") and C findings ("cytoreduction-requiring") [2-4] follow:

●B Findings – High disease burden or significant organ enlargement without organ dysfunction.

•High mast cell burden – >30 percent infiltration of bone marrow cellularity by mast cells in focal, dense aggregates plus serum total tryptase >200 ng/mL.

•Dysplasia/myeloproliferation – Dysplasia or myeloproliferation in nonmast cell lineages (with normal or slightly abnormal blood counts), but the criteria to diagnose an AHN are not met; KIT D816V with VAF ≥10 percent in bone marrow cells or peripheral blood leukocytes qualifies.

•Organomegaly/lymphadenopathy – Hepatomegaly without impairment of liver function; palpable splenomegaly without hypersplenism; and/or lymphadenopathy by examination or imaging.

●C Findings – Impaired organ function due to mast cell infiltration.

•Bone marrow dysfunction – ≥1 cytopenia due to infiltration by neoplastic mast cells: absolute neutrophil count <1 x 10⁹/L; hemoglobin <10 g/dL; and/or <100 x 10⁹ platelets/L.

•Liver dysfunction – Palpable hepatomegaly with impairment of liver function, ascites, and/or portal hypertension.

•Hypersplenism – Palpable splenomegaly with hypersplenism.

•Skeletal – Large (≥2 cm) osteolytic lesions, with or without pathologic fractures; note that fractures due to osteoporosis do not qualify.

•Gastrointestinal (GI) – Malabsorption with weight loss due to GI mast cell infiltrates.

Details of diagnostic criteria for the International Consensus Classification and World Health Organization 5th edition are presented separately. (See "Systemic mastocytosis: Determining the subtype of disease".)

Imaging is used to define B findings and C findings.

●Computed tomography (CT), magnetic resonance imaging (MRI), or ultrasound of abdomen/pelvis to document organomegaly, lymphadenopathy, and ascites.

●Chest radiography or CT of the thorax to detect pleural effusions in patients with respiratory symptoms.

●Metastatic skeletal survey to assess osteolytic lesions in patients with bone pain.

OVERVIEW OF MANAGEMENT — 

The goals of management for advSM are to control symptoms, mitigate organ damage, improve the quality of life, and extend survival.

When possible, we encourage referral to a specialized center for evaluation, diagnosis and classification, and management by a multidisciplinary team that is experienced with SM. If that is not possible, a consultation with SM experts and an enrollment in a clinical trial are strongly encouraged.

Prior to initiating treatment for advSM, the following should be considered:

●Disease variant – The management of advSM varies according to the disease subtype, which is defined by pathology and clinical findings, including the nature and severity of B findings and C findings.

Criteria for the diagnosis and classification of advSM subtypes are presented separately. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis", section on 'Differential diagnosis' and "Systemic mastocytosis: Determining the subtype of disease".)

Pitfalls that should be considered in classifying advSM include:

•SM with an associated hematologic/myeloid neoplasm (SM-AHN) – An associated neoplasm may be masked in bone marrow by the SM component (eg, high-burden mast cell leukemia [MCL]). Conversely, SM may be masked by the AHN; detection of KIT D816V in another hematologic neoplasm may be clue to the presence of SM that is obscured in bone marrow by the other malignancy.

•Well-differentiated SM – Well-differentiated variants of SM can be seen with any subtype (including advSM subtypes and non-advSM subtypes). Well-differentiated advSM generally has a more favorable prognosis than other forms of advSM, especially if an imatinib-sensitive KIT mutation is present.

Pathologically, well-differentiated SM is typically manifest by round, rather than spindle-shaped, mast cells, CD25 expression is low or negative, and KIT is generally unmutated, or mutations are outside of exon 17. Further details of the diagnosis of well-differentiated SM are presented separately. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis", section on 'Well-differentiated systemic mastocytosis'.)

The management of well-differentiated SM is distinct from that of other forms of advSM, as discussed below. (See 'Well-differentiated aggressive SM' below.)

●Eligibility for transplantation – Hematopoietic cell transplantation (HCT) is the only treatment that is proven to cure advSM. We encourage early referral of patients with advSM for consultation with experts in HCT.

Eligibility for HCT is discussed separately. (See "Allogeneic hematopoietic cell transplantation: Indications, eligibility, and prognosis".)

Allogeneic HCT may be a consideration in patients with advSM with adverse prognostic features and for refractory disease, as discussed below. (See 'Adverse prognostic features' below and 'Refractory/relapsed disease' below.)

●Counseling – Patients should be educated about symptoms of advSM, potential triggers of mast cell activation, avoidance of triggers, and emotional aspects of these diseases. Patients should carry an epinephrine autoinjector in the event of an anaphylactic reaction. (See "Indolent and smoldering systemic mastocytosis: Management and prognosis", section on 'Trigger avoidance'.)

Our approach to patient selection is consistent with a consensus opinion about indications for allogeneic HCT in advSM [5].

FRONT-LINE THERAPY — 

The initial treatment of advSM is guided by the disease subtype and comorbid conditions.

The management of the rare cases of well-differentiated SM is discussed below. (See 'Well-differentiated aggressive SM' below.)

Aggressive SM or mast cell leukemia — For most patients with aggressive SM (ASM) or mast cell leukemia (MCL), we suggest avapritinib rather than midostaurin or other agents (algorithm 1), based on superior outcomes and acceptable toxicity.

Avapritinib should not be given with <50,000 platelets/microL or in patients with recent intracranial bleeding or brain surgery; midostaurin is acceptable in those settings.

For patients with rapidly progressive disease, such as ASM transforming to MCL, some experts favor treatment with induction therapy like that used for acute myeloid leukemia (AML), as discussed separately. (See "Acute myeloid leukemia: Induction therapy in medically fit adults".)

Avapritinib was associated with superior survival compared with midostaurin and other agents in retrospective studies of advSM, including patients with ASM or MCL. No randomized trials have directly compared avapritinib with midostaurin.

●A retrospective multicenter study of advSM outcomes reported that patients treated with avapritinib had superior overall survival (OS), longer duration of treatment (DOT), and better reduction of serum tryptase compared with patients who received best available therapy (BAT) [6]. In a risk-adjusted analysis, compared with 141 patients treated with BAT (one-half of whom received midostaurin), the 176 patients treated with avapritinib had superior median OS (49 versus 27 months; hazard ratio [HR] 0.48 [95% CI 0.29-0.79]), longer DOT (HR 0.36 [95% CI 0.26-0.51]), and greater maximum reduction of serum tryptase (93 versus 37 percent). SM with an associated hematologic/myeloid neoplasm (SM-AHN), ASM, and MCL accounted for 55, 31, and 15 percent of patients, respectively, treated with BAT, while the avapritinib cohort included 68 percent with SM-AHN, 17 percent with ASM, and 16 percent with MCL. This report did not compare adverse effects (AEs) between avapritinib and BAT.

●A systematic review reported that avapritinib was more effective than midostaurin for the treatment of advSM [7]. An analysis of two single-arm studies of avapritinib and two single-arm studies of midostaurin reported better outcomes with avapritinib, including superior OS (HR 0.44 [95% CI 0.25-0.76]), adjusted odds ratio (OR) for overall response rate (4.06 [95% CI 3.09-5.33]), and adjusted OR for complete response (CR; 9.56 [95% CI 0.97-93.81]).

Administration, toxicity, and other studies of avapritinib for advSM are presented below. (See 'Avapritinib' below.)

SM with associated hematologic/myeloid neoplasm — SM-AHN must fulfill the diagnostic criteria for both SM and another hematologic neoplasm [2,3], as discussed separately. (See "Systemic mastocytosis: Determining the subtype of disease", section on 'Systemic mastocytosis with an associated hematologic neoplasm'.)

Prioritization of treatment — For patients with SM-AHN, we determine whether the AHN or SM component requires more urgent treatment (algorithm 1).

Determining which disease component has a higher priority for treatment must be individualized and is based on the disease burden, symptoms, and prognostic features of the SM and the AHN components. Factors to consider include organ damage; AHN-related cytopenias, blood/bone marrow blast count, karyotypic abnormalities/gene mutations; and available treatments. Disease-specific prognostic scoring systems can be useful for assessing whether the AHN requires more urgent treatment than the SM component. In selected cases, organ-directed biopsy (eg, liver biopsy in a patient with liver dysfunction) can help to determine if organ damage is related to the SM, the AHN, or both disorders.

We generally treat one disease component at a time (ie, either the AHN or SM) to avoid drug interactions and overlapping toxicity when combination regimens are used. Thus, if the AHN requires more urgent treatment, we manage it while monitoring SM-related symptoms and disease progression. Conversely, if the SM component requires more urgent treatment, we continue to monitor the status of the AHN. In some cases, the same treatment may be effective for both disorders, as discussed below. (See 'If the AHN requires more urgent treatment' below.)

If the SM requires more urgent treatment — For patients with a greater urgency to treat the SM component, we suggest avapritinib rather than other treatments (as with ASM or MCL, as discussed above). (See 'Aggressive SM or mast cell leukemia' above.)

While receiving treatment for SM, the patient should be monitored for progression of the AHN, as described in disease-specific topics.

If the AHN requires more urgent treatment — When the AHN component requires more urgent treatment, we treat the AHN component while monitoring the status of the SM.

Treatment of the AHN is described in disease-specific topics. Monitoring of SM-associated symptoms and disease progression is described below. (See 'Monitoring and response' below.)

In some cases, the same treatment may be effective for both the SM and AHN components. Examples include:

●When KIT D816V is detected, it may reside in both the mast cells of SM and in cells of the AHN component (eg, neoplastic monocytes in chronic myelomonocytic leukemia); in such cases, KIT inhibitors (eg, avapritinib, midostaurin) may be effective for treating both disease components. (See 'Midostaurin' below.)

●If midostaurin is incorporated into the induction regimen for AML with an FLT3 mutation, it may also be effective against the SM component, even though the dose used to treat AML is lower than that for advSM. (See "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'AML with mutated FLT3'.)

●When the AHN is chronic myeloid leukemia (CML), rare cases of SM have a KIT mutation that is not KIT D816V or other exon 17 KIT variants; in such cases, imatinib may be effective against both disease components. (See 'Imatinib' below.)

●Allogeneic hematopoietic cell transplantation (HCT) may be effective for both the SM and the AHN (eg, consolidation therapy for AML). (See 'Adverse prognostic features' below.)

Well-differentiated aggressive SM — For well-differentiated SM, we suggest imatinib rather than avapritinib or midostaurin, based on modest toxicity and good efficacy with this rare variant.

Well-differentiated ASM can be seen in any subtype of SM. It is typically manifest by round (rather than spindle-shaped) mast cells, CD25 expression is low or negative, and KIT is generally unmutated or has a mutation outside of exon 17. Further details of the diagnosis of well-differentiated ASM are presented separately. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis", section on 'Well-differentiated systemic mastocytosis'.)

Case reports have reported sensitivity to imatinib for SM with KIT mutations in exons 8 to 10. Examples include KIT F522C (transmembrane mutation), germline KIT K509I, deletion of codon 419 in exon 8, and p.A502_Y503dup exon 9 mutation [8-13]. Some earlier reports of imatinib-responsive SM likely involved such KIT mutations or were misdiagnoses (eg, FIP1L1::PDGFRA-positive myeloid/lymphoid neoplasms with eosinophilia). (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Systemic mastocytosis with eosinophilia'.)

MONITORING AND RESPONSE — 

Patients are seen regularly to assess the response to treatment and overall clinical status.

Assessment — Patients are evaluated every one to three months when beginning treatment of advSM.

The subsequent schedule of assessment and monitoring is individualized according to symptoms, presence of an associated hematologic/myeloid neoplasm (AHN), and concerns of the clinicians and patient, as described below. (See 'Monitoring' below.)

Response monitoring should include:

●Clinical

•Interval history and physical examination.

Quality of life can be monitored using the Mastocytosis Quality of Life Questionnaire (MQLQ) and/or the Mastocytosis Symptom Assessment Form (MSAF) [1].

•Laboratory studies

-Complete blood count (CBC) and differential – Initially every two to four weeks; subsequently, CBCs are repeated as clinically warranted.

-Complete metabolic panel – Kidney function and liver function tests (including alkaline phosphatase, albumin) are initially performed every two to four weeks; subsequent testing is guided by the response of C findings to treatment.

-Serum tryptase – Initially monthly, then every two to three months.

●Bone marrow examination – We perform a bone marrow aspirate/biopsy after two to three months of treatment.

Analysis should include reticulin staining (to evaluate peri-mast cell fibrosis), immunohistochemistry for CD117, CD25, and tryptase (to assess mast cell burden), cytogenetics, and KIT D816V variant allele frequency (VAF).

A bone marrow examination should be repeated every three to six months. Analysis should include next-generation sequencing (NGS) to assess molecular response (ie, KIT D816V VAF) in responding patients and new mutations in patients with progression of the SM and/or AHN disease components.

After one year of therapy, bone marrow examinations can be performed once or twice each year. Some experts perform bone marrow examinations only if there are signs of disease progression of the SM or AHN component (eg, worsening symptoms, increasing serum tryptase level, worsening cytopenias, progression of other C findings).

●Imaging – Imaging is used to monitor the response of B and C findings, as described above. (See 'B findings and C findings' above.)

•Abdominal ultrasound, CT, or MRI of the abdomen/pelvis to follow hepatosplenomegaly, ascites, and/or lymphadenopathy.

•Chest radiograph or chest CT to monitor pleural effusions.

For patients with worsening symptoms, organ dysfunction, or disease markers that suggest disease progression, we repeat the bone marrow examination with NGS analysis, laboratory studies, and imaging to document organ damage.

Treatment response — Criteria for treatment response are evolving with recognition that potent KIT inhibitors can yield deep molecular responses.

We judge treatment response by the burden of symptoms, hematologic parameters, serum tryptase level, KIT D816V VAF, and extent of bone marrow/organ involvement, as described above. (See 'Assessment' above.)

Response criteria have been created for clinical trials, but there are no consensus response criteria for routine clinical practice. We evaluate treatment response in a tiered fashion [14] and generally can be undertaken when bone marrow biopsies are performed:

●Tier 1 (Pathology) – Response of SM (and AHN, if applicable) in bone marrow and/or other organs.

The preferred method for quantifying bone marrow mast cell burden is immunohistochemistry (ie, CD25, CD117, tryptase) on a bone marrow core biopsy; changes in marrow fibrosis (especially peri-aggregate fibrosis) are assessed with reticulin stain.

Conventional morphology, flow cytometry, immunohistochemistry, and/or molecular studies can be used to assess the AHN.

●Tier 2 (Molecular) – KIT D816V VAF response; changes in the cytogenetic response and NGS mutational profile may also be evaluated.

●Tier 3 (Clinical) – Response of organ damage based on International Working Group (IWG) or modified IWG criteria [14].

●Tier 4 (Symptoms) – Symptoms measured by a validated symptom assessment instrument [1].

Monitoring — Patients with advSM require ongoing monitoring of SM-related symptoms, KIT D816V burden, and disease in bone marrow or organs (as applicable), as described above. (See 'Treatment response' above.)

The schedule of long-term follow-up is guided by the symptoms, organ damage, disease biomarkers (eg, serum tryptase level and bone marrow mast cell burden, KIT D816V VAF, NGS results), and concerns of the patient and clinicians.

For patients with disease relapse, we manage as described below. (See 'Refractory/relapsed disease' below.)

TREATMENT-RESPONSIVE DISEASE — 

Most patients with advSM have a robust response to a KIT inhibitor. After assessing the response to therapy, further management is based on prognostic features of the disease and patient fitness.

Adverse prognostic features — The prognosis of advSM is informed by the disease subtype and certain cytogenetic and molecular features.

●SM subtype – Details of the prognosis according to advSM subtypes are presented below. (See 'Disease variant' below.)

•Mast cell leukemia (MCL) is generally associated with the worst prognosis among advSM subtypes. In patients with MCL, the presence of an associated hematologic/myeloid neoplasm (AHN) carries a worse prognosis than MCL alone.

•Aggressive SM (ASM) is generally associated with more favorable outcomes than MCL.

•SM with an AHN (SM-AHN) has variable outcomes, and the prognosis is often influenced by the AHN.

●Cytogenetic/molecular features – The following features are associated with an adverse prognosis (see 'Molecular/cytogenetic features' below):

•High-risk karyotype – Monosomy 7, complex karyotype

•Molecular findings – ≥1 high-risk non-KIT mutation (eg, SRSF2, ASXL1, and/or RUNX1)

Further management

Transplant eligible with adverse features — For transplant-eligible patients with adverse prognostic features, options include continued medical treatment or allogeneic hematopoietic cell transplantation (HCT).

This choice of approach must be individualized. Allogeneic HCT can cure advSM in a subset of patients, whereas the durability of a robust response to a KIT inhibitor is not well-defined at present. We generally favor allogeneic HCT for patients who have MCL and for patients with any advSM subtype with higher-risk features in the SM or AHN compartments (by respective scoring systems for each disease component). For patients with SM-AHN, we favor transplantation when the associated malignancy would otherwise require allogeneic transplantation, such as when it is considered higher risk by the relevant AHN-associated prognostic scoring system.

The choice of approach should be made jointly with the patient and should weigh the balance of potential long-term disease control against the short-term and long-term adverse effects (AEs) of transplantation, availability of a histocompatible donor, comorbid conditions, and patient preferences. Transplant eligibility varies among institutions, but many centers limit allogeneic HCT to patients ≤65 years without major comorbid conditions. Other aspects of transplant eligibility are discussed separately. (See "Allogeneic hematopoietic cell transplantation: Indications, eligibility, and prognosis".)

For patients with responsive disease who decline allogeneic HCT, we manage as described below. (See 'Other treatment-responsive patients' below.)

No clinical trials have randomly assigned allogenic HCT versus continued medical therapy to patients with advSM. It is difficult to compare outcomes among separate studies because most reports of transplantation are from periods prior to the availability of potent KIT inhibitors.

●Allogeneic HCT

•A series of 57 patients with advSM (median age 46 years) who received various conditioning regimens and graft sources reported a 57 percent three-year overall survival (OS) with allogeneic HCT [15]. According to disease type, the three-year OS was 74 percent among the 38 patients with SM-AHN, 43 percent for the 7 patients with ASM, and 17 percent for the 12 patients with MCL. No deaths or relapses were observed after 15 and 24 months from transplantation, respectively. Reduced-intensity conditioning was associated with a lower OS than myeloablative conditioning. Treatment-related mortality (TRM) was like that with allogeneic HCT for other hematologic malignancies (11 and 20 percent at 6 and 12 months after transplantation, respectively).

•A retrospective study reported outcomes of allogeneic HCT for 71 patients with advSM from two national registries [16]. Patients transplanted for ASM/SM-AHN (30 patients), SM-acute myeloid leukemia (AML; 28 patients), and MCL (with or without AHN; 13 patients) experienced median OS of 9.0, 3.3, and 0.9 years, respectively. Improved OS was associated with the response of the SM and/or the AHN to therapy prior to transplantation, while adverse predictors were the absence of KIT D816V and complex karyotype. A human leukocyte antigen match and conditioning regimen were not associated with outcomes. Five years post-transplantation, TRM was 35 percent, while 23 percent of deaths were relapse-related.

●Medical treatment – There are no long-term studies of survival in patients treated with avapritinib or other contemporary medical therapies.

•Avapritinib

-Avapritinib was associated with a 76 percent two-year OS and 63 percent two-year progression-free survival (PFS) in the phase 1 EXPLORER study [17]. For patients with ASM, SM-AHN, and MCL, rates of two-year OS were 100, 67, and 92 percent, respectively.

-A retrospective study of advSM reported a 49-month median OS in patients treated with avapritinib [6]. Rates of OS after one, two, three, four, and five years were 87, 78, 71, 59, and 50 percent, respectively.

•Midostaurin

-A study of 116 patients with advSM who were treated with midostaurin (89 patients had mastocytosis-related organ damage) reported a 29-month median OS and 14-month median PFS [18]. Compared with the transplant outcomes data described above [15], the three-year OS with midostaurin was lower for patients with SM-AHN (44 percent) but better for those with ASM (65 percent) and MCL (26 percent) [18].

Other treatment-responsive patients — We continue medical therapy for patients who do not have adverse prognostic features and for patients who are ineligible for or decline transplantation.

We generally continue treatment for as long as the patient continues to respond to medical therapy and is tolerating therapy.

For patients who experience AEs of treatment, we reduce the dose or increase the treatment interval and reassess the response after the dose adjustment. Treatment with adjunctive agents to control SM-related symptoms should be optimized. (See "Mast cell disorders: An overview", section on 'Initial management'.)

For patients who no longer respond to treatment, we manage as described below. (See 'Refractory/relapsed disease' below.)

REFRACTORY/RELAPSED DISEASE — 

We strongly encourage participation in a clinical trial when there is an inadequate response to front-line therapy or progressive/refractory disease while receiving treatment.

Management of refractory or relapsed (r/r) advSM is guided by the patient's eligibility for allogeneic hematopoietic cell transplantation (HCT):

●Eligible for allogeneic HCT – For medically fit patients with refractory disease or relapse, we suggest allogeneic HCT.

We generally continue treatment with avapritinib while searching for a suitable donor, since this is the most effective treatment for controlling symptoms and keeping advSM in check.

If needed, bridging therapy can reduce the burden of disease prior to transplantation. The choice of bridging therapy is influenced by the disease subtype, tempo, extent of disease control, and medical fitness. Cladribine or acute myeloid leukemia-like induction therapy can be effective bridging therapy for patients with advSM, while appropriate AHN-directed therapy can be effective for selected patients with SM with an associated hematologic/myeloid neoplasm (AHN; eg, a hypomethylating agent for myelodysplastic syndromes/neoplasms).

Other aspects of the management and outcomes with allogeneic HCT are presented above. (See 'Adverse prognostic features' above.)

●Not transplant eligible – We favor enrollment in a clinical trial.

For advSM that is refractory to KIT inhibitors, we generally treat with cladribine. (See 'Cladribine' below.)

Some patients instead favor a focus on palliation of symptoms using adjunctive treatments. (See "Mast cell disorders: An overview", section on 'Initial management'.)

MEDICAL THERAPIES

Mast cell-related symptoms — Symptoms related to mast cell activation are often prominent features of advSM.

Mast cell activation may manifest as cutaneous findings (eg, reddish brown macules, urticaria pigmentosa), flushing, tachycardia, diarrhea, recurrent anaphylaxis, or other symptoms, as discussed separately. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)

Patients with anaphylaxis should be supplied with an epinephrine autoinjector and instructed on how and when to use it properly. Other agents for symptom management may include nonsedating H1 antihistamines, H2 antihistamines, antileukotriene agents, cromolyn sodium, and/or omalizumab. (See "Mast cell disorders: An overview", section on 'Initial management'.)

Avapritinib — Avapritinib is a potent kinase inhibitor with selective activity against mutated KIT (including KIT D816V) and PDGFRA A-loop mutants [19].

●Administration – The starting dose of avapritinib for advSM is 200 mg daily by mouth on an empty stomach. For patients with a robust response who are experiencing side effects, the dose can later be reduced (eg, 100 mg daily).

Avapritinib should not be used with <50,000 platelets/microL or in patients who had recent intracranial bleeding or brain surgery.

Coadministration of avapritinib with strong or moderate CYP3A inducers and inhibitors should be avoided. If coadministration with a moderate CYP3A inhibitor cannot be avoided, the avapritinib dose should be reduced.

Avapritinib should be discontinued permanently for any occurrence of intracranial hemorrhage. The dose should be held for platelets <50,000/microL and resumed at a lower dose when the platelet count recovers.

Avapritinib is approved by the US Food and Drug Administration (FDA) for the treatment of advSM. Avapritinib is approved by the European Medicines Agency (EMA) for second-line therapy of advSM.

●Toxicity – The avapritinib label includes warnings for intracranial hemorrhage, cognitive adverse reactions, and embryo-fetal toxicity. It should not be given to patients with <50,000 platelets/microL.

Periorbital edema is common with avapritinib. The most common grade ≥3 adverse effects (AEs) are fatigue/asthenia (9 percent), cognitive impairment (5 percent), and diarrhea (5 percent). Avapritinib may cause photosensitivity in some patients; patients should limit direct ultraviolet exposure during treatment.

The incidence of intracranial bleeding was 2 percent in the PATHFINDER study, which required >50,000 platelets/microL [20]. Intracranial hemorrhage was not observed in studies of avapritinib for indolent SM, which is treated with a much lower dose (eg, 25 mg daily) [17,21].

●Outcomes – Retrospective studies that reported avapritinib was more efficacious than other treatments for advSM are discussed above. (See 'Aggressive SM or mast cell leukemia' above.)

•Interim analysis of the phase 2 study of avapritinib 200 mg daily reported a 75 percent overall response rate (ORR), including a 19 percent complete response (CR) in 32 evaluable patients with advSM [20]. The median time to CR was six months; most responses were maintained after dose a reduction to ≤100 mg daily. Avapritinib was associated with a rapid and durable reduction in SM-associated symptoms, improved quality of life, reduced spleen size, and ≥50 percent improvement in bone marrow mast cells and serum tryptase in 90 percent of patients. Grade ≥3 cytopenias occurred in one-quarter of patients and grade ≥3 facial/periorbital edema in 3 percent.

•Results from a phase 1 study (NCT02561988) reported similar responses to avapritinib [17].

Midostaurin — Midostaurin is a multikinase inhibitor that inhibits KIT D816V. Responses are seen with all subtypes of advSM.

Midostaurin is acceptable for the initial treatment of patients with contraindications to avapritinib (eg, thrombocytopenia, intracranial hemorrhage, as discussed above). (See 'Aggressive SM or mast cell leukemia' above.)

●Administration – Midostaurin 100 mg twice daily is taken orally, with food.

No dose adjustment is needed for mild to moderate kidney or liver impairment. The dose should be held for three days (six doses) for grade ≥3 nausea or vomiting despite optimal antiemetic therapy.

Midostaurin is continued until allogeneic hematopoietic cell transplantation (HCT), or it is continued indefinitely until disease progression or drug intolerance for others.

Midostaurin is approved by the FDA and EMA for the treatment of advSM [22].

●Toxicity – Midostaurin is associated with mild to moderate nausea/vomiting, diarrhea, and embryo-fetal toxicity. Prophylaxis with antiemetics (eg, ondansetron) should be considered before each dose.

Very rarely, midostaurin has been associated with severe interstitial lung disease and pneumonitis.

●Outcomes – Midostaurin can improve cytopenias, liver dysfunction, and other organ damage; lower serum tryptase levels; decrease bone marrow mast cell burden; and reduce KIT mutant allele burden. Midostaurin is associated with responses in two-thirds of patients with advSM; approximately one-half of treated patients have a major response in which organ damage is normalized. Responses are generally sustained for 18 to 24 months, but longer-term responses (>5 years) have been observed in some patients.

Studies that compared midostaurin with avapritinib are presented above. (See 'Aggressive SM or mast cell leukemia' above.)

Other studies include:

•A phase 2 study of midostaurin in 116 patients with advSM reported a 29-month median overall survival (OS) and 14-month median progression-free survival (PFS) [18]. All advSM subtypes responded to midostaurin: aggressive SM (ASM; 75 percent ORR), SM with an associated hematologic/myeloid neoplasm (SM-AHN; 58 percent ORR), and mast cell leukemia (MCL; 50 percent ORR). There were no CRs, 45 percent major responses, and 15 percent partial responses (PRs). Patients experienced significant improvements of quality of life and mast cell mediator-related symptoms that were durable for 36 months [23].

•A retrospective study of midostaurin in 28 patients with advSM reported a 71 percent ORR (no CRs, 57 percent major response, 14 percent PR, 11 percent stable disease, 18 percent progressive disease) [24]. Responses were detectable within the first three months of treatment, and the median duration of response (DOR) was 17 months. After a median follow-up of 19 months, OS was 43 percent. The risk of death for patients treated with midostaurin was approximately one-half of that seen in a control group that was matched for SM variant and age at diagnosis.

•A study of midostaurin in 26 patients (3 ASM, 17 SM-AHN, 6 MCL) reported similar outcomes with an ORR of 69 percent; no unexpected toxicities emerged after a median follow-up of 10 years [25].

Other agents

Imatinib — Imatinib should not be used to treat SM with KIT D816V, which is present in >90 percent of advSM.

Imatinib is approved by the FDA only for the treatment of ASM in patients with the uncommon finding of advSM with unmutated KIT or KIT mutations status unknown. FDA approval was primarily based on a cohort of patients that was enriched for the FIP1L1::PDGFRA fusion, which is very sensitive to imatinib. However, these patients do not have advSM; instead, the proper diagnosis is myeloid neoplasm with eosinophilia. Although the number of CD25-positive, spindle-shaped mast cells may be increased in these patients, this entity may be recognized because the cells usually present in an interstitial pattern, rather than as dense aggregates, that are characteristic of advSM.

Imatinib may have activity in patients with KIT mutations outside of exon 17, as has been observed in patients with well-differentiated SM. For patients who may be candidates for imatinib, a high-sensitivity assay should be used to exclude KIT D816V to avoid false negatives. A technique such as KIT D816V allele-specific polymerase chain reaction (PCR; sensitivity approximately 0.1 percent) is considerably more sensitive for detecting KIT D816V than next-generation sequencing myeloid gene panels (approximately 5 percent).

●Administration – The starting dose for SM is imatinib 100 mg daily [26].

The dose should be adjusted for changes in liver and kidney function. Older patients and those with cardiovascular comorbidities should be monitored closely for fluid retention.

Further management is informed by the response to imatinib:

•Molecular CR – For patients who achieve a molecular CR, daily dosing should continue indefinitely. Reduced dosing (eg, three times weekly) or imatinib discontinuation has not been well-studied in this setting.

•Incomplete response – For persistent measurable residual disease or partial hematologic response, we increase the daily dose to imatinib 200 to 400 mg daily. Other treatments, including nilotinib [27], avapritinib, or midostaurin, may be effective in this setting.

Imatinib is approved by the FDA for patients with ASM who do not have KIT D816V or who have unknown mutational status.

●Toxicity – AEs are generally mild and may include cytopenias, edema, nausea, diarrhea, rash, and muscle cramps.

●Outcomes – In a study of 10 patients with well-differentiated SM who did not have KIT D816V (including three patients with MCL), imatinib was associated with a 50 percent ORR, including an early and sustained CR in four patients and a PR in one patient with wild-type KIT [28].

Imatinib has demonstrated activity against KIT F522C (transmembrane mutation), KIT V560G (juxtamembrane mutation), germline KIT K509I mutation, deletion of codon 419 in exon 8, and p.A502_Y503dup mutation in exon 9 [8,9,11,28-32].

Cladribine — Cladribine (2-chlorodeoxyadenosine) is acceptable for patients with advSM who do not respond adequately to a potent KIT inhibitor and for use as a bridge to transplantation. Cladribine has been shown to reduce the total mast cell burden [33-35].

Patients with advSM can receive up to six cycles of cladribine at four- to eight-week intervals as a bridge to allogeneic HCT. Doses from 0.10 to 0.14 mg/kg/day or 5 mg/m² daily, infused over two hours for five days, are reported [36,37].

Cladribine is a teratogen, and patients should use contraception.

In one study, cladribine achieved a 50 percent ORR in patients with ASM or SM-AHN [33]. In a retrospective analysis, 32 patients with advSM had a 50 percent ORR (38 percent major response, 13 percent minor response) and 2.5-year median DOR (median 3.7 courses) [38]. The most common grade ≥3 AEs were lymphopenia (82 percent), neutropenia (47 percent), and opportunistic infections (13 percent).

Patients can experience transient responses to cladribine, but nearly all will eventually relapse [39,40]. AEs are mainly related to bone marrow suppression [34,37]. Prophylaxis to prevent Pneumocystis jirovecii pneumonia should continue for ≥3 months after cladribine therapy is complete and until the CD4 count is >200/microL [41]. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)

Interferon alfa — Pegylated interferon alfa-2a (IFNa) is rarely used to treat advSM.

The administration of IFNa should be reserved for patients with symptomatic but slowly progressive advSM who are not candidates for other therapies. The response to IFNa is generally slow.

●Administration – Pegylated IFNa is generally started at 45 micrograms/week subcutaneously. The dose is incrementally escalated according to tolerability and efficacy. Treatment can be continued for as long as there is a clinical response and IFNa is tolerated. Some experts add a glucocorticoid for a time-limited period to enhance the effect of IFNa against SM and lessen AEs.

●Toxicity – AEs include flu-like symptoms, cytopenias, fatigue, and depression. Elevated serum aminotransferases and myelosuppression are the most common laboratory abnormalities.

●Outcomes – Most reports of IFNa for advSM are older case reports or small series that included a mix of indolent SM and advSM.

In one study, IFNa was associated with a 60 percent ORR with ASM and a 45 percent ORR with SM-AHN [33]. Some studies suggested that responses may be higher when IFNa is administered with prednisone [33,42-46]. Up to 20 percent of patients may experience relief of bone pain, but CRs are rare [33,42-45]. IFNa can reduce C findings related to mast cell mediator release and improve cutaneous lesions and bone marrow mast cell burden.

IFNa increases bone density and can be useful in patients with severe bone disease and multiple fractures. It is also an option for patients with organ involvement limited to the liver with ascites [5].

ALLOGENEIC TRANSPLANTATION — 

Allogeneic hematopoietic cell transplantation (HCT) may be used in patients with adverse prognostic features or disease that is refractory to a KIT inhibitor. (See 'Transplant eligible with adverse features' above and 'Refractory/relapsed disease' above.)

Transplantation-associated management includes:

●Bridging therapy – For patients who will proceed to allogeneic HCT, avapritinib, midostaurin, or cladribine can be used as a bridge to reduce the advSM disease burden prior to transplantation. Some experts treat rapidly progressive disease using cladribine or intensive induction chemotherapy, like that used to treat acute myeloid leukemia.

●Conditioning – Selection of a conditioning regimen is guided by institutional practice. Treatment for mast cell activation-related symptoms (eg, antihistamines, leukotriene inhibitors, epinephrine on demand) should be used as needed before and during the transplant process [15].

●Maintenance therapy – There is no proven role for KIT inhibitors as maintenance therapy in the post-transplant setting.

PROGNOSIS — 

Outcomes of advSM are associated with certain clinical and laboratory findings at the time of diagnosis. An international registry has been established to better define prognostic features in SM [47].

Prognostic models for advSM are discussed below. (See 'Prognostic models' below.)

Disease variant — Outcomes vary according to the advSM subtype (table 1) and the associated hematologic/myeloid neoplasm (AHN), if present:

●Mast cell leukemia – Patients with mast cell leukemia (MCL) have the worst prognosis among advSM subtypes. The ECNM (European Competence Network on Mastocytosis) registry reported a median overall survival (OS) of 1.6 years among 92 patients with MCL (one-third of whom had an AHN); however, some patients survived >5 or even >10 years [48]. Other studies reported median OS ranging from 0.5 to 2.6 years [49-51].

●Aggressive SM – A single-institution study reported that in 41 patients with aggressive SM (ASM), the median OS was 41 months, and 5 percent progressed to leukemia after median follow-up of 21 months [52].

●Systemic mastocytosis with associated hematologic/myeloid neoplasm – Among 138 patients with SM with an AHN (SM-AHN) in the single-institution case series, the median OS was 24 months, and 13 percent progressed to leukemia after 21 months [52].

A study that included 123 patients with SM-AHN reported that the median OS varied with the type of AHN [53]:

•Myeloproliferative neoplasm (55 patients): OS 31 months

•Chronic myelomonocytic leukemia (36 patients): OS 15 months

•Myelodysplastic syndrome (28 patients): OS 13 months

•Acute myeloid leukemia (AML; 4 patients): OS 11 months

Note that the presence of SM is often a poor prognostic finding for the AHN. As an example, KIT D816V is an adverse prognostic finding for AML and may indicate the presence of an occult underlying SM [54,55].

Other studies also reported that outcomes were associated with the type of AHN [52,56]. In one study that included molecular analysis, the subtype was an independent prognostic feature [57], but it was not in another study [58].

Clinical features — Outcomes in advSM are associated with various clinical and laboratory features.

●In a registry-based study, certain serum chemistry parameters were associated with outcomes in patients with advSM [59]. Among patients with advSM, serum lactate dehydrogenase (LDH) correlated with OS; patients with LDH <260 units/L, ≥260 to 400 units/L, and ≥400 units/L had median OS of 2.1, 1.9, and 0.9 years, respectively [59]. Vitamin B12 <2000 units/L versus ≥2000 units/L was associated with median OS of 4.1 and 2.6 years, respectively.

●In a single-institution study of 342 patients, advanced age, weight loss, anemia, thrombocytopenia, hypoalbuminemia, and excess bone marrow blasts were independent adverse prognostic factors for OS [52].

●Splenomegaly and elevated alkaline phosphatase were adverse prognostic markers in a study of 67 patients with advSM [60].

●Circulating mast cells, hepatomegaly, elevated LDH, and low serum albumin have also been reported to be associated with adverse outcomes [57,61-64].

●Hazard ratios (HRs) for OS with certain clinical variables are presented below. (See 'Mayo clinical model' below.)

Molecular/cytogenetic features — Molecular and cytogenetic abnormalities are associated with outcomes in advSM.

●OS was inferior in patients with advSM who had additional molecular abnormalities besides KIT D816V [65]. The mutation of SRSF2, ASXL1, or RUNX1 was associated with an adverse prognosis, and the OS was influenced by the number of mutated genes [66]. Other studies have also associated adverse outcomes with mutations in SRSF2, ASXL1, or RUNX1 [49,60,66].

●A study of 38 patients with advSM reported that prognosis and response to midostaurin were associated with additional mutations and the depth of reduction of KIT D816V allele burden [67]. The OS was superior in patients who experienced ≥25 percent reduction of KIT D816V expressed allele burden compared with lesser responses (HR 6.8 [95% CI 1.8-25.3]). Patients with an additional mutation of SRSF2, ASXL1, and/or RUNX1 had a 39 percent overall response rate (ORR) compared with a 75 percent ORR in patients with none of those mutations. The acquisition of additional mutations or an increasing variant allele frequency in K/NRAS, RUNX1, IDH2, or NPM1 was found in patients with disease progression.

●Poor-risk karyotype (eg, monosomy 7, complex karyotype) is an independent adverse prognostic variable in advSM. In one report, compared with good-risk karyotype or normal karyotype, patients with poor-risk karyotype had an inferior OS (4 versus 39 months; HR 11.7 [95% CI 5.0-27.3]) [68]. The prognostic impact of karyotype was independent of mutation status.

PROGNOSTIC MODELS — 

There is no consensus choice among SM prognostic models. The following are commonly applied prognostic models.

Mutation-adjusted risk score — Mutation-adjusted risk score (MARS) was developed from an international registry that included 383 patients with advSM, and it included treatment with midostaurin, cladribine, or midostaurin followed by cladribine [69]. Outcomes were independent of SM subtype.

The following variables are included in MARS [69]:

●Age >60 years (one point)

●Hemoglobin <10 g/dL (one point)

●Platelets <100 x 10⁹/L (one point)

●One mutation of SRSF2, ASXL1, and/or RUNX1 (one point)

●Two or more mutations of SRSF2, ASXL1, and/or RUNX1 (two points)

With a median follow-up of 2.2 years, the following median outcomes were reported, according to MARS risk category:

●Low risk (0 to 1 point): overall survival (OS) not reached, leukemia-free survival (LFS) 12.4 years

●Intermediate risk (2 points): OS 4.3 years, LFS 3.9 years

●High risk (3 to 5 points): OS 1.9 years, LFS 1.4 years

Mayo clinical model — A prognostic model for mastocytosis (including advSM and indolent or smoldering SM) that uses only clinical variables was created from a Mayo Clinic cohort of 580 patients with SM [57].

The Mayo clinical model identified the following clinical variables and associated hazard ratios (HRs):

●Age >60 years (HR 2.5 [95% CI 1.9-3.4])

●AdvSM versus indolent or smoldering SM (HR 2.7 [95% CI 1.8-4.0])

●Platelets <150 x 10⁹/L (HR 2.5 [95% CI 1.9-3.4])

●Hemoglobin level below the sex-adjusted normal reference range (HR 2.1 [95% CI 1.6-3.1])

●Increased serum alkaline phosphatase (HR 2.1 [95% CI 1.5-3.0])

In 277 patients with advSM, with a median follow-up of 34 months, the number of adverse clinical features were associated with the following values for the median OS [57]:

●Zero features (21 patients): OS not reached

●One feature (42 patients): 157-month median OS

●Two features (63 patients): 57-month median OS

●Three features (94 patients): 27-month median OS

●Four features (57 patients): 9-month median OS

Mayo hybrid model — A hybrid clinical-molecular prognostic model identified age, SM category, thrombocytopenia, and increased alkaline phosphatase plus the mutation of ASXL1, RUNX1, or NRAS (HR 2.6 [95% CI 1.6-4.4]) as risk factors in the same cohort of Mayo clinic patients [57]. Each adverse factor was assigned one point, while advSM versus indolent or smoldering SM was assigned two points because of its greater impact in this model (HR 4 [95% CI 1.8-10.0]) than in the Mayo clinical model described above. (See 'Mayo clinical model' above.)

The prognostic categories and median OS were as follows [57]:

●Low risk (≤2 points): 198 months

●Intermediate-1 (3 points): 85 months

●Intermediate-2 (4 points): 36 months

●High (≥5 points): 12 months

International Prognostic Scoring System for SM — The International Prognostic Scoring System for SM (IPSM) was generated from patients in the ECNM (European Competence Network on Mastocytosis) database [70]. The analysis identified four risk categories of patients with advSM that differed in OS and progression-free survival (PFS), and the prognostic value for advSM was confirmed in a validation cohort of 49 patients.

Among 259 patients with advSM, significant prognostic variables included [70]:

●Age ≥60 years (HR 2.14 [95% CI 1.42-3.22])

●Serum tryptase ≥125 ng/mL (HR 1.81 [95% CI 1.20-2.75])

●Leukocytes ≥16 × 10⁹/L (HR 1.88 [95% CI 1.27-2.79])

●Hemoglobin ≤11 g/dL (HR 1.71 [95% CI 1.13-2.57])

●Platelets ≤100 × 10⁹/L (HR 1.63 [95% CI 1.13-2.34])

●Skin involvement (HR 0.46 [95% CI 0.30-0.69])

In the IPSM, patients are assigned one point for each of these parameters, while one point is subtracted for skin involvement; thus, patients can have a total score between -1 and 5 points [70]. Four risk categories with different OS and PFS outcomes were found for patients with advSM.

The prognostic value of IPSM can be further refined by incorporating other prognostically useful serum markers. Among 55 patients with advSM who had an IPSM risk score of -1 to 1, assigning 1 point for each abnormal value among five serum parameters (serum tryptase, alkaline phosphatase, beta2-microglobulin, lactate dehydrogenase [LDH], albumin) further distinguished prognosis, with median OS for low-risk (0 points; 9 patients) versus high-risk (2-4 points, 46 patients) groups of 9.9 versus 3.6 years, respectively [59].

Global prognostic score for SM — The Spanish Network on SM (REMA) created the global prognostic score for SM (GPSM) model using a discovery cohort of 422 patients and validated it with an independent cohort of 853 patients [71]. GPSM effectively predicted OS and PFS in patients with advSM.

●The following were significant prognostic factors for OS:

•Hemoglobin ≤11 g/dL

•Alkaline phosphatase ≥140 IU/L

•Mutation in ≥1 of the following: SRSF2, ASXL1, RUNX1, DNMT3A

●The following were significant prognostic factors for PFS:

•Platelets ≤100 x 10⁹/L

•Beta2 microglobulin ≥2.5 microg/mL

•Serum tryptase ≥125 ng/mL

CLINICAL TRIALS — 

We suggest participation in a clinical trial, when possible.

Clinical trials for SM in the United States are listed at clinicaltrials.gov.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines are provided separately. (See "Society guideline links: Mast cell disorders".)

INFORMATION FOR PATIENTS — 

Information for patients, including lists of triggers for mast cell degranulation, is available online on the Mastocytosis Society website and the National Institute of Allergy and Infectious Diseases website. Additional information is available on the National Institutes of Health Genetic and Rare Diseases (GARD) website.

SUMMARY AND RECOMMENDATIONS

●Description – Systemic mastocytosis (SM) describes a diverse group of neoplasms characterized by an accumulation of clonal mast cells in skin, bone marrow, and/or other extracutaneous tissues.

SM subtypes are (table 1):

•Indolent SM (ISM)

•Smoldering SM (SSM)

Management and prognosis of ISM and SSM are discussed separately. (See "Indolent and smoldering systemic mastocytosis: Management and prognosis".)

•Advanced SM (advSM)

-Aggressive systemic mastocytosis (ASM)

-Systemic mastocytosis with an associated hematologic/myeloid neoplasm (SM-AHN)

-Mast cell leukemia (MCL)

●Evaluation – Classify the advSM subtype, assess B findings (eg, higher burden disease/organ enlargement without organ dysfunction) and C findings (organ damage due to mast cell infiltration), and determine eligibility for hematopoietic cell transplantation (HCT). (See 'Pretreatment evaluation' above.)

Details of SM classification are presented separately. (See "Systemic mastocytosis: Determining the subtype of disease".)

●Overview – The goals of management are to control symptoms, mitigate organ damage, improve quality of life, and extend survival. (See 'Overview of management' above.)

Referral to a specialized center for diagnosis, classification, and management by an experienced multidisciplinary team is preferred. We encourage participation in a clinical trial.

●Front-line therapy – Varies according to advSM subtype:

•ASM or MCL – For most patients with ASM or MCL, we suggest avapritinib rather than midostaurin or other agents (algorithm 1) (Grade 2C). (See 'Aggressive SM or mast cell leukemia' above.)

•SM-AHN – For SM-AHN, we determine if the SM component or the AHN (eg, myeloproliferative neoplasm, acute leukemia, myelodysplastic syndrome, or myelodysplastic/myeloproliferative neoplasm overlap) requires more urgent treatment (algorithm 1).

We treat one disease component at a time to avoid overlapping toxicity. (See 'Prioritization of treatment' above.)

-If SM requires priority – For greater urgency to treat the SM component, we suggest avapritinib (as for ASM or MCL) (Grade 2C). (See 'Aggressive SM or mast cell leukemia' above.)

-If AHN requires priority – When the AHN requires more urgent management, we treat that condition first, while monitoring SM-related symptoms and complications. (See 'If the AHN requires more urgent treatment' above.)

•Well-differentiated SM – For well-differentiated SM, we suggest imatinib rather than other agents (Grade 2C). (See 'Well-differentiated aggressive SM' above.)

●Response assessment – The treatment response includes symptoms, hematologic parameters, and disease response in blood and bone marrow/organs, as discussed above. (See 'Monitoring and response' above.)

●Treatment-responsive disease – Further management is guided by prognostic features (advSM subtype, cytogenetic/molecular features) described above. (See 'Adverse prognostic features' above.)

•Adverse features in HCT-eligible patients – We suggest continued medical therapy or allogeneic HCT (Grade 2C). The decision is individualized according to patient and clinician views of the balance of toxicity versus potential cure with HCT versus the uncertain duration of response and less toxicity with medical therapy. (See 'Transplant eligible with adverse features' above.)

•Other patients – For patients without adverse prognostic factors or who are ineligible for allogeneic HCT, we continue medical therapy until disease progression or treatment intolerance. (See 'Other treatment-responsive patients' above.)

●Refractory/relapsed advSM – We encourage participation in a clinical trial or allogeneic HCT in transplant-eligible patients. (See 'Refractory/relapsed disease' above.)

●Prognostic features – Disease subtype, clinical features, and molecular abnormalities are associated with inferior outcomes in advSM. (See 'Prognosis' above.)

●Prognostic models – Various prognostic models are available; there is no consensus model. (See 'Prognosis' above.)

ACKNOWLEDGMENT — 

The editorial staff at UpToDate acknowledge Cem Akin, MD, PhD and Mariana C Castells, MD, PhD, who contributed to earlier versions of this topic review.