INTRODUCTION — Systemic mastocytosis (SM) comprises a heterogeneous group of disorders characterized by excessive accumulation of mast cells (MC) in bone marrow and other extracutaneous tissues. Based on the presence of "B" findings (which indicate a high burden of MCs and expansion of the neoplastic process into multiple hematopoietic lineages, but no evidence of organ damage) and "C" findings (organ damage produced by MC infiltration), SM can be broadly categorized as (table 1):
●Indolent systemic mastocytosis (ISM) and smoldering systemic mastocytosis (SSM) – ISM and SSM usually have a clinically indolent course, with median survival measured in decades. Previously, SSM was described as a subcategory of ISM, but the 2017 World Health Organization classification of hematolymphoid neoplasms redefined SSM as a distinct subtype of SM .
●Advanced systemic mastocytosis, which has a more aggressive course with median survival measured in months to years and includes the following disease variants:
•Aggressive systemic mastocytosis (ASM)
•Systemic mastocytosis with an associated hematologic neoplasm (SM-AHN)
•Mast cell leukemia (MCL)
This topic will discuss management and prognosis of advanced SM.
Clinical manifestations, evaluation, diagnosis, and classification of SM in adults and children are discussed separately.
Management of ISM and SSM in adults is discussed separately. (See "Indolent and smoldering systemic mastocytosis: Management and prognosis".)
PRETREATMENT EVALUATION — We suggest referral to a specialized center for evaluation by a multidisciplinary team that is experienced with advanced SM. Pretreatment evaluation of the patient with advanced SM should determine the following:
●Disease variant – Determination of the disease variant should be performed by experienced hematopathologists and clinicians. The most common advanced disease variant is SM with an associated hematologic neoplasm (AHN), but the AHN may be masked by the SM component on a bone marrow biopsy. Misdiagnosis, misclassification, or failure to detect an AHN might influence the selection of initial treatment and outcomes. As examples, an AHN may be masked by high-burden mast cell disease (eg, mast cell leukemia), or a FIP1L1-PDGFRA-positive myeloid neoplasm with eosinophilia may be misdiagnosed as SM with chronic eosinophilic leukemia (SM-CEL). Classification of SM variants and other conditions that may be misclassified as SM are discussed separately. (See "Systemic mastocytosis: Determining the subtype of disease" and "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis", section on 'Differential diagnosis'.)
●Urgency of treatment for an AHN versus the SM disease component – For patients with SM with an AHN, it is important to determine if more urgent treatment is needed for SM versus the AHN component or vice versa. This judgment is based on clinical evaluation and assessment of the disease burden/stage of both the SM and the AHN in bone marrow and/or other extracutaneous sites. (See 'SM with an associated hematologic neoplasm (SM-AHN)' below.)
●Suitability for transplantation – We suggest early referral for consultation with experts in hematopoietic cell transplantation (HCT) for selected patients (see 'Hematopoietic cell transplantation' below):
•Adverse risk features: High-risk karyotype (eg, monosomy 7, complex karyotype) and/or one or more high-risk non-KIT mutations (eg, SRSF2, ASXL1, and/or RUNX1) (see 'Molecular/cytogenetic features' below)
•Refractory or resistant disease (either SM or an AHN) despite medical therapy
Evaluation of the individual's suitability for transplantation is described separately. (See "Determining eligibility for allogeneic hematopoietic cell transplantation".)
Initial evaluation, including a history of symptoms related to mast cell activation, assessment for organ involvement, laboratory studies, bone marrow examination, and other studies are discussed separately. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)
GENERAL MEASURES — Patients with any category of SM may experience episodic symptoms of mast cell activation, including allergic-like reactions triggered by a variety of exposures. All patients with SM should carry injectable epinephrine and be educated about anaphylaxis, be informed about medications and other triggers for mast cell degranulation, and counseled for emotional aspects of these chronic diseases. General measures, along with management of osteoporosis and preparation for medical or surgical procedures are discussed separately. (See "Indolent and smoldering systemic mastocytosis: Management and prognosis".)
We suggest referral to a specialized center for evaluation by a multidisciplinary team that is experienced with advanced SM.
GOALS — The goals of treatment for advanced SM are to control symptoms, mitigate organ damage, improve the quality of life (QOL), and extend survival. Medical therapy is the mainstay of treatment, and some patients have achieved long-term disease control with targeted agents. However, allogeneic hematopoietic cell transplantation (HCT) is the only treatment that has been proven to cure advanced SM. Medical therapies and the role of allogeneic HCT for advanced SM are discussed below. (See 'Medical therapies' below and 'Hematopoietic cell transplantation' below.)
INITIAL TREATMENT — We suggest treatment on a clinical trial, when possible. (See 'Clinical trials' below.)
Outside of a clinical trial, the choice of treatment is informed by the subtype of advanced SM (algorithm 1), as described below.
SM with an associated hematologic neoplasm (SM-AHN) — For patients with SM-AHN, we first determine whether the AHN or SM component requires more urgent treatment (algorithm 1). In general, we treat one disease component (ie, either the AHN or SM) at a time, because of the potential for drug interactions and overlapping toxicity when combination regimens are used. When the AHN requires more urgent treatment, we suggest approaching it as if there is no associated SM. Similarly, if treatment is required more urgently for the SM component, we manage the SM as if there is no AHN.
There is no consensus regarding when an AHN requires more urgent treatment than the SM component. This judgment should include clinical evaluation, assessment of disease burden of both the SM and the AHN in bone marrow and/or other extracutaneous sites, and weigh the severity of associated clinical findings, prognosis, and available treatments for the AHN. As an example, acute myeloid leukemia (AML) generally requires urgent management because of the adverse prognosis if it is not treated promptly. Urgent treatment may also be needed if a myeloproliferative neoplasm (MPN) is associated with thrombohemorrhagic complications or a substantial symptom burden. A need for multiple transfusions due to severe cytopenias, severe infections, or significant bleeding may warrant urgent treatment in a patient with a myelodysplastic syndrome (MDS).
If the AHN does not require urgent treatment, management is similar to that of other subtypes of advanced SM, as described below. (See 'Aggressive SM (ASM) or mast cell leukemia (MCL)' below.)
In some cases, the same treatment may be effective for both disorders. Examples include:
●When a KIT D816V mutation is detected, it often resides in both mast cells of SM and cells from the AHN component (eg, monocytes in chronic myelomonocytic leukemia); in such a case, an inhibitor of KIT D816V (eg, midostaurin) would be appropriate for treatment of both the SM and AHN components. (See 'Midostaurin' below.)
●Treatment with midostaurin may benefit both SM and AML with a FLT3 mutation.
MPNs, MDS, MDS/MPNs, chronic eosinophilic leukemia, or AML are the myeloid AHNs that are most commonly associated with SM; less often, SM is associated with a lymphoproliferative neoplasm. Categories of AHNs associated with SM are described separately. (See "Systemic mastocytosis: Determining the subtype of disease", section on 'Systemic mastocytosis with an associated hematologic neoplasm'.)
Aggressive SM (ASM) or mast cell leukemia (MCL) — For most patients with ASM, MCL, and for SM-AHN in which the SM component requires more urgent treatment than the accompanying AHN, we suggest initial systemic treatment with midostaurin or avapritinib, rather than cladribine, other TKIs, interferon alfa (IFN-a), or other agents. Compared with the other agents, midostaurin or avapritinib offer a more favorable balance of response versus toxicity; note that avapritinib should not be given when the platelet count is <50,000/microL due to an increased potential risk of intracranial hemorrhage in these patients. No studies have directly compared the efficacy and toxicity of midostaurin and avapritinib.
●Well-differentiated SM – For well-differentiated advanced SM (which is typically associated with unmutated KIT or KIT mutations outside of exon 17) we suggest initial treatment with imatinib rather than midostaurin or other agents, because these cases are generally sensitive to imatinib and this TKI is well-tolerated. (See 'Imatinib' below.)
Well-differentiated advanced 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, as described separately. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis", section on 'Well-differentiated systemic mastocytosis'.)
●Others – Other agents are acceptable alternatives to midostaurin in certain settings. As an example, IFN-a may be useful for a patient with slowly progressive advanced SM with multiple fractures and/or severe bony disease. (See 'Interferon alfa' below.)
No randomized trials have directly compared various initial treatments for advanced SM, and outcomes data are generally derived from case series or single-arm prospective trials, as described in the sections below. (See 'Medical therapies' below.)
Response assessment to initial therapy is described below. (See 'Response assessment' below.)
MEDICAL THERAPIES — We suggest treatment on a clinical trial, when possible. (See 'Clinical trials' below.)
Settings — Medical therapy for SM is used in the following settings:
●Initial treatment of patients with advanced SM. (See 'Aggressive SM (ASM) or mast cell leukemia (MCL)' above.)
●Bridging treatment for patients with advanced SM who plan to undergo allogeneic hematopoietic cell transplantation (HCT). (See 'Hematopoietic cell transplantation' below.)
●Selected patients with indolent systemic mastocytosis (ISM) or smoldering systemic mastocytosis (SSM) who suffer from recurrent anaphylaxis that cannot be controlled with antimediator treatments and in whom all other options have been exhausted, as discussed separately. (See "Indolent and smoldering systemic mastocytosis: Management and prognosis".)
Midostaurin — Midostaurin is a multi-kinase/KIT inhibitor that inhibits the protein product of KIT, including the kinase encoded by D816V-mutated KIT, which is the most common driver mutation in SM (present in 90 to 95 percent of patients). Midostaurin is suggested for initial treatment of most patients with advanced SM, as described above. (See 'Aggressive SM (ASM) or mast cell leukemia (MCL)' above.)
All subtypes of SM respond to midostaurin, including aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL). Midostaurin achieves responses in approximately two-thirds of patients with advanced SM; approximately half of treated patients have a major response. Midostaurin can lessen organ damage (eg, cytopenias, liver dysfunction), decrease bone marrow mast cell (MC) burden, reduce KIT mutant allele burden, and lower serum tryptase levels. Responses are generally sustained for 18 to 24 months, but longer-term responses (>5 years) have been observed in some patients. Midostaurin is generally well-tolerated, with the most common adverse effects being lower grade nausea/vomiting and diarrhea .
Midostaurin 100 mg is administered twice daily by mouth until allogeneic HCT. For patients who are not candidates for transplantation, we continue treatment indefinitely, unless there is evidence of disease progression or intolerance to midostaurin. Exceptions to the use of midostaurin as initial therapy and monitoring of response to therapy are described above and below. (See 'Aggressive SM (ASM) or mast cell leukemia (MCL)' above and 'Response assessment' below.)
Midostaurin has not been directly compared with other treatments in advanced SM. Studies that examined midostaurin in advanced SM include:
●In a global, phase 2 study of 116 patients (among whom 89 patients with advanced SM had evaluable organ damage), midostaurin achieved 60 percent overall response rate (ORR); there were no complete responses, 45 percent major responses, and 15 percent partial responses . All subtypes responded to midostaurin, including ASM (75 percent ORR), SM-AHN (58 percent ORR), and MCL (50 percent ORR). Midostaurin decreased objective measures of MC burden (eg, bone marrow MC aggregates, serum tryptase levels), improved symptoms and quality of life, reverted organ damage, and decreased splenomegaly. Median duration of response (DOR) was 24 months, median overall survival (OS) was 29 months, and median progression-free survival (PFS) was 14 months. A post-hoc analysis reported that longer OS was associated with a partial or major response or >50 percent reduction in bone marrow MC burden.
●In a retrospective study of 28 patients with advanced SM, midostaurin achieved 71 percent ORR (no complete responses [CR], 57 percent major response, 14 percent partial response, 11 percent stable disease, 18 percent progressive disease) . Responses were detectable within the first three months and median 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.
Avapritinib — Avapritinib is an oral, type I multikinase inhibitor with highly selective and potent activity against mutated KIT (including D816V) and PDGFRA A-loop mutants, and a tolerable safety profile . Avapritinib is suggested for adults with advanced SM, but it should not be given with platelet counts <50,000/microL due to an increased potential risk of intracranial hemorrhage in these patients. (See 'Aggressive SM (ASM) or mast cell leukemia (MCL)' above.)
A prespecified interim analysis of a phase 2 study, presented in abstract form, reported 75 percent ORR (19 percent CR) among 32 evaluable patients with advanced SM . Median time to CR was 6 months and with 10-month median follow-up, all responses were ongoing and most were maintained following dose reduction to ≤100 mg daily. Avapritinib was associated with 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 approximately 90 percent of patients. Results from a phase I trial (NCT02561988), also published in abstract form, reported comparable responses . Grade ≥3 cytopenias occurred in up to one-quarter of patients and facial/periorbital edema (any grade) in one-half (3 percent grade ≥3 facial/periorbital edema) .
Cladribine — Cladribine (2-chlorodeoxyadenosine) may be effective for patients with rapidly progressive advanced SM and for advanced SM that failed to respond adequately to other agents. Cladribine has been shown to reduce the total MC burden [10-12].
Patients with rapidly progressing advanced SM can receive up to six cycles of cladribine at four- to eight-week intervals as a bridge to allogeneic HCT. Dose ranges that have been reported include 0.10 to 0.14 mg/kg/day or 5 mg/m2 daily, infused over two hours for five days [13,14].
In one study, cladribine achieved ORR of 50 and 55 percent in patients with ASM and SM-AHN, respectively . In a retrospective analysis of a French cohort, 32 patients with advanced SM had 50 percent ORR (major 38 percent, minor 13 percent) and 2.5 year median DOR (median 3.7 courses; range 1 to 9) . The most common severe (grade 3/4) adverse events 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 [16,17]. Side effects are mainly related to bone marrow suppression [11,14]. Prophylaxis to prevent Pneumocystis jirovecii pneumonia is suggested for at least three months after therapy is complete and until the CD4 count is >200/microL . Cladribine is a teratogen and patients should use contraception. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)
Imatinib — Most patients with SM should not be treated with imatinib, because the most common mutation (ie, KIT D816V mutation) is resistant to imatinib . Imatinib is appropriate as initial therapy only for the rare patients with advanced SM who have unmutated KIT or KIT mutations outside of exon 17, or patients with well-differentiated SM (which is typically associated with those KIT mutations) [19-24].
For patients who are considered candidates for imatinib, we suggest using a high-sensitivity assay to exclude the presence of KIT D816V. A technique such as KIT D816V allele-specific polymerase chain reaction (PCR; sensitivity approximately 0.1 percent) is considerably more sensitive than next-generation sequencing using myeloid mutation panels (approximately 5 percent) for detection of the KIT D816V mutation.
For treatment of SM, therapy should begin with imatinib 100 mg daily . Imatinib is generally well-tolerated, as described separately. (See "Initial treatment of chronic myeloid leukemia in chronic phase", section on 'Imatinib'.)
Subsequent management of advanced SM is informed by the response to treatment:
●For patients who achieve a molecular complete response, we suggest continuing imatinib rather than switching to midostaurin or proceeding to HCT, because of the generally excellent long-term outcomes in these rare patients. For those who achieve a molecular complete response, the role of reduced dosing (eg, three times weekly) or imatinib discontinuation has not been well-studied and, at present, we suggest continued daily dosing of imatinib.
●For incomplete responses (eg, persistence of measurable residual disease, partial hematologic response), we suggest increasing the imatinib dose to 200 to 400 mg daily before switching to an alternative approach.
Imatinib is generally effective only for unmutated KIT or KIT mutations outside of exon 17 [19-24]. Case reports have reported sensitivity to imatinib for SM with mutations in exons 8 to 10 of KIT: F522C (transmembrane mutation), germline K509I mutation, deletion of codon 419 in exon 8, and p.A502_Y503dup exon 9 mutation [22,26-30]. It is important to recognize that many previously reported responses to imatinib were likely to be rare KIT mutations that are sensitive to imatinib or misdiagnoses (eg, FIP1L1-PDGFRA-positive myeloid/lymphoid neoplasms with eosinophilia that can also exhibit an increase in bone marrow MC numbers and elevated serum tryptase levels). (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Systemic mastocytosis with eosinophilia'.)
Imatinib is approved by the FDA for patients with ASM who do not have a KIT D816V mutation or for those with unknown mutational status.
Other TKIs — Other tyrosine kinase inhibitors (TKI) have been evaluated against advanced SM:
Other TKIs that are under investigation for treatment of advanced SM are described below. (See 'Clinical trials' below.)
Interferon alfa — Interferon alfa (IFN-a) or pegylated IFN-a is usually reserved for patients with slowly progressive, symptomatic advanced SM who are not candidates for other therapies (eg, older adults). The response to IFN-a is generally slow and may be associated with substantial toxicities .
We suggest pretreatment with prednisone and hospitalization for the first few days of IFN-a administration, as there have been reports of anaphylaxis when IFN-a is initiated without steroids . One approach is to administer prednisone (1 mg/kg body weight daily) for three to seven days and begin IFN-a at 3 million units three times weekly . The dose of prednisone is then gradually reduced as the dose of IFN-a is increased to a maximum of 5 million units daily, if tolerated. In patients with severe mediator-related symptoms or ascites, a small maintenance dose of prednisone (≤5 to 10 mg/day) should be continued. Otherwise, prednisone is discontinued, if possible, to minimize the risk of osteoporosis . IFN-a can be continued as long as there is clinical response and it is tolerated.
Pegylated interferon-alfa-2a has a longer half-life and generally exhibits a more favorable toxicity profile. The starting dose is typically 45 micrograms/week subcutaneously and it is incrementally escalated according to tolerability and efficacy.
In one study, IFN-a achieved 60 and 45 percent ORR, respectively, for ASM and SM-AHN . Some studies suggest that the ORR may be higher when IFN-a is administered with prednisone, but results have been inconclusive [10,36-40]. Up to 20 percent of patients may experience partial remission of bone pain and lesions, but complete remissions are rare [10,36-39]. IFN-a can reduce symptoms (C-findings) related to MC mediator release and can improve cutaneous lesions, bone marrow MC burden, and serum and urine metabolites of MC activation. IFN-a increases bone density and can be particularly 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 . Fatigue, depression, and thrombocytopenia are the most common toxicities.
In addition to an anaphylactic reaction when treating SM, adverse effects of IFN-a include flu-like symptoms, thrombocytopenia, cardiac toxicity, and depression. Elevated serum aminotransferases and myelosuppression are the most common laboratory abnormalities.
Hydroxyurea — Hydroxyurea is rarely used to treat advanced SM and is generally used to treat the AHN component associated with a high white blood cell count or splenomegaly. There are few published data on the efficacy of hydroxyurea for advanced SM .
The initial dose is hydroxyurea 500 mg daily for the first four to six weeks. There are relatively few side effects compared with other chemotherapy agents, although hematologic toxicity and gastrointestinal side effects may be problematic at higher doses. Complete blood counts and liver function tests should be monitored regularly. If tolerated, the dose can be increased to 1000 to 1500 mg daily. Patients should use contraception because hydroxyurea is a teratogen.
RESPONSE ASSESSMENT — There is no consensus regarding the optimal method of response assessment for advanced SM nor a preferred schedule or protocol for monitoring the patient. Response criteria have been developed for use in clinical trials that assess hematologic parameters (eg, peripheral blood counts, bone marrow response) and nonhematologic parameters, but these have not been widely adopted outside of the context of clinical trials .
We initially see the patient every one to three months, but the schedule should be adjusted according to the burden of symptoms, overall clinical status, and the presence of an associated hematologic neoplasm (AHN). The interval between visits should be adjusted over time, based on clinical judgment.
At follow-up visits, we assess the interval history for symptomatic response, perform a physical examination, and evaluate the following laboratory studies:
●Complete blood count (CBC) with differential count
●Serum tryptase levels (which reflects mast cell burden)
●Serum chemistry panel to monitor renal and liver function tests
We generally perform a bone marrow examination every 6 to 12 months. This examination should include molecular testing for the underlying mutation and assessment for progression to leukemia. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis", section on 'Bone marrow examination'.)
RESISTANT/REFRACTORY SM — There is no consensus regarding further management of patients who do not tolerate initial therapy or who fail to achieve adequate relief of symptoms or improvement in organ function. We suggest participation in a clinical trial, when possible.
Outside of the context of a clinical trial, subsequent management is informed by the initial treatment:
●Adverse effects – For patients who did not tolerate initial treatment with midostaurin 100 mg twice daily, depending on the severity of the adverse effect, consideration should be given to treatment with midostaurin 50 mg twice daily. If this lower dose is tolerated and there is evidence of response to therapy, we suggest continuing at this dose. If the lower dose is not tolerated or if there is disease progression, we suggest proceeding as described below for refractory/resistant disease.
●Refractory/resistant disease – For patients who do not have an initial response to midostaurin (ie, refractory disease), who progress while taking midostaurin (ie, disease resistance), or who do not tolerate or respond to a reduced dose, we suggest participation in a clinical trial, prompt evaluation for allogeneic hematopoietic cell transplantation (if appropriate based on disease status, performance status, and availability of a suitable donor), or consideration of alternative SM-directed therapies. (See 'Clinical trials' below and 'Hematopoietic cell transplantation' below and 'Other agents' above.)
Agents under investigation for advanced SM are described below. (See 'Clinical trials' below.)
HEMATOPOIETIC CELL TRANSPLANTATION — Allogeneic hematopoietic cell transplantation (HCT) is the only treatment that has the proven ability to cure advanced SM, but the role of transplantation is evolving as more effective medical therapies are developed. HCT is only appropriate for medically fit patients and there is no consensus regarding patient selection, conditioning regimen, or graft source. Eligibility for allogeneic HCT is discussed separately. (See "Determining eligibility for allogeneic hematopoietic cell transplantation".)
A decision to proceed with allogeneic HCT is made on a case-by-case basis and should consider medical fitness, availability of a suitable donor, disease status, and prognostic factors. The potential for long-term disease control must be weighed against the short-term and long-term toxicities of transplantation. Allogeneic HCT is primarily used in the following settings:
●SM with an associated hematologic neoplasm (AHN) or mast cell leukemia (MCL)-AHN, in which the SM component manifests a significant response, but the AHN has not demonstrated a meaningful response or progresses. Examples include persistence (or worsening) of clinically significant cytopenias and/or elevated blood counts with dysplasia, monocytosis, eosinophilia, and/or increased peripheral blood and/or bone marrow blasts.
●High-risk molecular and/or karyotypic features in a patient whose best response to midostaurin is stable disease or a partial response of either the SM or AHN component. (See 'Molecular/cytogenetic features' below.)
In some institutions, allogeneic HCT is offered only to patients who are ≤60 years of age with a human-leukocyte antigen (HLA)-identical related donor. However, there has been increasing use of both matched-unrelated and mismatched-related grafts and transplantation of older adults. (See "Donor selection for hematopoietic cell transplantation".)
As a bridge to transplant, midostaurin (or a KIT inhibitor as part of a clinical trial) or cladribine may be used to reduce the SM burden, and for patients with SM-AHN a similar strategy may be used to reduce disease burden of a higher-risk myeloid neoplasm (eg, treatment with a hypomethylating agent for chronic myelomonocytic leukemia with increased blasts). There is no consensus regarding an optimal conditioning regimen or graft source for allogeneic HCT in this setting. Prophylactic antimediator drug therapy with corticosteroids, antihistamines, and epinephrine should be used during the conditioning regimen. Currently, no data exist for the safety or efficacy of midostaurin or other agents in the post-transplant setting to minimize relapse.
Reports of allogeneic HCT for advanced SM are limited, with only small retrospective case series and comparisons to historical controls [43-46]. No studies have randomly assigned patients to allogeneic HCT versus medical therapy alone. Furthermore, most studies describe outcomes from an era before the widespread use of potent KIT inhibitors, so their applicability to contemporary treatment of advanced SM is uncertain.
The largest series (57 patients), which included various conditioning regimens and graft sources, reported 70 percent overall response rate (28 percent complete response, 21 percent stable disease) and 57 percent three-year overall survival (OS) . The median follow-up among survivors was 32 months (range, 3 to 202 months), and no deaths or relapses were observed after 15 and 24 months, respectively. The following rates of three-year OS were reported: SM-AHN (38 patients) 74 percent; MCL (12 patients) 43 percent; aggressive SM (ASM; 7 patients) 17 percent. Reduced intensity conditioning was associated with lower survival than myeloablative conditioning. Recognizing that patient groups are not matched, these outcomes with transplantation appear to be comparable to treatment with midostaurin or other potent KIT inhibitors. As an example, three-year OS for midostaurin-treated patients was relatively better for patients with ASM (65 percent) and MCL (26 percent), but lower for SM-AHN patients (44 percent) .
PROGNOSIS — Certain clinical and laboratory findings at the time of diagnosis are associated with outcomes for advanced SM. An international registry has been established to better define prognostic features in SM .
Disease variant — Some studies have reported an association between outcomes and disease subtype (table 1), but some of these reports preceded the current World Health Organization (WHO) classification for SM and widespread application of mutation analysis:
●Overall survival (OS) and progression to leukemia varied according to disease variant, in a retrospective, single institution study that followed patients for a median of 21 months (range 0 to 35 years) :
•Aggressive SM (41 cases): median OS 41 months; 5 percent progression to leukemia
•SM with associated hematologic malignancy (AHN; 138 cases): median OS 24 months; 13 percent progression
•Mast cell leukemia (MCL; 4 cases): median OS 2 months
●The impact of disease subtype varied in studies that included molecular analysis. In some studies disease subtype remained a significant feature , while in others it was not an independent risk factor for outcomes .
●A study that included 123 patients with SM-AHN reported that median OS varied with the category of AHN :
•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 (4 patients): OS 11 months
Other studies have also reported that outcomes were associated with the category of AHN [48,52].
Clinical features — Various clinical features have been reported to be associated with outcomes in advanced SM.
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 . In another study of 67 patients with advanced SM, splenomegaly and elevated alkaline phosphatase were adverse prognostic markers . Circulating mast cells, hepatomegaly, elevated lactate dehydrogenase, and low serum albumin have also been reported to be associated with adverse outcomes [49,54-57].
Hazard ratios (HR) 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 advanced SM.
●OS was significantly shorter in patients with advanced SM and additional molecular abnormalities besides KIT D816V . In particular, mutation of SRSF2, ASXL1, or RUNX1 was associated with an adverse prognosis, and OS was influenced by the number of mutated genes in this panel . Other studies have also identified mutations in SRSF2, ASXL1, or RUNX1 as associated with adverse outcomes [53,59,60].
●A study of 38 patients with advanced SM reported that overall response rate (ORR) to midostaurin and prognosis were associated with the depth of reduction of KIT D816V allele burden and by the presence of additional mutations . Patients with an additional mutation of SRSF2, ASXL1, and/or RUNX1 had ORR 39 percent, compared with 75 percent ORR in patients with none of those mutations. OS was superior in patients who responded to midostaurin with ≥25 percent reduction in KIT D816V expressed allele burden, compared with lesser responses (HR 6.8; 95% CI, 1.8-25.3). Acquisition of additional mutations or increasing variant allele frequency in K/NRAS, RUNX1, IDH2, or NPM1 was found in patients with disease progression.
●A poor-risk karyotype (eg, monosomy 7, complex karyotype) is an independent adverse prognostic variable in advanced SM. In one report, compared with good-risk or normal karyotype, patients with poor-risk karyotype had inferior OS (4 versus 39 months; HR 11.7, 95% CI 5.0-27.3), and the prognostic impact of karyotype was independent of mutation status .
Prognostic models — Several prognostic models for SM have been developed, but there is no consensus regarding the preferred approach for defining prognosis.
MARS — The mutation-adjusted risk score (MARS) is a prognostic model that is independent of WHO subtype . MARS was developed from an international registry that included 383 patients with advanced SM. The following variables are included:
●Age >60 years (1 point)
●Hemoglobin <10 g/dL (1 point)
●Platelets <100 x 109/L (1 point)
●One mutation of SRSF2, ASXL1, and/or RUNX1 (1 point)
●Two or more mutations of SRSF2, ASXL1, and/or RUNX1 (2 points)
Patients were treated with midostaurin, cladribine, and sequential midostaurin followed by cladribine. With median follow-up of 2.2 years (range: 0 to 23 years), the following median values for OS and leukemia-free survival (LFS), respectively, were reported, according to risk category:
●Low risk (0 to 1 point): OS not reached, 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 that uses only clinical variables was created from a Mayo Clinic cohort of 580 patients with SM . The model identified the following clinical variables and associated HRs:
●Age >60 years (HR 2.5; 95% CI 1.9-3.4)
●WHO-defined advanced SM 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 advanced SM with median follow-up of 34 months, the number of adverse clinical features were associated with the following values for median OS:
●0 features (21 patients): not reached
●1 feature: (42 patients): 157 months
●2 features (63 patients): 57 months
●3 features (94 patients): 276 months
●4 features (57 patients): 9 months
Mayo hybrid model — A hybrid clinical-molecular prognostic model identified age, SM category, thrombocytopenia, and increased alkaline phosphatase plus mutation of ASXL1, RUNX1, or NRAS (HR 2.6; 95% CI 1.6-4.4) as risk factors in the same cohort of patients . Each adverse factor was assigned one point, while advanced SM versus indolent/smoldering was assigned two points, because of its greater impact in this model (HR 4.0; 95% CI 1.8-10.0) than in the Mayo clinical model described above.
Prognostic categories and median OS were as follows :
●Low risk (≤2 points): 198 months
●Intermediate-1 (3 points): 85 months
●Intermediate-2 (4 points): 36 months
●High (≥5 points): 12 months
Other prognostic models for SM have been proposed .
CLINICAL TRIALS — We suggest participation in a clinical trial, when possible. Following is a sample of agents that are under investigation for treatment of SM:
●Ripretinib is a type II switch control kinase inhibitor with activity against multiple KIT and PDGFR mutants, and antineoplastic activity in preclinical models using KIT D816V-transfected MC lines . A phase II study with a dose of 150 mg twice daily (NCT02571036) for advanced SM is in progress.
●Brentuximab vedotin – Brentuximab vedotin (BV) is an antibody-drug conjugate directed against CD30, which is expressed by neoplastic MC in SM [64-66]. A phase 2 study reported that none of 10 patients treated with BV demonstrated better than stable disease, and that there were no significant reductions in bone marrow MC burden, serum tryptase levels, or MC expression of CD30 . Based on this trial, BV monotherapy is not considered an active regimen in CD30+ advanced SM.
●Other antibody-drug conjugates – Based on the expression of CD123 (interleukin 3 [IL-3] receptor-alpha) on neoplastic mast cells , an anti-CD123 antibody linked to diphtheria toxin, SL-401, is being evaluated in advanced SM (clinicaltrials.gov identifier: NCT02268253).
SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The coronavirus disease 2019 (COVID-19) pandemic has increased the complexity of cancer care. Important issues include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. Additionally, immunocompromised patients are candidates for a modified vaccination schedule (figure 1), other preventive strategies (including pre-exposure prophylaxis), and the early initiation of COVID-directed therapy. These issues and recommendations for cancer care during the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world 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
●Systemic mastocytosis (SM) refers to a heterogeneous group of disorders that exhibit excessive mast cell (MC) accumulation, typically in bone marrow and other extracutaneous tissues (table 1) that includes (see "Systemic mastocytosis: Determining the subtype of disease"):
•Indolent systemic mastocytosis (ISM) and smoldering systemic mastocytosis (SSM)
•Advanced systemic mastocytosis:
-Aggressive systemic mastocytosis (ASM)
-Systemic mastocytosis with an associated hematologic neoplasm (SM-AHN)
-Mast cell leukemia (MCL)
●Patients with SM should be evaluated by a multidisciplinary team that includes clinicians and hematopathologists who are experienced with these disorders. Pretreatment evaluation should include classification of the subtype of advanced SM. For patients with SM-AHN, the urgency of treatment of the AHN should be determined. In some patients, eligibility for allogeneic hematopoietic cell transplantation (HCT) should be evaluated. (See 'Pretreatment evaluation' above.)
●The goals of treatment of advanced SM are to mitigate organ damage, lessen symptoms, improve the quality of life, and achieve long-term disease control. (See 'Goals' above.)
●We suggest treatment on a clinical trial, when available. Outside of a clinical trial, treatment is informed by the subtype of advanced SM (algorithm 1):
•For patients with SM-AHN, we first determine whether the SM component or the AHN (eg, myeloproliferative neoplasm, acute leukemia, myelodysplastic syndrome) requires more urgent treatment. In general, we treat one component at a time because of the potential for drug interactions and overlapping toxicity. When the AHN requires more urgent treatment, we suggest approaching it as if there is no associated SM, and vice versa. (See 'SM with an associated hematologic neoplasm (SM-AHN)' above.)
•For most patients with ASM, MCL, and for SM-AHN in which the SM component requires more urgent treatment than the accompanying AHN, we suggest initial systemic treatment with midostaurin rather than cladribine, other tyrosine kinase inhibitors (TKIs), interferon alfa (IFN-a), or other agents (Grade 2B). Compared with these other agents, midostaurin offers the most favorable balance of response versus toxicity.
●Specific agents for treatment of advanced SM are discussed above. (See 'Medical therapies' above.)
●Monitoring of disease status, including schedule of follow-up visits, laboratory studies, and other aspects of monitoring are discussed above. (See 'Response assessment' above.)
●For patients who do not tolerate initial treatment or who fail to achieve adequate response to therapy, we suggest participation in a clinical trial. Outside of the context of a clinical trial, subsequent management is informed by the initial treatment and medical fitness. (See 'Resistant/refractory SM' above.)
●Allogeneic HCT has the potential to cure advanced SM, but it is generally reserved for patients who have failed to respond adequately or relapsed after initial therapy and for selected medically fit patients with adverse prognostic features. (See 'Hematopoietic cell transplantation' above.)
●Outcomes for advanced SM are affected by the category of SM and by certain clinical, laboratory, cytogenetic, and molecular findings. (See 'Prognosis' above.)
ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge Cem Akin, MD, PhD and Mariana C Castells, MD, PhD, who contributed to an earlier version of this topic review.