Innovative Therapeutic Approaches in Systemic Mastocytosis: an Updated Review

Abstract

Introduction

Systemic mastocytosis (SM) is a heterogeneous clonal disorder characterized by the accumulation of abnormal mast cells in various tissues, predominantly the bone marrow. Given the rarity of the disease, the available data in Romania are extremely limited. It is estimated that the total number of diagnosed patients is approximately 170. In recent years, significant advances have been made in understanding the molecular pathogenesis of SM, leading to the development of targeted therapies that have transformed the management of this condition. The approval of tyrosine kinase inhibitors (TKIs), particularly midostaurin and avapritinib, has provided new therapeutic options for patients with advanced SM, demonstrating significant improvements in overall survival (OS) and symptom control.

Objective

To conduct a systematic review of clinical trials, observational studies and international or national guidelines published since 2000 to evaluate the efficacy, safety and mechanistic rationale of innovative therapeutic approaches for SM – including KIT inhibitors, monoclonal antibody-based therapies, stem cell transplant – and to compare the impact of these interventions with conventional cytoreductive and symptomatic treatments on overall response rate, survival, mediator-related symptom burden, quality of life and treatment-related adverse events.

Materials and methods

A comprehensive search was performed in MEDLINE ( via PubMed), Embase, the Cochrane Central Register of Controlled Trials and Web of Science from 1 January 2000 to 1 May 2025. ClinicalTrials.gov, WHO ICTRP. Search strings combined controlled vocabulary ( e.g. , “Mastocytosis”) and free-text terms for the disease (systemic mastocytosis, advanced SM, indolent SM) with key innovative interventions (KIT inhibitors, avapritinib, midostaurin, monoclonal antibodies, stem cell transplant). No language limits were set at the search stage; non-English full texts were excluded only if an accurate translation could not be obtained. As the review relied exclusively on published or publicly available data, ethical approval and informed consent were not required.

Conclusion

The present review provides an updated overview of the evolving therapeutic landscape of SM, emphasizing recent clinical trial data, novel targeted therapies and emerging treatment paradigms. We discuss the implications of this progress on patient outcomes and future directions for personalized medicine in SM.

Keywords: advanced systemic mastocytosis, KIT inhibitors, treatment.

INTRODUCTION

Systemic mastocytosis (SM) is a rare hematologic disorder characterized by the infiltration of neoplastic mast cells in extracutaneous tissues, leading to a wide range of clinical manifestations. The disease spectrum ranges from indolent forms with minimal symptoms to aggressive variants with multiorgan involvement and poor prognosis. The prevalence of mastocytosis has been found to be 10–13 per 100,000 adult persons. A higher prevalence of 23.9 per 100,000 adult persons was found in a recent Swedish register study (1-4). The disease spectrum includes indolent systemic mastocytosis (ISM), smoldering SM (SSM), aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN) and mast cell leukemia (MCL) (5). The classification and prognosis of SM have been refined through the updated World Health Organization (WHO) and International Consensus Classification (ICC) guidelines, which emphasize molecular markers such as KIT mutations and their impact on targeted treatment approaches (6, 7). Given the variability in disease progression and severity, accurate classification and risk stratification are crucial for optimizing patient management. While ISM generally has a favorable prognosis with normal life expectancy, AdvSM subtypes are associated with significant morbidity and reduced survival. Recent advancements in molecular profiling and targeted therapies have significantly improved outcomes, but challenges remain in refining treatment strategies to address disease progression and resistance mechanisms. A diagnosis of SM requires one major and one minor criterion, or three minor criteria.

Risk assessment of patients with systemic mastocytosis

In 2022, updated classification and diagnostic criteria for SM were introduced by both the WHO and ICC (11, 12). Patients with indolent or smoldering SM often present at a younger age, are more frequently affected by skin lesions and gastrointestinal symptoms, and have a lower incidence of constitutional symptoms or hepatosplenomegaly (11). The WHO fifth edition (2022) introduced bone marrow mastocytosis (BMM), a new variant of SM not previously recognized in the 2016 classification or by the ICC. Bone marrow mastocytosis is defined by a neoplastic proliferation of mast cells restricted exclusively to the bone marrow. It is characterized by limited bone marrow infiltration, absence of skin lesions, normal or slightly elevated serum tryptase levels (<125 ng/mL), presentation at older age and a male predominance. Patients exhibiting isolated bone marrow involvement by neoplastic mast cells who additionally present with B-findings or elevated tryptase levels (≥125 ng/mL) demonstrate reduced progression-free survival (PFS) and overall survival (OS) compared to those with BMM or ISM lacking these clinical characteristics (13). Smoldering systemic mastocytosis is an established diagnostic subtype, positioned as an intermediate disease category defined by the presence of two or more "B-findings". Its prognosis is less favorable than that of indolent systemic mastocytosis but remains better compared to advanced systemic mastocytosis (AdvSM). Patients diagnosed with SSM typically present at an older age, exhibit higher mast cell burden in the bone marrow, elevated serum tryptase levels, and more frequently demonstrate palpable hepatosplenomegaly. Additionally, SSM is linked to decreased OS and carries a greater risk of progressing to ASM relative to other ISM variants (6). Aggressive systemic mastocytosis is defined by the presence of at least one "C-finding", which indicates organ dysfunction or damage directly caused by mast cell infiltration, alongside meeting standard SM diagnostic criteria. Clinical manifestations commonly include constitutional symptoms, hepatosplenomegaly associated with liver dysfunction, ascites, or portal hypertension, lymphadenopathy, significant anemia (hemoglobin <10 g/dL), thrombocytopenia (platelet count <100 × 10 9 /L) and leukopenia [ absolute neutrophil count (ANC) <1.0 × 10 9 /L resulting from bone marrow infiltration ]. Patients frequently present gastrointestinal symptoms due to mast cell infiltration, such as abdominal pain, nausea, vomiting, diarrhea, gastrointestinal bleeding, malabsorption, hypoalbuminemia and weight loss. Additionally, musculoskeletal involvement can cause bone pain, osteopenia, osteoporosis and pathological fractures (14, 15). The subsequent category, SM-AHN, is defined by fulfilling diagnostic criteria for both systemic mastocytosis (SM) and another distinct hematologic malignancy. Typically, SM-AHN exhibits a more aggressive clinical evolution compared to other SM subtypes. The associated hematologic neoplasm commonly includes chronic myelomonocytic leukemia (CMML), myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), acute myeloid leukemia (AML), B-cell lymphomas, or plasma cell disorder (16). Although SM-AHN is associated with inferior OS, the prognosis largely depends on the nature and aggressiveness of the accompanying hematological malignancy (17). Mast cell leukemia (MCL) represents the rarest and most aggressive subtype of systemic mastocytosis, characterized by rapid clinical progression and the highest mortality rate among all SM categories (18). This subtype represents less than 1% of all systemic mastocytosis cases. Mast cell leukemia is classified as an acute leukemia characterized by at least 20% neoplastic immature mast cells in the bone marrow and at least 10% in the peripheral blood. Mast cell leukemia may present as either primary disease or secondary leukemia following the progression of another SM subtype (19).

Associated mutations (concomitant molecular and genetic alterations) in systemic mastocytosis

Over 90% of typical ISM cases and approximately 70% of AdvSM cases harbor an acquired point mutation in the KIT gene. Additional somatic mutations involving genes such as ASXL1, RUNX1, SRSF2 and NRAS have been identified in around 90% of ASM patients (20). A recent next-generation sequencing study involving 150 patients showed that the KITD816V mutation was present in 75% of cases. Of these patients, 63 (42%) had either no mutations or only the KITD816V mutation without additional genetic alterations. In the remaining 87 patients, a total of 148 mutations beyond KIT were discovered: 46 (31%) patients had one mutation, 24 (16%) two mutations, 14 (9%) three mutations and three (2%) had four mutations. The most frequently mutated non-KIT genes included TET2 (29%), ASXL1 (17%), CBL (11%), SF3B1, DNMT3A and JAK2 (each 6%), U2AF1 (4%) and RUNX1 (3%). Mutations in ASXL1 and RUNX1 were associated with poorer survival outcomes, independently of patient age and WHO-defined subtype (21). Notably, these mutations were significantly more common in AdvSM, with 19 out of 27 identified non-KIT mutations predominantly occurring in patients with advanced forms of SM (14).

Prognostic scoring systems

Several prognostic scoring systems assist in classifying AdvSM based on clinical and molecular criteria. However, integrating these scoring systems into routine clinical practice often proves challenging. The Mayo Alliance Prognostic System (MAPS), introduced in 2018, consists of two models derived from a cohort of 580 patients evaluated at the Mayo Clinic between 1968 and 2015. The first model includes five clinical variables: AdvSM versus ISM or SSM, age above 60 years, platelet count below 150x10 9 /L, anemia below sex-adjusted normal ranges and serum alkaline phosphatase levels above normal. Survival directly correlates with the number of risk factors, demonstrating a favorable prognosis for patients with ≤ one risk factor (median survival not reached) and poor outcomes for those presenting four or five risk factors (median survival ranging between 9–27 months). This model demonstrated similar effectiveness for patients with AdvSM and ISM/SSM. The second model adds adverse molecular factors, specifically mutations in ASXL1, RUNX1, or NRAS genes, to the previously mentioned clinical variables. Median OS was 70 months in patients without adverse mutations compared to only 10 months for those carrying these mutations (22). To reduce subjectivity, a subsequent WHO-independent MAPS scoring system was developed, focusing exclusively on age, platelet count, sex-adjusted hemoglobin levels, elevated alkaline phosphatase and serum albumin. The Mayo Clinic group subsequently proposed the Mutation-Augmented Prognostic Scoring System (MAPSS), based on next-generation sequencing analysis of 27 relevant genes in a cohort of 150 patients with SM. Multivariate analysis identified several factors associated with decreased survival, including age >60 years, hemoglobin <10 g/dL or transfusion dependence, platelet count <150x10 9 /L, serum albumin <3.5 g/dL and the presence of an ASXL1 mutation. This scoring system allowed stratification of ASM patients into three distinct prognostic categories: low-risk, intermediate-risk, and high-risk, with corresponding median survival times of 86, 21 and five months, respectively (21). In 2019, the International Prognostic Scoring System for Mastocytosis (IPSM) was developed based on research by Sperr et al (23). This study used data from a cohort of 1639 patients with SM, categorizing them into three groups according to two factors: age above 60 years and elevated alkaline phosphatase levels. These groups were defined as low-risk (no risk factors), intermediate-1 (one risk factor) and intermediate-2 (two risk factors). In AdvSM patients (n=259), multivariate analysis revealed several independent prognostic factors associated with OS, including age ≥60 years, serum tryptase concentration ≥125 ng/mL, leukocyte count ≥16×10 9 /L, hemoglobin (Hb) ≤11 g/dL, platelet count ≤100×10 9 /L and the presence of skin involvement. Risk factors with a hazard ratio (HR) exceeding 1.50 were assigned one point each, whereas those with an HR of 0.50 or lower received −1 point. Summation of these scores allowed the definition of four distinct risk categories (23). The global prognostic score for mastocytosis (GPSM) further identified factors influencing disease progression (GPSM-PFS) and survival (GPSM-OS). For PFS, significant variables included platelet count ≤100 × 10 9 /L, serum β 2-microglobulin ≥2.5 µ g/mL, and baseline serum tryptase ≥125 µ g/L. For OS, prognostic variables were Hb ≤11 g/dL, serum alkaline phosphatase ≥140 IU/L and the presence of at least one mutation in the SRSF2, ASXL1, RUNX1, or DNMT3 genes. Both GPSM-PFS and GPSM-OS models effectively differentiated low-risk from high-risk patients in both discovery and validation patient cohorts (24). The Mutation-Adjusted Risk Score (MARS) was developed based on an analysis of 383 patients with AdvSM from the German Registry on Disorders of Eosinophils and Mast Cells (GRM). Multivariable analysis revealed several independent risk factors associated with OS: age above 60 years, Hb level below 10 g/dL, thrombocytopenia (platelet count <100 × 10 9 /L), the presence of at least one high-risk gene mutation (SRSF2, ASXL1 and/or RUNX1) and the presence of two or more high-risk gene mutations. The prognostic value of MARS was found to be independent of the WHO classification and was further validated in a separate patient cohort (25). A registry-based study evaluated 2607 patients enrolled in the European Competence Network on Mastocytosis (ECNM) and 575 patients from the GRM. This analysis revealed that many patients with AdvSM experience either misdiagnosis or delayed diagnosis, particularly if skin involvement or symptoms related to mast cell mediator release are absent at initial presentation. The study identified key serum markers with significant relevance, including tryptase, alkaline phosphatase, β 2-microglobulin, lactate dehydrogenase, albumin, vitamin B 12 and C-reactive protein. It concluded that comprehensive serum chemistry profiling is essential for accurate diagnosis and prognosis (26). Additionally, an expert panel from the ECNM and the American Initiative in Mast Cell Diseases (AIM) recommended using the IPSM and GPSM-PFS scoring systems for patients with non-aggressive SM, while for AdvSM, the IPSM, GPSM and MARS scores were advised (26).

Current therapeutic landscape

The management of SM requires a multifaceted approach tailored to disease subtype and symptom severity. Treatment strategies focus on symptom control, cytoreduction in advanced cases and targeted inhibition of key molecular pathways. Antihistamines, leukotriene receptor antagonists, and cromoglicic acid are commonly used to alleviate mediator-related symptoms. TKIs, such as midostaurin and avapritinib, have revolutionized treatment by directly inhibiting KIT D816V mutations, a key driver of mast cell proliferation. In refractory cases, cytoreductive therapies like cladribine and interferon-alpha may be employed. Omalizumab, an anti-IgE monoclonal antibody, has shown efficacy in controlling severe allergic manifestations. In advanced cases, hematopoietic stem cell transplantation remains a potential curative option, albeit with significant risks. Ongoing research aims to refine therapeutic strategies through novel TKIs and combination regimens.

1. Supportive therapy and symptom management

• Antihistamines (H1 and H2 blockers) – control mediator-related symptoms such as flushing, pruritus and gastrointestinal distress. Frequently used medications include (27):

- H1 blockers: Cetirizine (10 mg/day), Loratadine (10 mg/day), Fexofenadine (180 mg/day);

- H2 blockers: Ranitidine (withdrawn in many regions), Famotidine (20-40 mg/day);

- Leukotriene receptor antagonists ( e.g., Montelukast 10 mg/day): help reduce bronchoconstriction and gastrointestinal symptoms;

- Corticosteroids: used for acute symptom relief but avoided long-term due to side effects.

• Bone health treatment – Osteoporosis and fractures are common, particularly in AdvSM. Bisphosphonates ( e.g., Zoledronic acid 4 mg IV every 3-6 months), Peginterferon alfa-2a useful for patients with refractory bone pain and/or worsening bone mineral density on bisphosphonate therapy, anti-RANKL monoclonal antibody ( e.g., denosumab) used as second-line therapy for patients with bone pain not responding to bisphosphonates or for those who are not candidates for bisphosphonates because of renal insufficiency and calcium/vitamin D supplementation are recommended to prevent and treat bone loss (28).

• Epinephrine autoinjectors are ssential for patients at risk of anaphylaxis due to mast cell degranulation.

• Sodium cromolyn is a mast cell stabilizer used to prevent mast cell degranulation, which is particularly effective in managing gastrointestinal symptoms such as diarrhea and abdominal pain, as well as cutaneous symptoms like flushing and pruritus. It is typically administered orally at a dose of 200 mg four times daily, though dosing may be adjusted based on patient response (29-31).

• Omalizumab is a monoclonal anti-IgE antibody that has been successfully used in mastocytosis patients with severe mediator-related symptoms, including recurrent anaphylaxis and urticaria. It acts by blocking free IgE and reducing mast cell activation. The standard dosing regimen is 150-300 mg subcutaneously every 2-4 weeks, with adjustments based on total IgE levels and patient response (32-36).

2. Tyrosine kinase inhibitors (TKIs) and their mechanisms of action

• Midostaurin (100 mg/day) – targets KIT D816V, FLT3 and PDGFR α / β, disrupting mast cell proliferation. Approved by the FDA in 2017 for ASM, it showed a 60% overall response rate in an open-label Phase 2 study with 116 patients, though post-hoc analysis adjusted this to 28%. The median duration of response was 24.1 months, with a median OS of 28.7 months and PFS of 14.1 months. Significant reductions in MC burden and improvements in organ damage were noted. However, gastrointestinal AEs were common, requiring dose reductions in 41% and leading to discontinuation in 22% of patients. Subsequent analysis showed superior OS compared to cladribine but noted clonal evolution with new mutations during treatment (37-40).

• Avapritinib (200 mg/day) – This highly selective KIT D816V inhibitor exhibits a potent activity against neoplastic mast cells with fewer off-target effects than midostaurin. However, its use is associated with cognitive side effects, including memory impairment and confusion. It is a highly selective type 1 inhibitor targeting KIT D816V, demonstrating superior potency compared to midostaurin. In the phase 1 EXPLORER trial involving 86 patients with advanced systemic mastocytosis (AdvSM), avapritinib achieved an overall response rate (ORR) of 75% among 69 evaluable participants, with an even higher response rate of 83% observed in patients previously untreated with midostaurin. Additionally, 36% of patients attained complete remission or complete remission with partial hematologic recovery (CR/CRh) and 30% of subjects achieved molecular complete remission (molecular CR). Bone marrow assessments showed significant improvements. Over a median follow-up period of 23 months, disease progression occurred in 20% of patients, including 9% who developed acute myeloid leukemia (AML) (41). In phase 2 PATHFINDER study, avapritinib demonstrated efficacy similar to earlier findings, with an ORR of 75%, including 19% of patients achieving CR/CRh. Remarkably, 60% of patients experienced complete clearance of mast cells from the bone marrow and 93% of subjects showed significant reductions in serum tryptase levels. Cognitive side effects occurred but were reversible upon dose adjustment. However, notable non-hematologic and hematologic adverse events (AEs) were reported (42-44). A retrospective comparative analysis between avapritinib and best available therapy (BAT) demonstrated superior OS and longer treatment duration among patients treated with avapritinib. These findings further strengthen the position of avapritinib as the current standard-of-care therapy for patients with AdvSM. However, caution is recommended when prescribing avapritinib for patients with baseline thrombocytopenia, particularly those diagnosed with SM-AHN, due to an increased risk of hematologic AEs. Careful patient selection, individualized dosing and vigilant monitoring for cytopenias are crucial to optimize treatment outcomes and safety profiles in this specific subgroup (45).

• Bezuclastinib and elenestinib – next-generation TKIs currently under investigation. These agents aim to improve upon avapritinib's efficacy while minimizing adverse effects. Bezuclastinib, for example, has shown promise in reducing cognitive toxicity while maintaining strong inhibitory activity against KIT D816V (46, 47). Elenestinib (BLU-263) is a highly selective and potent small-molecule inhibitor targeting KITD816V, characterized by minimal central nervous system (CNS) penetration and administered via a convenient daily dosing schedule. In a phase 1 clinical trial, this drug demonstrated a favorable safety and tolerability profile. Currently, elenestinib is being evaluated in the ongoing randomized double-blind phase 2/3 HARBOR trial (NCT04910685) involving patients with ISM. After 12 weeks of treatment, elenestinib showed significant improvement in total symptom scores and markers of mast cell disease burden. Patients treated with elenestinib at doses of 25 mg, 50 mg and 100 mg experienced notable reductions from baseline in serum tryptase levels (−15.4%, −50.9% and −68.4%, respectively, versus 3.3% with placebo) and KITD816V variant allele frequency (VAF) (−37.5%, −70.3% and −77.0%, respectively, compared to −2.5% with placebo). Additionally, elenestinib is being studied in the ongoing phase 1/2 AZURE trial (NCT05609942) for patients with AdvSM, either as monotherapy or combined with azacitidine when an AHN requires treatment (47). Bezuclastinib (CGT9486) is a highly potent and selective inhibitor targeting KIT D816V, with minimal off-target kinase activity. Due to its low CNS penetration, remarkable selectivity and favorable pharmacokinetic profile, bezuclastinib is designed to minimize both systemic and CNS-related adverse effects. Currently, bezuclastinib is being assessed in the Phase 2 APEX clinical trial (NCT04996875), which includes approximately 140 adult patients diagnosed with AdvSM according to WHO criteria, presenting with organ damage related to SM and baseline serum tryptase levels ≥20 ng/mL. The trial includes both patients naive to and previously treated with TKIs. As of April 2023, enrollment was complete for Part 1 of the trial, comprising 33 AdvSM patients. Preliminary data from 32 evaluable patients demonstrated an ORR of 56%, with a 75% ORR specifically noted, accompanied by significant improvements in biomarkers indicative of mast cell disease activity. Specifically, 94% of patients experienced at least a 50% reduction in serum tryptase levels, 93% achieved at least a 50% reduction in KIT D816V variant allele frequency (VAF) and 97% had at least a 50% decrease in bone marrow mast cell infiltration. Most AEs observed were mild, reversible and manageable. The most commonly reported AEs were hair color changes (34%), thrombocytopenia (22%), elevated transaminase levels (22%), neutropenia (19%) and taste disturbances (19%). Importantly, no cognitive impairment or bleeding complications were observed in this patient cohort (46, 48, 49).

3. Cladribine and other cytoreductive agents

• Cladribine (0.13-0.17 mg/kg/day for five days per cycle, repeated every 4-6 weeks) – used in ASM or refractory cases; reduces mast cell burden but requires infection monitoring (50-52).

• Hydroxyurea and interferon-alpha – considered in cases where TKIs are ineffective (53, 54).

4. Allogeneic hematopoietic stem cell transplantation (allo-HSCT)

Allogeneic stem cell transplantation (ASCT) is considered a potentially curative therapy for patients with AdvSM, though most available data relate specifically to SM-AHN. The largest retrospective study included 57 patients (38 with SM-AHN, seven with ASM and 12 with MCL) and demonstrated varied outcomes. Among SM-AHN patients, ASCT showed promising results, with a three-year OS of 74%; however, relapse was observed, and five patients eventually succumbed to progressive disease. Patients with MCL experienced notably high rates of transplant-related mortality and primary treatment resistance, reflected by a much lower three-year OS rate of 17%. For ASM patients, the three-year OS was intermediate at 43%. Overall, despite being considered potentially curative, ASCT outcomes differ significantly depending on disease subtype, with particularly challenging outcomes observed in patients diagnosed with MCL (55).

Consensus guidelines addressing the role of ASCT in AdvSM recommend reducing mast cell burden through KIT inhibition or chemotherapy before proceeding to transplantation, especially in patients with extensive mast cell infiltration. This approach is particularly important in patients undergoing ASCT for SM-AHN or aggressive subtypes. Notably, recent follow-up data from a phase 1 study evaluating avapritinib demonstrated favorable two-year OS rates of 100% in ASM, 92% in MCL and 67% in SM-AHN, outcomes which compare positively with historical ASCT results, except in cases of SM-AHN. Given these findings, while ASCT remains a valuable option, especially for eligible SM-AHN patients, targeted therapy with selective KIT inhibitors like avapritinib may offer comparable or even superior survival outcomes in certain AdvSM subgroups. Consequently, ASCT continues to be prioritized primarily for suitable SM-AHN patients, for whom targeted therapies alone may not adequately control disease progression.

Emergency treatment for mast cell degranulation crisis patients experiencing acute mast cell degranulation crises require immediate intervention with:

- epinephrine (0.3-0.5 mg IM every 5-15 minutes as needed) for severe anaphylaxis;

- intravenous antihistamines: diphenhydramine (25-50 mg IV), ranitidine or famotidine (IV, as available);

- systemic corticosteroids: hydrocortisone (100-200 mg IV) to reduce delayed reactions;

- intravenous fluids, used to o counteract hypotension and stabilize cardiovascular function;

- Bronchodilators: nebulized albuterol for bronchospasm (27).

CONCLUSION

The therapeutic landscape of SM has undergone remarkable evolution, driven primarily by the introduction and advancement of TKIs. The targeted inhibition of mutated KIT kinase has offered unprecedented opportunities for improved disease control, symptomatic relief, and enhanced quality of life for patients. Despite these advancements, significant therapeutic challenges persist, particularly within the aggressive subsets of SM such as SM-AHN and MCL. These forms of SM continue to exhibit limited responsiveness to standard therapies, thereby underscoring an urgent need for novel treatment modalities. Emerging therapeutic strategies hold promise, including the exploration of next-generation TKIs with superior potency, specificity, and tolerability profiles. Furthermore, combination therapies involving TKIs alongside other targeted agents, immunotherapeutic approaches, or conventional chemotherapy warrant rigorous evaluation in clinical trials to determine optimal treatment regimens. Such multidrug approaches could potentially overcome mechanisms of resistance frequently encountered in advanced SM cases. Personalized medicine, leveraging detailed molecular characterization and genomic profiling, represents another pivotal frontier in SM management. Clinicians are encouraged to integrate advanced molecular diagnostic tools routinely in clinical practice, enabling tailored therapeutic decisions based on individual patient profiles and disease-specific mutations. An integrated approach combining precise molecular diagnostics, innovative targeted therapies, and supportive care measures is essential to enhance clinical outcomes comprehensively. Ultimately, future research endeavors must prioritize the development and validation of novel therapeutics, including targeted agents beyond KIT inhibitors, epigenetic modulators, and immunotherapy combinations. Collaborative efforts among clinicians, researchers and the pharmaceutical industry will be instrumental in accelerating these advances. Continued investment in translational research, alongside robust clinical trials focusing on efficacy, safety, and patient-reported outcomes, is crucial to significantly improve survival rates, disease control and overall quality of life for patients with systemic mastocytosis.

TABLE 1.

Diagnostic criteria for systemic mastocytosis

TABLE 2.

Classification of systemic mastocytosis (6, 8)

TABLE 3.

B- and C-findings in systemic mastocytosis (6, 10, 11)

TABLE 4.

Outcomes of midostaurin and avapritinib clinical trials in advanced systemic

TABLE 5.

Adverse effects and management of tyrosine kinase inhibitors (TKIs)

TABLE 6.

Summarized criteria for treatment response in systemic mastocytosis (56)

Authors’ contributions

conceptualization – Delia Soare; methodology – Delia Soare and Horia Bumbea; investigation – Delia Soare; resources – Delia Soare; writing (original draft preparation, review and editing) – Delia Soare; project administration – Delia Soare, Poliana Leru and Horia Bumbea. All authors have read and agreed to the published version of the manuscript.

Institutional review board

The present paper was elaborated in accordance with the Declaration of Helsinki and Good Clinical Practices. The paper was approved by the Ethics Committee of Emergency University Hospital of Bucharest (protocol code 88221/31.12.2024).

Informed consent

As the review relied exclusively on published or publicly available data, ethical approval and informed consent were not required.

Conflicts of interest

None declared.

Financial Support

None declared.