A new era of serum biomarkers for diagnosis and prognostication of systemic mastocytosis
In recent years, several tools have improved systemic mastocytosis (SM) assessment, but there is still a critical need for more precise serum biomarkers to improve diagnosis, subvariant classification and risk stratification. Lübke et al. rigorously evaluated key serum chemistry parameters for diagnosis, prognosis and organ damage in SM, drawing on newly available patient registries.1
Classification of SM
SM is a complex disorder characterised by the accumulation of neoplastic mast cells across multiple organ systems. It is classified into advanced (AdvSM) and non-advanced (non-AdvSM) forms, each with subvariants telling a different story.2 These subvariants come with highly varied prognoses, ranging from a few years of survival to over 10 years, but accurately predicting outcomes remains a significant challenge with current methods.
Challenges in accurate classification and prognostication of SM
A critical challenge in managing SM is the accurate classification of its subvariants, given its varied presentations and potential for severe organ damage such as in AdvSM, where patients present with C-findings.3 Appropriate classification using serum chemistry parameters not only influences risk stratification but also impacts treatment decisions.1 The revised 2022 WHO/ICC classification criteria emphasise the need for more refined markers.
Serum chemistry parameters offer a promising avenue for stratification and prognosis. While serum tryptase and KIT D816V are well-established markers, additional parameters such as alkaline phosphatase (AP), hypoalbuminaemia and β2-microglobulin (part of the Global Prognostic Score for SM [GPSM]) show potential. However, systematic analyses of these biomarkers are limited. Lübke et al. aimed to address this paucity of data by examining these markers in patients from the European Competence Network on Mastocytosis (ECNM) and the German Registry on Eosinophils and Mast Cells (GREM).1
Markers for differentiating subvariants
In this study, serum tryptase was highlighted as the most specific marker, in line with previous literature and analyses.4 To find out more about tryptase, click here. Lübke et al. found a median tryptase level of ≥135 µg/L in patients with AdvSM, compared with 202 µg/L in smouldering systemic mastocytosis and a range of 21–32 µg/L in indolent systemic mastocytosis (ISM) and bone marrow mastocytosis. The optimal cut-offs for differentiation between ISM and AdvSM for various serum parameters have been described in Table 1.1
Table 1. Optimal cut-off values for discrimination between ISM and AdvSM
Additionally, a baseline lactate dehydrogenase (LDH) level ≥260 U/L was associated with the presence of an associated haematological neoplasm (AHN), found in 33% of AHN patients (77/236) vs 12% of non-AHN patients (199/1715; P < 0.001), and linked to shorter overall survival (OS). These findings underscore the potential importance of these serum chemistry parameters in identifying SM subvariants and enabling accurate prognostication.1
Markers correlated to OS and risk stratification
The aforementioned elevated tryptase levels observed in non-AdvSM, specifically levels ≥125 µg/L, are associated with reduced OS compared with those with lower tryptase levels (9.7 years vs 15.1 years; P = 0.045), which corroborates the presence of advanced disease.1
The inclusion of data from the GREM database enabled the authors to analyse markers such as AP isoenzymes, vitamin B12 and creatinine-adjusted β2-microglobulin, not available in the ECNM database. These markers were associated with worse outcomes, with cut-offs of AP at ≥150 U/L, vitamin B12 at ≥2000 U/L and β2-microglobulin at ≥2.5 mg/L associated with reduced OS.1
Prognostication regarding OS was determined in 649 SM patients with a diagnosis of SM. A points system using tryptase, AP, β2-microglobulin, LDH and albumin levels discriminated patients with worse OS well (P < 0.001). These results highlight the value of combining different serum chemistry profiles for risk stratification and the potential of this approach to guide treatment decisions for high-risk patients.1
Integrating biomarkers for assessment of SM and AHN
Lübke et al. suggested that careful cross-assessment of serum tryptase (reflecting the mast cell component), LDH (along with monocytes/eosinophils, indicating the AHN component) and KIT D816V variant allele frequency (potentially relevant to both components) can provide a rapid and comprehensive evaluation of how much the SM or the AHN contributes to organ damage, such as cytopenias and liver dysfunction.1 This approach aligns with recent analyses recommending additional immunohistochemical studies to identify under-recognised SM in AHNs when KIT mutations are detected by molecular assays.5
Conclusion
Based on data obtained from two registries, Lübke et al. have established various serum chemistry parameters for diagnosis, classification, risk stratification and prognostication in SM. Further research is needed to validate these findings and refine their use in clinical practice. Their integration into the diagnostic and prognostic processes for SM offers a promising path towards more accurate and personalised patient care. This paper highlights the potential of these biomarkers to transform SM management, aligning with the ongoing advancements in our understanding of this complex disease.1
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