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. 2024 Jun 11;8(11):2890-2900.
doi: 10.1182/bloodadvances.2024012756.

Serum chemistry profiling and prognostication in systemic mastocytosis: a registry-based study of the ECNM and GREM

Johannes Lübke  1 , Alicia Schmid  1 , Deborah Christen  2   3 , Hanneke N G Oude Elberink  4 , Lambert F R Span  5 , Marek Niedoszytko  6 , Aleksandra Gorska  6 , Magdalena Lange  7 , Karoline V Gleixner  8   9 , Emir Hadzijusufovic  8   9   10 , Alex Stefan  11 , Irena Angelova-Fischer  12 , Roberta Zanotti  13 , Massimiliano Bonifacio  13 , Patrizia Bonadonna  14 , Khalid Shoumariyeh  15   16 , Nikolas von Bubnoff  15   16   17 , Sabine Müller  18 , Cecelia Perkins  19 , Chiara Elena  20 , Luca Malcovati  20 , Hans Hagglund  21 , Mattias Mattsson  21 , Roberta Parente  22 , Judit Varkonyi  23 , Anna Belloni Fortina  24 , Francesca Caroppo  24 , Knut Brockow  25 , Alexander Zink  25 , Christine Breynaert  26 , Toon Leven  26 , Akif Selim Yavuz  27 , Michael Doubek  28 , Vito Sabato  29 , Tanja Schug  30 , Karin Hartmann  31   32 , Massimo Triggiani  22 , Jason Gotlib  19 , Olivier Hermine  33 , Michel Arock  34 , Hanneke C Kluin-Nelemans  5 , Jens Panse  2   3 , Wolfgang R Sperr  8   9 , Peter Valent  8   9 , Andreas Reiter  1 , Juliana Schwaab  1
Affiliations

Serum chemistry profiling and prognostication in systemic mastocytosis: a registry-based study of the ECNM and GREM

Johannes Lübke et al. Blood Adv. .

Abstract

Certain laboratory abnormalities correlate with subvariants of systemic mastocytosis (SM) and are often prognostically relevant. To assess the diagnostic and prognostic value of individual serum chemistry parameters in SM, 2607 patients enrolled within the European Competence Network on Mastocytosis and 575 patients enrolled within the German Registry on Eosinophils and Mast Cells were analyzed. For screening and diagnosis of SM, tryptase was identified as the most specific serum parameter. For differentiation between indolent and advanced SM (AdvSM), the following serum parameters were most relevant: tryptase, alkaline phosphatase, β2-microglobulin, lactate dehydrogenase (LDH), albumin, vitamin B12, and C-reactive protein (P < .001). With regard to subvariants of AdvSM, an elevated LDH of ≥260 U/L was associated with multilineage expansion (leukocytosis, r = 0.37, P < .001; monocytosis, r = 0.26, P < .001) and the presence of an associated myeloid neoplasm (P < .001), whereas tryptase levels were highest in mast cell leukemia (MCL) vs non-MCL (308μg/L vs 146μg/L, P = .003). Based on multivariable analysis, the hazard-risk weighted assignment of 1 point to LDH (hazard ratio [HR], 2.1; 95% confidence interval [CI], 1.1-4.0; P = .018) and 1.5 points each to β2-microglobulin (HR, 2.7; 95% CI, 1.4-5.4; P = .004) and albumin (HR, 3.3; 95% CI, 1.7-6.5; P = .001) delineated a highly predictive 3-tier risk classification system (0 points, 8.1 years vs 1 point, 2.5 years; ≥1.5 points, 1.7 years; P < .001). Moreover, serum chemistry parameters enabled further stratification of patients classified as having an International Prognostic Scoring System for Mastocytosis-AdvSM1/2 risk score (P = .027). In conclusion, serum chemistry profiling is a crucial tool in the clinical practice supporting diagnosis and prognostication of SM and its subvariants.

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Conflict of interest statement

Conflict-of-interest disclosure: The authors declare no conflict of interest within this study and declare the following conflict of interests outside of this study. D.C. received consulting fees from Blueprint Medicines, Novartis, Pfizer and BeiGene, honoraria from Blueprint Medicines, Novartis and AstraZeneca and travel support from Amgen and Janssen. H.N.G.O.E. serves on the advisory board of, and received honoraria from, Blueprint Medicines. R.Z. serves on the advisory board of, and received honoraria from, Blueprint Medicines, Novartis, and Cogent Biosciences. P.B. serves on the advisory board of, and received honoraria from, Blueprint Medicines and Novartis. K.S. serves on the advisory board of, and received honoraria from, Blueprint Medicines and Novartis; and is a member of the study steering committee for the CGT9486 Study of Cogent Biosciences. C.E. serves on the advisory board of, and received honoraria from, Blueprint Medicines and Gilead. K.B. serves on the advisory board of, and received honoraria from, Blueprint Medicines and Novartis. V.S. serves on the advisory board of Blueprint Medicines and Novartis. K.H. received research funding from ThermoFisher; and serves on the advisory board of, and received honoraria from ALK-Abello, Allergopharma, Blueprint, Deciphera, Leo Pharma, Menarini, Novartis, Pfizer, Sanofi, Takeda, and ThermoFisher. M.T. serves on the advisory board of, and received honoraria from, Blueprint Medicines, Novartis, and Cogent. J.G. received research grants (funds for administration of clinical trials) from Novartis, Blueprint Medicines, and Cogent Biosciences; serves on the advisory board of, and received honoraria from, Blueprint Medicines, Novartis, Deciphera, and Cogent Biosciences; and received reimbursement of travel expenses from Novartis and Blueprint Medicines. M.A. received research grants from Blueprint Medicines; and serves on the advisory board of, and received honoraria from, AB Science, Blueprint Medicines, Novartis, and ThermoFisher. H.C.K.-N. served as a nonpaid independent monitoring committee member of the avapritinib study. J.P. serves on the advisory board of, and received honoraria from, Blueprint Medicines, Novartis, and Deciphera; is a member of the study steering committee for the HARBOR Study of BLU-263 for indolent systemic mastocytosis. W.R.S. serves on the advisory board of, and received honoraria from, AbbVie, Novartis, Bristol Myers Squibb/Celgene, Pfizer, Teva, and Stemline. P.V. serves on the advisory board of, and received honoraria from, Novartis, Blueprint, Bristol Myers Squibb/Celgene, Pfizer, Incyte, AOP Orphan, Cogent, and Stemline. A.R. is a member of the study steering committee for the global trial of midostaurin in AdvSM (Novartis); is a member of the response adjudication committee for studies of avapritinib in AdvSM (Blueprint Medicines), and the study steering committee for the phase 2 trial of ripretinib in AdvSM (Deciphera Pharmaceuticals); has received funding for the conduct of these trials; and has received honoraria and reimbursement of travel expenses from Novartis, Blueprint Medicines, and Deciphera Pharmaceuticals. J.S. serves on the advisory board of, and received honoraria from, Blueprint Medicines and Novartis. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
ECNM. Violin plots on the distribution of various serum chemistry markers throughout the systemic mastocytosis subtypes. The P values refer to the Mann-Whitney U test. AdvSM, advanced systemic mastocytosis; ASM, aggressive systemic mastocytosis; BMM, bone marrow mastocytosis; ISM, indolent systemic mastocytosis; MCL, mast cell leukemia; SM-AHN, systemic mastocytosis with an associated hematologic neoplasm; SSM, smoldering systemic mastocytosis.
Figure 2.
Figure 2.
ECNM. (A) Kaplan-Meier estimates of overall survival (OS) in patients with systemic mastocytosis (SM) with 0 points, 1 to 2 points, vs 3 to 5 points by assignment of 1 point each to serum tryptase ≥125 μg/L, alkaline phosphatase (AP) ≥150 U/L, lactate dehydrogenase (LDH) ≥260 U/L, albumin ≤34 mg/dL, and β2-microglobulin ≥2.5 mg/L; apower =1.000, bpower = 1.000. (B) Kaplan-Meier estimates of OS in patients with SM based on the multivariable model with 0 points, 1.5 points, vs ≥1.5 points by assignment of 1 point to LDH ≥260 U/L, and 1.5 points each to albumin ≤34 mg/dL and β2-microglobulin ≥2.5 mg/L; cpower = 1.000, dpower = 0.998. (C) Kaplan-Meier estimates of OS in patients weighted as International Prognostic Scoring System for Mastocytosis-advanced SM1/2 with 0 points vs ≥1 points. epower = 0.441. The P values refer to the log-rank test.
Figure 3.
Figure 3.
ECNM. (A) Pearson correlation of the lactate dehydrogenase (LDH) levels with other disease parameters. ∗Significant P values adjusted by Holm-Bonferroni method. (B) Kaplan-Meier estimates of overall survival (OS) in patients with systemic mastocytosis (SM) stratified according to LDH levels (260-400 U/L vs ≥400 U/L); apower = 0.995. (C) Kaplan-Meier estimates of OS in patients with AdvSM according to LDH levels (260-400 U/L vs ≥400 U/L); bpower = 0.720. The P values refer to the log-rank test. ANC, absolute neutrophil count; β2MG, β2-microglobulin; Eos, eosinophil count; Hb, hemoglobin; KIT, KIT D816V allele burden; MC-I, mast cell infiltration; Monos, monocyte count; Plt, platelets; WBC, white blood cells.
Figure 4.
Figure 4.
GREM. (A) Violin plots on the distribution of the alkaline phosphatase (AP) subtypes in 24 patients with advanced systemic mastocytosis (AdvSM). (B) Pearson and Spearman correlations of the AP levels with other (liver and bone marrow) specific parameters. ∗Significant P values adjusted by Holm-Bonferroni method. (C) Kaplan-Meier estimates of overall survival in patients with AdvSM stratified according to AP levels ≥150 U/L/<150 U/L. apower = 0.974. Alb, albumin; ASAT, aspartate aminotransferase; Bili, bilirubin; MC-I, BM mast cell infiltration; O.lysis, osteolysis; O.poris, osteoporosis.
Figure 5.
Figure 5.
GREM. (A) Pearson correlation of the vitamin B12 levels with other disease specific parameters. ∗Significant P values adjusted by Holm-Bonferroni method. (B) Receiver operating characteristic-curve for optimal cutoff assessment regarding diagnosis of indolent systemic mastocytosis (ISM) vs advanced SM (AdvSM). (C) Kaplan-Meier estimates of overall survival (OS) in patients with SM according to vitamin B12 levels (<800 U/L vs ≥800-1800 U/L vs ≥1800 U/L); apower = 0.948, bpower = 0.627. (D) Kaplan-Meier estimates of OS in patients with AdvSM (≥2000 U/L vs <2000 U/L); cpower = 0.586. The P values refer to the log-rank test. ANC, absolute neutrophil count; β2MG, β2-microglobulin; Eos, eosinophil count; Hb, hemoglobin; KIT, KIT D816V allele burden; MC-I, mast cell infiltration; Monos, monocyte count; Plt, platelets; WBC, white blood cells.
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