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Systemic Mastocytosis (SM)

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Risk Factors

Numerous studies over the years have identified factors that increase the risk for the development of systemic mastocytosis (SM) and factors that increase the risk for disease progression. Some of the risk factors found to be associated with different subcategories of SM are given below.

A recent study1 analyzed 1639 patients from the European Competence Network on Mastocytosis (ECNM) registry and identified age of 60 years or older and serum alkaline phosphatase (ALP) level of 100 U/L or higher as factors associated with disease progression in patients who had non-advanced mastocytosis (cutaneous mastocytosis, indolent SM, or smoldering SM). Elevated levels of ALP may reflect mastocytosis-mediated organ damage in the bones, liver, or both.

For patients with advanced mastocytosis (aggressive SM, SM with associated hematological neoplasm, or mast cell leukemia), factors associated with disease progression were found to be age of 60 years or older, serum tryptase level of 125 ng/mL or higher, leukocyte count of 16 x 109/L or higher, hemoglobin level of 11 g/dL or lower, platelet count of 100 x 109/L or lower, and absence of skin involvement.1 

In a 2009 study from the Spanish Network on Mastocytosis in adults with indolent SM, an increased serum β2-microglobulin level and the presence of a KIT mutation (KIT D816V) in all hematopoietic lineages were strong risk factors for transformation into a more aggressive form of SM.2

Increased plasma levels of circulating CD25 (or IL-2R) have also been associated with inferior survival in patients with advanced or indolent SM.3

Mutations in the genes ASXL1, RUNX1, NRAS, and SRSF2 in patients with advanced SM have been found to be associated with severe and aggressive disease, short survival, and a poor response rate.4

A 2018 study of 580 patients with SM seen at the Mayo Clinic between 1968 and 2015 identified 5 easily accessible clinical parameters as independent risk factors for inferior patient survival. These included age older than 60 years, advanced SM, thrombocytopenia (platelet count＜150 x 109/L), hemoglobin level below the sex-adjusted normal range, and increased serum ALP.  In addition, mutations in the ASXL, RUNX1, and NRAS genes were independently associated with inferior survival.5,6

Another study, of 383 patients with advanced SM, identified risk factors for inferior survival. These were age of 60 years, anemia (hemoglobin level＜10 g/dL), platelet count ＜100 x 109/L, the presence of 1 high-molecular-risk gene mutation (SRSF2, ASXL1, and/or RUNX1), and the presence of 2 or more high-molecular-risk gene mutations.7

In a study of 376 patients with indolent, smoldering, or aggressive SM, the survival of patients with smoldering SM was inferior to the survival of patients with indolent SM and was associated with a higher prevalence of such risk factors as older age, anemia, thrombocytopenia, and high serum levels of ALP in the patients with smoldering SM.8

References

  1. Sperr WR, Kundi M, Alvarez-Twose I, et al. International prognostic scoring system for mastocytosis (IPSM): a retrospective cohort study. Lancet Haematol. 2019;6(12):e638-e649. doi:10.1016/S2352-3026(19)30166-8
  2. Escribano L, Alvarez-Twose I, Sánchez-Muñoz L, et al. Prognosis in adult indolent systemic mastocytosis: a long-term study of the Spanish Network on Mastocytosis in a series of 145 patients. J Allergy Clin Immunol. 2009;124(3):514-521. doi:10.1016/j.jaci.2009.05.003
  3. Pardanani A, Finke C, Abdelrahman RA, Lasho TL, Hanson CA, Tefferi A. Increased circulating IL-2Rα (CD25) predicts poor outcome in both indolent and aggressive forms of mastocytosis: a comprehensive cytokine-phenotype study. Leukemia. 2013;27(6):1430-1433. doi:10.1038/leu.2013.11
  4. Jawhar M, Schwaab J, Schnittger S, et al. Additional mutations in SRSF2, ASXL1 and/or RUNX1 identify a high-risk group of patients with KIT D816V(+) advanced systemic mastocytosis. Leukemia. 2016;30(1):136-143. doi:10.1038/leu.2015.284 
  5. Pardanani A, Shah S, Mannelli F, et al. Mayo alliance prognostic system for mastocytosis: clinical and hybrid clinical-molecular models. Blood Adv. 2018;2(21):2964-2972. doi:10.1182/bloodadvances.2018026245
  6. Pardanani A, Lasho TL, Reichard KK, Hanson CA, Tefferi A. World Health Organization class-independent risk categorization in mastocytosis. Blood Cancer J. 2019;9(3):29. doi:10.1038/s41408-019-0189-5
  7. Jawhar M, Schwaab J, Álvarez-Twose I, et al. MARS: mutation-adjusted risk score for advanced systemic mastocytosis. J Clin Oncol. 2019;37(31):2846-2856. doi:10.1200/JCO.19.00640
  8. Tefferi A, Shah S, Reichard KK, Hanson CA, Pardanani A. Smoldering mastocytosis: survival comparisons with indolent and aggressive mastocytosis. Am J Hematol. 2019;94(1):E1-E2. doi:10.1002/ajh.25302

Reviewed by Kyle Habet, MD, on 4/24/2022.

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