Erum Naqvi obtained her Ph.D. in Molecular Medicine from Hannover Medical School (Germany) after completing her Masters in Biomedical Science and Bachelors in Microbiology from University of Delhi (India). She has several years of experience as a science writer.
Systemic mastocytosis (SM) is a progressive neoplastic disorder in which adult patients have a shorter life expectancy than that of the general population. In general, most deaths occur within the first 3 to 5 years after diagnosis. However, the prognosis of patients with SM varies due to the variable clinical phenotype, which ranges from indolent forms to aggressive subtypes that rapidly progress to leukemia.
Younger patients or those with mild symptoms tend to have a better prognosis with little or no disease progression. In contrast, older patients and those with extensive and systemic disease involving other organ systems have a poorer prognosis, with shorter survival times of a few years or less.2
Thus, correct classification of patients with SM is important because it serves as a major tool to establish prognosis; this may then be used to determine the course of treatment.
World Health Organization Classification System for Systemic Mastocytosis
Systemic mastocytosis is classified into 5 subcategories based on the 2016 World Health Organization (WHO) classification system: indolent SM (ISM), smoldering SM (SSM), aggressive SM (ASM), SM with an associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL).3
A 2009 retrospective study of 342 adult patients with SM, conducted at Mayo Clinic between 1976 and 2007, validated the prognostic value of the WHO classification system for SM.4
The study found that patients with ISM had a significantly better prognosis than that of ASM and SM-AHN patients. The life expectancy of patients with ISM was found to be similar to that of the general US population. Additionally, the study found that leukemic transformation rarely occurred in patients with ISM. In contrast, SM-AHN and ASM patients were found to have poor prognoses, with median survival times of 24 and 41 months, respectively. Patients with MCL had the poorest prognosis, with a median survival of 2 months.4
This prognostic data are clinically relevant and can be useful for guiding treatment decisions in patients with SM.
Indolent Systemic Mastocytosis
In the Mayo Clinic study from 2009, the median overall survival (OS) of patients with ISM was 198 months, which was similar to that of the general population.4
However, in a recent Danish population-based matched cohort study, patients with ISM had a significantly increased risk of death compared to the general population.5
In a European Competence Network on Mastocytosis (ECNM) cohort, the median OS of patients with ISM was found to be 28.4 years.6
A long-term study of the Spanish Network on Mastocytosis found that patients with ISM had a low rate of disease progression (3%), with increased serum β2-microglobulin levels and the presence of a KIT D816V mutation identified as predictors of disease progression.7
Smoldering Systemic Mastocytosis
In a recent study, the median OS of patients with SSM was found to be significantly lower than that of patients with ISM. This was explained by a higher prevalence of risk factors in patients with SSM, including older age and anemia.8
Aggressive Systemic Mastocytosis
In the 2009 Mayo study, the overall median OS in patients with ASM was 41 months, and leukemic transformation occurred in 5% of cases.4 In the ECNM registry data, the median OS for patients with ASM was 5.7 years.9
Systemic Mastocytosis With an Associated Hematological Neoplasm
In the 2009 Mayo Clinic study, the median OS for patients with SM-AHN was 24 months, with leukemic transformation occurring in 13% of cases.4 In the ECNM registry data, the median OS for patients with SM-AHN was 2.9 years.9
Mast Cell Leukemia
In the 2009 study, patients with MCL were found to have a very poor prognosis, with a very short median OS of only 2 months.4 In the ECNM registry data, the median OS for patients with MCL was 1.9 years.9
Prognostic Score Systems
Over the years, several models have been developed that risk stratify patients with SM using clinical or molecular parameters and, thus, serve as useful tools to establish prognosis.
International Prognostic Scoring System for Mastocytosis
A 2019 study used data from a large cohort of patients in the ECNM registry to identify independent prognostic variables that were predictive of disease transformation and overall survival in patients with non advanced mastocytosis (age ≥60 years and serum alkaline phosphatase [ALP] ≥100 U/L) and advanced mastocytosis (tryptase >125 ng/mL, leukocyte count ≥16 × 109/L, hemoglobin ≤11 g/dL, platelet count ≤100 × 109/L, and skin involvement) to establish a simple prognostic score system referred to as the International Prognostic Scoring System for Mastocytosis (IPSM) model.9
WHO-Dependent Mayo Alliance Prognostic Systems
In a recent study, 2 complementary prognostic risk models for SM were developed, referred to as the Mayo Alliance Prognostic Systems (MAPS). One model, the clinical prognostic model, was solely based on easily accessible clinical variables (age >60 years, WHO-defined SM type, thrombocytopenia <150 x 109/L, hemoglobin level adjusted below the sex-adjusted normal range, and increased serum ALP), while the other model, the hybrid clinical-molecular prognostic model, included the presence of adverse mutations (ASXL/RUNX1/NRAS) along with the clinical parameters.10
Based on the clinical prognostic model, patients were grouped as those with 1 risk factor (median OS not reached), those with 2 risk factors (median OS, 148 months), those with 3 risk factors (median OS, 56 months), those with 4 risk factors (median OS, 27 months), and those with 5 risk factors (median OS, 9 months).10
The hybrid clinical-molecular model stratified patients with SM into low-risk (median OS, 198 months), intermediate-1-risk (median OS, 85 months), intermediate-2-risk (median OS, 36 months), and high-risk (median OS, 12 months) groups.10
WHO-Independent Mayo Alliance Prognostic Systems
The previous prognostic models were dependent on the WHO SM classification system, which can be difficult to employ in practice. Thus, a recent follow-up study developed a WHO class-independent risk model for mastocytosis (WHO-independent MAPS). It is based on the widely available clinical and laboratory parameters: age >60 years, platelets <150 x 109/L, anemia (hemoglobin < sex-adjusted lower normal range), increased serum ALP level, and serum albumin <3.5 g/dL.11
The SM patients were stratified into 5 risk groups: low-risk (0 points; median OS not reached), intermediate-1-risk (1-2 points; median OS, 291 months), intermediate-2-risk (3 points; median OS, 99 months), high-risk (4-6 points; median OS, 38 months), and very high-risk (7-8 points; median OS, 8 months).11
Mutation-Adjusted Risk Score Model for Prognosis
The presence of mutations in additional genes (ASXL1, RUNX1, NRAS, and SRSF2) have been found to be prognostically detrimental in patients with advanced SM, often resulting in more severe and aggressive disease with poor response rates and short survival times. Thus, assessing the molecular profile of patients with SM may be useful in establishing prognosis.12,13
The mutation-adjusted risk score (MARS) for advanced SM, derived from the German registry on Disorders of Eosinophils and Mast Cells, is a validated, 5-parameter, WHO-independent prognostic score that defines 3 risk groups in patients with advanced SM. It integrates the following risk factors to identify low- (median OS not reached), intermediate- (median OS, 3.9 years), and high-risk (median OS, 1.9 years) patient groups: age >60 years, anemia (hemoglobin <10 g/dL), thrombocytopenia (platelets <100 x 109/L), and the presence of 1 or ≥2 high-risk gene mutations (ASXL1/SRSF2/RUNX1).14
- Pardanani A. Systemic mastocytosis in adults: 2021 update on diagnosis, risk stratification and management. Am J Hematol. 2021;96(4):508-525. doi:10.1002/ajh.26118
- Systemic mastocytosis. Genetic and Rare Diseases Information Center (GARD). Accessed April 11, 2022.
- Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-2405. doi:10.1182/blood-2016-03-643544
- Lim KH, Tefferi A, Lasho TL, et al. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood. 2009;113(23):5727-5736. doi:10.1182/blood-2009-02-205237
- Kibsgaard L, Deleuran M, Flohr C, Langan S, Braae Olesen A, Vestergaard C. How “benign” is cutaneous mastocytosis? A Danish registry-based matched cohort study. Int J Womens Dermatol. 2020;6(4):294-300. doi:10.1016/j.ijwd.2020.05.013
- Trizuljak J, Sperr WR, Nekvindová L, et al. Clinical features and survival of patients with indolent systemic mastocytosis defined by the updated WHO classification. Allergy. 2020;75(8):1927-1938. doi:10.1111/all.14248
- 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
- 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
- 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
- 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
- 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
- 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
- Jawhar M, Schwaab J, Naumann N, et al. Response and progression on midostaurin in advanced systemic mastocytosis: KIT D816V and other molecular markers. Blood. 2017;130(2):137-145. doi:10.1182/blood-2017-01-764423
- 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
Reviewed by Kyle Habet, MD, on 4/27/2022.