Clinical and Molecular Models of Prognostication in Mastocytosis: Analysis Based on 580 Consecutive Cases

Background: The 2016 World Health Organization (WHO) system lists five morphological categories of systemic mastocytosis (SM): indolent (ISM), smoldering (SSM), SM with an associated hematological neoplasm (SM-AHN), aggressive (ASM) and mast cell leukemia (MCL) ( Blood . 2016;127:2391 ). In the current study, we capitalized on the large number of accumulated cases of SM seen at the Mayo Clinic, between 1968 and 2015 ( n =580), in order to devise two separate but complementary prognostic models that are based on either clinically-derived variables, or a combination of both clinical and molecular information. Methods : Study patients ( n =580) were recruited from the Mayo Clinic, Rochester, MN, USA. Diagnoses of SM and its morphological subcategories were confirmed by both clinical and bone marrow examinations, in line with the 2016 WHO criteria ( Blood . 2016;127:2391 ). Next-generation sequencing (NGS) was performed in a subset of the study population ( n =150). Statistical analyses considered clinical and laboratory data collected at the time of initial diagnosis at the Mayo Clinic. Conventional statistics was used for calculation and of overall survival and determination of inter-independent risk factors. Receiver operating characteristic (ROC) curves were used to determine the prognostically most discriminative platelet threshold. The JMP® Pro 13.0.0 software from SAS Institute, Cary, NC, USA, was used for all calculations. Results: 580 patients with SM (median age 55 years; range 18-88 years; 52% males) were included in the current study; 291 (50%) constituted indolent and 289 (50%) advanced variants; the latter included 85 (15%) ASM, 199 (34%) SM-AHN and 5 MCL cases. At presentation, anemia defined by hemoglobin level below the lower limit of the sex-adjusted reference range, was present in 41% of the patients, hemoglobin 9 /l in 26%, serum albumin below the lower normal limit (LNL) of the reference range in 22%, serum alkaline phosphatase (ALP) above the upper normal limit (UNL) of the reference range in 54%, urticaria pigmentosa in 41%, mast cell mediator symptoms in 46%, palpable hepatomegaly in 21%, palpable splenomegaly in 31%, "C" findings in 23% and "B" findings in 42%. Median follow-up was 34 months with 239 (41%) deaths and 9 (1.5%) leukemic transformations documented. Cytogenetic information was available in 342 cases, including 51 (15%) with abnormal karyotype and 27 (8%) with unfavorable karyotype. NGS-derived mutation information was available in 150 cases and most frequent mutations were KIT (75%), TET2 (29%), ASXL1 (17%) and CBL (11%). Age-adjusted multivariable analysis of clinical variables, which did not include mutation or cytogenetic information, identified age >60 years (HR 2.5, 95% CI 1.8-3.4), advanced vs ISM (HR 2.3, 95% CI 1.5-3.7), thrombocytopenia 9 /l (HR 2.4, 95% CI 1.8-3.4), anemia (HR 2.1, 95% CI 1.5-3.0), ALP above UNL (HR 2.1, 95% CI 1.5-3.1) and albumin below LNL (HR 1.4, 95% CI 1.0-1.9). A similar age-adjusted multivariable analysis for mutations identified ASXL1 (HR 3.3, 95% CI 1.9-5.5), RUNX1 (HR 4.1, 95% CI 1.2-10.2) and NRAS (HR 5.7, 95% CI 1.7-14.9) as independent molecular risk factors; these mutations were henceforth labelled as "adverse". The addition of "adverse" mutations (HR 2.7, 95% CI 1.6-4.7) to the list of the aforementioned clinical risk factors resulted in loss of significance for age and anemia while platelets below 150 x 10 9 /l (HR 2.9, 95% CI 1.8-4.8), ALP above UNL (HR 3.2, 95% CI 1.8-6.1), albumin below LNL (HR 2.5, 95% CI 1.6-4.0) and advanced vs ISM (HR4.2, 95% CI 1.9-10.7) remained significant. Subsequently, based on the number of risk factors present, a "clinical" (figure 1a; n =380 informative cases) and "clinical-molecular" (figure 1b; n =129 informative cases) risk models were prepared; both risk models performed effectively for advanced and indolent SM, when analyzed separately (data not shown). Conclusions: The current study advances two separate but complimentary risk models for SM and illustrates the additional prognostic contribution of mutations and underlines the importance of thrombocytopenia and serum ALP and albumin levels in both risk models. Furthermore, we show effective application of both risk models in advanced and indolent SM. Disclosures No relevant conflicts of interest to declare.