Mayo alliance prognostic system for mastocytosis: clinical and hybrid clinical-molecular models

Abstract

Systemic mastocytosis (SM) is a clinically heterogeneous disease with prognosis chiefly assigned based on World Health Organization (WHO) morphologic subclassification. We assessed the feasibility of developing contemporary risk models for SM based on clinical and integrated clinical-genetics information. Diagnosis of SM was per WHO criteria, and karyotype and next-generation sequencing data were available in a subset of the total 580 patients (median age, 55 years; range, 18-88 years) seen at the Mayo Clinic between 1968 and 2015. Morphologic subcategories were indolent/smoldering in 291 (50%) and “advanced” in 289 (50%): SM with an associated hematological neoplasm in 199, aggressive SM in 85, and mast cell leukemia in 5. Multivariable analysis of clinical variables identified age >60 years, advanced SM, thrombocytopenia <150 × 109/L, anemia below sex-adjusted normal, and increased alkaline phosphatase (ALP) as independent risk factors for survival; respective hazard ratios (HRs) 95% confidence intervals (95% CIs) were 2.5 (1.9-3.4), 2.7 (1.8-4.0), 2.5 (1.9-3.4), 2.2 (1.6-3.1), and 2.1 (1.5-3.0). In addition, ASXL1 (HR, 4.5; 95% CI, 2.6-7.6), RUNX1 (HR, 4.3; 95% CI, 1.3-10.8), and NRAS (HR, 5.0, 95% CI, 1.5-13.2) mutations were independently associated with inferior survival. Combined clinical, cytogenetic, and molecular risk factor analysis confirmed the independent prognostic contribution of adverse mutations (2.6, 1.6-4.4), advanced SM (4.0, 1.8-10.0), thrombocytopenia (2.8, 1.7-4.5), increased ALP (2.1, 1.2-4.0), and age >60 years (2.2, 1.3-3.6). These data were subsequently used to develop clinical and hybrid clinical-molecular risk models. The current study advances 2 complementary risk models for SM and highlights the independent prognostic contribution of mutations.

MARS: Mutation-Adjusted Risk Score for Advanced Systemic Mastocytosis

“…Some recently published risk scores from our own group and from others also included variables such as anemia, thrombocytopenia, elevated alkaline phosphatase, and high molecular risk gene mutations. 10 , 22 The pivotal strengths of the current analyses include the following: indolent SM was excluded in the prognostic models because it has a nearly normal life expectancy; this analysis included the greatest number of clinically, morphologically, and genetically well-characterized patients with AdvSM ever reported; most patients had access to targeted treatment modalities such as midostaurin; and the vast majority of patients in the training set were diagnosed through fully centralized pathology and genetic analyses. An addition strength was the homogenous mutation profile (clinical and outcome characteristics) of the training set and the large and independent validation set (derived from centers with expertise in mastocytosis), particularly regarding the individual frequency of gene mutations in the S/A/R panel.…”

Systemic mastocytosis in adults: 2019 update on diagnosis, risk stratification and management

“…Further, one study showed inferior clinical outcomes (ie, response rates, survival and disease progression) in advanced SM patients receiving midostaurin treatment, for those harboring poor‐risk mutations as compared to those without such mutations . In a recent study, two complementary risk models for SM were developed, referred to as the Mayo Alliance Prognostic System (MAPS) for SM; one model (clinical) was based on clinical variables alone while the other (hybrid clinical‐molecular) included adverse mutations as an independent risk factor . The study included 580 patients, of which 291 had indolent/smoldering SM (ISM/SSM), and 289 had “advanced” SM (100 SM‐AHN, 85 ASM and 5 MCL).…”

International prognostic scoring system for mastocytosis (IPSM): a retrospective cohort study

“…Several attempts have been made to improve prognostication of mastocytosis by establishing scoring systems. 13,20,21 However, currently available scores are based on a limited number of patients and have not been validated in independent cohorts. More importantly, current scoring systems do not address the point that non-advanced mastocytosis and advanced systemic mastocytosis are completely different disease groups with divergent disease biology and distinct patterns of prognostic factors.…”