Clinical, molecular, and demographic features of systemic mastocytosis: Analysis of a large cohort

Abstract

Abstract Introduction Systemic Mastocytosis (SM) is a rare and clinically heterogeneous myeloid neoplasm defined by clonal mast cell accumulation in diverse tissues. As targeted therapies emerge, establishing robust benchmarks from large U.S. cohorts is critical to define unmet clinical needs and guide therapeutic development. The World Health Organization (WHO) classifies SM into advanced (AdvSM) subtypes (aggressive SM, SM associated with a hematological neoplasm, and mast cell leukemia) and non-advanced (nonAdvSM) subtypes (indolent SM and smoldering SM) based on histopathology, disease burden, and disease-related organ damage. Leveraging over two decades of institutional experience at MD Anderson Cancer Center, we characterize the clinical, molecular, and demographic landscape of SM. Methods We retrospectively reviewed the clinical charts, imaging, and laboratory data of 342 adult patients with confirmed SM who presented to our center between 2001 and 2024. Patients were classified into SM subtypes by clinical evaluation and bone marrow histopathology according to WHO criteria. Statistical analyses were conducted on clinical and laboratory data from the initial presentation to our center. Descriptive and correlative analyses were conducted to evaluate associations between clinical, molecular, and demographic variables across SM subtypes. Survival analysis was performed using Kaplan-Meier estimates, censored at 360 months, and stratified by SM subtype to assess differences in overall survival. Results Our cohort comprised 342 adult patients with a confirmed diagnosis of SM (mean age 53.0, range 19.7-94.9 years; males 40.9%). The distribution of WHO-defined subtypes of SM included ISM (n=207; 60.5%), SSM (n=19; 5.6%), ASM (n=37; 10.8%), SM-AHN (n=75; 21.9%), and MCL (n=4; 1.2%). In SM-AHN, the most common hematologic neoplasms were MDS (n=23; 30.7% of SM-AHN) and CMML (n=17; 22.7%). Additional myeloid malignancies included AML (n=8; 10.7%) and ET (n=3; 4.0%), and lymphoid malignancies included MM (n=7; 9.3%), CLL (n=4; 5.3%) and ALL (n=1; 1.3%). The mean age at diagnosis was significantly higher for AdvSM subtypes compared to nonAdvSM (60.8 vs 49.0 years, p<0.001). Advanced vs. non-advanced lab findings were significantly different for tryptase (154.0 vs. 83.2 ng/mL, p<0.001); hemoglobin (11.1 vs. 13.5 g/dL, p<0.001); WBC (14.2 vs. 7.2 × 10⁹/L, p=0.026); platelets (222.8 vs. 268.1 × 10⁹/L, p=0.034); albumin (4.2 vs. 4.5 g/dL, p<0.001); absolute neutrophil count (6.7 vs. 4.4 × 10⁹/L, p=0.001); lactate dehydrogenase (412.1 vs. 311.4 IU/L, p<0.001); uric acid (6.0 vs. 5.1 mg/dL, p<0.001); and alkaline phosphatase (228.1 vs. 92.5 IU/L, p<0.001), respectively.Blasts constituted 5.3% of the bone marrow in AdvSM patients vs. 1.4% in nonAdvSM (p=0.002). Cutaneous involvement was observed in 43.1% of AdvSM patients compared to 66.8% of nonAdvSM (p<0.001). Skeletal involvement (osteolytic lesions or fractures) was identified in 89/333 (26.7%) of SM patients with available data. Bone pain was reported in 119/330 (36.1%) SM patients. Hepatosplenomegaly and lymphadenopathy were observed in 85/220 (38.6%) and 16/141 (11.3%) SM patients, respectively, based on physical examination and imaging results. 25.1% of the SM cohort had a history of anaphylaxis. Of the 239 patients with KIT mutation analyses, 153 had KIT mutations (151 had KIT D816V). Flow cytometry detected CD2 expression in 74.5% of SM patients. 174 patients received SM-targeted treatment at MDACC. Median overall survival (OS) was shortest in MCL (0.9 years), followed by ASM (6.1 years), SM-AHN (10.3 years), SSM (11.3 years), and ISM (not reached). Higher median OS for SM-AHN at MDACC may be attributed to the institution's expertise in treating associated hematologic neoplasms. Conclusion Patients with systemic mastocytosis display highly variable clinical presentations and outcomes across subtypes, necessitating tailored diagnostic and therapeutic strategies. Our comprehensive analysis of a large, real-world U.S. cohort at MD Anderson highlights the importance of capturing clinical, molecular, and demographic features to better define disease heterogeneity. Establishing real-life clinical benchmarks informs risk stratification and therapeutic planning and helps identify persistent gaps in symptom control and quality of life. Incorporating patient-reported outcomes into future efforts will be key to addressing the full spectrum of unmet needs as new therapies emerge.