Cytogenetic and molecular aberrations and worse outcome for male patients in systemic mastocytosis

Abstract

In systemic mastocytosis (SM), the clinical features and survival vary greatly. Patient-related factors determining the outcome in SM are largely unknown. Methods: We examined the impact of sex on the clinical features, progression-free survival (PFS), and overall survival (OS) in 3403 patients with mastocytosis collected in the registry of the European Competence Network on Mastocytosis (ECNM). The impact of cytogenetic and molecular genetic aberrations on sex differences was analyzed in a subset of patients. Results: Of all patients enrolled, 55.3% were females. However, a male predominance was found in a subset of advanced SM (AdvSM) patients, namely SM with an associated hematologic neoplasm (SM-AHN, 70%; p < 0.001). Correspondingly, organomegaly (male: 23% vs. female: 13%, p = 0.007) was more, whereas skin involvement (male: 71% vs. female: 86%, p = 0.001) was less frequent in males. In all patients together, OS ( p < 0.0001) was significantly inferior in males, and also within the WHO sub-categories indolent SM, aggressive SM (ASM) and SM-AHN. PFS was significantly ( p = 0.0002) worse in males when all patients were grouped together; due to low numbers of events, this significance persisted only in the subcategory smoldering SM. Finally, prognostically relevant cytogenetic abnormalities (10% vs. 5%, p = 0.006) or molecular aberrations ( SRSF2 / ASXL1 / RUNX1 profile; 63% vs. 40%, p = 0.003) were more frequently present in males. Conclusions: Male sex has a major impact on clinical features, disease progression, and survival in mastocytosis. Male patients have an inferior survival, which seems related to the fact that they more frequently develop a multi-mutated AdvSM associated with a high-risk molecular background.

A Multidisciplinary Diagnostic Approach Reveals a Higher Prevalence of Indolent Systemic Mastocytosis: 15-Years’ Experience of the GISM Network

“…We could confirm in our series that advanced variants of SM are associated with older age and male sex, in line with previous reports [ 27 , 28 ], but their frequency was less than 9% of cases, much lower than reported in the past [ 10 ], and also lower than recently reported in the ECNM registry [ 13 ]. Of interest, the number of new diagnoses of SM-AHN progressively increased from 2006 to 2021, along with a greater experience of the dedicated pathologist, thus confirming that SM-AHN is still an underestimated variant, often diagnosed with a substantial delay [ 28 ].…”

New Insights into the Pathogenesis of Systemic Mastocytosis

“…Other, less common (<5%) somatic KIT mutations have also been identified in adult SM patients, including V560G, D815K, D816Y, D816F, D816H, and D820G. Interestingly, the KIT D816V mutation was detected in 84% of men and 75% of women analyzed ( p < 0.001), which is consistent with generally worse outcomes observed for male patients with SM [ 17 ]. Generally, the KIT D816V mutation is less frequently detected in cases of childhood-onset mastocytosis than in adult patients (approximately 40% vs. >80%).…”

“…So far, there are only a few reports of cytogenetic analyses in SM patients. Interestingly, cytogenetic abnormalities are highly restricted to patients with advanced SM in two recent publications [ 17 , 70 ], suggesting that they are unlikely to be primary events in the pathogenesis of SM but rather that these abnormalities promote progression to advanced SM.…”

The Role of Avapritinib for the Treatment of Systemic Mastocytosis

“…This type of mutation promotes SCF-independent KIT autophosphorylation, which in turn facilitates uncontrolled cellular growth and tumorigenesis [6]. Men were found to be more prone to the KIT D816V mutation and were more likely to acquire advanced forms of SM, translating to worse overall survival (OS) and progression-free survival (PFS) [13]. A small minority of AdvSM cases have also been associated with the V560G, D815K, D816Y, D816F, D816H, and D820G mutations in the KIT gene [14][15][16][17][18][19].…”

“…Longley et al have suggested that KIT mutations affect the regulation of the kinase molecule and alter certain amino acids within the enzymatic domain of the tyrosine kinase [ 20 ]. Although KIT mutations are thought to be crucial in the development of SM, it is postulated that mutations in other genes, such as TET2, SRSF2, RUNX1 and ASXL1, are also required for SM to develop [ 13 , 14 , 21 - 23 ].…”