Mastocytosis among elderly patients

Abstract

Mastocytosis is a heterogeneous group of diseases with a young median age at diagnosis. Usually indolent and self-limited in childhood, the disease can exhibit aggressive progression in mid-adulthood. Our objectives were to describe the characteristics of the disease when diagnosed among elderly patients, for which rare data are available.The French Reference Center conducted a retrospective multicenter study on 53 patients with mastocytosis >69 years of age, to describe their clinical, biological, and genetic features.The median age of our cohort of patients was 75 years. Mastocytosis variants included were cutaneous (n = 1), indolent systemic (n = 5), aggressive systemic (n = 11), associated with a hematological non-mast cell disease (n = 34), and mast cell leukemia (n = 2). Clinical manifestations were predominantly mast cell activation symptoms (75.5%), poor performance status (50.9%), hepatosplenomegaly (50.9%), skin involvement (49.1%), osteoporosis (47.2%), and portal hypertension and ascites (26.4%). The main biological features were anemia (79.2%), thrombocytopenia (50.9%), leucopenia (20.8%), and liver enzyme abnormalities (32.1%). Of the 40 patients tested, 34 (85%), 2 (5%), and 4 (10%) exhibited the KIT D816V mutant, other KIT mutations and the wild-type form of the KIT gene, respectively. Additional sequencing detected significant genetic defects in 17 of 26 (65.3%) of the patients with associated hematological non-mast cell disease, including TET2, SRSF2, IDH2, and ASLX1 mutations. Death occurred in 19 (35.8%) patients, within a median delay of 9 months, despite the different treatment options available.Mastocytosis among elderly patients has a challenging early detection, rare skin involvement, and/or limited skin disease; it is heterogeneous and has often an aggressive presentation with nonfortuitous associated myeloid lineage malignant clones, and thus a poor overall prognosis.

Comprehensive Analysis of Acquired Genetic Variants and Their Prognostic Impact in Systemic Mastocytosis

“…In line with this, next generation sequencing (NGS) studies have confirmed the presence of recurrent mutations in genes involved in posttranscriptional mRNA processing, epigenetic modification of DNA and transcription and signal transduction factors, in both SM and other myeloid neoplasms [10,11,51,81,87]. Among others, mutations have been recurrently reported in AdvSM in the ASXL1, CBL, DNMT3A, NRAS, RUNX1, SRSF2 and TET2 genes in AdvSM [10,12,13,29,32,46,50,51,68,80,81,87,96,97]. In contrast, the presence of these additional mutations is a relatively infrequent finding in BMM and ISM patients [10,29,51,80,87].…”

“…In adults, these mutations are mostly located at codons 814-822 within exon 17 [9,[26][27][28][29][30][31], including several mutant variants at codon 816 [9,[32][33][34][35][36][37][38][39][40][41][42][43][44][45][46] (Table 1). KIT mutations located outside exon 17 include rare mutations that mostly affect exons 2 [29], 5 [40], 7-11 [29,32,40,[46][47][48][49][50][51][52][53][54][55][56][57][58], 13 [29,59] and 18 [29]. Of note, most mutations other than KIT D816V correspond to isolated cases of SM-AHN, MCL or WDSM (Table 1).…”

“…To date, mutations in a total of 11 genes related to transcription factors and signalling pathways have been described in patients with different subtypes of SM; of note, while some of these genes have been sporadically reported to be mutated in SM (EPHA7 [12,13], FLT3 [29], IKZF1 [13], PIK3CD [12,13], ROS1 [12,13] and TP53 [29]) (Tables S1 and S2), others (e.g., CBL, JAK2, K/NRAS and RUNX1) are recurrently found to be altered in SM, particularly among SM-AHN patients (Table 3). [10] 1/216 (0.5) [12] 0/6 (0) [13] 0/44 (0) [29] 0/1 (0) [50] 1/29 (3.4) [51] 0/26 (0) [68] 0/15 (0) [80] 0/6 (0) [85] 1% BMM 0/65 (0) [12] 0% ISM 1/10 (10) [10] 0/3 (0) [13] 0/1 (0) [50] 0/26 (0) [68] 0/4 (0) [85] 1/144 (1) [12] 0/44 (0) [29] 1/28 (4) [51] 0/15 (0) [80] 1% SSM 0/2 (0) [10] 0/3 (0) [13] 0/2 (0) [85] 0/7 (0) [12] 0/1 (0) [51] 0% ASM 0/1 (0) [10] 0/9 (0) [13] 0/2 (0) [50] 0/3 (0) [68] 0/1 (0) [85] 0/9 (0) [12] 1/25 (4) [29] 0/9 (0) [51] 0/2 (0) [80]...…”

“…Non-AdvSM 0/12 (0) [10] 2/97 (2) [12] 0/6 (0) [13] 0/44 (0) [29] 0/1 (0) [50] 0/29 (0) [51] 2/26 (8) [68] 0/6 (0) [85] 0/13 (0) [88] 2% BMM 1/23 (4) [12] 4% ISM 0/10 (0) [10] 0/3 (0) [13] 0/1 (0) [50] 2/26 (8) [68] 0/13 (0) [88] 1/70 (1) [12] 0/44 (0) [29] 0/28 (0) [51] 0/4 (0) [85] 2% SSM 0/2 (0) [10] 0/3 (0) [13] 0/2 (0) [85] 0/4 (0) [12] 0/1 (0) [51] 0% ASM 0/1 (0) [10] 0/9 (0) [13] 0/2 (0) [50] 0/3 (0) [68] 0/5 (0) [88] 0/7 (0) [12] 0/25 (0) [29] 0/9 (0) [51] 0/1 (0) [ (7) [88] 10% MCL 0/3 (0) [10] 0/1 (0) [50] 0/8 (0) [68] 0/1 (0) [29] 0/3 (0) [51] 0/1 (0) [88] 0%…”

Combined Nevus–Mastocytosis; Random Coincidence or Complex Biological Relationship?

“…Activating KIT mutation is the main underlying genomic alteration in children and adults with mastocytosis that serves as a diagnostic criterion and has been reported in >90% of patients using highly sensitive mutation detection methods. 11 KIT functions as a proto oncogene that encodes a Type III receptor tyrosine kinase “KIT,” which is composed of extracellular, transmembrane, juxta membrane, and tyrosine kinase domains, and is normally activated by SCF. 1 It is expressed by germ cells, hematopoietic progenitor cells, mast cells, and melanocytes.…”