Improving prognostic tools in systemic mastocytosis: Insights from mutations
Authors: Lisa Pieri, Alessandro M. Vannucchi
Journal: American Journal of Hematology (2016)

Systemic mastocytosis (SM) is a chronic myeloproliferative neoplasm that is highly heterogeneous in terms of clinical manifestations whilst apparently homogeneous in terms of molecular pathogenesis. As a matter of fact, in at least 90% of patients who meet the diagnostic criteria of the World Health Organization 1 the disease is associated with a mutation in the KIT gene, that encodes for the KIT receptor (CD117), a type III receptor tyrosine kinase that is expressed in hematopoietic stem/progenitor cells, melanocytes, interstitial cells of Cajal in the gastrointestinal tract and in germ cells. The prototype D816V mutation is an activating gain-of-function mutation located in the tyrosine-kinase (TK) domain; the autonomously activated TK is not sensitive in vivo to imatinib inhibition while the multi-kinase inhibitor midostaurin showed marked clinical efficacy in a recent study 2. However, the role of KIT mutations in the pathogenesis of SM is not completely understood yet, in particular it is unclear whether such mutations are necessary and sufficient to cause transformation of mast cells and eventually of other hematopoietic progenitors, as it may occur in the forms of SM that are associated with another hematological neoplasm (SM-AHN). Murine models expressing the KITD816V (or homologous) mutation only imperfectly reproduced the disease 3, 4. Also, the prognostic impact of the different cell hierarchy level at which the KIT mutation is expressed, and its quantitative representation, remain debated. The presence of KITD816V mutation in myeloid and/or lymphoid cells other than mast cells was associated with more aggressive forms of disease 5 and, for patients initially diagnosed as indolent systemic mastocytosis (ISM), with a higher probability to progress to aggressive SM (ASM) and die 6. There are also initial data suggesting a correlation of KITD816V allele burden and disease subtypes (indolent versus aggressive forms) and serum levels of tryptase 7. SM ranges from indolent forms (ISM) with very good prognosis to aggressive disease (ASM) with severe systemic symptoms affecting quality of life, multi-organ involvement, evolution to acute leukemia 8. Although some clinical variables have been associated with different outcomes, the most important parameter for prognosis assessment is (simply) the diagnostic variant of SM 9. However, this approach fails in identifying patients at different risk within the individual subtypes, thereby representing an unmet clinical need eventually impacting on therapeutic decisions that include hematopoietic stem cell transplantation for younger patients. Recent data produced with targeted next generation sequencing (NGS) analysis of SM genoma have started to illuminate the molecular landscape and promise to improve the prognostic assessment of patients with SM. Schwaab et al. 10 described the mutation status of 39 KITD816V mutated patients, 59% of which had a diagnosis of SM-AHN 1. Analyzed genes included most of those known to associate with myeloid malignances, such as CBL, IDH1, IDH2, KRAS, U2AF1, SRSF2, SF3B1, SETBP1, TP53, TET2, EZH2, ETV6, RUNX1, ASXL1, JAK2, NRAS, NPM1, and MLL-PTD. There were 89% of patients with advanced SM who harbored any one of these mutated genes as compared to 25% of the indolent forms; 78% of advanced SM had three or more mutations. The five most frequently affected genes were TET2, SRSF2, ASXL1, RUNX1, and CBL, and the presence of one or more additional mutations to KITD816V was associated with inferior overall survival (OS). Limitations of the study were the low number of subjects included, the relatively short follow-up (median 8 months) and the large majority of patients with SM-AHN. In a subsequent study from the same group, Jawhar et al. 11 performed target resequencing in 70 patients with SM-AHN, including indolent (n = 26) and aggressive SM-AHN (n = 34) and mast cell leukemia (MCL)-AHN (n = 10), who were followed for a median of 3.7 years. All patients had at least one additional mutation to KIT; mutations in TET2, SRSF2, ASXL1, RUNX1, N/KRAS, or IDH2 were most frequently identified in ASM/MCL-AHN while mutations in JAK2, ETV6, U2AF1, EZH2, and SF3B1 were enriched in ISM-AHN. Multivariate analysis pointed to SRSF2 and ASXL1 mutations as independent poor risk factors for OS. The study by Pardanani et al. published in the current issue of the Journal goes far beyond previous reports and provides novel important information both for understanding the molecular asset of different forms of SM and particularly for the use of such information in the clinical setting 12. The analysis concerned 150 patients with SM, including 44 ISM, 25 ASM, 80 SM-AHN, and 1 MCL, with a median follow of 25 months, who were genotyped for an extended panel of 27 genes by NGS. Therefore, this is the largest cohort ever reported and, of relevance, includes a substantial number of cases of SM not associated with other hematologic neoplasms, that was barely represented in previous studies. The mutation profile was similar to previous studies; mutations were detected particularly in TET2, ASXL1, CBL, SF3B1, DNMT3A, JAK2, U2AF1, and RUNX 1. There was a gradient in mutation frequency from SM-AHN to ASM to ISM. The low frequency of KITD816V mutation (75%) in the current study compared to other series 13 might not be totally unexpected owing to the use of NGS that suffers from lower sensitivity compared to ASO-RT-PCR techniques in the detection of very low KIT mutant allele burden. This indirectly underlines the importance of using adequate detection methods in the diagnostic path for patients suspected to have SM. On age-adjusted multivariate analysis, only ASXL1 and RUNX1 were independently associated with reduced OS; a negative impact of the number of mutations on OS was also confirmed. Taking advantage of the cases with extensive information (n = 94), Pardanani et al. have analyzed the impact of ASXL1 and RUNX1 mutations in the context of other clinical variables. Older age, anemia, transfusion-dependency, thrombocytopenia, low serum albumin, and ASXL1 mutations independently predicted for dismal outcome. Inclusion of these variables in a ranked model resulted in three distinct risk groups with statistically different survival ranging from 86 months (low risk) to 21 months (intermediate risk) and 5 months (high risk category). The mutation-augmented prognostic scoring system (MAPSS) for advanced SM developed by Pardanani and colleagues represents the first attempt to formally incorporate mutation information in a prognostic score for SM, in line with current efforts in other acute and chronic myeloid neoplasms. Of course, the score remains to be validated in large series of patients; owing to the rarity of disease, this task might be accomplished through international networks. Only availability of larger patient number will allow to answer the many questions that arise from this study, first of all how the MAPSS score works in identifying different risk categories in the settings of individual mastocytosis subtypes, particularly for conventionally low-risk patients, and how it might help guiding treatment in a disease where new drugs are producing important advantages but are still far from extending significantly life expectancy.