Systemic mastocytosis: evolving lessons from large patient registry datasets
Authors: Animesh Pardanani
Journal: American Journal of Hematology (2016)

Systemic mastocytosis (SM) is a clinically heterogeneous and relatively infrequent chronic myeloproliferative neoplasm 1. In the Danish nationwide cohort study, the incidence and prevalence rates were 0.89 per 100,000 inhabitants per year and 9.59 per 100,000 inhabitants, respectively, for the period between 1997 and 2010 2. Similarly, in the Groningen region, The Netherlands, prevalence of indolent SM (ISM) was estimated at 13 per 100,000 inhabitants, albeit with a roughly five- to sixfold increase in cases from 1998 to 2010, the latter likely relating to a recent increased awareness of SM combined with advances in diagnostic testing and expertise in specialized centers for this disease 3. The increasing number of cases diagnosed with SM at least partly reflects the development of standardized diagnostic, classification and treatment-response criteria by international collaborative organizations such as the World Health Organization (WHO) and European Competence Network on Mastocytosis (ECNM) 4-6. Prior to these larger-scale projects, most SM related data emerged from single center or single country registry studies, which despite their inherent limitations helped establish the early foundational principles of SM evaluation and treatment 7-13. The article by Pieri et al. in the current issue of the American Journal of Hematology represents a large study of SM patients from 10 Italian centers with dedicated mastocytosis programs participating in the Italian Registry of Mastocytosis 14. There are two aspects of special note related to the study by Pieri et al. First, it represents the largest study of SM patients diagnosed by WHO 2008 criteria ever published 5. Second, patients in this study were diagnosed relatively recently, with 75% being diagnosed between the years 2009 and 2014. The latter aspect ensured the use of relatively state-of-the-art diagnostic testing in the current study, which is not the case in older studies wherein a significant subset of patients was diagnosed prior to the development of such tests. A downside, however, of the recency bias in the article by Pieri et al. is the short patient follow up which limits the conclusions one might draw regarding clinical outcomes in SM patients. There are several additional observations that flow from the above two points: first, while the study by Pieri et al. includes 460 patients, as compared with the erstwhile largest study of 342 patients from the Mayo Clinic group 8, it is unclear whether either study is generalizable to the SM patient at large. While both were multidisciplinary studies, the former is predominantly a study of ISM patients (89% of all cases), likely reflecting a bias toward patient enrollment via dermatology and/or allergy clinics (73% had allergy/anaphylaxis symptoms). In contrast, the study by Lim et al. exhibited a hematology bias with 46% and 40% presenting with ISM and SM with associated clonal non-mast cell lineage disease (SM-AHNMD), respectively. This has to be taken into account when extrapolating data from either study to individual patients. Interestingly, in the Danish nationwide cohort study, the distribution of subtypes was 82% ISM and 4% SM-AHNMD 3, which is more in line with the findings by Pieri et al. The study by Pieri et al. also reflects the recent trend toward diagnosing SM (mostly indolent cases) based on minor diagnostic criteria only, with the absence of mast cell aggregates (i.e., major criterion) likely reflecting detection of “early-stage/low-burden” disease based on increasing use of highly sensitive diagnostic tests such as allele-specific PCR for the KITD816V mutation. Another potential contributor in this regard is the proportion of patients enrolled via allergy clinics where there is a higher index of suspicion for underlying SM. The aforementioned observations are also consistent with detection of low-burden clonal mast cells in symptomatic patients in specific clinical contexts (e.g., “idiopathic anaphylaxis”) 15, 16, where some patients are found to satisfy only 1 or 2 minor SM diagnostic criteria, with this entity being termed “monoclonal mast cell activation syndrome” or “subdiagnostic SM” 17, 18. The highest proportion of patients without mast cell aggregates (60%) in the study by Pieri et al. belonged to the ISM subgroup without skin involvement (ISM-). This was also the subset with highest prevalence of allergic/anaphylactic symptoms (96%) and lowest burden of bone marrow mast cell involvement (7%); these observations are consistent with those previously reported for patients characterized as having “isolated bone marrow mastocytosis” 19. It is currently unclear as to whether SM diagnosed by minor criteria only represents “early stage” disease or a forme fruste expression of the disease. While not directly assessed in the current study, Pieri et al. will have a unique opportunity to analyze this aspect as the follow period for their cohort matures. Perhaps the weakest aspect of the article by Pieri et al. is the data on disease progression and overall survival. This relates not only to the short overall patient follow up (4% disease progression, 6% deaths) but also the relatively low number of patients with aggressive SM (ASM) and SM-AHNMD, precisely the subgroups that are at highest risk for disease progression. Further, certain criteria for disease progression in the current study (e.g., acquisition of B-findings for ISM patients) cannot be considered as standard practice in the field. A third of patients with ASM were reported as having transformed to acute leukemia (as compared with 5% with SM-AHNMD) after a median follow up of only 24 months. The rate of leukemic transformation for ASM is likely too high to be considered credible and raises concern that in the absence of central pathology review, some patients may have been misdiagnosed as having ASM instead of SM-AHNMD. By extrapolation, since most of the deaths (79%) in the current cohort were due to disease progression, the variables found to be prognostic for overall survival will also likely need to be reexamined as patient follow up matures. The survival analysis is further limited by the fact that detailed molecular findings were not reported. Recent studies have demonstrated adverse survival outcomes in SM patients harboring mutations in specific genes (e.g., ASXL1, SRSF2) 10, 20. Overall, the article by Pieri et al. represents an important scientific contribution to the study of SM. The large cohort size and detailed clinical and pathologic descriptive analyses set a high bar for similar future studies in the field. Importantly, this comprehensive dataset also helps reset the balance toward “fact” from “opinion” in that it facilitates a rational data-based analytic approach toward SM, and thereby decreases our reliance on expert consensus based opinions that have hitherto played an outsized role in the field.