Practice‐relevant demarcation of systemic mastocytosis associated with another hematologic neoplasm
Authors: Ayalew Tefferi, Sahrish Shah, Terra L. Lasho, Mrinal M. Patnaik, Kaaren K. Reichard, Curtis A. Hanson, Rhett P. Ketterling, Animesh Pardanani
Journal: American Journal of Hematology (2018)

The World Health Organization (WHO) system lists five morphological categories of systemic mastocytosis (SM): indolent (ISM), smoldering (SSM), SM with an associated hematological neoplasm (SM-AHN), aggressive (ASM) and mast cell leukemia (MCL).1 SM-AHN includes both lymphoid and a spectrum of myeloid malignancies.2 In routine clinical practice, the term "SM-AHN" has limited practical value and its scientific relevance remains dubious.3 In the current study, we tapped into the large Mayo Clinic database of patients with SM, in order to describe the phenotypic and molecular diversity of SM-AHN and submit a proposal for practice-relevant re-classification. After approval from the institutional review board, study patients were recruited from the Mayo Clinic, Rochester, MN; with data updated in July 2018. Diagnoses of SM and its morphological subcategories were confirmed by both clinical and bone marrow examinations, in line with the 2016 WHO criteria.1 Previously described methods were used for next-generation sequencing (NGS),4 which was performed in a subset of the study population. Statistical analyses considered clinical and laboratory data collected at the time of initial diagnosis at the Mayo Clinic. Conventional statistics was used for calculation of overall survival and determination of risk factors. JMP Pro 13.0.0 software from SAS Institute, Cary, NC, was used for all calculations. A total of 580 patients with SM (median age 55 years; range 18-88 years; 52% males) were seen at our institution between October 1968 and September 2015, and had adequate clinical and laboratory information for outcome analysis; the four-tiered WHO morphologic subcategories were ISM in 291 (50%) patients, ASM in 85 (15%) patients, MCL in five patients and SM-AHN in 199 (34%) patients; survival comparison between these formal WHO categories clearly showed distinct survival outcomes with dismal prognosis in MCL (median survival 4 months), best outcome for ISM (median survival 281 months) and an intermediate prognosis for ASM and SM-AHN; however, in univariate analysis, survival was significantly worse in SM-AHN, compared to ASM (median survival 25 vs 87 months; HR 2.1, 95% CI 1.5-3.0; Figure 1A). The current study was primarily focused on the 199 patients (median age 65 years; 66% males) with SM-AHN; the AHN component was myeloid neoplasm in 178 patients and lymphoid in 21 (Table 1). Figure 1B depicts that survival was significantly superior in SM-AHN lymphoid, compared to SM-AHN-myeloid (HR 2.2, 95% CI 1.2-4.0), and somewhat comparable to that of ASM (HR 1.0, 95% CI 0.5-2.0). Also evident from Table 1 was the absence of adverse mutations in SM-AHN-lymphoid; the latter also displayed younger age distribution and lower likelihood of KITD816V detection, anemia and thrombocytopenia (Table 1). Patients with SM-AHN-myeloid, compared to those with SM-AHN-lymphoid, were also more likely to display higher serum tryptase level, serum alkaline phosphatase level and bone marrow mast cell burden (Table 1). .01 "N" evaluable = 69 "N" Evaluable = 70 Next, we focused on SM-AHN-myeloid (n = 178), which included 11 (6%) patients with SM associated with acute myeloid leukemia (SM-AML), 50 (28%) patients with SM associated with myeloproliferative neoplasms (SM-MPN), 24 (13%) patients with SM associated with myelodysplastic syndromes (SM-MDS), 39 (22%) patients with SM associated with chronic myelomonocytic leukemia (SM-CMML) and 54 (30%) patients with SM associated with MDS/MPN/unclassified (SM-MDS/MPN/Unclassified). Figure 1C confirms the survival superiority of SM-AHN-lymphoid, compared to any other specific category of SM-AHN-myeloid. Prognostic comparison in SM-AHN-myeloid (Figure 1C) is confounded by significant variation in age and risk distribution of the specific myeloid components but appears to favor SM-MPN and SM-MDS over other subcategories, including SM-CMML and SM-MDS/MPN/Unclassified (Figure 1C). We conclude that patients with SM-AHN-lymphoid are phenotypically and prognostically different than those with SM-AHN-myeloid and should be cited as such in both clinical practice and future survival studies in SM. Similarly, prognosis in SM-AHN-myeloid appears to be dictated by the specific AHN component, which underscores the need to be more specific in diagnostic assignment and treatment directions. This is particularly important since sensitivity to drug therapy or to other treatment modalities in SM might be different for neoplastic mast cells vs the associated myeloid neoplasm clone.5