Smoldering mastocytosis: Survival comparisons with indolent and aggressive mastocytosis
Authors: Ayalew Tefferi, Sahrish Shah, Kaaren K. Reichard, Curtis A. Hanson, Animesh Pardanani
Journal: American Journal of Hematology (2018)

The 2016 World Health Organization (WHO) system classifies systemic mastocytosis (SM) into five categories: indolent (ISM), smoldering (SSM), SM with an associated hematological neoplasm (SM-AHN), aggressive (ASM), and mast cell leukemia (MCL).1 WHO morphologic distinctions within SM were based on presence or absence of B (high mast cell burden, evidence of nonmast cell morphologic dysplasia or myeloproliferation, organomegaly without functional consequence) and C (cytopenia related to mast cell infiltration, palpable organomegaly with functional consequence, skeletal involvement with large osteolytic lesions, and malabsorption with weight loss secondary to gastrointestinal mast cell infiltrates) findings, presence, or absence of an associated hematological neoplasm, and presence or absence of criteria for MCL (≥20% mast cells on bone marrow aspirate smears or ≥ 10% circulating mast cells).1, 2 In general, C findings are absent in both ISM and SSM and present in ASM; SSM is distinguished from ISM by the presence of ≥2 B findings including high mast cell burden, organomegaly, and evidence for multilineage involvement.3 Given that SSM is clearly distinguished from ISM, as outlined above, we sought to examine the impact of this distinction on survival. The current study was approved by the institutional review board. Study patients were recruited from the Mayo Clinic, Rochester, MN database for SM. Diagnoses of SM and its morphological subcategories were confirmed by both clinical and bone marrow examinations, in line with the 2016 WHO criteria.1 Particular attention was paid to potential C findings, in order to avoid inadvertent labeling of ASM as SSM; patients with subthreshold complete blood counts were scrutinized to clarify the contribution of bone marrow mast cell infiltrates. Next-generation sequencing was performed in a subset of the study population.4 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 survival and comparison of disease features. The JMP Pro 13.0.0 software from SAS Institute, Cary, NC, was used for all analysis. A total of 376 consecutive patients with SSM (n = 17), ISM (n = 274) or ASM (n = 85) constituted the study population. Respective values for SSM vs ISM vs ASM were age 64, 47, and 61 years; male sex percentage 47%, 43%, and 45%; median hemoglobin level 12.6, 14, and 12.3 g/dL; median platelet count 217, 260, and 219 × 109/L; presence of sex-adjusted anemia in 47%, 12%, and 52%; platelet count <150 × 109/L in 13%, 4%, and 27%; serum alkaline phosphatase (ALP) above the upper limit of normal in 82%, 35%, and 71%; and serum albumin <3.5 g/dL in 6%, 12%, and 25%. Among 69 informative cases, adverse mutations (ie, ASXL1, RUNX1, and NRAS) were not seen in 4 SSM or 39 ISM cases but were present in 4 (15%) of 26 patients with ASM. Among 191 patients with available cytogenetic studies, abnormal karyotype was seen in 12 (6%) total patients, including none of 3 cases with SSM, 8 (6%) of 139 cases with ISM, and 4 (8%) of 49 patients with ASM. Compared to ISM, SSM was associated with older age (P < .001) and, as expected from disease definition, with higher bone marrow mast cell burden (P < .001), higher serum tryptase level (<.001), higher prevalence of palpable hepatomegaly (P < .001), and palpable splenomegaly (P < .001; Supporting Information Table S1). SSM, as opposed to ISM, was also associated with adverse disease features including anemia (P = .001), thrombocytopenia (P = .03), and higher serum ALP level (P < .001); in contrast, there was no significant difference in the expression of mast cell mediator symptoms, urticaria pigmentosa, abnormal karyotype or KIT mutational frequency; the number of informative cases was too small to comment of the prevalence of non-KIT mutations, although the higher incidence of TET2 mutations in SSM would be consistent with the observed difference in age distribution (Supporting Information Table S1). In a separate analysis comparing SSM (n = 17) with ASM (n = 85), age distribution was similar (P = .4), as were most other disease features, including prevalence of KIT and non-KIT mutations. After median follow-up of 32 months for ISM, 39 months for SSM, and 26 months for ASM, a total of 86 (23%) deaths and only one (0.3%) leukemic transformation was recorded; the single case of leukemic transformation occurred in a patient with ASM. In univariate analysis, survival appeared significantly shorter in SSM vs ISM (HR 5.5, 95% CI 2.8-10.2) whereas it was similar between SSM and ASM (HR 0.9, 95% CI 0.5-1.8; Figure 1). However, the significant difference in survival between ISM and SSM was not sustained during age-adjusted multivariable analysis that also included other previously established risk factors in SM, which instead confirmed the independent adverse survival effect of advanced age (P < .001) and hemoglobin level below the lower limit of the sex-adjusted hemoglobin level (P < .001). In contrast, the difference in survival between ASM and ISM remained significant during a similar multivariable analysis; HR (95% CI) were 2.0 (1.1-3.5) for ASM vs ISM, 2.2 (1.3-3.8) for sex-adjusted anemia), 2.2 (1.2-3.9) for thrombocytopenia <150 × 109/L, and 2.3 (1.2-4.9) for ALP above upper limit of normal; P value for age as a continuous variable was <.001. The current study highlights the older age distribution of patients with SSM (median 64 years), which was similar to that of patients with ASM (median 61 years) but significantly different than that of patients with ISM (median 47 years). The particular observation underscores the need to account for age when comparing survival between these WHO morphologic categories. The current study also suggests clustering of adverse disease features with SSM, when compared to ISM. Consistent with these differences in phenotype, univariate analysis favored ISM over SSM, in terms of survival. However, the difference in survival was not sustained during age-adjusted multivariable analysis that also included other previously established risk factors. By contrast, a similar analysis confirmed the independent survival effect of ASM, when compared to ISM. These observations suggest that functional consequences rather than mast cell burden dictate prognosis in SM. From a practical standpoint, when confronted with the diagnostic dilemma of distinguishing ISM from SSM, survival prediction appears to depend more on age and the presence or absence of risk factors, rather than the specific morphologic distinction. Finally, we emphasize the need for additional studies with larger number of informative cases, before endorsing the findings in the current study, considering the relatively small sample size.5 Nothing to report. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.