WHO subvariants of indolent mastocytosis: clinical details and prognostic evaluation in 159 consecutive adults.

The 2008 World Health Organization (WHO) proposal recognizes 2 provisional indolent systemic mastocytosis (ISM) subvariants: smoldering systemic mastocytosis (SSM) and isolated bone marrow (BM) mastocytosis (BMM).1 SSM is characterized by a high burden of mast cells (MCs; Table 1), whereas BMM is defined by BM involvement without concurrent skin involvement or presence of multiorgan visceral lesions. To date, prognostic relevance of the proposed ISM subclassification has not been validated by primary data. In the current study, we reviewed clinical/BM data for 159 ISM patients drawn from a previously reported larger study of 342 adult SM patients,2 ensuring that patients were accurately classified into ISM subgroups per the WHO proposal. The current study was approved by the Mayo Clinic institutional review board, and mutational (KITD816V and JAK2V617F) and statistical analyses were performed as previously described.2,3 Twenty-two patients (14%) had SSM, 36 (23%) had BMM, and the remaining 101 (63%) did not fit either category and were designated as “ISM-other” (ISMo; Table 1). Age at presentation was significantly higher in SSM than in BMM or ISMo (median 64, 45, and 48 years, respectively; P .01). SSM patients also displayed significantly higher incidence of constitutional symptoms (45%; P .01), anemia (55%; P .01), and MC mediator levels. The latter correlated with BM MC burden (P .01) but, interestingly, not with MC mediator symptoms, which were more frequent in BMM (86%; P .03). Of the 55 (35%) patients studied, only 1 patient (ISMo) exhibited an abnormal karyotype (46,XX,fra(10)(q25)). Fifty-nine (37%) patients were screened for KITD816V and JAK2V617F. JAK2V617F was universally absent, and KITD816V distribution was as follows: SSM (n 7; 100%), BMM (n 13; 92%), and ISMo (n 39; 69%). At a median follow-up of 27 months (range, 1417 months), 26 deaths (16%) were recorded: ISMo 14 (14%), SSM 10 (46%), and BMM 2 (6%). The combined median survival was 198 months: ISMo 301 months, SSM 120 months, and BMM not reached (P .01). In a multivariable analysis, advanced age was the primary determinant of inferior survival and accounted for the marked difference in survival between SSM and the other 2 groups. Causes of death were available for 14 of the 26 deaths (Table 1); transformation to acute leukemia was seen in 1 patient (SSM) and aggressive systemic mastocytosis (ASM) in 4 patients (3 SSM and 1 ISMo). We recently showed that overall, ISM patients have a life expectancy that is not significantly different from the control population.2 Here, we show that SSM and BMM are not as rare as previously believed and may constitute approximately one-third of all ISM cases. Furthermore, we found no significant association between the incidence of MC mediator symptoms and the level of MC mediators. In fact, there was a strong positive correlation between MC mediator levels and BM MC burden (P .01). Finally, SSM may be distinct from both BMM and ISMo in terms of age distribution and risk of disease transformation. However, given the small number of SSM patients, additional studies are required to clarify the age-independent survival impact of SSM.