Systemic Mastocytosis with Eosinophilia: A Novel Diagnostic Approach To Distinguish Imatinib-Resistant Kit D816V-Associated Mast Cell Disease from Imatinib-Sensitive FIP1L1/PDGFRA-Associated Hypereosinophilic Syndrome.
Authors: Wilson Todd M. , Maric Irina , Klion Amy D. , Akin Cem , Carter Melody , Fu Weiming , Stoddard Jennifer , Scott Linda , Kirshenbaum Arnold , Fay Michael , Nutman Thomas B. , Noel Pierre , Metcalfe Dean D. , Robyn Jamie 
Published: October 2019

Abstract
Systemic mastocytosis (SM) is a clonal myeloproliferative disease with variable clinical manifestations. The D816V mutation in the c-kit gene, present in over 90% of adult patients with SM, results in constitutive activation of the receptor tyrosine kinase and is believed to be related to disease pathogenesis. Although the majority of patients with SM lack peripheral blood eosinophilia, a subgroup exists and is classified as SM with eosinophilia (SM-eo). Recently, several reports of patients with SM-eo described the presence of either the Kit D816V mutation or the FIP1L1/PDGFRA fusion oncogene. Numerous similarities between patients with FIP1L1/PDGFRA and KIT D816V-associated peripheral blood eosinophilia have caused confusion about the management and specifically the role of imatinib in the treatment of these patients. It is of paramount importance to distinguish these two groups with pathologically similar, but molecularly and clinically distinct diseases. We thus compared the clinical, laboratory, and molecular features of 12 patients who met WHO criteria for SM (including presence of the D816V kit mutation) and had associated peripheral eosinophilia with those of 17 patients with peripheral eosinophilia and the FIP1L1/PDGFRA fusion oncogene (diagnosed with HES and evaluated at the same institution) and to the published reports of FIP1L1/PDGFRA-HES patients. Based on these comparisons, a number of clinical features appeared to be of potential use in distinguishing these two disorders. The presence of cardiac symptoms, a total serum tryptase under 60 ng/ml or the presence of either scattered mast cells or loose aggregates was found to be suggestive of FIP1L1/PDGFRA-associated disease. The presence of urticaria pigmentosa, a total serum tryptase over 150 ng/ml, the presence of dense mast cell aggregates and female sex were suggestive of Kit D816V-associated disease. To confirm and standardize this clinical classification, statistical methods were employed to test 21 possible risk factors for their ability to distinguish Kit and FIP1L1/PDGFRA-associated disease. Calculated risk factor scores were developed based on this analysis. Applying this risk factor based system, 16/17 FIP1L1/PDGFRA patients were classified correctly, with one patient neutral and all 12 Kit D816V SM-eo patients were classified correctly. Thirty four FIP1L1/PDGFRA patients in the literature were available for analysis, although all risk factors to create the score were not available for all patients. Despite this, 25/34 FIP1L1/PDGFRA patients were correctly predicted as FIP1L1/PDGFRA, 4/34 patients were neutral and 5/34 were misclassified as Kit D816V-associated SM-eo. These data suggest that the risk factor-based system presented in this study is useful in distinguishing imatinib-sensitive FIP1L1/PDGFRA-associated disease from imatinib-resistant Kit D816V-associated disease.
Parameter SM-eo FIP1L1/PDGFRA HES Number patients 12 17 Male/Female 7/5 17/0 Cardiac symptoms 0/12 6/15 UP 7/12 0/15 Mean serum tryptase (ng/ml) 229 28 (n=13) Dense marrow aggregates 12/12 1/10