scholarly journals Hypereosinophilic Syndrome of Undetermined Significance – Difficulties in Clinical and Therapeutic Approach

2018 ◽  
Vol 15 (4) ◽  
pp. 61-65
Author(s):  
Vlad Florin Anton ◽  
Polliana Mihaela Leru
Keyword(s):  
Systemic Mastocytosis ◽  
Hypereosinophilic Syndrome ◽  
Genetic Mutation ◽  
High Serum ◽  
Parasitic Infections ◽  
High Dose ◽  
Serum Tryptase ◽  
Major Criterion ◽  
Kit D816v

AbstractWe report a case of a 69-year-old woman who is followed since seven years for persistent blood hypereosinophilia up to 5100/mmc. She has been extensively investigated for other diseases known to induce hypereosinophilia, including allergies, parasitic infections and neoplasia. No end-organ dysfunction could be confirmed. We considered a possible primary hypereosinophilic syndrome (HES) and determined the genetic mutation FIP1L1-PDGFRA characteristic for HES, which was negative.Bone marrow showed reactive eosinophilia with no malignant cells and rare mast cells, less than 15 in aggregates, which is the major criterion for diagnosing mastocytosis. Knowing the association between HES and mastocytosis, we measured and found high serum tryptase levels and positive c-kit D816V genetic mutation, characteristic for systemic mastocytosis. The patient was closely monitored, with regular hematologic and clinical evaluation, mainly for cardiac and neurologic manifestations.A short trial of high dose corticotherapy induced remission of hypereosinophilia, but this could not be maintained with lower doses. The clinical outcome during follow-up period was rather good, except mild cognitive decline and atrial fibrillation.The reported case is illustrative for versatile presentation and difficulties in management of hypereosinophilia in clinical practice.

Comprehensive Cytokine Profiling in Systemic Mastocytosis: Prognostic Relevance of Increased Plasma IL-2R Levels.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2836-2836 ◽  
Author(s):  
Animesh Pardanani ◽  
Christy Finke ◽  
Terra L Lasho ◽  
Ayalew Tefferi
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Mast Cell ◽  
Median Survival ◽  
Systemic Mastocytosis ◽  
B Cell Lymphoma ◽  
World Health ◽  
Serum Tryptase ◽  
Who Criteria

Abstract Abstract 2836 Background: The clinical phenotype of systemic mastocytosis (SM) is highly variable; establishing prognosis in terms of overall survival or risk of transformation to aggressive disease for those with non-indolent and indolent disease variants, respectively, is not trivial. Similar to other clonal hemopathies, mast cell (MC) activation and/or stromal response to clonal MC expansion likely results in a dysregulated immuno cellular/cytokine profile; analysis of this aspect of SM may provide additional prognostic information within the context of well established parameters such as the World Health Organization (WHO) SM classification system. Here, we conducted a comprehensive analysis of circulating cytokines/chemokines with clinicopathologic and clinical outcome correlations in a cohort of SM patients seen at our institution. Methods: The diagnosis of SM and its subclassification were established according to WHO criteria. Inclusion in this study required availability of archived plasma, bone marrow biopsy, and cytogenetic information at the time of first referral. Follow up information including data on survival and disease progression were updated in July 2012. Concentrations of plasma cytokines were analyzed in duplicate by using Multiplex Bead-Based Luminex technology (Invitrogen, Carlsbad, CA). Results: Forty six SM patients met the above stipulated criteria; 25 (54%) were male and the median age at referral was 61 years (range 21–85). Subclassification of patients per WHO criteria was: indolent SM (ISM) 23 (50%), aggressive SM (ASM) 8 (17%) and SM with associated clonal hematological non-MC lineage disease (SM-AHNMD) 15 (33%). When the distribution of 30 cytokines was considered across the 3 SM sub groups, only interleukin (IL)-8 was significantly different (SM-AHNMD > ISM/ASM; p=0.0002). For ISM patients, increased levels of sIL-2R were associated with presence of B-findings (p=0.0046) including splenomegaly (p=0.001) and serum tryptase levels >200 ng/mL (p=0.0046), and decreased levels of IL-8 and hepatocyte growth factor (HGF) with MC mediator-release symptoms (p <0.05). Increased levels of sIL-2R (r2=0.6; p<0.0001) and RANTES (r2=0.37; p=0.0013) were correlated with bone marrow MC burden, and sIL-2R (r2=0.34; p=0.004) and MIG (r2=0.42; p=0.0012) with serum tryptase levels in ISM patients; similar findings were noted for the overall cohort. At a median follow up of 28 months (range 0–116), 20 (43%) deaths, and 3 (13%) and 1 (2%) transformations to ASM and mast cell leukemia, respectively, were recorded for the overall cohort. In univariate analysis, increased sIL-2R levels were predictive for inferior overall survival (p=0.005); this prognostic significance was maintained in multivariate analysis after adjusting for other known prognostic variables individually (i.e. WHO SM subtypes, age >65 years, hemoglobin <10 g/dL, thrombocytopenia, weight loss or hypoalbuminemia) (all p <0.05). Increased sIL-2R (>75th percentile) effectively stratified patients in the overall cohort into 2 well-delineated risk groups for overall survival (median survival 109 vs. 26 months; p=0.0004) (Figure). This sIL-2R threshold was also able to risk stratify patients within ISM (median survival not reached vs. 38 months) and non-ISM (median survival 31 vs. 5 months) categories (p <0.0001). Conclusions: The current study demonstrates s-IL2R to be a key inflammatory cytokine in SM; it is significantly correlated with a phenotype of high systemic MC burden and in this regard, is an attractive surrogate for treatment response in clinical practice, if validated. The predictive value of sIL-2R for overall survival is akin to similar observations in primary myelofibrosis and diffuse large B-cell lymphoma; in this study, it was noted to be independent of conventional measures of organopathy from MC infiltration, and thus may reflect a novel pathogenetic process in SM, mediated by dysregulated inflammatory and/or immuno cellular pathways. Disclosures: No relevant conflicts of interest to declare.

KIT D816V Mutation Burden Predicts Prognosis and Survival In Patients With Mastocytosis and Correlates With The WHO Type Of The Disease

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4052-4052
Author(s):  
Gregor Hoermann ◽  
Karoline V. Gleixner ◽  
Graziella E. Dinu ◽  
Georg Greiner ◽  
Friedrich Wimazal ◽  
...  
Keyword(s):  
Prognostic Significance ◽  
Melting Curve ◽  
Curve Analysis ◽  
Melting Curve Analysis ◽  
Serum Tryptase ◽  
Allele Burden ◽  
Mutation Burden ◽  
Kit D816v ◽  
Allelic Burden

Abstract Mastocytosis is characterized by abnormal expansion and accumulation of neoplastic mast cells in one or more organ systems. Traditionally, mastocytosis is divided into cutaneous mastocytosis (CM) and systemic mastocytosis (SM). In most patients with SM, the transforming somatic mutation KIT D816V is detected. However, only few studies have quantified the KIT D816V allele burden in CM and SM. The aim of the present study was to quantify KIT D816V in various forms of mastocytosis and to correlate the allele burden of KIT D816V with the disease category, serum tryptase levels and clinical outcomes. KIT D816V was quantified in bone marrow (BM) and peripheral blood (PB) cells by a real-time PCR (qPCR) assay based on allele-specific primers. In addition, BM and PB cells were also examined for the presence of KIT D816V by melting curve analysis after PCR clamping in all patients. Overall, 225 DNA samples (BM, n=112; PB, n=113) from 107 patients with mastocytosis (females: n=57; males, n=50; median age 49 years; range 18-73 years) were analyzed. Based on WHO criteria, 14 patients had CM, 3 the provisional diagnosis of mastocytosis in the skin (MIS), 66 indolent SM (ISM), 6 smouldering SM (SSM), 7 aggressive SM (ASM), one mast cell leukemia (MCL) and 10 patients SM with an associated hematologic non-mast cell lineage disorder (SM-AHNMD). KIT D816V was found in in 76/107 patients (71%) by melting curve analysis after PCR clamping, and in 92/107 patients (86%) by qPCR (p<0.005). In paired BM and PB samples of 43 patients an excellent correlation of the KIT D816V burden with almost identical results was found (r=0.98, p<0.001). When examining the KIT D816V allele burden in KIT D816V+ patients (n=92) in various categories of the disease, significant differences were found between CM (median KIT D816V allele fraction: 0.042%), MIS (median: 0.084%), ISM (median: 0.286%), SSM (median: 3.012%), ASM (median: 9.346%) and SM-AHNMD (median: 3.761%) (p<0.001). Moreover, we found that the KIT D816V allele burden correlates significantly with the serum tryptase level in our patients (r=0.50, p<0.005). Consecutive studies revealed that the KIT D816V allele fraction is of prognostic significance concerning survival as determined by Cox regression (p=0.015). As assessed by Kaplan Meier estimates and log rank testing, patients with a KIT D816V allele burden of ≥2% were found to have a significantly shorter survival than those with an allele burden of less than 2% (p=0.001) (Figure 1). Thirty patients were evaluated at diagnosis and during the follow up. In untreated patients with stable disease, the KIT D816V allele burden remained within a constant range. By contrast, in patients with disease progression, an increase in the KIT D816V burden over time was detectable. In patients responding to cytoreductive agents (cladribine n=4; hydroxyurea n=1) a significant decrease in the median KIT D816V allele burden (by 91.6%) after therapy compared to pre-therapeutic samples was observed (p=0.027). In summary, our data show that qPCR is a highly sensitive approach for the detection and quantification of KIT D816V in patients with mastocytosis and that the KIT D816V mutation burden differs significantly among patients in different WHO subtypes. Moreover, the KIT D816V allele burden correlates with serum tryptase levels and is of prognostic significance concerning survival in patients with mastocytosis. Finally, quantification of KIT D816V may serve as follow up parameter useful for determining the natural course and treatment responses in patients with mastocytosis. We recommend that the KIT D816V mutation burden is included as a novel parameter in daily practice and clinical trials in advanced SM.Figure 1Overall survival of patients with KIT D816V+ mastocytosis. Patients were split into those with a KIT D816V allele burden of<2% and those with an allelic burden of ≥2%. Survival was estimated by the method of Kaplan and Meier (p=0.001).Figure 1. Overall survival of patients with KIT D816V+ mastocytosis. Patients were split into those with a KIT D816V allele burden of<2% and those with an allelic burden of ≥2%. Survival was estimated by the method of Kaplan and Meier (p=0.001). Disclosures: Valent: Novartis: Consultancy, Honoraria, Research Funding.

KIT D816V and JAK2 V617F Point Mutations Are Recurrently Found In Suspected Hypereosinophilic Syndrome

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4100-4100
Author(s):  
Juliana Popa ◽  
Philipp Erben ◽  
Georgia Metzgeroth ◽  
Georg Bolz ◽  
Martin C Mueller ◽  
...  
Keyword(s):  
Clinical Features ◽  
Hypereosinophilic Syndrome ◽  
Point Mutations ◽  
Jak2 V617f ◽  
Molecular Testing ◽  
Rt Pcr ◽  
Serum Tryptase ◽  
Molecular Abnormalities ◽  
Number Of Patients ◽  
Kit D816v

Abstract Abstract 4100 In some patients with suspected hypereosinophilic syndrome (HES), clonality of eosinophils may be proven by identification of an acquired chromosome or molecular abnormality leading to the diagnosis of chronic eosinophilic leukemia (CEL). The most common molecular aberrations are fusion genes with involvement of PDGFRA, e.g. FIP1L1-PDGFRA (FP), or PDGFRB, e.g. ETV6-PDGFRB. Molecular testing for FP by RT-PCR or FISH is nowadays performed early in the diagnostic work-up of suspected non-reactive eosinophilia. However, eosinophilia is also present at variable frequency in patients with systemic mastocytosis (SM) and other subtypes of myeloproliferative neoplasms (MPN). Recurrent molecular markers for those entities are KIT D816V (80-90% positivity in SM) and JAK2 V617F (60-70% positivity in MPN). We therefore sought to evaluate the relative frequency of FP (by RT-PCR), KIT D816V (by D-HPLC plus direct sequencing) and JAK2 V617F (by ARMS-PCR) in 300 samples from patients with suspected HES/CEL and to correlate molecular findings with clinical features. Molecular abnormalities were identified in 42 (14%) cases; 22 (7.3%) were positive for FP, 14 (4.6%) for KIT D816V and 6 (2.0%) for JAK2 V617F, respectively. Most baseline clinical characteristics, e.g. leukocytes, absolute and relative number of eosinophils, hemoglobin, platelets or splenomegaly, were not different between the three entities. Significant differences were found regarding age, gender, serum tryptase levels and course of disease. FP positive patients were significantly younger (p<0.001) and exclusively male while a female prepoderance was observed for KIT and JAK2 mutated patients. Significantly elevated serum tryptase levels (normal value <11.4μ g/l) were found in all cases of FP and KIT D816V positive patients. However, serum tryptase levels >50μ g/l were almost exclusively seen in KIT D816V positive SM patients. Aggressive SM (ASM) was diagnosed in 6 of 14 (43%) KIT D816V positive patients due to characteristic bone marrow morphology and the presence of diverse C-findings (e.g. anemia <10g/dl, n=2, and/or thrombocytopenia <100×109/μ l, n=7). Frequent additional clinical features included lymphadenopathy (n=9) and urticaria pigmentosa (n=6). Two ASM patients died within first year of diagnosis while 21 (95%) FP positive CEL patients are in complete molecular remission on imatinib after a median treatment time of 28 months (range 8–149). We conclude that the serum tryptase level is an important diagnostic and prognostic marker in eosinophilia. We suggest that FP negative HES patients should be screened for KIT D816V and JAK2 V617F point mutations, both of which are potentially targetable by small molecule inhibitors. FIP1L1-PDGFRA KIT D816V JAK2 V617F Number of patients 22 (7.3%) 14 (4.6%) 6 (2.0%) Age (median, years) 4418–73 6342–81 7269–87 Gender (m/f) 22/0 6/8 4/6 Leukocytes (median, range, ×109/l) 13.57.2–85.6 10.06.8–124.0 26.812.7–61.1 Eosinophil (median, range, ×109/l) 6.51.4–34.8 2.21.2–100.0 10.03.2–16.5 Eosinophils (%) 469–74 246–81 378–61 Hemoglobin (median, range, g/dl) 12.67.1–15.8 11.77.9–15.7 13.511.4–16.2 Platelets (median, range, ×109/l) 16034–375 11215–945 17434–364 Splenomegaly 14/14 (100%) 13/13 (100%) 4/4 (100%) Serum tryptase >50μ g/l 1/13 (8%) 8/9 (88%) not done >100μ g/l 0/13 (-) 7/7 (100%) not done Disclosures: Erben: Novartis: Honoraria, Research Funding.

Idiopathic anaphylaxis

2019 ◽  
Vol 40 (6) ◽  
pp. 457-461
Author(s):  
Canting Guo ◽  
Paul A. Greenberger
Keyword(s):  
Systemic Mastocytosis ◽  
Clinical Manifestations ◽  
Panic Attacks ◽  
Serum Tryptase ◽  
C1 Esterase Inhibitor ◽  
Disease Modifying Therapy ◽  
Indolent Systemic Mastocytosis ◽  
Idiopathic Anaphylaxis ◽  
Esterase Inhibitor

Idiopathic anaphylaxis (IA) is defined as anaphylaxis without any identifiable precipitating agent or event. The clinical manifestations of IA are the same as allergen-associated (immunologic) anaphylaxis and include urticaria, angioedema, hypotension, tachycardia, wheezing, stridor, pruritus, nausea, vomiting, flushing, diarrhea, dysphagia, light-headedness, and loss of consciousness. Patients usually tend to have the same manifestations on repeated episodes. IA is a prednisone-responsive disease that is ultimately a diagnosis of exclusion. Approximately 40% of patients are atopic. Serum tryptase (or urine histamine or its metabolite) will be elevated acutely, but, if elevated in the absence of anaphylaxis, should suggest alternative diagnoses, including indolent systemic mastocytosis. A focused history, examination, and follow-up will dictate whether a patient's symptoms may be attributable to disorders that mimic anaphylaxis, such as indolent systemic mastocytosis, carcinoid syndrome, pheochromocytoma, hereditary angioedema or acquired C1 esterase inhibitor deficiency, or panic attacks. The presence of urticaria may help limit the differential diagnosis because urticaria does not usually accompany any of the above-mentioned disorders, except for indolent systemic mastocytosis. IA is classified according to the symptoms as well as the frequency of attacks. Patients who experience six or more episodes in a year, or two or more episodes in 2 months are classified as having IA-frequent (IA-F). Patients who experience fewer episodes are classified as having IA-infrequent (IA-I). This distinction is important because patients with IA-F will initially require prednisone as disease-modifying therapy, whereas most patients who with IA-I will not require prednisone. Patients with IA must carry and know when and how to self-administer epinephrine.

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.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2683-2683
Author(s):  
Todd M. Wilson ◽  
Irina Maric ◽  
Amy D. Klion ◽  
Cem Akin ◽  
Melody Carter ◽  
...  
Keyword(s):  
Risk Factor ◽  
Systemic Mastocytosis ◽  
Total Serum ◽  
Peripheral Eosinophilia ◽  
Serum Tryptase ◽  
Blood Eosinophilia ◽  
Cardiac Symptoms ◽  
Imatinib Resistant ◽  
Kit D816v ◽  
Peripheral Blood Eosinophilia

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

Detection of c-Kit Mutation in Peripheral Blood vs. Bone Marrow Aspirates in Patients with Systemic Mastocytosis: Comparison Study of Pathological and Clinical Laboratory Findings in Patients with and without Detectable c-Kit Mutation in the Peripheral Blood.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3596-3596 ◽  
Author(s):  
Irina Maric ◽  
Jamie Robyn ◽  
Weiming Fu ◽  
Jennifer Stoddard ◽  
Dean D. Metcalfe ◽  
...  
Keyword(s):  
Mast Cells ◽  
Peripheral Blood ◽  
Mutational Analysis ◽  
Clinical Laboratory ◽  
Systemic Mastocytosis ◽  
Flow Cytometric Analysis ◽  
Serum Tryptase ◽  
Kit Mutation ◽  
Flow Cytometric ◽  
Kit D816v

Abstract The identification of the KIT D816V mutation in patients with systemic mastocytosis (SM) has lately gained a major prognostic significance, largely because of the availability of tyrosine kinase receptor inhibitors such as imatinib. Imatinib was shown to be ineffective in patients carrying KIT D816V mutation, but effective in cases with some other c-kit mutations. Therefore, it is of paramount importance to correctly identify SM patients with KIT D816V mutation. However, the reported frequency of the KIT D816V mutation in SM patients is highly variable in the literature (30%-over 95%). It has been suggested that such variability is due to patient selection, sensitivity of the molecular methods used to detect the mutation or the source of the tested specimen (peripheral blood (PB) vs. bone marrow (BM) aspirate). To date, there has been no systematic study comparing PB and BM mutational findings in SM patients. In this study, we performed mutational analysis of both PB and BM samples in SM patients and compared the results with pathological, clinical laboratory and flow cytometric findings in patients with and without a detectable c-kit mutation in PB. We analyzed in parallel BM aspirates and PB from 55 patients who came to our clinic for evaluation of SM. After diagnostic workup (physical evaluation, measurement of serum tryptase level, study of BM biopsy, flow cytometric analysis of mast cells and mutational analysis by RT-PCR/RFLP), 46 of 55 patients were diagnosed with SM using the WHO diagnostic criteria. Nine patients did not fulfill the WHO diagnostic criteria for SM and all tested negative for c-kit mutation. Out of 46 patients diagnosed with SM, all but two patients (44/46; 95.6%) tested positive for KIT D816V mutation in the BM aspirate, but only 9/46 patients (19.5%) had the mutation detectable in the PB. Two patients who tested negative for KIT D816V mutation in the BM were shown to carry different c-kit mutation by sequencing. No tested patients carried the FIP1L1-PDGFRa fusion gene. 42/46 patients (91%) fulfilled major WHO pathological criteria for diagnosis of SM (dense mast cell aggregates in the BM biopsy). The other 9% had increased atypical spindle-shaped mast cells in the BM biopsy without dense aggregates. Flow cytometric analysis of PB showed no significant increase in circulating mast cells in patients with a detectable KIT D816V mutation in PB (average less than 0.01% mast cells). Comparison of patients with and without a detectable PB mutation showed more extensive BM biopsy involvement by mast cells in PB positive patients (average 45% vs. 15%), higher average serum tryptase levels (266 ng/ml vs. 85 ng/ml) and higher average PB absolute eosinophil counts (710 vs. 234/uL). Flow cytometric analysis of BM mast cells showed that 100% of KIT D816V positive patients had aberrant CD25 expression on mast cells. CD2 expression was more variable, but comparable in both groups of patents (67% vs. 69%). We conclude that the source of the specimen for c-kit analysis is of crucial importance for correct diagnosis, and recommend that all patients with suspected SM should always have BM aspirates tested for the KIT D816V mutation. PB testing yields falsely negative results in over 80% of cases and identifies only SM patients with a markedly increased mast cell burden.

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