Prevalence of hypersensitivity reactions in various forms of mastocytosis: A pilot study of 2485 adult patients with mastocytosis collected in the ECNM registry.

BACKGROUND: Hypersensitivity reactions (HR) are common in mastocytosis. However, little is known about triggers and risk factors. The registry of the European Competence Network on Mastocytosis (ECNM) enables reliable studies in a larger cohort of mastocytosis patients. We assessed prevalence, triggers and risk factors of HR in adults with mastocytosis in the ECNM registry. METHODS: Data were collected in 27 ECNM centers. We analyzed potential triggers (Hymenoptera venoms, food, drug, inhalant and others) and risk factors at diagnosis and during follow-up. The study group consisted of 2485 adults with mastocytosis, 1379 women (55.5%) and 1106 men (44.5%). Median age was 48.2 years (range 18-91 years). RESULTS: Nine hundred and forty eight patients (38.1%) reported one or more HR`. Most common triggers were Hymenoptera venoms in cutaneous mastocytosis (CM) and indolent systemic mastocytosis (ISM), whereas in advanced SM (advSM), most common elicitors were drugs, including nonsteroidal anti-inflammatory agents and penicillin. In multivariate analyses, tryptase level < 90 ng/mL, <15% infiltration by mast cells in bone marrow biopsy-sections, and diagnosis of ISM were identified as independent risk factors for HR. For drug-induced HR, prominent risk factors were advSM and high tryptase levels. New reactions were observed in 4.8% of all patients during 4 years follow-up. CONCLUSIONS: HR are mainly triggered by Hymenoptera venoms in patients with CM and ISM and by drugs in patients with advSM. Tryptase levels <90 ng/mL, mast cell bone marrow infiltration <15%, and WHO category ISM are predictors of HR. New HR occur in 4.8% of all patients within 4 years.

Serum chemistry profiling and prognostication in systemic mastocytosis: a registry-based study of the ECNM and GREM.

Certain laboratory abnormalities correlate with subvariants of systemic mastocytosis (SM) and are often prognostically relevant. To assess the diagnostic and prognostic value of individual serum chemistry parameters in SM, 2607 patients enrolled within the European Competence Network on Mastocytosis (ECNM) and 575 patients enrolled within the German Registry on Eosinophils and Mast Cells (GREM) were analyzed. For screening and diagnosis of SM, tryptase was identified as the most specific serum parameter. For differentiation between indolent and advanced SM (AdvSM), the following serum parameters were most relevant: tryptase, alkaline phosphatase (AP), ß2-microglobulin, lactate dehydrogenase (LDH), albumin, vitamin B12, and C-reactive protein (P<0.001). With regard to subvariants of AdvSM, an elevated LDH ≥260U/L was associated with multi-lineage expansion (leukocytosis, r=0.37, P<0.001; monocytosis, r=0.26, P<0.001) and the presence of an associated myeloid neoplasm (P<0.001), whereas tryptase levels were highest in mast cell leukemia (MCL vs. non-MCL, 308 µg/L vs. 146 µg/L, P=0.003). Based on multivariable analysis, the hazard-risk weighted assignment of 1 point to lactate dehydrogenase (HR 2.1 [95% CI 1.1-4.0], P=0.018) and 1.5 points each to ß2-microglobulin (HR 2.7 [95% CI 1.4-5.4], P=0.004) and albumin (HR 3.3 [95% CI 1.7-6.5], P=0.001) delineated a highly predictive three-tier risk classification system (0 points, 8.1 years vs. 1 point, 2.5 years, ≥1.5 points, 1.7 years; P<0.001). Moreover, serum chemistry parameters enabled further stratification of IPSM-AdvSM1/2 risk-score classified patients (P=0.027). In conclusion, serum chemistry profiling is a crucial tool in the clinical practice supporting diagnosis and prognostication of SM and its subvariants.

Effect of hypoxia on HIF-1α and NOS3 expressions in CD34+ cells of JAK2V617F-positive myeloproliferative neoplasms.

PURPOSE: Myeloproliferative neoplasms (MPN) are a heterogeneous group of hematopoietic stem-cell diseases with excessive proliferation of one or more blood cell lines. In this study, we evaluated the effect of different oxygen concentrations on HIF-1α and NOS3 gene expression to determine the effect of the bone marrow microenvironment on JAK2V617F positive Philadelphia chromosome negative (Ph-) MPNs. PATIENTS AND METHODS: Peripheral blood mononuclear cells (MNC) of 12 patients with Ph- MPN were collected. The presence of JAK2V617F allele status was determined with allele-specific nested PCR analysis. MPN CD34+ and CD34depleted populations were isolated from MNC by magnetic beads. Separate cell cultures of CD34+/depleted populations were managed at different oxygen concentrations including anoxia (∼0%), hypoxia (∼3%), and normoxia (∼20%) conditions for 24 â€‹h. HIF-1α and NOS3 gene expression changes were examined in each population related to JAK2V617F status with real time RT-PCR. RESULT: It was revealed that relative HIF-1α and NOS3 expressions were significantly increased in response to decreased oxygen concentration in all samples. Relative HIF-1α and NOS3 expressions were found to be higher especially in CD34+ and CD34depleted populations carrying JAK2V617F mutations compared to MPN patients carrying wild-type JAK2. CONCLUSION: JAK2V617F might have specific role in HIF-1α and NOS3 regulations with respect to low oxygen concentrations in Ph- MPN. Further evaluations might reveal the effect of JAK2V617F on Ph- MPN pathogenesis in bone marrow microenvironment.

Comprehensive mastocytosis data analysis from a single center.

Mastocytosis is a very rare disorder and is divided into three prognostically distinct variants by World Health Organization: Cutaneous mastocytosis (CM), systemic mastocytosis (SM), and mast cell sarcoma or localized mast cell (MC) tumors. The wide range of complaints may cause patients to consult various clinics, with resulting mis- or underdiagnosis. Therefore, cooperation between different subspecialties is of paramount importance. In this article, we have compiled 104 adult mastocytosis cases diagnosed and followed in our Hematology and other clinics. 86 (82.7%) of 104 patients had systemic mastocytosis. Osteoporosis, disease-related complications, and secondary malignancies are important topics in this group. We know that indolent form has great survival. But smoldering or aggressive mastocytosis has a poor prognosis. CM and indolent SM have a significantly better prognosis compared to aggressive SM (p < 0.001). We found that the presence of more than 25% of mast cells in the bone marrow, the presence of concomitant marrow dysplasia, and the presence of disease-related complications affect survival (p < 0.001). In addition to the WHO classification, the IPSM scoring system is indicative of the prognosis in this rare disease.

Prognostic Impact of Organomegaly in Mastocytosis: An Analysis of the European Competence Network on Mastocytosis.

BACKGROUND: Organomegaly, including splenomegaly, hepatomegaly, and/or lymphadenopathy, are important diagnostic and prognostic features in patients with cutaneous mastocytosis (CM) or systemic mastocytosis (SM). OBJECTIVES: To investigate the prevalence and prognostic impact of 1 or more organomegalies on clinical course and survival in patients with CM/SM. METHODS: Therefore, 3155 patients with CM (n = 1002 [32%]) or SM (n = 2153 [68%]) enrolled within the registry of the European Competence Network on Mastocytosis were analyzed. RESULTS: Overall survival (OS) was adversely affected by the number of organomegalies (OS: #0 vs #1 hazard ratio [HR], 4.9; 95% CI, 3.4-7.1, P < .001; #1 vs #2 HR, 2.1, 95% CI, 1.4-3.1, P < .001; #2 vs #3 HR, 1.7, 95% CI, 1.2-2.5, P = .004). Lymphadenopathy was frequently detected in patients with smoldering SM (SSM, 18 of 60 [30%]) or advanced SM (AdvSM, 137 of 344 [40%]). Its presence confered an inferior outcome in patients with AdvSM compared with patients with AdvSM without lymphadenopathy (median OS, 3.8 vs 2.6 years; HR, 1.6; 95% CI, 1.2-2.2; P = .003). OS was not different between patients having organomegaly with either ISM or SSM (median, 25.5 years vs not reached; P = .435). At time of disease progression, a new occurrence of any organomegaly was observed in 17 of 40 (43%) patients with ISM, 4 of 10 (40%) patients with SSM, and 33 of 86 (38%) patients with AdvSM, respectively. CONCLUSIONS: Organomegalies including lymphadenopathy are often found in SSM and AdvSM. ISM with organomegaly has a similar course and prognosis compared with SSM. The number of organomegalies is adversely associated with OS. A new occurrence of organomegaly in all variants of SM may indicate disease progression.

Circulating CD133+/­CD34­ Have Increased c-MYC Expression in Myeloproliferative Neoplasms

Objective: Myeloproliferative neoplasms (MPNs) are hematopoietic stem cell (HSC)-originated diseases with clonal myeloproliferation. The constitutive activation of the JAK/STAT pathway is frequently detected in patients with Philadelphia chromosome-negative (Ph­) MPNs with an acquired JAK2V617F mutation. The c-MYC proto-oncogene is associated with malignant growth and cellular transformation, and JAK2V617F was previously shown to induce constitutive expression of c-MYC. This study examines the expressional profile of c-MYC in Ph­ MPNs with JAK2V617F and highlights its hierarchical level of activation in circulating hematopoietic stem/progenitor cell (HSPC) subgroups. Materials and Methods: Mononuclear cells (MNCs) of Ph­ MPNs were fluorochrome-labeled in situ with wild-type (wt) JAK2 or JAK2V617F mRNA gold nanoparticle technology and sorted simultaneously. Isolated populations of JAK2wt or JAK2V617F were evaluated for their c-MYC expressions. The MNCs of 14 Ph­ MPNs were further isolated for the study of HSPC subgroups regarding their CD34 and CD133 expressions, evaluated for the presence of JAK2V617F, and compared to cord blood (CB) counterparts for the expression of c-MYC. Results: The mRNA-labeled gold nanoparticle-treated MNCs were determined to have the highest ratio of c-MYC relative fold-change expression in the biallelic JAK2V617F compartment compared to JAK2wt. The relative c-MYC expression in MNCs of MPNs was significantly increased compared to CB (p=0.01). The circulating HSPCs of CD133+/­CD34− MPNs had statistically significantly elevated c-MYC expression compared to CB. Conclusion: This is the first study of circulating CD133+/­CD34− cells in Ph­ MPNs and it has revealed elevated c-MYC expression levels in HSCs/endothelial progenitor cells (HSCs/EPCs) and EPCs. Furthermore, the steady increase in the expression of c-MYC within MNCs carrying no mutations and monoallelic or biallelic JAK2V617F transcripts was notable. The presence of JAK2V617F with respect to c-MYC expression in the circulating HSCs/EPCs and EPCs of MPNs might provide some evidence for the initiation of JAK2V617F and propagation of disease. Further studies are needed to clarify the implications of increased c-MYC expression in such populations.

Mast cell leukemia: clinical and molecular features and survival outcomes of patients in the ECNM Registry.

Mast cell leukemia (MCL) is a rare subtype of systemic mastocytosis defined by ≥20% mast cells (MC) on a bone marrow aspirate. We evaluated 92 patients with MCL from the European Competence Network on Mastocytosis registry. Thirty-one (34%) patients had a diagnosis of MCL with an associated hematologic neoplasm (MCL-AHN). Chronic MCL (lack of C-findings) comprised 14% of patients, and only 4.5% had "leukemic MCL" (≥10% circulating MCs). KIT D816V was found in 62/85 (73%) evaluable patients; 9 (11%) individuals exhibited alternative KIT mutations, and no KIT variants were detected in 14 (17%) subjects. Ten evaluable patients (17%) had an abnormal karyotype and the poor-risk SRSF2, ASXL1, and RUNX1 (S/A/R) mutations were identified in 16/36 (44%) patients who underwent next-generation sequencing. Midostaurin was the most common therapy administered to 65% of patients and 45% as first-line therapy. The median overall survival (OS) was 1.6 years. In multivariate analysis (S/A/R mutations excluded owing to low event rates), a diagnosis of MCL-AHN (hazard ratio [HR], 4.7; 95% confidence interval [CI], 1.7-13.0; P = .001) and abnormal karyotype (HR, 5.6; 95% CI, 1.4-13.3; P = .02) were associated with inferior OS; KIT D816V positivity (HR, 0.33; 95% CI, 0.11-0.98; P = .04) and midostaurin treatment (HR, 0.32; 95% CI, 0.08-0.72; P = .008) were associated with superior OS. These data provide the most comprehensive snapshot of the clinicopathologic, molecular, and treatment landscape of MCL to date, and should help further inform subtyping and prognostication of MCL.

OCT-1 Expression in Patients with Chronic Myeloid Leukemia: A Comparative Analysis with Respect to Response to Imatinib Treatment.

The introduction of tyrosine kinase inhibitors (TKI) has resulted in a significant improvement in the treatment of CML patients. However, some CML patients are resistant to imatinib therapy, the initial TKI therapy in the CML. Therefore, it is important to find prognostic markers for resistance. The OCT-1 gene involved in imatinib uptake is also suspected to cause imatinib resistance. The aim of this study was to investigate the role of OCT-1 in imatinib resistance by comparing OCT-1 expression levels in imatinib resistant and imatinib sensitive patients with chronic myeloid leukemia (CML). This study was conducted on 101 patients with CML [imatinib sensitive (n = 51) and imatinib resistant (n = 50)] who were treated with imatinib. Gene expression analysis was done using QRT-PCR. The relative expression levels of OCT-1 were calculated using 2(-ΔΔCT) method. OCT1 mRNA expression levels were 0.149 (0.011-2.532) and 0.119 (0.008-2.868) in imatinib-sensitive group and imatinib-resistant group, respectively. OCT-1 expression levels were not significantly different in the imatinib-sensitive group when compared to imatinib resistant group (p > 0.05). OCT-1 expression was also similar in BCR-ABL1 kinase domain mutation positive and negative cases (p > 0.05). The imatinib-resistant group had a higher rate of hydroxyurea or interferon-alpha treatment prior to imatinib therapy and a lower rate for first-line imatinib as the only treatment than the imatinib-sensitive group (p = 0.002 and p = 0.002, respectively). According to the results of our study, OCT-1 does not have a biomarker feature in the evaluation of imatinib response. In addition, the study should be performed in larger patient groups.

Refined diagnostic criteria for bone marrow mastocytosis: a proposal of the European competence network on mastocytosis.

In the current classification of the World Health Organization (WHO), bone marrow mastocytosis (BMM) is a provisional variant of indolent systemic mastocytosis (ISM) defined by bone marrow involvement and absence of skin lesions. However, no additional diagnostic criteria for BMM have been proposed. Within the registry dataset of the European Competence Network on Mastocytosis, we compared characteristics and outcomes of 390 patients with BMM and 1175 patients with typical ISM. BMM patients were significantly older, predominantly male, had lower tryptase and lower burden of neoplastic mast cells, and displayed a higher frequency of allergic reactions, mainly triggered by Hymenoptera, than patients with typical ISM. The estimated 10-year progression-free survival of BMM and typical ISM was 95.9% and 92.6%, respectively. In BMM patients defined by WHO-based criteria, the presence of one B-Finding and tryptase level ≥125 ng/mL were identified as risk factors for progression in multivariate analyses. BMM patients without any of these risk factors were found to have better progression-free survival (p < 0.05) and better overall survival (p < 0.05) than other ISM patients. These data support the proposal to define BMM as a separate SM variant characterized by SM criteria, absence of skin lesions, absence of B-Findings, and tryptase levels <125 ng/mL.

Overview of clinical and genetic features of CML patients with variant Philadelphia translocations involving chromosome 7: A case series.

Variant Philadelphia (Ph) translocations involving chromosome 7 are rarely seen in Chronic Myeloid Leukemia (CML) patients. It is aimed to contribute new cases to the literature by reviewing the cases in our archive and shed light into the understanding of the role of chromosome 7 in CML. This study was carried out in 237 newly diagnosed CML patients with variant Ph translocations. Among the patients, those with variant Ph translocation involving chromosome 7 were evaluated in terms of clinical and genetic characteristics. Chromosome analysis was performed on 24 and 48 h of bone marrow cultures. FISH analysis was performed with BCR-ABL1 dual color dual fusion translocation probes. BCR-ABL1 transcript levels were analysed by QRT-PCR and results were reported as BCR-ABL1/ABL1 (BCR-ABL1 (IS) %) according to international scale. Four of the patients had variant Ph translocations including chromosome 7. The karyotypes were 46,XX,t(7;9;22)(p13;q34;q11); 46,XX,t(7;9;22)(p21;q34;q11); 46,XX,t(7;9;22)(q22;q34;q11) and 46,XY,t(7;9;22)(q22;q34;q11). The breakpoints demonstrated by cytogenetic analysis were confirmed by FISH analysis. Monitoring by QRT-PCR showed that patients with variant Ph translocation including 7p13 and 7p21 had a dramatic decrease in BCR-ABL1 levels resulting in complete hematological, complete cytogenetic and deep molecular responses. Despite achieving complete hematological, complete cytogenetic response in two patients with variant Philadelphia translocation, including 7q22, no major molecular response was achieved and both patients are still in the warning category. Response to tyrosine kinase inhibitör therapy may be associated with both the variant translocation mechanism and new gene interactions that occur due to the breakpoints of additional chromosomes involved in translocation.

Impaired endothelial function irrespective of systemic inflammation or atherosclerosis in mastocytosis.

BACKGROUND: Knowledge on endothelial dysfunction and its relation to atherosclerosis in mastocytosis is limited. OBJECTIVE: To investigate the endothelial function in mastocytosis by flow-mediated dilatation (FMD) and biomarkers related to vascular endothelia and to evaluate its relationship with the presence of subclinical atherosclerosis by carotid intima media thickness (CIMT). METHODS: A total of 49 patients with mastocytosis and 25 healthy controls (HCs) were included. The FMD and CIMT during transthoracic echocardiography biomarkers including endocan, endothelin-1, and vascular endothelial growth factor (VEGF) were measured in the sera of participants. Tumor necrosis factor-alpha, interleukin 6, and high-sensitive C-reactive protein were determined as inflammatory biomarkers. RESULTS: The mean FMD % was lower in the patients than HCs (11.26% ± 5.85% vs 17.84% ± 5.27% P < .001) and was the lowest in the advanced systemic mastocytosis and smoldering systemic mastocytosis group among the patients (P = .03). The median value of VEGF was considerably higher in patients than HCs (73.30 pg/mL; minimum-maximum 32.46-295.29 pg/mL vs 46.64 pg/mL; minimum-maximum, 11.09-99.86 pg/mL; P = .001) and it was the highest in the advanced systemic mastocytosis and smoldering systemic mastocytosis group (P = .01). The FMD was inversely correlated with endocan (r = -0.390; P = .006), endothelin-1 (r = -0.363; P = .01) and VEGF (r = -0.402; P = .004) but there were no correlations between FMD and tumor necrosis factor-alpha, interleukin 6, and high-sensitive C-reactive protein. No differences in CIMT values between patients and HCs and no correlation between CIMT and the biomarkers were observed. CONCLUSION: Endothelial dysfunction in mastocytosis becomes evident with decreased FMD and elevated serum VEGF in the absence of atherosclerosis or systemic inflammation and is related to disease severity.

Cytogenetic and molecular aberrations and worse outcome for male patients in systemic mastocytosis.

In systemic mastocytosis (SM), the clinical features and survival vary greatly. Patient-related factors determining the outcome in SM are largely unknown. Methods: We examined the impact of sex on the clinical features, progression-free survival (PFS), and overall survival (OS) in 3403 patients with mastocytosis collected in the registry of the European Competence Network on Mastocytosis (ECNM). The impact of cytogenetic and molecular genetic aberrations on sex differences was analyzed in a subset of patients. Results: Of all patients enrolled, 55.3% were females. However, a male predominance was found in a subset of advanced SM (AdvSM) patients, namely SM with an associated hematologic neoplasm (SM-AHN, 70%; p < 0.001). Correspondingly, organomegaly (male: 23% vs. female: 13%, p = 0.007) was more, whereas skin involvement (male: 71% vs. female: 86%, p = 0.001) was less frequent in males. In all patients together, OS (p < 0.0001) was significantly inferior in males, and also within the WHO sub-categories indolent SM, aggressive SM (ASM) and SM-AHN. PFS was significantly (p = 0.0002) worse in males when all patients were grouped together; due to low numbers of events, this significance persisted only in the subcategory smoldering SM. Finally, prognostically relevant cytogenetic abnormalities (10% vs. 5%, p = 0.006) or molecular aberrations (SRSF2/ASXL1/RUNX1 profile; 63% vs. 40%, p = 0.003) were more frequently present in males. Conclusions: Male sex has a major impact on clinical features, disease progression, and survival in mastocytosis. Male patients have an inferior survival, which seems related to the fact that they more frequently develop a multi-mutated AdvSM associated with a high-risk molecular background.

Graft-versus-mastocytosis effect after donor lymphocyte infusion: Proof of principle.

Advanced systemic mastocytosis is a relatively rare entity where allogeneic stem cell transplantation can lead to the cure of the disease in selected patients. Delayed incomplete responses with graft-versus-mastocytosis effect were published in a few cases. In this particular patient's report, we describe the direct evidence and potency of graft-versus-mastocytosis effect of donor lymphocyte infusions in a patient with systemic mastocytosis with associated hematological neoplasm (SM-AHN). In a 53-year-old female patient, an allogeneic stem cell transplantation after conventional induction treatment was performed for transformed acute myeloid leukemia (AML) during the course of polycythemia vera. After 6 years of remission period of AML and PV, the patient developed aleukemic mast cell leukemia and JAK2-positive myeloproliferative neoplasm (SM-AHN). We were able to achieve a sustained complete remission of SM-AHN lasting for 6 years with only donor lymphocyte infusions in a status of mixed chimerism. The patient is in a good clinical condition and remission. The potent graft-versus-mastocytosis effect in this patient resembles the favorable effect of donor lymphocyte infusions in relapsing chronic myeloid leukemia patients after transplantation. This patient is, to our knowledge, the first case showing the proof of principle of graft-versus-mastocytosis effect.

Scoring the Risk of Having Systemic Mastocytosis in Adult Patients with Mastocytosis in the Skin.

BACKGROUND: Mastocytosis in adults often presents with skin lesions. A bone marrow biopsy is necessary to confirm or exclude the presence of systemic mastocytosis (SM) in these cases. When a bone marrow biopsy is not performed, the provisional diagnosis is mastocytosis in the skin (MIS). No generally accepted scoring system has been established to estimate the risk of SM in these patients. OBJECTIVE: To develop a risk score to predict SM in adults with MIS. METHODS: We examined 1145 patients with MIS from the European Competence Network on Mastocytosis Registry who underwent a bone marrow biopsy. A total of 944 patients had SM and 201 patients had cutaneous mastocytosis; 63.7% were female, and 36.3% were male. Median age was 44 ± 13.3 years. The median serum tryptase level amounted to 29.3 ± 81.9 ng/mL. We established a multivariate regression model using the whole population of patients as a training and validation set (bootstrapping). A risk score was developed and validated with receiver-operating curves. RESULTS: In the multivariate model, the tryptase level (P < .001), constitutional/cardiovascular symptoms (P = .014), and bone symptoms/osteoporosis (P < .001) were independent predictors of SM (P < .001; sensitivity, 90.7%; specificity, 69.1%). A 6-point risk score was established (risk, 10.7%-98.0%) and validated. CONCLUSIONS: Using a large data set of the European Competence Network on Mastocytosis Registry, we created a risk score to predict the presence of SM in patients with MIS. Although the score will need further validation in independent cohorts, our score seems to discriminate safely between patients with SM and with pure cutaneous mastocytosis.

The impact of CYP2D6*4 and GSTP1 Ile105Val polymorphisms on the susceptibility to develop BCR-ABL1 negative myeloproliferative neoplasms.

Inter-individual variations in the genes encoding xenobiotic-metabolizing enzymes have been reported to alter susceptibility to various diseases involving hematological disorders. The purpose of this case-control study was to investigate the relationship between CYP2D6*4 and GSTP1 Ile105Val polymorphisms and the risk of developing BCR-ABL1 negative myeloproliferative neoplasms (MPN). PCR-RFLP was used for genotyping single nucleotide polymorphisms (SNP) in CYP2D6 and GSTP1 in 139 patients with MPN and 126 controls. There was a significantly increased risk for developing BCR-ABL1 negative MPN for the group bearing the CYP2D6*4 variant allele (X2: 4.487; OR 1.738; 95% CI 1.040-2.904; p = 0.034). The platelet count was higher in CYP2D6*4 allele carriers (p = 0.047). There was no association between the GSTP1 Ile105Val polymorphism and the risk of developing MPNs. MPN patients bearing the GSTP1 Ile105Val variant allele had a higher prevalence of bleeding complications (X2: 7.510; OR 4.635; 95% CI 1.466-14.650; p = 0.006). Our study provides new data that the CYP2D6*4 polymorphism may be associated with an increased risk to develop MPNs while the GSTP1 Ile105Val polymorphism does not show such an association. To our knowledge, the current study is the first to investigate the relationship between CYP2D6*4 and GSTP1 Ile105Val polymorphisms and the risk of developing MPNs in the Turkish population. Further studies with more patients and controls are needed to support our data.

Patterns of Hydroxyurea Prescription and Use in Routine Clinical Management of Polycythemia Vera: A Multicenter Chart Review Study

Objective: This study aimed to evaluate real-life data on patterns of hydroxyurea prescription/use in polycythemia vera (PV). Materials and Methods: This retrospective chart review study included PV patients who had received hydroxyurea therapy for at least 2 months after PV diagnosis. Data were collected from 10 representative academic medical centers. Results: Of 657 patients, 50.9% were in the high-risk group (age ≥60 years and/or history of thromboembolic event). The median duration of hydroxyurea therapy was 43.40 months for all patients; 70.2% of the patients had ongoing hydroxyurea therapy at last follow-up. Hydroxyurea was discontinued in 22.4% of the patients; the most common reason was death (38.5%). The predicted time until hydroxyurea discontinuation was 187.8 months (standard error: ±21.7) for all patients. This duration was shorter in females (140.3±37.7 vs. 187.8±29.7) (p=0.08). This trend was also observed in surviving patients aged ≥50 years at hydroxyurea initiation (122.2±12.4 vs. 187.8±30.7, p=0.03). Among the patients who were still on hydroxyurea therapy, 40.3% had a hematocrit concentration of ≥45% at their last follow-up visit, and the rate of patients with at least one elevated blood cell count was 67.8%. Conclusion: Hydroxyurea prescription patterns and treatment aims are frequently not in accordance with the guideline recommendations. Its discontinuation rate is higher in females.

Prognostic impact of eosinophils in mastocytosis: analysis of 2350 patients collected in the ECNM Registry.

Systemic mastocytosis (SM) is frequently associated with eosinophilia. To examine its prevalence and clinical impact in all WHO classification-based subcategories, we analyzed eosinophil counts in 2350 mastocytosis patients using the dataset of the European Competence Network on Mastocytosis. Ninety percent of patients had normal eosinophil counts, 6.8% mild eosinophilia (0.5-1.5 × 109/l), and 3.1% hypereosinophilia (HE; >1.5 × 109/l). Eosinophilia/HE were mainly present in patients with advanced SM (17%/19%), and only rarely recorded in patients with indolent and smoldering SM (5%/1%), and some patients with cutaneous mastocytosis. The eosinophil count correlated with organomegaly, dysmyelopoiesis, and the WHO classification, but not with mediator-related symptoms or allergy. Eosinophilia at diagnosis had a strong prognostic impact (p < 0.0001) on overall survival (OS) and progression-free survival (PFS), with a 10-year OS of 19% for patients with HE, 70% for those with mild eosinophilia, and 88% for patients with normal eosinophil counts. In 89% of patients with follow-up data (n = 1430, censored at start of cytoreductive therapy), eosinophils remained stable. In those with changing eosinophil counts (increase/decrease or mixed pattern), OS and PFS were inferior compared with patients with stable eosinophil counts. In conclusion, eosinophilia and HE are more prevalent in advanced SM and are predictors of a worse outcome.

International prognostic scoring system for mastocytosis (IPSM): a retrospective cohort study.

BACKGROUND: The WHO classification separates mastocytosis into distinct variants, but prognostication remains a clinical challenge. The aim of this study was to improve prognostication for patients with mastocytosis. METHODS: We analysed data of the registry of the European Competence Network on Mastocytosis including 1639 patients (age 17-90 years) diagnosed with mastocytosis according to WHO criteria between Jan 12, 1978, and March 16, 2017. Univariate and multivariate analyses with Cox regression were applied to identify prognostic variables predicting survival outcomes and to establish a prognostic score. We validated this International Prognostic Scoring System in Mastocytosis (IPSM) with data of 462 patients (age 17-79 years) from the Spanish network Red Española de Mastocitosis diagnosed between Jan 22, 1998, and Nov 2, 2017. FINDINGS: The prognostic value of the WHO classification was confirmed in our study (p<0·0001). For patients with non-advanced mastocytosis (n=1380), we identified age 60 years or older (HR 10·75, 95% CI 5·68-20·32) and a concentration of alkaline phosphatase 100 U/L or higher (2·91, 1·60-5·30) as additional independent prognostic variables for overall survival. The resulting scoring system divided patients with non-advanced mastocytosis into three groups: low (no risk factors), intermediate 1 (one risk factor), and intermediate 2 (two risk factors). Overall survival and progression-free survival differed significantly among these groups (p<0·0001). In patients with advanced mastocytosis (n=259), age 60 years or older (HR 2·14, 95% CI 1·42-3·22), a concentration of tryptase 125 ng/mL or higher (1·81, 1·20-2·75), a leukocyte count of 16 × 109 per L or higher (1·88, 1·27-2·79), haemoglobin of 11 g/dL or lower (1·71, 1·13-2·57), a platelet count of 100 × 109 per L or lower (1·63, 1·13-2·34), and skin involvement (0·46, 0·30-0·69) were prognostic variables. Based on these variables, a separate score for advanced mastocytosis with four risk categories was established, with significantly different outcomes for overall survival and progression-free survival (p<0·0001). The prognostic value of both scores was confirmed in 413 patients with non-advanced disease and 49 with advanced mastocytosis from the validation cohort. INTERPRETATION: The IPSM scores for patients with non-advanced and advanced mastocytosis can be used to predict survival outcomes and guide treatment decisions. However, the predictive value of the IPSM needs to be confirmed in forthcoming trials. FUNDING: Austrian Science Fund, Deutsche Forschungsgemeinschaft, Koeln Fortune Program, Charles and Ann Johnson Foundation, Instituto de Salud Carlos III, Fondos FEDER, Research-Foundation Flanders/Fonds Wetenschappelijk Onderzoek, Clinical Research-Fund of the University Hospitals Leuven, and Research-Foundation Flanders/Fonds Wetenschappelijk Onderzoek.

The Data Registry of the European Competence Network on Mastocytosis (ECNM): Set Up, Projects, and Perspectives.

Mastocytosis is a unique hematologic neoplasm with complex biology and pathology and a variable clinical course. The disease can essentially be divided into cutaneous mastocytosis (CM) and systemic mastocytosis (SM). In adults, SM is diagnosed in most cases and manifests as either indolent or advanced disease. Patients with advanced SM have an unfavorable prognosis with reduced survival. However, so far, little is known about the prevalence of various categories of SM and about prognostic factors. In an attempt to learn more about the behavior and evolution of various forms of CM and SM, the European Competence Network on Mastocytosis (ECNM) initiated a mastocytosis registry in 2012. In this article, the set up and start phase of this registry are described. Until 2018, more than 3000 patients from 12 countries and 25 centers have been enrolled. In a majority of all patients, robust follow-up data and relevant clinical end points are available. Using this data set, a series of registry projects have been launched, with the aim to validate previously identified diagnostic and prognostic variables and to identify new disease-related and patient-related parameters in various forms of mastocytosis. Moreover, the core data set of the registry will be useful to establish multiparametric scoring systems through which prognostication and individualized management of patients with mastocytosis should improve in the foreseeable future.