Publications by authors named "Andreas Reiter"

158 Publications

Clinical and histopathological features of myeloid neoplasms with concurrent Janus kinase 2 (JAK2) V617F and KIT proto-oncogene, receptor tyrosine kinase (KIT) D816V mutations.

Br J Haematol 2021 Jun 1. Epub 2021 Jun 1.

Haematology and Oncology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

We report on 45 patients with myeloid neoplasms and concurrent Janus kinase 2 (JAK2) V617F and KIT proto-oncogene, receptor tyrosine kinase (KIT) D816V (JAK2 /KIT ) mutations, which are individually identified in >60% of patients with classical myeloproliferative neoplasms (MPN) and >90% of patients with systemic mastocytosis (SM) respectively. In SM, the concurrent presence of a clonal non-mast cell neoplasm [SM with associated haematological neoplasm (SM-AHN)] usually constitutes a distinct subtype associated with poor survival. All 45 patients presented with a heterogeneous combination of clinical/morphological features typical of the individual disorders (e.g. leuco-/erythro-/thrombocytosis and elevated lactate dehydrogenase for MPN; elevated serum tryptase and alkaline phosphatase for SM). Overlapping features identified in 70% of patients included splenomegaly, cytopenia(s), bone marrow fibrosis and additional somatic mutations. Molecular dissection revealed discordant development of variant allele frequency for both mutations and absence of concurrently positive single-cell derived colonies, indicating disease evolution in two independent clones rather than monoclonal disease in >60% of patients examined. Overall survival of JAK2 /KIT patients without additional somatic high-risk mutations [HRM, e.g. in serine and arginine-rich splicing factor 2 (SRSF2), additional sex combs like-1 (ASXL1) or Runt-related transcription factor 1 (RUNX1)] at 5 years was 77%, indicating that the mutual impact of JAK2 V617F and KIT D816V on prognosis is fundamentally different from the adverse impact of additional HRM in the individual disorders.
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http://dx.doi.org/10.1111/bjh.17567DOI Listing
June 2021

Eosinophils and eosinophil-associated disorders: immunological, clinical, and molecular complexity.

Semin Immunopathol 2021 May 30. Epub 2021 May 30.

Division of Allergy and Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Eosinophils and their mediators play a crucial role in various reactive states such as bacterial and viral infections, chronic inflammatory disorders, and certain hematologic malignancies. Depending on the underlying pathology, molecular defect(s), and the cytokine- and mediator-cascades involved, peripheral blood and tissue hypereosinophilia (HE) may develop and may lead to organ dysfunction or even organ damage which usually leads to the diagnosis of a HE syndrome (HES). In some of these patients, the etiology and impact of HE remain unclear. These patients are diagnosed with idiopathic HE. In other patients, HES is diagnosed but the etiology remains unknown - these patients are classified as idiopathic HES. For patients with HES, early therapeutic application of agents reducing eosinophil counts is usually effective in avoiding irreversible organ damage. Therefore, it is important to systematically explore various diagnostic markers and to correctly identify the disease elicitors and etiology. Depending on the presence and type of underlying disease, HES are classified into primary (clonal) HES, reactive HES, and idiopathic HES. In most of these patients, effective therapies can be administered. The current article provides an overview of the pathogenesis of eosinophil-associated disorders, with special emphasis on the molecular, immunological, and clinical complexity of HE and HES. In addition, diagnostic criteria and the classification of eosinophil disorders are reviewed in light of new developments in the field.
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http://dx.doi.org/10.1007/s00281-021-00863-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164832PMC
May 2021

COVID-19 Vaccination in Mastocytosis: Recommendations of the European Competence Network on Mastocytosis (ECNM) and American Initiative in Mast Cell Diseases (AIM).

J Allergy Clin Immunol Pract 2021 Jun 5;9(6):2139-2144. Epub 2021 Apr 5.

Department of Hematological Biology, Pitié-Salpêtrière Hospital, Paris Sorbonne University, Paris, France.

Mastocytosis is a neoplasm characterized by an accumulation of mast cells in various organs and increased risk for severe anaphylaxis in patients with concomitant allergies. Coronavirus disease 2019 (COVID-19) is a pandemic that is associated with a relatively high rate of severe lung disease and mortality. The mortality is particularly high in those with certain comorbidities and increases with age. Recently, several companies have developed an effective vaccination against COVID-19. Although the reported frequency of severe side effects is low, there is an emerging discussion about the safety of COVID-19 vaccination in patients with severe allergies and mastocytosis. However, even in these patients, severe adverse reactions are rare. We therefore recommend the broad use of COVID-19 vaccination in patients with mastocytosis on a global basis. The only well-established exception is a known or suspected allergy against a constituent of the vaccine. Safety measures, including premedication and postvaccination observation, should be considered in all patients with mastocytosis, depending on the individual personal risk and overall situation in each case. The current article provides a summary of published data, observations, and expert opinion that form the basis of these recommendations.
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http://dx.doi.org/10.1016/j.jaip.2021.03.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019658PMC
June 2021

Adverse Prognostic Impact of the D816V Transcriptional Activity in Advanced Systemic Mastocytosis.

Int J Mol Sci 2021 Mar 4;22(5). Epub 2021 Mar 4.

Department of Hematology and Oncology, University Hospital Mannheim, Heidelberg University, 68167 Mannheim, Germany.

In systemic mastocytosis (SM), qualitative and serial quantitative assessment of the D816V mutation is of diagnostic and prognostic relevance. We investigated peripheral blood and bone marrow samples of 161 patients (indolent SM (ISM), = 40; advanced SM, AdvSM, = 121) at referral and during follow-up for the D816V variant allele frequency (VAF) at the DNA-level and the D816V expressed allele burden (EAB) at the RNA-level. A round robin test with four participating laboratories revealed an excellent correlation ( > 0.99, > 0.98) between three different DNA-assays. VAF and EAB strongly correlated in ISM ( 0.91, coefficient of determination, 0.84) but only to a lesser extent in AdvSM ( 0.71; = 0.5). However, as compared to an EAB/VAF ratio ≤2 (cohort A, 77/121 patients, 64%) receiver operating characteristic (ROC) analysis identified an EAB/VAF ratio of >2 (cohort B, 44/121 patients, 36%) as predictive for an advanced phenotype and a significantly inferior median survival (3.3 vs. 11.7 years; = 0.005). In terms of overall survival, Cox-regression analysis was only significant for the EAB/VAF ratio >2 ( = 0.006) but not for VAF or EAB individually. This study demonstrates for the first time that the transcriptional activity of D816V may play an important role in the pathophysiology of SM.
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http://dx.doi.org/10.3390/ijms22052562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961551PMC
March 2021

Clinical Impact of Skin Lesions in Mastocytosis: A Multicenter Study of the European Competence Network on Mastocytosis.

J Invest Dermatol 2021 Feb 11. Epub 2021 Feb 11.

Department of Internal Medicine IV, Oncology, Hematology, Hemostaseology, University Halle (Saale), Halle (Saale), Germany.

Mastocytosis is a rare neoplasm characterized by the expansion and accumulation of mast cells in various organ systems. Systemic mastocytosis (SM) may or may not present with cutaneous lesions. To examine the frequency and clinical impact of cutaneous involvement, data on 1,510 patients with mastocytosis collected in the registry of the European Competence Network on Mastocytosis were analyzed. Cutaneous involvement was found in 1,195 of 1,510 patients (79.1%). Of these, 286 had cutaneous mastocytosis, and 721 had SM with skin involvement. Adult patients with skin involvement who did not have a bone marrow examination (n = 188) were defined as having mastocytosis in the skin. In 315 patients, SM without skin involvement was found. The percentage of cases with cutaneous involvement was higher in indolent SM (100%) and smoldering SM (87.9%) compared to aggressive SM (46.8%) or mast cell leukemia (38.5%). After a median follow-up of 5.6 years, no patient with cutaneous mastocytosis had died, but 2.6% of the patients with mastocytosis in the skin, 5.7% of the patients with SM with skin involvement, and 28.95% of the patients with SM without skin involvement had died. Overall survival was longer in patients with skin involvement (cutaneous mastocytosis and/or mastocytosis in the skin and/or SM with skin involvement) than in patients with SM without skin involvement (P < 0.0001). These data argue for a thorough examination of both the skin and bone marrow in adult patients with mastocytosis.
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http://dx.doi.org/10.1016/j.jid.2020.12.030DOI Listing
February 2021

Nintedanib targets KIT D816V neoplastic cells derived from induced pluripotent stem cells of systemic mastocytosis.

Blood 2021 Apr;137(15):2070-2084

Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen University Medical School, Aachen, Germany.

The KIT D816V mutation is found in >80% of patients with systemic mastocytosis (SM) and is key to neoplastic mast cell (MC) expansion and accumulation in affected organs. Therefore, KIT D816V represents a prime therapeutic target for SM. Here, we generated a panel of patient-specific KIT D816V induced pluripotent stem cells (iPSCs) from patients with aggressive SM and mast cell leukemia to develop a patient-specific SM disease model for mechanistic and drug-discovery studies. KIT D816V iPSCs differentiated into neoplastic hematopoietic progenitor cells and MCs with patient-specific phenotypic features, thereby reflecting the heterogeneity of the disease. CRISPR/Cas9n-engineered KIT D816V human embryonic stem cells (ESCs), when differentiated into hematopoietic cells, recapitulated the phenotype observed for KIT D816V iPSC hematopoiesis. KIT D816V causes constitutive activation of the KIT tyrosine kinase receptor, and we exploited our iPSCs and ESCs to investigate new tyrosine kinase inhibitors targeting KIT D816V. Our study identified nintedanib, a US Food and Drug Administration-approved angiokinase inhibitor that targets vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and fibroblast growth factor receptor, as a novel KIT D816V inhibitor. Nintedanib selectively reduced the viability of iPSC-derived KIT D816V hematopoietic progenitor cells and MCs in the nanomolar range. Nintedanib was also active on primary samples of KIT D816V SM patients. Molecular docking studies show that nintedanib binds to the adenosine triphosphate binding pocket of inactive KIT D816V. Our results suggest nintedanib as a new drug candidate for KIT D816V-targeted therapy of advanced SM.
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http://dx.doi.org/10.1182/blood.2019004509DOI Listing
April 2021

Proposed global prognostic score for systemic mastocytosis: a retrospective prognostic modelling study.

Lancet Haematol 2021 Mar 25;8(3):e194-e204. Epub 2021 Jan 25.

Institut Català d'Oncologia, Hospital Germans Trias i Pujol, Badalona, Spain; Josep Carreras Leukemia Research Institute, Universitat Autònoma de Barcelona.

Background: Several risk stratification models have been proposed in recent years for systemic mastocytosis but have not been directly compared. Here we designed and validated a risk stratification model for progression-free survival (PFS) and overall survival (OS) in systemic mastocytosis on the basis of all currently available prognostic factors, and compared its predictive capacity for patient outcome with that of other risk scores.

Methods: We did a retrospective prognostic modelling study based on patients diagnosed with systemic mastocytosis between March 1, 1983, and Oct 11, 2019. In a discovery cohort of 422 patients from centres of the Spanish Network on Mastocytosis (REMA), we evaluated previously identified, independent prognostic features for prognostic effect on PFS and OS by multivariable analysis, and designed a global prognostic score for mastocytosis (GPSM) aimed at predicting PFS (GPSM-PFS) and OS (GPSM-OS) by including only those variables that showed independent prognostic value (p<0·05). The GPSM scores were validated in an independent cohort of 853 patients from centres in Europe and the USA, and compared with pre-existing risk models in the total patient series (n=1275), with use of Harrells' concordance index (C-index) as a readout of the ability of each model to risk-stratify patients according to survival outcomes.

Findings: Our GPSM-PFS and GPSM-OS models were based on unique combinations of independent prognostic factors for PFS (platelet count ≤100 × 10 cells per L, serum β2-microglobulin ≥2·5 μg/mL, and serum baseline tryptase ≥125 μg/L) and OS (haemoglobin ≤110 g/L, serum alkaline phosphatase ≥140 IU/L, and at least one mutation in SRSF2, ASXL1, RUNX1, or DNMT3A). The models showed clear discrimination between low-risk and high-risk patients in terms of worse PFS and OS prognoses in the discovery and validation cohorts, and further discrimination of intermediate-risk patients. The GPSM-PFS score was an accurate predictor of PFS in systemic mastocytosis (C-index 0·90 [95% CI 0·87-0·93], vs values ranging from 0·85 to 0·88 for pre-existing models), particularly in non-advanced systemic mastocytosis (C-index 0·85 [0·76-0·92], within the range for pre-existing models of 0·80 to 0·93). Additionally, the GPSM-OS score was able to accurately predict OS in the entire cohort (C-index 0·92 [0·89-0·94], vs 0·67 to 0·90 for pre-existing models), and showed some capacity to predict OS in advanced systemic mastocytosis (C-index 0·72 [0·66-0·78], vs 0·64 to 0·73 for pre-existing models).

Interpretation: All evaluated risk classifications predicted survival outcomes in systemic mastocytosis. The REMA-PFS and GPSM-PFS models for PFS, and the International Prognostic Scoring System for advanced systemic mastocytosis and GPSM-OS model for OS emerged as the most accurate models, indicating that robust prognostication might be prospectively achieved on the basis of biomarkers that are accessible in diagnostic laboratories worldwide.

Funding: Carlos III Health Institute, European Regional Development Fund, Spanish Association of Mastocytosis and Related Diseases, Rare Diseases Strategy of the Spanish National Health System, Junta of Castile and León, Charles and Ann Johnson Foundation, Stanford Cancer Institute Innovation Fund, Austrian Science Fund.
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http://dx.doi.org/10.1016/S2352-3026(20)30400-2DOI Listing
March 2021

Genome-wide association study identifies novel susceptibility loci for KIT D816V positive mastocytosis.

Am J Hum Genet 2021 02 8;108(2):284-294. Epub 2021 Jan 8.

School of Medicine, University of Southampton, Southampton SO17 1BJ, UK.

Mastocytosis is a rare myeloid neoplasm characterized by uncontrolled expansion of mast cells, driven in >80% of affected individuals by acquisition of the KIT D816V mutation. To explore the hypothesis that inherited variation predisposes to mastocytosis, we performed a two-stage genome-wide association study, analyzing 1,035 individuals with KIT D816V positive disease and 17,960 healthy control individuals from five European populations. After quality control, we tested 592,007 SNPs at stage 1 and 75 SNPs at stage 2 for association by using logistic regression and performed a fixed effects meta-analysis to combine evidence across the two stages. From the meta-analysis, we identified three intergenic SNPs associated with mastocytosis that achieved genome-wide significance without heterogeneity between cohorts: rs4616402 (p = 1.37 × 10, OR = 1.52), rs4662380 (p = 2.11 × 10, OR = 1.46), and rs13077541 (p = 2.10 × 10, OR = 1.33). Expression quantitative trait analyses demonstrated that rs4616402 is associated with the expression of CEBPA (p = 2.3 × 10), a gene encoding a transcription factor known to play a critical role in myelopoiesis. The role of the other two SNPs is less clear: rs4662380 is associated with expression of the long non-coding RNA gene TEX41 (p = 2.55 × 10), whereas rs13077541 is associated with the expression of TBL1XR1, which encodes transducin (β)-like 1 X-linked receptor 1 (p = 5.70 × 10). In individuals with available data and non-advanced disease, rs4616402 was associated with age at presentation (p = 0.009; beta = 4.41; n = 422). Additional focused analysis identified suggestive associations between mastocytosis and genetic variation at TERT, TPSAB1/TPSB2, and IL13. These findings demonstrate that multiple germline variants predispose to KIT D816V positive mastocytosis and provide novel avenues for functional investigation.
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http://dx.doi.org/10.1016/j.ajhg.2020.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895845PMC
February 2021

Clinical Impact of Inherited and Acquired Genetic Variants in Mastocytosis.

Int J Mol Sci 2021 Jan 2;22(1). Epub 2021 Jan 2.

Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, Austria.

Mastocytosis is a rare and complex disease characterized by expansion of clonal mast cells (MC) in skin and/or various internal organ systems. Involvement of internal organs leads to the diagnosis of systemic mastocytosis (SM). The WHO classification divides SM into indolent SM, smoldering SM and advanced SM variants, including SM with an associated hematologic neoplasm, aggressive SM, and MC leukemia. Historically, genetic analysis of individuals with pure cutaneous mastocytosis (CM) and SM have focused primarily on cohort studies of inherited single nucleotide variants and acquired pathogenic variants. The most prevalent pathogenic variant (mutation) in patients with SM is p.D816V, which is detectable in most adult patients. Other somatic mutations have also been identified-especially in advanced SM-in , , , , and , and shown to impact clinical and cellular phenotypes. Although only small patient cohorts have been analyzed, disease associations have also been identified in several germline variants within genes encoding certain cytokines or their receptors (, , , , ) and toll-like receptors. More recently, an increased prevalence of hereditary alpha-tryptasemia (HαT) caused by increased copy number encoding alpha-tryptase has been described in patients with SM. Whereas HαT is found in 3-6% of general Western populations, it is identified in up to 17% of patients with SM. In the current manuscript we review the prevalence, functional role and clinical impact of various germline and somatic genetic variants in patients with mastocytosis.
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http://dx.doi.org/10.3390/ijms22010411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795405PMC
January 2021

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

Theranostics 2021 1;11(1):292-303. Epub 2021 Jan 1.

Department of Dermatology and Venereology, Allergy Centrr, Kepler University Hospital, Linz, Austria.

In systemic mastocytosis (SM), the clinical features and survival vary greatly. Patient-related factors determining the outcome in SM are largely unknown. 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. 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%; 0.001). Correspondingly, organomegaly (male: 23% female: 13%, 0.007) was more, whereas skin involvement (male: 71% female: 86%, 0.001) was less frequent in males. In all patients together, OS ( 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 ( 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% 5%, 0.006) or molecular aberrations (// profile; 63% 40%, 0.003) were more frequently present in males. 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.
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http://dx.doi.org/10.7150/thno.51872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681091PMC
January 2021

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

J Allergy Clin Immunol Pract 2021 04 23;9(4):1705-1712.e4. Epub 2020 Dec 23.

Division of Allergy and Clinical Immunology, Department of Medicine, University of Salerno, Salerno, Italy.

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.
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http://dx.doi.org/10.1016/j.jaip.2020.12.022DOI Listing
April 2021

Sustained Complete Molecular Remission With Imatinib Monotherapy in a Child Presenting With Blast Phase -Associated Myeloid Neoplasm With Eosinophilia.

Hemasphere 2020 Dec 6;4(6):e486. Epub 2020 Nov 6.

Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta and Emory University, Atlanta, Georgia, USA.

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http://dx.doi.org/10.1097/HS9.0000000000000486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655083PMC
December 2020

Practical management of adverse events in patients with advanced systemic mastocytosis receiving midostaurin.

Expert Opin Biol Ther 2021 Apr 15;21(4):487-498. Epub 2021 Jan 15.

University Hospital Mannheim, Heidelberg University, Mannheim, Germany.

Introduction: Systemic mastocytosis (SM) is characterized by the overproduction and accumulation of neoplastic mast cells (MCs) in the bone marrow, skin, and visceral organs. The D816V mutation is found in approximately 90% of cases. In advanced SM (advSM), inferior survival often relates to MC-induced organ damage that may impact multiple organ systems. In addition, mediator symptoms related to MC activation can severely impact the quality of life. The oral multikinase/KIT inhibitor midostaurin was approved by the US Food and Drug Administration and the European Medicines Agency as monotherapy for advSM based on data from phase 2 clinical studies.

Areas Covered: This review discusses the management of common adverse events (AEs) in patients with advSM who participated in phase 2 clinical studies that led to the approval of midostaurin.

Expert Opinion: In the advSM population undergoing treatment with midostaurin, treatment-related AEs are often difficult to distinguish from disease-related symptoms, which can lead to premature discontinuation and improper dose reduction of midostaurin therapy in patients who might have benefitted from continued therapy. Here we present strategies to help optimize AE management and maximize the potential benefits of midostaurin in advSM.
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http://dx.doi.org/10.1080/14712598.2021.1837109DOI Listing
April 2021

Mast cells as a unique hematopoietic lineage and cell system: From Paul Ehrlich's visions to precision medicine concepts.

Theranostics 2020 29;10(23):10743-10768. Epub 2020 Aug 29.

Departments of Pathology and of Microbiology and Immunology, and the Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, USA.

The origin and functions of mast cells (MCs) have been debated since their description by Paul Ehrlich in 1879. MCs have long been considered 'reactive bystanders' and 'amplifiers' in inflammatory processes, allergic reactions, and host responses to infectious diseases. However, knowledge about the origin, phenotypes and functions of MCs has increased substantially over the past 50 years. MCs are now known to be derived from multipotent hematopoietic progenitors, which, through a process of differentiation and maturation, form a unique hematopoietic lineage residing in multiple organs. In particular, MCs are distinguishable from basophils and other hematopoietic cells by their unique phenotype, origin(s), and spectrum of functions, both in innate and adaptive immune responses and in other settings. The concept of a unique MC lineage is further supported by the development of a distinct group of neoplasms, collectively referred to as mastocytosis, in which MC precursors expand as clonal cells. The clinical consequences of the expansion and/or activation of MCs are best established in mastocytosis and in allergic inflammation. However, MCs have also been implicated as important participants in a number of additional pathologic conditions and physiological processes. In this article, we review concepts regarding MC development, factors controlling MC expansion and activation, and some of the fundamental roles MCs may play in both health and disease. We also discuss new concepts for suppressing MC expansion and/or activation using molecularly-targeted drugs.
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http://dx.doi.org/10.7150/thno.46719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482799PMC
May 2021

Real-world non-interventional long-term post-authorisation safety study of ruxolitinib in myelofibrosis.

Br J Haematol 2020 12 24;191(5):764-774. Epub 2020 Jun 24.

Department of Hematology and Blood Coagulation, Medical University of Vienna, Vienna, Austria.

Primary objective of this non-interventional, post-authorisation safety study was to provide real-world safety data [incidence of adverse drug reactions (ADRs)/serious adverse events (SAEs)] on adult patients with myelofibrosis exposed/or not exposed to ruxolitinib. Key secondary objectives included the incidence/outcome of events of special interest (bleeding events, serious/opportunistic infections, second primary malignancies, and deaths). Overall, 462 patients were included [prevalent users = 260, new users = 32, non-exposed = 170 (inclusive of ruxolitinib-switch, n = 57)]. The exposure-adjusted incidence rates (per 100 patient-years) of ADRs (19·3 vs. 19·6) and SAEs (25·2 vs. 25·0) were comparable amongst new-users versus prevalent-users cohorts, respectively; most frequent ADRs across all cohorts included thrombocytopenia, anaemia, epistaxis, urinary tract infection, and herpes zoster. Anaemia, pneumonia, general physical health deterioration, sepsis, and death were the most frequent SAEs across all cohorts. Incidence rates of bleeding events (21·6) and serious/opportunistic infections (34·5) were higher in ruxolitinib-switch cohort versus other cohorts. The incidence rate of second primary malignancies was higher in the prevalent-users cohort (10·1) versus other cohorts. The observed safety profile of ruxolitinib in the present study along with the safety findings from the COMFORT/JUMP/EXPAND studies support the use of ruxolitinib for long-term treatment of patients with myelofibrosis.
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http://dx.doi.org/10.1111/bjh.16729DOI Listing
December 2020

Risk and management of patients with mastocytosis and MCAS in the SARS-CoV-2 (COVID-19) pandemic: Expert opinions.

J Allergy Clin Immunol 2020 08 17;146(2):300-306. Epub 2020 Jun 17.

Division of Allergy, Department of Dermatology, and Department of Biomedicine, University of Basel, Basel, Switzerland.

The coronavirus disease 2019 (COVID-19) (caused by severe acute respiratory syndrome coronavirus 2) pandemic has massively distorted our health care systems and caused catastrophic consequences in our affected communities. The number of victims continues to increase, and patients at risk can only be protected to a degree, because the virulent state may be asymptomatic. Risk factors concerning COVID-19-induced morbidity and mortality include advanced age, an impaired immune system, cardiovascular or pulmonary diseases, obesity, diabetes mellitus, and cancer treated with chemotherapy. Here, we discuss the risk and impact of COVID-19 in patients with mastocytosis and mast cell activation syndromes. Because no published data are yet available, expert opinions are, by necessity, based on case experience and reports from patients. Although the overall risk to acquire the severe acute respiratory syndrome coronavirus 2 may not be elevated in mast cell disease, certain conditions may increase the risk of infected patients to develop severe COVID-19. These factors include certain comorbidities, mast cell activation-related events affecting the cardiovascular or bronchopulmonary system, and chemotherapy or immunosuppressive drugs. Therefore, such treatments should be carefully evaluated on a case-by-case basis during a COVID-19 infection. In contrast, other therapies, such as anti-mediator-type drugs, venom immunotherapy, or vitamin D, should be continued. Overall, patients with mast cell disorders should follow the general and local guidelines in the COVID-19 pandemic and advice from their medical provider.
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http://dx.doi.org/10.1016/j.jaci.2020.06.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297685PMC
August 2020

Midostaurin improves quality of life and mediator-related symptoms in advanced systemic mastocytosis.

J Allergy Clin Immunol 2020 08 11;146(2):356-366.e4. Epub 2020 May 11.

University Medical Center Groningen, Department of Hematology, University of Groningen, Groningen, The Netherlands.

Background: Advanced systemic mastocytosis (advSM) is characterized by presence of the KIT D816V mutation and pathologic accumulation of neoplastic mast cells (MCs) in various tissues, leading to severe symptoms and organ damage (eg, cytopenias, liver dysfunction, portal hypertension, malabsorption, and weight loss). Treatment with midostaurin, an orally active multikinase/KIT inhibitor now approved for advSM in the United States and the European Union, resulted in a high rate of response accompanied by reduced MC infiltration of the bone marrow and lowered serum tryptase level.

Objective: We aimed to determine whether midostaurin improves health-related quality of life (QOL) and MC mediator-related symptoms in patients with advSM.

Methods: In 116 patients with systemic mastocytosis (89 patients with advSM fulfilling the strict inclusion criteria of the D2201 study [ClinicalTrials.gov identifier NCT00782067]), QOL and symptom burden were assessed during treatment with midostaurin by using the 12-Item Short-Form Health Survey (SF-12) and the Memorial Symptom Assessment Scale patient-reported questionnaires, respectively. MC mediator-related symptoms were evaluated by using a specific physician-reported questionnaire.

Results: Over the first 6 cycles of treatment with midostaurin (ie, 6 months), patients experienced significant improvements in total SF-12 and Memorial Symptom Assessment Scale scores, as well as in subscores of each instrument. These improvements were durable during 36 months of follow-up. Similarly, we found substantial improvements (67%-100%) in all MC mediator-related symptoms.

Conclusion: QOL and MC mediator-related symptoms significantly improve with midostaurin treatment in patients with advSM (ClinicalTrials.gov identifier, NCT00782067).
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http://dx.doi.org/10.1016/j.jaci.2020.03.044DOI Listing
August 2020

Importance of Adequate Diagnostic Workup for Correct Diagnosis of Advanced Systemic Mastocytosis.

J Allergy Clin Immunol Pract 2020 10 15;8(9):3121-3127.e1. Epub 2020 May 15.

Department of Hematology and Oncology, University Hospital Mannheim, Heidelberg University, Mannheim, Germany. Electronic address:

Background: Little is known about the epidemiology of advanced systemic mastocytosis (advSM).

Objectives: To investigate epidemiologic features and diagnostic pitfalls of advSM in Germany.

Methods: Therefore, 140 patients from a single German reference center of the European Competence Network on Mastocytosis between 2003 and 2018 were analyzed.

Results: The patients' median age was 68 years (range, 26-86 years), and male versus female ratio was 2:1. An elevated serum tryptase, a KIT D816 mutation, and additional somatic mutations, for example, in SRSF2, ASXL1, or RUNX1, were identified in 95%, 91%, and 74% of patients, respectively. Median overall survival was 3.5 years (range, 0.03-14.3 years; male vs female 2.6 vs 4.2 years; P = .02). Two categories of misdiagnoses were identified in 51 of 140 (36%) patients: First, systemic mastocytosis (SM) was overlooked in 28 of 140 (20%) patients primarily diagnosed with various subtypes of myeloid neoplasms. Second, 23 of 140 (16%) patients were diagnosed with supposed progression from indolent SM to advSM; however, combination of an elevated KIT D816V variant allele frequency in peripheral blood (n = 22), monocytosis (n = 9), eosinophilia (n = 6), and/or mutations in SRSF2, ASXL1, or RUNX1 (n = 10) suggest that distinct signs of potential advSM were overlooked in virtually all patients. Based on locally diagnosed patients in an area of 2.5 million inhabitants, but obviously without considering more, yet unrecognized cases, the incidence and prevalence of advSM is at least 0.8 and 5.2, respectively, per 1 million inhabitants.

Conclusions: Adequate analyses of tryptase levels, bone marrow morphology, and genetics in patients with myeloid neoplasms or SM would help to prevent the significant underdiagnosis of advSM.
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http://dx.doi.org/10.1016/j.jaip.2020.05.005DOI Listing
October 2020

Response to tyrosine kinase inhibitors in myeloid neoplasms associated with PCM1-JAK2, BCR-JAK2 and ETV6-ABL1 fusion genes.

Am J Hematol 2020 07 28;95(7):824-833. Epub 2020 Apr 28.

Department of Hematology and Oncology, University Hospital Mannheim, Heidelberg University, Mannheim, Germany.

We report on 18 patients with myeloid neoplasms and associated tyrosine kinase (TK) fusion genes on treatment with the TK inhibitors (TKI) ruxolitinib (PCM1-JAK2, n = 8; BCR-JAK2, n = 1) and imatinib, nilotinib or dasatinib (ETV6-ABL1, n = 9). On ruxolitinib (median 24 months, range 2-36 months), a complete hematologic response (CHR) and complete cytogenetic response (CCR) was achieved by five of nine and two of nine patients, respectively. However, ruxolitinib was stopped in eight of nine patients because of primary resistance (n = 3), progression (n = 3) or planned allogeneic stem cell transplantation (allo SCT, n = 2). At a median of 36 months (range 4-78 months) from diagnosis, five of nine patients are alive: four of six patients after allo SCT and one patient who remains on ruxolitinib. In ETV6-ABL1 positive patients, a durable CHR was achieved by four of nine patients (imatinib with one of five, nilotinib with two of three, dasatinib with one of one). Because of inadequate efficacy (lack of hematological and/or cytogenetic/molecular response), six of nine patients (imatinib, n = 5; nilotinib, n = 1) were switched to nilotinib or dasatinib. At a median of 23 months (range 3-60 months) from diagnosis, five of nine patients are in CCR or complete molecular response (nilotinib, n = 2; dasatinib, n = 2; allo SCT, n = 1) while two of nine patients have died. We conclude that (a) responses on ruxolitinib may only be transient in the majority of JAK2 fusion gene positive patients with allo SCT being an important early treatment option, and (b) nilotinib or dasatinib may be more effective than imatinib to induce durable complete remissions in ETV6-ABL1 positive patients.
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http://dx.doi.org/10.1002/ajh.25825DOI Listing
July 2020

Clinical features and survival of patients with indolent systemic mastocytosis defined by the updated WHO classification.

Allergy 2020 08 16;75(8):1927-1938. Epub 2020 Mar 16.

Departement of Hematology, Centre National de Référence des Mastocytoses, Imagine Institute, INSERM U1123, Université Paris Descartes, Sorbonne, Paris Cité, Hôpital Necker, Assistance Publique des Hôpitaux de Paris (APHP), Paris, France.

Background: In indolent systemic mastocytosis (ISM), several risk factors of disease progression have been identified. Previous studies, performed with limited patient numbers, have also shown that the clinical course in ISM is stable and comparable to that of cutaneous mastocytosis (CM). The aim of this project was to compare the prognosis of patients with ISM with that of patients with CM.

Methods: We employed a dataset of 1993 patients from the registry of the European Competence Network on Mastocytosis (ECNM) to compare outcomes of ISM and CM.

Results: We found that overall survival (OS) is worse in ISM compared to CM. Moreover, in patients with typical ISM, bone marrow mastocytosis (BMM), and smoldering SM (SSM), 4.1% of disease progressions have been observed (4.9% of progressions in typical ISM group, 1.7% in BMM, and 9.4% in SSM). Progressions to advanced SM were observed in 2.9% of these patients. In contrast, six patients with CM (1.7%) converted to ISM and no definitive progression to advanced SM was found. No significant differences in OS and event-free survival (EFS) were found when comparing ISM, BMM, and SSM. Higher risk of both progression and death was significantly associated with male gender, worse performance status, and organomegaly.

Conclusion: Our data confirm the clinical impact of the WHO classification that separates ISM from CM and from other SM variants.
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http://dx.doi.org/10.1111/all.14248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115854PMC
August 2020

New developments in diagnosis, prognostication, and treatment of advanced systemic mastocytosis.

Blood 2020 04;135(16):1365-1376

Division of Hematology, Stanford University School of Medicine/Stanford Cancer Institute, Stanford, CA.

Systemic mastocytosis (SM) has greatly benefited from the broad application of precision medicine techniques to hematolymphoid neoplasms. Sensitive detection of the recurrent KIT D816V mutation and use of next-generation sequencing (NGS) panels to profile the genetic landscape of SM variants have been critical adjuncts to the diagnosis and subclassification of SM, and development of clinical-molecular prognostic scoring systems. Multilineage KIT involvement and multimutated clones are characteristic of advanced SM (advSM), especially SM with an associated hematologic neoplasm (AHN). A major challenge is how to integrate conventional markers of mast cell disease burden (percentage of bone marrow mast cell infiltration and serum tryptase levels) with molecular data (serial monitoring of both KIT D816V variant allele frequency and NGS panels) to lend more diagnostic and prognostic clarity to the heterogeneous clinical presentations and natural histories of advSM. The approval of the multikinase/KIT inhibitor midostaurin has validated the paradigm of KIT inhibition in advSM, and the efficacy and safety of second-generation agents, such as the switch-control inhibitor ripretinib (DCC-2618) and the D816V-selective inhibitor avapritinib (BLU-285) are being further defined in ongoing clinical trials. Looking forward, perhaps the most fruitful marriage of the advances in molecular genetics and treatment will be the design of adaptive basket trials that combine histopathology and genetic profiling to individualize treatment approaches for patients with diverse AHNs and relapsed/refractory SM.
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http://dx.doi.org/10.1182/blood.2019000932DOI Listing
April 2020

Treatment-free remission in FIP1L1-PDGFRA-positive myeloid/lymphoid neoplasms with eosinophilia after imatinib discontinuation.

Blood Adv 2020 Feb;4(3):440-443

Department of Hematology and Oncology, University Hospital Mannheim, Heidelberg University, Mannheim, Germany.

FIP1L1-PDGFRA-positive myeloid/lymphoid neoplasms with eosinophilia (MLN-eo) are exquisitely sensitive to imatinib. Almost all patients achieve a complete molecular remission (CMR) by nested reverse transcription polymerase chain reaction, which can be maintained with low-dose imatinib (eg, 3 × 100 mg/wk). Because imatinib can be safely stopped in a substantial proportion of patients with BCR-ABL1-positive CML, we sought to analyze the clinical and molecular follow-up of 12 FIP1L1-PDGFRA-positive patients with MLN-eo in chronic phase who discontinued imatinib after achievement of a CMR. Median time of treatment and median time of CMR before imatinib discontinuation (last dose at 3 × 100 mg/wk, n = 8; or 100 mg/d, n = 4) were 80 (range, 43-175) and 66 (range, 37-174) months, respectively. A molecular relapse was observed in 4 patients after 10, 22 (n = 2), and 24 months. A second CMR was achieved in 3 patients after 3, 4, and 21 months. Eight patients (62%) are in ongoing CMR (median, 17 months; range, 3-71 months). Molecular relapse-free survival was 91% at 12 months and 65% at 24 months. No significant differences (eg, dose and duration of imatinib treatment or duration of CMR before imatinib discontinuation) were identified between patients with and without molecular relapse. Our data demonstrate that imatinib can be safely stopped in FIP1L1-PDGFRA-positive MLN-eo because of a high treatment-free remission at 12 and 24 months and because most patients achieve a rapid second CMR after restart of imatinib.
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http://dx.doi.org/10.1182/bloodadvances.2019001111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013256PMC
February 2020

An increased bone mineral density is an adverse prognostic factor in patients with systemic mastocytosis.

J Cancer Res Clin Oncol 2020 Apr 24;146(4):945-951. Epub 2020 Jan 24.

Department of Hematology and Oncology, University Hospital Mannheim, Heidelberg University, Mannheim, Germany.

Purpose: Systemic mastocytosis (SM) is characterized by the expansion of clonal mast cells that infiltrate various organ systems. The extent of organ infiltration and subsequent organ damage distinguishes between indolent SM (ISM) defined by a nearly normal life expectancy and advanced SM (AdvSM) defined by poor prognosis. In ISM, measurement of the bone mineral density (BMD) frequently reveals osteoporosis. In contrast, the clinical implication of an increased BMD and osteosclerosis remains unclear.

Methods: BMD was evaluated in 61 patients with mastocytosis (ISM, n = 29, 48%; AdvSM, n = 32, 52%). We correlated the prevalence of osteoporosis, increased BMD and osteosclerosis with clinical parameters, disease variant and prognosis.

Results: Osteoporosis was detected in 11/29 (38%) patients with ISM but only in 2/32 (6%) patients with AdvSM (p = 0.004). An increased BMD was detected in 1/29 (3%) patients with ISM and 24/32 (75%) patients with AdvSM (p < 0.001) while osteosclerosis was only detected in AdvSM patients (16/32, 50%). AdvSM patients with increased BMD had higher levels of bone marrow mast cell infiltration, higher serum tryptase and alkaline phosphatase levels compared to ISM as well as higher number of high-molecular risk mutations (p < 0.05). In addition, we found that the prognosis of AdvSM patients with increased BMD is inferior compared to those without increased BMD (median overall survival 3.6 years versus not reached, p = 0.031).

Conclusions: Osteoporosis is a common feature in ISM but not in AdvSM. An increased BMD is frequently present in AdvSM but not in ISM and is associated with more advanced disease and inferior outcome.
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http://dx.doi.org/10.1007/s00432-019-03119-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085471PMC
April 2020

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

Leukemia 2020 04 18;34(4):1090-1101. Epub 2019 Nov 18.

Department Immunol, Genetics and Pathology (MM) and Dept Hematol (MM, HH), Uppsala University Hospital, Uppsala University, Uppsala, Sweden.

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 × 10/l), and 3.1% hypereosinophilia (HE; >1.5 × 10/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.
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http://dx.doi.org/10.1038/s41375-019-0632-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115841PMC
April 2020

LCP1 triggers mTORC2/AKT activity and is pharmacologically targeted by enzastaurin in hypereosinophilia.

Mol Carcinog 2020 01 6;59(1):87-103. Epub 2019 Nov 6.

Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.

Hypereosinophilia (HE) is caused by a variety of disorders, ranging from parasite infections to autoimmune diseases and cancer. Only a small proportion of HE cases are clonal malignancies, and one of these, the group of eosinophilia-associated tyrosine kinase fusion-driven neoplasms, is sensitive to tyrosine kinase inhibitors, while most subtypes lack specific treatment. Eosinophil functions are highly dependent on actin polymerization, promoting priming, shape change, and infiltration of inflamed tissues. Therefore, we investigated the role of the actin-binding protein lymphocyte cytosolic protein 1 (LCP1) in malignant and nonmalignant eosinophil differentiation. We use the protein kinase C-β (PKCβ) selective inhibitor enzastaurin (Enza) to dephosphorylate and inactivate LCP1 in FIP1L1-platelet-derived growth factor receptor α (PDGFRA)-positive Eol-1 cells, and this was associated with reduced proliferation, metabolic activity, and colony formation as well as enhanced apoptosis and impaired migration. While Enza did not alter FIP1L1-PDGFRA-induced signal transducer and activator of transcription 3 (STAT3), STAT5, and ERK1/2 phosphorylation, it inhibited STAT1 and AKT (but not AKT ) phosphorylation, and short hairpin RNA knockdown experiments confirmed that this process was mediated by LCP1 and associated mammalian target of rapamycin complex 2 (mTORC2) activity loss. Homeobox protein HoxB8 immortalized murine bone marrow cells showed impaired eosinophilic differentiation upon Enza treatment or LCP1 knockdown. Furthermore, Enza treatment of primary HE samples reduced eosinophil differentiation and survival. In conclusion, our data show that HE involves active LCP1, which interacts with mTOR and triggers mTORC2 activity, and that the PKCβ inhibitor Enza as well as targeting of LCP1 may provide a novel treatment approach to hypereosinophilic disorders.
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http://dx.doi.org/10.1002/mc.23131DOI Listing
January 2020

Magnetic resonance imaging reveals distinct bone marrow patterns in indolent and advanced systemic mastocytosis.

Ann Hematol 2019 Dec 5;98(12):2693-2701. Epub 2019 Nov 5.

Department of Hematology and Oncology, University Hospital Mannheim, Heidelberg University, Mannheim, Germany.

Systemic mastocytosis (SM) is broadly subcategorized according to mast cell (MC) burden and organ involvement into indolent (ISM), smoldering (SSM), and advanced SM (AdvSM). However, the pattern and extent of bone involvement remains controversial. In this institutional review board (IRB)-approved study, 115 patients with different forms of SM (ISM (n = 37, 32%), SSM (n = 9, 8%), and AdvSM (n = 69, 60%)) underwent a whole-body magnetic resonance imaging including sagittal and coronal T1 and turbo inversion recovery magnitude (TIRM) sequences of the spine. The evaluation included the pattern and extent of pathologic bone marrow (BM) signals in the spine and extremities, osteolytic lesions, and vertebral fractures. A pathologic BM pattern was observed in 4/37 (11%), 8/9 (89%), and 66/69 (96%); affection of the appendicular skeleton in 3/37 (8%), 8/9 (89%), and 67/69 (97%); and vertebral fractures in 7/37 (19%), 0/9, and 13/69 (19%) patients with ISM, SSM, and AdvSM, respectively. In AdvSM, pathologic BM pattern included activated (62%), diffuse sclerotic (25%), and small-spotted BM (9%), respectively. Only activated/sclerotic BM was associated with significantly higher MC burden, organ damage, and inferior median survival (2.9 years, p = 0.04). Vertebral fractures resembled classical multi-segmental osteoporotic fractures in ISM but not in AdvSM in which they were only found in activated/sclerotic BM. Only one patient with AdvSM had a focal osteolytic lesion in the femur. Activated/sclerotic BM changes of the spine and affection of the appendicular skeleton are indicative for SSM or AdvSM. Osteolytic lesions, which are very rare, and osteoporotic fractures are ineligible for the diagnosis of AdvSM.
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http://dx.doi.org/10.1007/s00277-019-03826-4DOI Listing
December 2019

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

Lancet Haematol 2019 Dec 31;6(12):e638-e649. Epub 2019 Oct 31.

Department of Oncology, Haematology, Haemostaseology and Stem Cell Transplantation, University Hospital RWTH Aachen, Aachen, Germany.

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 × 10 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 × 10 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.
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http://dx.doi.org/10.1016/S2352-3026(19)30166-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115823PMC
December 2019

MARS: Mutation-Adjusted Risk Score for Advanced Systemic Mastocytosis.

J Clin Oncol 2019 11 11;37(31):2846-2856. Epub 2019 Sep 11.

University Hospital Mannheim, Heidelberg University, Mannheim, Germany.

Purpose: To develop a risk score for patients with advanced systemic mastocytosis (AdvSM) that integrates clinical and mutation characteristics.

Patients And Methods: The study included 383 patients with AdvSM from the German Registry on Disorders of Eosinophils and Mast Cells (training set; n = 231) and several centers for mastocytosis in the United States and Europe, all within the European Competence Network on Mastocytosis (validation set; n = 152). A Cox multivariable model was used to select variables that were predictive of overall survival (OS).

Results: In multivariable analysis, the following risk factors were identified as being associated with OS: age greater than 60 years, anemia (hemoglobin < 10 g/dL), thrombocytopenia (platelets < 100 × 10/L), presence of one high molecular risk gene mutation (ie, in , , and/or ), and presence of two or more high molecular risk gene mutations. By assigning hazard ratio-weighted points to these variables, the following three risk categories were defined: low risk (median OS, not reached), intermediate risk (median OS, 3.9 years; 95% CI, 2.1 to 5.7 years), and high risk (median OS, 1.9 years; 95% CI, 1.3 to 2.6 years; < .001). The mutation-adjusted risk score (MARS) was independent of the WHO classification and was confirmed in the independent validation set. During a median follow-up time of 2.2 years (range, 0 to 23 years), 63 (16%) of 383 patients experienced a leukemic transformation to secondary mast cell leukemia (32%) or secondary acute myeloid leukemia (68%). The MARS was also predictive for leukemia-free survival ( < .001).

Conclusion: The MARS is a validated, five-parameter, WHO-independent prognostic score that defines three risk groups among patients with AdvSM and may improve up-front treatment stratification for these rare hematologic neoplasms.
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http://dx.doi.org/10.1200/JCO.19.00640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823885PMC
November 2019

Bilateral Inguinal Ulcerations as First Presentation of Acute Myeloid Leukaemia.

Acta Derm Venereol 2019 Oct;99(11):1041-1042

Department of Dermatology, Venereology and Allergy, University Medical Center Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, 68167 Mannheim, Germany.

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http://dx.doi.org/10.2340/00015555-3252DOI Listing
October 2019

Multidisciplinary Challenges in Mastocytosis and How to Address with Personalized Medicine Approaches.

Int J Mol Sci 2019 Jun 18;20(12). Epub 2019 Jun 18.

Division of Allergy and Clinical Immunology, University of Salerno, 84131 Salerno, Italy.

Mastocytosis is a hematopoietic neoplasm defined by abnormal expansion and focal accumulation of clonal tissue mast cells in various organ-systems. The disease exhibits a complex pathology and an equally complex clinical behavior. The classification of the World Health Organization (WHO) divides mastocytosis into cutaneous forms, systemic variants, and localized mast cell tumors. In >80% of patients with systemic mastocytosis (SM), a somatic point mutation in at codon 816 is found. Whereas patients with indolent forms of the disease have a normal or near-normal life expectancy, patients with advanced mast cell neoplasms, including aggressive SM and mast cell leukemia, have a poor prognosis with short survival times. In a majority of these patients, multiple somatic mutations and/or an associated hematologic neoplasm, such as a myeloid leukemia, may be detected. Independent of the category of mastocytosis and the serum tryptase level, patients may suffer from mediator-related symptoms and/or osteopathy. Depending on the presence of co-morbidities, the symptomatology in such patients may be mild, severe or even life-threatening. Most relevant co-morbidities in such patients are IgE-dependent allergies, psychiatric, psychological or mental problems, and vitamin D deficiency. The diagnosis and management of mastocytosis is an emerging challenge in clinical practice and requires vast knowledge, a multidisciplinary approach, and personalized medicine procedures. In this article, the current knowledge about mastocytosis is reviewed with special emphasis on the multidisciplinary aspects of the disease and related challenges in daily practice.
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http://dx.doi.org/10.3390/ijms20122976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627900PMC
June 2019