Andrés C. García-Montero

Prognosis in adult indolent systemic mastocytosis: A long-term study of the Spanish Network on Mastocytosis in a series of 145 patients

BACKGROUND Indolent systemic mastocytosis is a group of rare diseases for which reliable predictors of progression and outcome are still lacking. OBJECTIVE Here we investigate the prognostic impact of the clinical, biological, phenotypic, histopathological, and molecular disease characteristics in adults with indolent systemic mastocytosis, who were followed using conservative therapy. METHODS A total of 145 consecutive patients were prospectively followed between January 1983 and July 2008; in addition, from 1967 to 1983, 20 patients were retrospectively studied. RESULTS Multivariate analysis showed that serum beta2-microglobulin (P = .003) together with the presence of mast/stem cell growth factor receptor gene (KIT) mutation in mast cells plus myeloid and lymphoid hematopoietic lineages (P = .02) was the best combination of independent parameters for predicting disease progression (cumulative probability of disease progression of 1.7% +/- 1.2% at 5-10 years and of 8.4% +/- 5.0% at 20-25 years). Regarding overall survival, the best predictive model included age >60 years (P = .005) and development of an associated clonal hematological non-mast cell disorder (P = .03) with a cumulative probability of death of 2.2% +/- 1.3% at 5 years and of 11% +/- 5.9% at 25 years. CONCLUSIONS Indolent systemic mastocytosis in adults has a low disease progression rate, and the great majority of patients have a normal life expectancy, with the presence of KIT mutation in all hematopoietic lineages and increased serum beta2-microglobulin the most powerful independent parameters for predicting transformation into a more aggressive form of the disease.

Clinical, biological, and molecular characteristics of clonal mast cell disorders presenting with systemic mast cell activation symptoms

BACKGROUND Systemic mast cell activation disorders (MCADs) are characterized by severe and systemic mast cell (MC) mediators-related symptoms frequently associated with increased serum baseline tryptase (sBt). OBJECTIVE To analyze the clinical, biological, and molecular characteristics of adult patients presenting with systemic MC activation symptoms/anaphylaxis in the absence of skin mastocytosis who showed clonal (c) versus nonclonal (nc) MCs and to provide indication criteria for bone marrow (BM) studies. METHODS Eighty-three patients were studied. Patients showing clonal BM MCs were grouped into indolent systemic mastocytosis without skin lesions (ISMs(-); n = 48) and other c-MCADs (n = 3)-both with CD25(++) BM MCs and either positive mast/stem cell growth factor receptor gene (KIT) mutation or clonal human androgen receptor assay (HUMARA) tests-and nc-MCAD (CD25-negative BM MCs in the absence of KIT mutation; n = 32) and compared for their clinical, biological, and molecular characteristics. RESULTS Most clonal patients (48/51; 94%) met the World Health Organization criteria for systemic mastocytosis and were classified as ISMs(-), whereas the other 3 c-MCAD and all nc-MCAD patients did not. In addition, although both patients with ISMs(-) and patients with nc-MCAD presented with idiopathic and allergen-induced anaphylaxis, the former showed a higher frequency of men, cardiovascular symptoms, and insect bite as a trigger, together with greater sBt. Based on a multivariate analysis, a highly efficient model to predict clonality before BM sampling was built that includes male sex (P = .01), presyncopal and/or syncopal episodes (P = .009) in the absence of urticaria and angioedema (P = .003), and sBt >25 microg/L (P = .006) as independent predictive factors. CONCLUSIONS Patients with c-MCAD and ISMs(-) display unique clinical and laboratory features different from nc-MCAD patients. A significant percentage of c-MCAD patients can be considered as true ISMs(-) diagnosed at early phases of the disease.

Recent advances in the understanding of mastocytosis: the role of KIT mutations*

Mastocytosis is a heterogeneous disorder characterised by the expansion and accumulation of mast cells in different organs and tissues. Mast cell physiology is closely dependent on activation of the stem cell factor/Kit signalling pathways and accumulating evidences confirm the physiopathological key role of activating KIT mutations (typically D816V) in mastocytosis and their relationship with the clinical manifestations of the disease. This paper reviews the most recent advances in the understanding of the molecular mechanisms associated with KIT mutations in mastocytosis, including recent data about the use of new therapies targeting the Kit molecule and its associated downstream signalling pathways.

Immunophenotypic analysis of mast cells in mastocytosis: When and how to do it. Proposals of the Spanish Network on Mastocytosis (REMA)

Mastocytosis is a term used for a heterogeneous group of disorders characterized by an abnormal proliferation and accumulation of mast cells (MCs) in one or multiple tissues including skin, bone marrow, liver, spleen, and lymph nodes, among others.

Quality, quantity and harmony: the DataSHaPER approach to integrating data across bioclinical studies

Background Vast sample sizes are often essential in the quest to disentangle the complex interplay of the genetic, lifestyle, environmental and social factors that determine the aetiology and progression of chronic diseases. The pooling of information between studies is therefore of central importance to contemporary bioscience. However, there are many technical, ethico-legal and scientific challenges to be overcome if an effective, valid, pooled analysis is to be achieved. Perhaps most critically, any data that are to be analysed in this way must be adequately ‘harmonized’. This implies that the collection and recording of information and data must be done in a manner that is sufficiently similar in the different studies to allow valid synthesis to take place. Methods This conceptual article describes the origins, purpose and scientific foundations of the DataSHaPER (DataSchema and Harmonization Platform for Epidemiological Research; http://www.datashaper.org), which has been created by a multidisciplinary consortium of experts that was pulled together and coordinated by three international organizations: P3G (Public Population Project in Genomics), PHOEBE (Promoting Harmonization of Epidemiological Biobanks in Europe) and CPT (Canadian Partnership for Tomorrow Project). Results The DataSHaPER provides a flexible, structured approach to the harmonization and pooling of information between studies. Its two primary components, the ‘DataSchema’ and ‘Harmonization Platforms’, together support the preparation of effective data-collection protocols and provide a central reference to facilitate harmonization. The DataSHaPER supports both ‘prospective’ and ‘retrospective’ harmonization. Conclusion It is hoped that this article will encourage readers to investigate the project further: the more the research groups and studies are actively involved, the more effective the DataSHaPER programme will ultimately be.

Mast cells from different molecular and prognostic subtypes of systemic mastocytosis display distinct immunophenotypes

BACKGROUND Systemic mastocytosis (SM) is a heterogeneous group of disorders with distinct clinical and biological behavior. Despite this, little is known about the immunophenotypic features of the distinct diagnostic categories of SM. OBJECTIVE To analyze the immunophenotypic characteristics of bone marrow (BM) mast cells (MCs) of different subtypes of SM. METHODS Bone marrow samples from 123 patients with different subtypes of SM and 92 controls were analyzed for a broad panel of immunophenotypic markers by flow cytometry. RESULTS Three clearly different maturation-associated immunophenotypic profiles were found for BMMCs in SM. These different profiles were associated with both genetic markers of the disease and its clinical behavior. BMMCs from poor-prognosis categories of SM (aggressive SM and MC leukemia) typically showed an immature phenotype with clonal involvement of all myeloid lineages by the D816V stem cell growth factor receptor gene (KIT) mutation. In turn, a mature activated versus resting BMMC immunophenotype was commonly found among patients with good-prognosis subtypes of SM depending on whether they carried (indolent SM and clonal MC activation disorders) or not (well differentiated SM) the D816V KIT mutation. CONCLUSION Bone marrow MCs from SM show 3 different maturation-related immunophenotypic profiles that are associated with both the genetic markers of the disease and its clinical behavior.

Safety and effectiveness of immunotherapy in patients with indolent systemic mastocytosis presenting with Hymenoptera venom anaphylaxis.

BACKGROUND Anaphylaxis after Hymenoptera sting has been described in patients with mastocytosis. Venom immunotherapy (VIT) is a safe and effective way to treat patients with Hymenoptera anaphylaxis, but few studies have addressed its usefulness in patients with systemic mastocytosis. OBJECTIVE To study the effectiveness and safety of VIT in patients with systemic mastocytosis having anaphylaxis after Hymenoptera sting. METHODS A total of 21 mastocytosis patients-4 women (19%) and 17 men (81%) with a median age of 50 years (range, 29-74 years)-with Hymenoptera sting anaphylaxis who were treated with VIT and followed for a median of 52 months (range, 2-250 months) were studied. RESULTS In 18 of 21 patients-16 of them lacking skin involvement-anaphylaxis was the presenting symptom. Six patients (29%) experienced adverse reactions during VIT, 3 during initiation and 3 during maintenance. Twelve patients (57%) were resting while undergoing VIT; 9 (75%) presented local reactions and 3 (25%) systemic reactions, 1 of which required intubation. The Hymenoptera specific IgE decreased from 4.15 kU/L (range, 0.44-100 kU/L) before immunotherapy to 1.2 kU/L (range, 0.34-69.4 kU/L) after 4 years (P < .003). CONCLUSION Venom immunotherapy is effective to treat IgE-mediated Hymenoptera anaphylaxis in patients with mastocytosis. Its use is recommended despite a relatively high risk of adverse reactions during the build-up phase because it provides protection from anaphylaxis in around 3/4 of the patients.

Quality, quantity and harmony: The DataSHaPER approach to integrating data across bioclinical studies

Background Vast sample sizes are often essential in the quest to disentangle the complex interplay of the genetic, lifestyle, environmental and social factors that determine the aetiology and progression of chronic diseases. The pooling of information between studies is therefore of central importance to contemporary bioscience. However, there are many technical, ethico-legal and scientific challenges to be overcome if an effective, valid, pooled analysis is to be achieved. Perhaps most critically, any data that are to be analysed in this way must be adequately ‘harmonized’. This implies that the collection and recording of information and data must be done in a manner that is sufficiently similar in the different studies to allow valid synthesis to take place. Methods This conceptual article describes the origins, purpose and scientific foundations of the DataSHaPER (DataSchema and Harmonization Platform for Epidemiological Research; http://www.datashaper.org), which has been created by a multidisciplinary consortium of experts that was pulled together and coordinated by three international organizations: P3G (Public Population Project in Genomics), PHOEBE (Promoting Harmonization of Epidemiological Biobanks in Europe) and CPT (Canadian Partnership for Tomorrow Project). Results The DataSHaPER provides a flexible, structured approach to the harmonization and pooling of information between studies. Its two primary components, the ‘DataSchema’ and ‘Harmonization Platforms’, together support the preparation of effective data-collection protocols and provide a central reference to facilitate harmonization. The DataSHaPER supports both ‘prospective’ and ‘retrospective’ harmonization. Conclusion It is hoped that this article will encourage readers to investigate the project further: the more the research groups and studies are actively involved, the more effective the DataSHaPER programme will ultimately be.

Evaluation of the WHO criteria for the classification of patients with mastocytosis

Diagnosis and classification of mastocytosis is currently based on the World Health Organization (WHO) criteria. Here, we evaluate the utility of the WHO criteria for the diagnosis and classification of a large series of mastocytosis patients (n=133), and propose a new algorithm that could be routinely applied for refined diagnosis and classification of the disease. Our results confirm the utility of the WHO criteria and provide evidence for the need of additional information for (1) a more precise diagnosis of mastocytosis, (2) specific identification of new forms of the disease, (3) the differential diagnosis between cutaneous mastocytosis vs systemic mastocytosis, and (4) improved distinction between indolent systemic mastocytosis and aggressive systemic mastocytosis. Based on our results, a new algorithm is proposed for a better diagnostic definition and prognostic classification of mastocytosis, as confirmed prospectively in an independent validation series of 117 mastocytosis patients.

KIT mutation analysis in mast cell neoplasms: recommendations of the European Competence Network on Mastocytosis.

Although acquired mutations in KIT are commonly detected in various categories of mastocytosis, the methodologies applied to detect and quantify the mutant type and allele burden in various cells and tissues are poorly defined. We here propose a consensus on methodologies used to detect KIT mutations in patients with mastocytosis at diagnosis and during follow-up with sufficient precision and sensitivity in daily practice. In addition, we provide recommendations for sampling and storage of diagnostic material as well as a robust diagnostic algorithm. Using highly sensitive assays, KIT D816V can be detected in peripheral blood leukocytes from most patients with systemic mastocytosis (SM) that is a major step forward in screening and SM diagnosis. In addition, the KIT D816V allele burden can be followed quantitatively during the natural course or during therapy. Our recommendations should greatly facilitate diagnostic and follow-up investigations in SM in daily practice as well as in clinical trials. In addition, the new tools and algorithms proposed should lead to a more effective screen, early diagnosis of SM and help to avoid unnecessary referrals.