Comparison of prognostic scores according to WHO classification in 170 patients with advanced mastocytosis and C-finding treated with midostaurin.

Advanced systemic mastocytosis (AdvSM) encompasses heterogeneous mastocytosis subtypes and is associated with poor outcomes. Although midostaurin was the first tyrosine kinase inhibitor to be approved for AdvSM patients, long-lasting responses are limited. The mutation-Adjusted Risk Score (MARS), the International Prognostic Scoring System for mastocytosis (IPSM) and the Global Prognostic Score for Systemic Mastocytosis (GPSM) have been established to characterize the outcomes of patients with overall AdvSM. However, given the outcome's dependency on the AdvSM subtype, prognostic characterization within each subtype is critical. We aimed to study the predictive ability using Harrell's concordance index of prognostic scores according to the AdvSM subtype. We conducted a nationwide retrospective study using the French mastocytosis reference center's registry and included all midostaurin-treated patients with C finding. Overall, 170 patients were identified: 46 aggressive SM (ASM), 11 mast cell leukemia (MCL), and 113 SM with associated hematological neoplasm (SM-AHN). All risk scores improved their discriminative value for overall survival (OS) when combined with the AdvSM subtype. The best predictive value was for adjusted MARS (C-index = 0.689), followed by GPSM (C-index = 0.677) and IPSM (C-index = 0.618). In a multivariable analysis, MARS stratification and the AdvSM subtype were both prognostic for OS. Accordingly, five subgroups of patients with AdvSM and a different median OS were identified: 9.9 months for MCL, 24 months for intermediate/high-risk SM-AHN, 33 months for intermediate/high-risk ASM, 58 months for low-risk SM-AHN and was not reached for low-risk ASM (p < 0.001). The AdvSM subtype and the MARS are the most predictive of OS and should prompt specific management.

Mastocytosis, MCAS, and Related Disorders-Diagnosis, Classification, and Therapy.

Mastocytosis is a heterogeneous group of hematologic neoplasms defined by an accumulation of neoplastic mast cells (MC) in the skin, bone marrow, and other visceral organs [...].

Systemic mastocytosis in adults: 2019 update on diagnosis, risk stratification and management.

OVERVIEW: Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MCs) in extra-cutaneous organs. DIAGNOSIS: The major criterion is presence of multifocal clusters of abnormal MC in the bone marrow. Minor diagnostic criteria include elevated serum tryptase level, abnormal MC CD25 expression, and presence of KITD816V mutation. RISK STRATIFICATION: Establishing SM subtype as per the World Health Organization classification system is an important first step. Broadly, patients either have indolent/smoldering SM (ISM/SSM) or advanced SM, the latter includes aggressive SM (ASM), SM with associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL). Identification of poor-risk mutations (ie, ASXL1, RUNX1, SRSF2, NRAS) further refines the risk stratification. Recently, clinical and hybrid clinical-molecular risk models have been developed to more accurately assign prognosis in SM patients. MANAGEMENT: ISM patients have a normal life expectancy and treatment is generally limited to anaphylaxis prevention/symptom control/osteoporosis treatment. Patients with advanced SM frequently need MC cytoreductive therapy to ameliorate disease-related organ dysfunction. High response rates have been seen with small-molecule inhibitors that target mutant-KIT, including midostaurin (Food and Drug Administration approved) or avapritinib (investigational). Other options for MC cytoreduction include cladribine or interferon-α, although head-to-head comparisons are lacking. Treatment of SM-AHN primarily targets the AHN component, if an aggressive disease such as acute myeloid leukemia is present. Allogeneic stem cell transplant can be considered in such patients, or in those with relapsed/refractory advanced SM. Imatinib has a limited therapeutic role in SM; effective cytoreduction is limited to those with imatinib-sensitive KIT mutations.

Telangiectasia macularis eruptiva perstans: an old terminology, still frequently used.

The term telangiectasia macularis eruptiva perstans (TMEP) was originally used to describe a rare form of cutaneous mastocytosis (CM) that was limited to the skin with lesions consisting of irregular, telangiectatic macules ranging in color from red to brown. Recent guidelines, however, recommended that the sole presence of telangiectasias should not form the basis of a distinct variant of CM. We conducted a review of the literature from 1930 to 2017 and found 76 cases that were reported as TMEP. Owing to a general misconception about diagnosis of CM and SM, there is a need for further discussion and awareness of the newly proposed World Health Organization (WHO) guidelines.

Clinical presentation and management practice of systemic mastocytosis. A survey on 460 Italian patients.

Systemic mastocytosis is a rare heterogeneous myeloproliferative neoplasm characterized by abnormal proliferation and activation of mast cells. We describe a large multicentre series of 460 adult patients with systemic mastocytosis, with a diagnosis based on WHO 2008 criteria, in a "real-life" setting of ten Italian centers with dedicated multidisciplinary programs. We included indolent forms with (n = 255) and without (n = 165) skin lesions, smouldering (n = 20), aggressive (n = 28), associated with other hematological diseases mastocytosis (n = 21) and mast cell leukemia (n = 1). This series was uniquely characterized by a substantial proportion of patients with low burden of neoplastic mast cells; notably, 38% of cases were diagnosed using only minor diagnostic criteria according to WHO 2008 classification, underlying the feasibility of early diagnosis where all diagnostic approaches are made available. This has particular clinical relevance for prevention of anaphylaxis manifestations, that were typically associated with indolent forms. In multivariate analysis, the most important features associated with shortened overall survival were disease subtype and age at diagnosis >60 years. Disease progression was correlated with mastocytosis subtype and thrombocytopenia. As many as 32% of patients with aggressive mastocytosis suffered from early evolution into acute leukemia. Overall, this study provides novel information about diagnostic approaches and current presentation of patients with SM and underlines the importance of networks and specialized centers to facilitate early diagnosis and prevent disease-associated manifestations. Am. J. Hematol. 91:692-699, 2016. © 2016 Wiley Periodicals, Inc.

Systemic mastocytosis with associated clonal hematological non-mast cell lineage disease: clinical significance and comparison of chomosomal abnormalities in SM and AHNMD components.

Some patients with systemic mastocytosis have concurrent hematological neoplasms, designated in the World Health Organization (WHO) classification as systemic mastocytosis with associated clonal hematological non-mast cell lineage disease (SM-AHNMD). In this study, we analyzed 29 patients with SM-AHNMD and compared them to 40 patients with pure SM. The AHNMDs were classified as chronic myelomonocytic leukemia (CMML) (n = 10), myelodysplastic syndrome (MDS) (n = 7), myeloproliferative neoplasms (n = 4), B-cell lymphoma/leukemia/plasma cell neoplasms (n = 7), and acute myeloid leukemia (n = 1). Patients with SM-AHNMD were older, more frequently had constitutional symptoms and hematological abnormalities, less often had skin lesions, and had an inferior overall survival compared with pure SM patients (48 months vs. not-reached, P < 0.001). Karyotypic abnormalities were detected in 9/28 (32%) patients with SM-AHNMD but not in pure SM patients (P < 0.001). Combined imaging/ fluorescence-in-situ hybridization performed in four SM-AHNMD cases revealed shared abnormal signals in mast cells and myeloid cells in two patients with SM-CMML and one patient with SM-MDS, but not in the mast cells of a case SM-associated with chronic lymphocytic leukemia with ATM-deletion. Quantitative mutation analysis showed higher levels of mutant KIT D816V in SM-CMML and SM-MDS than in pure SM (P < 0.001). Our data indicate that the SM-AHNMD category in the WHO classification is heterogeneous, including clonally related and unrelated forms of AHNMD. The presentation, treatment, and outcome of patients with SM-AHNMD is often dictated by the type of AHNMD.

Indolent systemic mastocytosis: a case and review of the current available treatment options.

Mastocytosis denotes a heterogeneous group of disorders characterized by abnormal growth and accumulation of mast cells. Cutaneous mastocytosis is characterized by skin-limited disease and is the most common subtype. Systemic mastocytosis has extracutaneous organ involvement with variable symptomatology and prognosis. Clinical manifestations are secondary to mediator release or direct organ infiltration of mast cells. Current available treatment for systemic mastocytosis is non-curative with conventional symptom-directed therapy for all subtypes. Cytoreductive agents are available for those with refractory symptoms or extensive extracutaneous disease. To date, clinical responses remain mixed and systemic mastocytosis is still an incurable condition.

Systemic mastocytosis in adults: 2012 Update on diagnosis, risk stratification, and management.

DISEASE OVERVIEW: Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MC) in one or more extra-cutaneous organs. DIAGNOSIS: The major criterion is presence of multifocal clusters of morphologically abnormal MC in the bone marrow. Minor diagnostic criteria include elevated serum tryptase level, abnormal MC expression of CD25 and/or CD2, and presence of KITD816V. RISK STRATIFICATION: The prognostic relevance of the 2008 World Health Organization (WHO) classification of SM has recently been confirmed. Classification of SM patients into indolent (SM), aggressive SM (ASM), SM associated with a clonal non-MC lineage disease (SM-AHNMD) and mast cell leukemia (MCL) subgroups is a useful first step in establishing prognosis. MANAGEMENT: SM treatment is generally palliative. ISM patients have a normal life expectancy and receive symptom-directed therapy; infrequently, cytoreductive therapy may be indicated for refractory symptoms. ASM patients have disease-related organ dysfunction; interferon-α (±corticosteroids) can control dermatological, hematological, gastrointestinal, skeletal, and mediator-release symptoms, but is hampered by poor tolerability. Similarly, cladribine has broad therapeutic activity, with particular utility when rapid MC debulking is indicated; the main toxicity is myelosuppression. Imatinib has a therapeutic role in the presence of an imatinib-sensitive KIT mutation or in KITD816-unmutated patients. Treatment of SM-AHNMD is governed primarily by the non-MC neoplasm; hydroxyurea has modest utility in this setting. INVESTIGATIONAL DRUGS: Dasatinib's in vitro anti-KITD816V activity has not translated into significant therapeutic activity in most SM patients. In contrast, preliminary data suggest that Midostaurin may produce significant decreases in MC burden in some patients.

[Mastocytosis and eosinophilic leukemia: diagnostics and classification]. / Mastozytosen und myeloische Neoplasien mit Eosinophilie: Diagnostik und Klassifikation.

Mastocytosis and myeloid eosinophilic neoplasms are rare diseases of the bone marrow and are often a diagnostic challenge for hematopathologists. In mastocytosis, compact mast cell infiltrates represent the main diagnostic criterion and for myeloid eosinophilic neoplasms, eosinophilic granulocytes dominate the histological picture. Both disease groups include phenotypically and prognostically very different entities which are each defined by WHO criteria. For systemic mastocytosis (SM), a differentiation between indolent and aggressive or even leukemic forms is of prognostic importance. In indolent variants of SM, a local and/or systemic, usually reactive increase in eosinophilic granulocytes (SM-eo) is often observed. In contrast, an increase in neoplastic eosinophils is often observed in advanced SM, predominantly in diseases designated SM with associated non-mastocytic hematological neoplasms (SM-AHNMD), e.g. in SM with chronic eosinophilic leukemia (SM-CEL). Apart from mastocytoses, immunophenotypically aberrant tissue mast cells are only observed in certain rare forms of myeloid neoplasms with eosinophilia, in particular in myeloproliferative neoplasms (MPN-eo) with cytogenic anomalies in the platelet-derived growth factor receptor (PDGFR). The World Health Organization (WHO) classification of eosinophilic leukemias, however, fulfils the morphological and clinical requirements in a limited way only and needs an update.

Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors.

Clinical phenotype in systemic mastocytosis (SM) is markedly variable, which complicates prognostication and decision making regarding the choice and timing of therapy. In a retrospective study of 342 consecutive adult patients with SM seen at the Mayo Clinic between 1976 and 2007, disease subdesignation according to the World Health Organization (WHO) proposal was indolent (ISM) in 159 (46%), with associated clonal hematologic non-mast cell lineage disease (SM-AHNMD) in 138 (40%), aggressive (ASM) in 41 (12%), and mast cell leukemia in 4 (1%). KITD816V was detected in bone marrow-derived DNA by allele-specific polymerase chain reaction (PCR) in 68% of 165 patients evaluated (ISM, 78%; ASM, 82%; SM-AHNMD, 60%; P = .03); JAK2V617F was detected in 4%, all in SM-AHNMD. Compared with those with nonindolent SM, life expectancy in ISM was superior and not significantly different from that of the age- and sex-matched US population. In addition, multivariable analysis identified advanced age, weight loss, anemia, thrombocytopenia, hypoalbuminemia, and excess bone marrow blasts as independent adverse prognostic factors for survival. The current study validates the prognostic relevance of the WHO subclassification of SM and provides additional information of value in terms of both risk stratification and interpretation of clinical presentation and laboratory results.

The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes.

Recently the World Health Organization (WHO), in collaboration with the European Association for Haematopathology and the Society for Hematopathology, published a revised and updated edition of the WHO Classification of Tumors of the Hematopoietic and Lymphoid Tissues. The 4th edition of the WHO classification incorporates new information that has emerged from scientific and clinical studies in the interval since the publication of the 3rd edition in 2001, and includes new criteria for the recognition of some previously described neoplasms as well as clarification and refinement of the defining criteria for others. It also adds entities-some defined principally by genetic features-that have only recently been characterized. In this paper, the classification of myeloid neoplasms and acute leukemia is highlighted with the aim of familiarizing hematologists, clinical scientists, and hematopathologists not only with the major changes in the classification but also with the rationale for those changes.

Utility of the World Heath Organization classification criteria for the diagnosis of systemic mastocytosis in bone marrow.

In the World Health Organization classification, one major and four minor criteria are specified for the diagnosis of systemic mastocytosis. We report our experience using these criteria to diagnose systemic mastocytosis involving bone marrow. A total of 59 patients with clinically suspected systemic mastocytosis underwent comprehensive bone marrow examination, including immunophenotyping by immunohistochemistry and/or flow cytometry and molecular studies for KIT exon 17 mutations. Serum tryptase levels were also assessed. Of these 59, 53 (90%) patients met the diagnostic criteria for systemic mastocytosis. In these patients, multifocal dense infiltrates of mast cells, the major criterion, was observed in 36 (68%) patients. Atypical mast cell morphology was observed in 53 (100%), an aberrant immunophenotype was identified in 50 of 52 (96%), KIT mutation was present in 33 of 44 (75%), and an elevated serum tryptase (>20 ng/ml) was detected in 44 of 52 (85%). In the six patients in which bone marrow examination could not confirm systemic mastocytosis, one had systemic mastocytosis involving spleen, one patient had chronic idiopathic myelofibrosis, and four had no specific diagnosis, but systemic mastocytosis was still considered most likely. Of these six patients, atypical mast cell morphology was identified in five, aberrant immunophenotype in five, KIT mutation in two, and elevated serum tryptase in two. None of these cases met the major criteria. We conclude that the World Health Organization criteria are useful for the diagnosis of systemic mastocytosis in bone marrow specimens. The results also show the relative values of traditional morphologic criteria (ie, major criterion) and the results of ancillary testing (ie, minor criteria). However, as illustrated by the case of splenic systemic mastocytosis as well as the patient with chronic idiopathic myelofibrosis, the current World Health Organization system is neither completely sensitive nor specific for systemic mastocytosis.

Cytoreductive therapy in 108 adults with systemic mastocytosis: Outcome analysis and response prediction during treatment with interferon-alpha, hydroxyurea, imatinib mesylate or 2-chlorodeoxyadenosine.

Cytoreductive therapy in systemic mastocytosis (SM) includes several drugs whose individual merit has not been well characterized. We retrospectively studied 108 Mayo Clinic patients who met the 2008 WHO diagnostic criteria for SM and received at least one cytoreductive drug. The numbers of patients who were evaluable for response to treatment with interferon-alpha with or without prednisone (IFN-alpha), hydroxyurea (HU), imatinib mesylate (IM) or 2-chlorodeoxyadenosine (2-CdA) were 40, 26, 22, and 22, respectively. The corresponding overall (major) response rates, according to recently published consensus criteria, were 53% (18%), 19% (0%), 18% (9%), and 55% (37%). The respective overall response rates in indolent SM, aggressive SM and SM associated with another clonal hematological nonmast cell lineage disease (SM-AHNMD) were 60%, 60%, 45% for IFN-alpha, 0, 0, 21% for HU, 14%, 50%, 9% for IM and 56%, 50%, 55% for 2-CdA. The absence of mast cell mediator release symptoms in IFN-alpha-treated patients and presence of circulating immature myeloid cells in 2-CdA-treated patients predicted inferior response. TET2 mutational status did not influence treatment response. Although the major response rates with these four cytoreductive agents were still suboptimal and HU was mainly used in patients with SM-AHNMD, the current study favors 2-CdA or IFN-alpha as first-line current therapy in SM and identifies patients who are likely to respond to such therapy.

Mast cells and mastocytosis.

Mast cells (MCs) typically reside at barrier sites of the body, including the intestinal mucosa, and play a vital role in innate host defence. Activated MCs release a wide variety of bioactive mediators. These include preformed mediators stored in the granules (e.g. histamine and tryptase) and newly synthesised mediators (e.g. prostaglandins, leukotrienes and cytokines). MCs are present in all layers throughout the gastrointestinal (GI) tract and there is a close bi-directional connection between MCs and enteric nerves that is of vital importance in the regulation of GI functions. Some gain-of-function mutations in c-kit, encoding the tyrosine kinase- receptor for stem cell factor, are associated with the rare disease entity, systemic mastocytosis. These patients present symptoms arising from MC mediator release or infiltration. GI manifestations are common in this patient group, mainly abdominal pain and diarrhoea. Endoscopy with biopsies reveals MC infiltration in the mucosa. Other diagnostic tools include bone marrow biopsy and serum tryptase. Treatment is symptomatic with antihistamines or cromoglycate in mild cases, whereas severe cases need cytoreductive therapy that should be managed with expert haematologists. From a day-to-day clinical perspective, the important role of MCs in neuroimmune interaction has been implicated in the intestinal response to stress, in alterations of mucosal and neuromuscular function in irritable bowel syndrome or inflammatory bowel disease, and in the pathogenesis of non-erosive oesophageal reflux disease. Thus, MCs have important regulatory and protective roles in innate defence, in addition to being a potential mediator of mucosal pathophysiology in GI diseases. We need to learn how to balance the response of these volatile cells to be able to benefit from their versatility.

[Current concepts and treatment advances in systemic mastocytosis]. / Actualités sur la compréhension et le traitement des mastocytoses systémiques.

PURPOSE: Mast cell disorders are defined by an abnormal accumulation of tissue mast cells in one or more organ systems. Clinical symptoms in mastocytosis result from mast cells derived mediators and, less frequently, from destructive infiltration of mast cells. Systemic mastocytosis is regressive among children, whereas the disease is persistent among adults. A clonal haematological non-mast cell lineage disease can be associated. The clinical course in these patients is variable ranging from asymptomatic for years to highly aggressive and rapidly devastating. Until recently, the only treatment of this incurable disease was symptomatic. CURRENT KNOWLEDGE AND KEY POINTS: Recent advances were done in understanding the physiopathology of this myeloproliferative syndrome which results from an activating mutation of the stem cell factor receptor: C-Kit. A somatic C-Kit mutation is usually detectable in mast cells and their progenitors. Different mutations were found and the mutation D816V is the most frequent. Their specific transduction paths were also studied. Diagnosis of systemic mastocytosis does not only rest upon pathological examination but also on molecular as well as immunological and immunochemical tools. FUTURE PROSPECTS AND PROJECTS: Physiopathological advancements led to suggest new treatments in order to directly inhibit proliferative paths of masts cells such as tyrosine kinase inhibitors and rapamycin.

Systemic mastocytosis associated with chronic idiopathic myelofibrosis: a distinct subtype of systemic mastocytosis associated with a [corrected] clonal hematological non-mast [corrected] cell lineage disorder carrying the activating point mutations KITD816V and JAK2V617F.

In approximately 20 to 30% of patients with systemic mastocytosis (SM), an associated clonal hematological nonmast cell lineage disorder (AHNMD) is diagnosed. Although SM may be considered to be closely related to the myeloproliferative disorders (MPDs), it is unknown whether JAK2(V617F+) MPD may occur as AHNMD in patients with SM. We here describe five patients with SM and co-existing chronic idiopathic myelofibrosis (SM-CIMF). In five of five patients, we detected the SM-related KIT mutation D816V, and in four of five patients, the MPD-related JAK2 mutation V617F. Surprisingly, JAK2(V617F) was found not only in the AHNMD component of the disease but also in microdissected mast cells in all four JAK2(V617F)-positive cases. Conversely, in two of the five patients, KIT(D816V) was found not only in neoplastic mast cells but also in microdissected CD15(+) neoplastic myeloid cells. Control experiments showed that 10 indolent SM patients without associated MPD did not carry the JAK2 mutation V617F and that 15 CIMF patients without SM did not carry the KIT mutation D816V. Altogether, these data suggest that KIT(D816V+) SM can co-exist with JAK2(V617F+) CIMF and that, in some of these SM-CIMF cases, the two mutations are present in the neoplastic cells of both disease components.

The origin of neoplastic mast cells in systemic mastocytosis with AML1/ETO-positive acute myeloid leukemia.

OBJECTIVE: Systemic mastocytosis with associated clonal hematological non-mast cell lineage disease (SM-AHNMD) is a distinct entity that was defined by World Health Organization. Systemic mastocytosis with acute myeloid leukemia (AML) is frequently seen among SM-AHNMD. However, the pathogenesis or origin of neoplastic mast cells has not been fully elucidated in this category of diseases. METHODS: We examined KIT mutation, chimeric status, and AML1/ETO mRNA concerning mast cells and immature hematopoietic cells of the bone marrow in a patient with systemic mastocytosis with AML1/ETO-positive AML following allogeneic hematopoietic stem cell transplantation (HSCT). RESULTS: Mast cells of the patient displayed KIT D816Y mutation, and were derived from the recipient. In contrast, immature hematopoietic cells as defined by CD34+ CD117+ were derived from the donor, which did not possess detectable KIT D816Y mutation. The ratio of AML1/ETO to 18S rRNA of the mast cells was 7.53, whereas that of immature hematopoietic cells was 1.67. CONCLUSIONS: In a patient with SM-AHNMD who underwent allogeneic HSCT, the major source of the detectable AML1/ETO mRNA of the bone marrow after transplantation was neoplastic mast cells with KIT mutation, which were thought to be derived from CD34+ CD117+ immature leukemic cells of the recipient.