scholarly journals Epigenetic Changes in Neoplastic Mast Cells and Potential Impact in Mastocytosis

2021 ◽  
Vol 22 (6) ◽  
pp. 2964
Author(s):  
Edyta Reszka ◽  
Ewa Jabłońska ◽  
Edyta Wieczorek ◽  
Peter Valent ◽  
Michel Arock ◽  
...  
Keyword(s):  
Mast Cells ◽  
Systemic Mastocytosis ◽  
Epigenetic Changes ◽  
Hematologic Neoplasm ◽  
Epigenetic Events ◽  
Organ Systems ◽  
Abnormal Accumulation ◽  
Current Article ◽  
Potential Impact ◽  
Methylation Patterns

Systemic mastocytosis (SM) is a hematologic neoplasm with abnormal accumulation of mast cells in various organ systems such as the bone marrow, other visceral organs and skin. So far, only little is known about epigenetic changes contributing to the pathogenesis of SM. In the current article, we provide an overview of epigenetic changes that may occur and be relevant to mastocytosis, including mutations in genes involved in epigenetic processes, such as TET2, DNMT3A and ASXL1, and global and gene-specific methylation patterns in neoplastic cells. Moreover, we discuss methylation-specific pathways and other epigenetic events that may trigger disease progression in mast cell neoplasms. Finally, we discuss epigenetic targets and the effects of epigenetic drugs, such as demethylating agents and BET-targeting drugs, on growth and viability of neoplastic mast cells. The definitive impact of these targets and the efficacy of epigenetic therapies in advanced SM need to be explored in future preclinical studies and clinical trials.

scholarly journals Place of cytology in the diagnosis of systemic mastocytosis: A case report

2021 ◽  
Vol 7 (2) ◽  
pp. 01-05
Author(s):  
W. Quiddi ◽  
H. Boumaazi ◽  
S. Ed-dyb ◽  
H. Yahyaoui ◽  
M. Aitameur ◽  
...  
Keyword(s):  
Mast Cells ◽  
Hematological Malignancies ◽  
Systemic Mastocytosis ◽  
Bone Marrow Involvement ◽  
Acute Leukemias ◽  
Activating Mutations ◽  
Myeloid Neoplasms ◽  
Organ Systems ◽  
Cutaneous Mastocytosis

Mastocytosis is a heterogeneous group of rare diseases related to the clonal, neoplastic proliferation of morphologically and immunophenotypically abnormal mast cells, that accumulate in one or more organ systems. Their pathophysiology is dominated by activating mutations in C-Kit (Stem Cell Factor receptor). Several pathological forms have been described ranging from isolated cutaneous mastocytosis affecting mainly children, to aggressive systemic mastocytosis described mainly in adults with bone marrow involvement. According to the WHO 2016 classification of hematological malignancies, systemic mastocytosis appear as a new entity of "myeloid neoplasms and acute leukemias" that combines cytology (abnormal mast cells) with other genetic and molecular criteria. We describe through this observation the practical side of hematological cytology in the diagnostic orientation of this serious, rare and underestimated pathology.

scholarly journals Response Criteria in Advanced Systemic Mastocytosis: Evolution in the Era of KIT Inhibitors

2021 ◽  
Vol 22 (6) ◽  
pp. 2983
Author(s):  
William Shomali ◽  
Jason Gotlib
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Systemic Mastocytosis ◽  
Myeloproliferative Neoplasms ◽  
Organ Damage ◽  
Response Criteria ◽  
Molecular Response ◽  
Tryptase Level ◽  
Hematologic Neoplasm ◽  
Kit D816v

Systemic mastocytosis (SM) is a rare clonal hematologic neoplasm, driven, in almost all cases, by the activating KIT D816V mutation that leads to the growth and accumulation of neoplastic mast cells. While patients with advanced forms of SM have a poor prognosis, the introduction of KIT inhibitors (e.g., midostaurin, and avapritinib) has changed their outlook. Because of the heterogenous nature of advanced SM (advSM), successive iterations of response criteria have tried to capture different dimensions of the disease, including measures of mast cell burden (percentage of bone marrow mast cells and serum tryptase level), and mast cell-related organ damage (referred to as C findings). Historically, response criteria have been anchored to reversion of one or more organ damage finding(s) as a minimal criterion for response. This is a central principle of the Valent criteria, Mayo criteria, and International Working Group-Myeloproliferative Neoplasms Research and Treatment and European Competence Network on Mastocytosis (IWG-MRT-ECNM) consensus criteria. Irrespective of the response criteria, an ever-present challenge is how to apply response criteria in patients with SM and an associated hematologic neoplasm, where the presence of both diseases complicates assignment of organ damage and adjudication of response. In the context of trials with the selective KIT D816V inhibitor avapritinib, pure pathologic response (PPR) criteria, which rely solely on measures of mast cell burden and exclude consideration of organ damage findings, are being explored as more robust surrogate of overall survival. In addition, the finding that avapritinib can elicit complete molecular responses of KIT D816V allele burden, establishes a new benchmark for advSM and motivates the inclusion of definitions for molecular response in future criteria. Herein, we also outline how the concept of PPR can inform a proposal for new response criteria which use a tiered evaluation of pathologic, molecular, and clinical responses.

Allogeneic Hematopoietic Cell Transplantation Is Effective In Patients With Advanced Systemic Mastocytosis: A Multicenter Retrospective Analysis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2145-2145
Author(s):  
Celalettin Ustun ◽  
Andreas Reiter ◽  
Bart L Scott ◽  
Ryotaro Nakamura ◽  
Damaj Gandhi ◽  
...  
Keyword(s):  
Mast Cell ◽  
Stem Cell ◽  
Mast Cells ◽  
Cell Transplantation ◽  
Research Funding ◽  
Systemic Mastocytosis ◽  
Conditioning Regimen ◽  
Hematopoietic Stem ◽  
Poor Outcome ◽  
Organ Systems

Abstract Systemic mastocytosis (SM) is a rare hematologic neoplasm characterized by abnormal growth and accumulation of tissue mast cells (MC) in various organ systems, including bone marrow (BM). Indolent and advanced forms of SM have been described. Whereas patients with ISM have a normal or near normal life-expectancy, patients with advanced SM, including those suffering from mast cell leukemia (MCL) have a poor prognosis. In these patients, neoplastic MC are usually resistant against conventional drugs and various targeted drugs. In rapidly progressive aggressive SM (ASM) and MCL, polychemotherapy followed by allogeneic hematopoietic stem cell transplantation (alloHCT) has been proposed. However, outcome of alloHCT in advanced SM is unknown, and it also remains uncertain whether clinically relevant graft-versus-SM (GVSM) effects may occur in these patients, as only sporadic case reports have been published. We performed a retrospective multi-center analysis to evaluate the outcome of alloHCT in patients with advanced SM. Fifty-four advanced SM patients receiving SCT in 32 transplantation centers in Europe and America were identified between 1990 and 2013. The median patient age was 45 years. Donors were: HLA identical siblings (31), unrelated donors (URD) (15), umbilical cord blood donors (UCB) (2), and haploidentical donors (1). In 5 patients, stem cell source was not defined (5). Thirty-four patients received myeloablative conditioning (MAC) and 18 received reduced intensity conditioning regimens (RIC). In 2 patients, conditioning regimen was not specified. Indications for alloHCT were SM with an associated clonal hematologic non-mast cell lineage disease (SM-AHNMD) (n=32), MCL (n=13, including one with MCL-AHNMD), 8 with ASM and 1 with myelomastocytic leukemia (MML). The most prevalent AHNMD was acute myeloid leukemia (AML, n=16). With follow-up of 35-6180 (median 365) days, SM responses (defined as ≥50% decrease in BM mast cells ± decrease in serum tryptase ± regression of other organ manifestations) were observed in 39 patients (72%), including complete responses (CR) documented in 12 patients (22%). Eleven patients had stable disease, whereas 4 patients (7%) progressed immediately after alloHCT (primary resistance). In addition, 10 patients progressed (5 of them within 100 days) after an initial response. Progression was most frequently seen in MCL patients (n=6, 50%). In the AHNMD group, only 8 patients relapsed/progressed (25%). The overall survival (OS) and SM progression-free survival (PFS) at 1 year were 63% and 50% for all patients, 77% and 68% for SM-AHNMD, 63% and 50% for ASM, and 25% and 17% for MCL, respectively. The strongest predictive variable associated with inferior survival was a diagnosis of MCL. Other factors associated with poor outcome were: Karnofsky performance status ≤70%, ≥2 SM regimens given before alloHCT (e.g., steroids, cladribine, chemotherapy, tyrosine kinase inhibitor), donor source (alternative donors-UCB and haploidentical compared to sibling or URD), SM progression within the first 100 days, normal cytogenetics (compared to t(8;21) (q22;q22), and RIC (compared to MAC). The following variables were not associated with poor outcome: patient and donor age, recipient-donor sex match status, graft source (BM vs. peripheral stem cells), BM mast cell percentage at time of alloHCT, and CR status of AML or SM response at time of alloHCT. This largest multi-center analysis of results in advanced SM provides evidence for clinical efficacy of alloHCT, presumably because of a GVSM effect of alloHCT (achieving CR, and response to donor-lymphocyte infusions and RIC alloHCT). However, responses varied among different SM categories: while patients with SM-AHNMD enjoyed excellent outcomes, the OS for MCL patients in general, was poor. Nevertheless it is remarkable that 3 of 13 patients with MCL – an otherwise fatal disease with a median survival of <12 months – became long-term survivors after alloHCT. In summary, our results support development of a prospective alloHCT study, with the aim to optimize therapy and to improve overall outcome in advanced SM. Based on our pilot study, alloHCT should also be considered in practice for eligible and fit patients with SM-AHNMD (if treatment of AHNMD component needs alloHCT or SM component is aggressive), rapidly progressing ASM, MCL and MML when a suitable HLA-matched sibling donor or URD is available. Disclosures: Vercellotti: Sangart Inc.: Research Funding; Seattle Genetics: Research Funding. Akin:Novartis: Consultancy. Valent:Novartis: Consultancy, Honoraria, Research Funding.

scholarly journals A Retrospective Case Series Describing the Efficacy of Omalizumab in Systemic Mastocytosis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5470-5470
Author(s):  
Calum Anthony Slapnicar ◽  
Conrad Scullion Smeenk ◽  
Lisa K. Hicks ◽  
Jessica Petrucci ◽  
Peter Vadas ◽  
...  
Keyword(s):  
Mast Cells ◽  
Conflicts Of Interest ◽  
Systemic Mastocytosis ◽  
Tertiary Care ◽  
Case Series ◽  
Response To Treatment ◽  
Cutaneous Manifestations ◽  
Organ Systems ◽  
Cardiovascular Involvement

Abstract Introduction Systemic mastocytosis (SM) represents a heterogeneous group of disorders characterized by accumulation of neoplastic mast cells (MCs) in one or more organ systems. Patients with SM present with a broad range of symptoms resulting from excessive mast cell mediator release, especially histamine, that frequently overlap with those of allergic disease. Episodes of life-threatening anaphylaxis are a recognized feature of SM. Here at St. Michael's Hospital we currently follow more than 50 SM patients, the largest patient cohort in Canada. Omalizumab is a subcutaneously administered monoclonal antibody which acts on circulating IgE, reducing binding to the high-affinity IgE receptor (FCεR1) on mast cells, thereby reducing the potential reactivity of these cells. At St. Michael's Hospital, omalizumab is used as an add-on, off-label therapy in SM patients at risk for recurrent anaphylaxis. The efficacy of omalizumab treatment for SM patients remains unclear. Typically, highly symptomatic patients who are refractory to all other medication are candidates for omalizumab therapy. Objectives Our primary objective was to describe the response to treatment by omalizumab in patients with SM in a tertiary care centre. Our secondary objective was to compare the markers of disease in SM patients between those who were non-responsive versus responsive to omalizumab. The clinical and biological markers to be studied are symptoms and tryptase levels. Methods This is an observational, retrospective study (n=6) of SM patients treated with omalizumab at St. Michael's Hospital between January, 2014 and June, 2018. Electronic medical records were reviewed for mastocytosis treatment, symptom progression and tryptase levels, if available. All patients included in the study were diagnosed with SM according to the 2016 WHO criteria by undergoing a bone marrow biopsy. A baseline was established 2-5 months pre omalizumab exposure, as well as two follow-ups, each ranging from 2-8 months post omalizumab exposure (av. 4.7 months). The Brown Anaphylaxis score was used to capture severity of anaphylaxis. Mild (1), moderate (2), and severe (3) scores were associated with cutaneous manifestations, systemic (GI, respiratory, cardiovascular) involvement and systemic (hypoxia, hypotension, neurological compromise) collapse, respectively. Results Our study consisted of 4 females and 2 males, with an average age of 49 years old [IQR 36-74]. All 6 patients were diagnosed with indolent SM, the more moderate of the six SM subtypes. In every system, except for respiratory, it appears that symptoms decreased once therapy began. From baseline to first follow-up: all three patients who were experiencing systemic symptoms, three of the six manifesting cutaneous symptoms, and two of the three with cardiovascular involvement, responded fully to treatment. At second follow-up, patient 1 presented to clinic asymptomatically. Overall, 100% of patients responded to treatment with responses ranging from 17% to 100% improvement of mastocytosis-related symptoms. The grading of anaphylaxis severity reported three of the six patients improving from scores of 3 (severe) to 1 (mild). The other three patients remained at scores of 2. Patients 1 and 2 (only patients with available tryptase levels at both baseline and follow-up) saw a decrease in tryptase level from 134 to 84.1 and 11.4 to 8.3, respectively. Conclusions Omalizumab appears to be an effective therapy for patients with SM with anaphylaxis and reduces tryptase levels. It should be readily considered in the management of this population. Next steps include following these patients prospectively to better capture the efficacy of omalizumab within this population. Disclosures No conflicts of interest to declare Disclosures No relevant conflicts of interest to declare.

scholarly journals The Recurrent Flush: A Case and Review of Systemic Mastocytosis

2018 ◽  
Vol 13 (2) ◽  
Author(s):  
Wasim Mansoor ◽  
Rodrigo Cavalcanti ◽  
Shaan Chugh
Keyword(s):  
Weight Loss ◽  
Mast Cells ◽  
Systemic Mastocytosis ◽  
Myeloproliferative Disorders ◽  
Acute Onset ◽  
Future Directions ◽  
Visceral Organs ◽  
Hematologic Neoplasm ◽  
Specific Symptoms ◽  
Current Practices

Systemic Mastocytosis (SM) is a hematologic neoplasm characterized by an abnormal proliferation of mast cells, which have the potential to infiltrate one or more visceral organs.  Patients can present with a wide constellation of symptoms making it a challenging diagnosis for clinicians.  Non-specific symptoms such as fatigue, headache, and weight loss may predominate; however, some patients may present with acute onset of urticaria, flushing, and diarrhea. Due to its rarity, clinicians often face a challenge in evaluating, diagnosing and effectively treating systemic mastocytosis.  Identification during the indolent phase is important as SM can progress to aggressive leukemias or myeloproliferative disorders. In this article, we present a case of SM, and discuss current practices in diagnosis, evaluation and management.  We conclude with future directions for treatments and diagnosis

scholarly journals Hypotension, Syncope, and Fever in Systemic Mastocytosis without Skin Infiltration and Rapid Response to Corticosteroid and Cyclosporin: A Case Report

2010 ◽  
Vol 2010 ◽  
pp. 1-4 ◽  
Author(s):  
Didem Ozdemir ◽  
Selcuk Dagdelen ◽  
Tomris Erbas ◽  
Kemal Agbaht ◽  
Songul Serefhanoglu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mast Cell ◽  
Case Report ◽  
Cell Activation ◽  
Systemic Mastocytosis ◽  
Mast Cell Activation ◽  
Organ Systems ◽  
Abnormal Accumulation ◽  
Skin Infiltration ◽  
Principles Of Treatment

Mast cell disorders are defined by an abnormal accumulation of tissue mast cells in one or more organ systems. In systemic mastocytosis, at least one extracutaneous organ is involved by definition. Although, systemic mastocytosis usually represents with skin lesion called urticaria pigmentosa, in a small proportion, there is extracutaneous involvement without skin infiltration. Other manifestations are flushing, tachycardia, dyspepsia, diarrhea, hypotension, syncope, and rarely fever. Various medications have been used but there is not a definite cure for systemic mastocytosis. The principles of treatment include control of symptoms with measures aimed to decrease mast cell activation. We describe a case of systemic mastocytosis presenting with hypotension, syncope attacks, fever, and local flushing. In bone marrow biopsy, increased mast cell infiltration was demonstrated. She had no skin infiltration. A good clinicopathological response was obtained acutely with combination therapy of glucocorticoid and cyclosporine.

Bosutinib Blocks Lyn and Btk Activation and Synergizes with the KIT D816V-Targeting Drug Midostaurin in Inducing Apoptosis in Neoplastic Human Mast Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1717-1717
Author(s):  
Karoline Veronika Gleixner ◽  
Matthias Mayerhofer ◽  
Gregor Hörmann ◽  
Karina Schuch ◽  
Sabine Cerny-Reiterer ◽  
...  
Keyword(s):  
Mast Cells ◽  
Growth Inhibition ◽  
Research Funding ◽  
Systemic Mastocytosis ◽  
Leukemia Cell ◽  
Target Function ◽  
Leukemia Cell Line ◽  
Thymidine Uptake ◽  
Organ Systems ◽  
Kit D816v

Abstract Abstract 1717 Poster Board I-743 Advanced systemic mastocytosis (SM) is a malignant hematopoietic neoplasm characterized by destructive growth of neoplastic mast cells (MC) in various organ systems. In these patients, the response to conventional cytoreductive therapy is poor and the prognosis is grave. The D816V-mutated variant of c-KIT is found in most patients and is considered to be a major transforming oncoprotein in SM that leads to abnormal survival and growth of neoplastic MC. Therefore, agents interfering with the kinase activity of KIT D816V have been developed. One promising agent is midostaurin (PKC412). However, in most patients with advanced SM, therapy with midostaurin is not sufficient to induce long term remissions. In addition, midostaurin is unable to block all pro-oncogenic signaling molecules, such as Lyn and Btk, in neoplastic MC, suggesting that additional oncoproteins and survival factors may play a role in malignant transformation in SM, and that novel therapeutic strategies are required to block such KIT-independent oncogenic pathways. Especially Lyn and Btk have attracted attention as potential new targets in neoplastic MC. Bosutinib (SKI-606) is a novel multikinase inhibitor that targets a broad spectrum of kinases including Lyn and Btk. The aim of the current study was to evaluate the effect of bosutinib on neoplastic MC, and potential cooperative drug interactions between bosutinib and midostaurin. As assessed by 3H-thymidine uptake, bosutinib was found to inhibit the growth of the MC leukemia cell line HMC-1, including the HMC-1.1 subclone that lacks KIT D816V and HMC-1.2 cells expressing KIT D816V, with similar IC50 values (1-5 μM). Furthermore, bosutinib was found to induce apoptosis in both HMC-1 subclones. Growth-inhibitory and apoptosis-inducing effects of bosutinib were also seen in primary neoplastic MC obtained from the bone marrow of patients with SM (n=3). As assessed by phosphoblotting, bosutinib did not inhibit the autophosphorylation of mutant KIT in HMC-1 cells, but was found to completely inhibit the phosphorylation of Lyn and Btk. To confirm the target-function of Lyn and Btk in neoplastic MC, siRNA experiments were performed. Knockdown of Lyn or Btk resulted in induction of apoptosis and growth-inhibition in HMC-1 cells. We next attempted to exploit target-specific and complementing effects of midostaurin and bosutinib by combining both substances. As expected, combined application of bosutinib and midostaurin resulted in a complete inhibition of phosphorylation of KIT, Lyn, and Btk in HMC-1.1 and HMC-1.2 cells. We were also able to show that bosutinib synergizes with midostaurin in inducing apoptosis in both HMC-1 subclones. Synergistic effects were also observed when combining midostaurin with Lyn- or Btk-siRNA. Together, we have identified Lyn and Btk as novel KIT-independent survival molecules in neoplastic MC. Inhibition of these kinases by siRNA-knockdown or by bosutinib leads to growth-inhibition and apoptosis. Synergistic pro-apoptotic effects were observed with the combination “bosutinib + midostaurin”, suggesting that simultaneous targeting of KIT and Lyn/Btk may be a powerful strategy to counteract the survival of neoplastic MC. This drug combination may therefore be an interesting approach to overcome drug-resistance in advanced forms of SM. Disclosures Valent: Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding.

Natural Tyrosinase Inhibitors: Role of Herbals in the Treatment of Hyperpigmentary Disorders

2019 ◽  
Vol 19 (10) ◽  
pp. 796-808 ◽  
Author(s):  
Kamal Uddin Zaidi ◽  
Sharique A. Ali ◽  
Ayesha Ali ◽  
Ishrat Naaz
Keyword(s):  
Critical Role ◽  
Enzymatic Browning ◽  
Melanin Production ◽  
Natural Sources ◽  
Pigmentary Disorders ◽  
Normal Manner ◽  
Abnormal Accumulation ◽  
Current Article ◽  
Tyrosinase Inhibitors

Cutaneous pigmentation plays critical role in determining the color of skin along with photo protection of skin from dreadful effects of ultraviolet radiations. Conversely, abnormal accumulation of melanin is responsible for hyper pigmentary disorders such as melasma, senile lentigines and freckles. Because of the visible nature of dermatologic diseases, they have a considerable psychosomatic effect on affected patients. Tyrosinase inhibitors are molecules that interrelate in some way with the enzyme to prevent it from working in the normal manner. Past many decades witnessed the quest for the development of natural tyrosinase inhibitors due to imperative role played by tyrosinase in the process of melanogenesis and fungi or fruit enzymatic browning. Mechanism of pigmentation is characterized by the intact process of the synthesis of specialized black pigment within melanosomes. Melanin is synthesized by a cascade of enzymatic and chemical reactions. For this reason, melanin production is mainly controlled by the expression and activation of tyrosinase. In the current article, we discussed tyrosinase inhibitors from the natural sources, which can be an essential constituent of cosmetics products and depigmenting agents for the treatment of hyperpigmentory disorders.

scholarly journals New Insights into the Pathogenesis of Systemic Mastocytosis

2021 ◽  
Vol 22 (9) ◽  
pp. 4900
Author(s):  
Zhixiong Li
Keyword(s):  
Molecular Mechanisms ◽  
Kinase Inhibitor ◽  
Systemic Mastocytosis ◽  
Treatment Strategies ◽  
The United States ◽  
European Medicines Agency ◽  
Myeloid Neoplasm ◽  
Organ Systems ◽  
United States Food ◽  
Kit D816v

Mastocytosis is a type of myeloid neoplasm characterized by the clonal, neoplastic proliferation of morphologically and immunophenotypically abnormal mast cells that infiltrate one or more organ systems. Systemic mastocytosis (SM) is a more aggressive variant of mastocytosis with extracutaneous involvement, which might be associated with multi-organ dysfunction or failure and shortened survival. Over 80% of patients with SM carry the KIT D816V mutation. However, the KIT D816V mutation serves as a weak oncogene and appears to be a late event in the pathogenesis of mastocytosis. The management of SM is highly individualized and was largely palliative for patients without a targeted form of therapy in past decades. Targeted therapy with midostaurin, a multiple kinase inhibitor that inhibits KIT, has demonstrated efficacy in patients with advanced SM. This led to the recent approval of midostaurin by the United States Food and Drug Administration and European Medicines Agency. However, the overall survival of patients treated with midostaurin remains unsatisfactory. The identification of genetic and epigenetic alterations and understanding their interactions and the molecular mechanisms involved in mastocytosis is necessary to develop rationally targeted therapeutic strategies. This review briefly summarizes recent developments in the understanding of SM pathogenesis and potential treatment strategies for patients with SM.

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