scholarly journals Indolent systemic mastocytosis or just ‘atypical enterocolic mast cell aggregates’?

2021 ◽  
Vol 156 (Supplement_1) ◽  
pp. S56-S56
Author(s):  
U Edema ◽  
Y Fang ◽  
L Qiang ◽  
Y Huang
Keyword(s):  
Bone Marrow ◽  
Mast Cell ◽  
Mast Cells ◽  
Systemic Mastocytosis ◽  
Case Reports ◽  
Cutaneous Lesion ◽  
Cell Aggregates ◽  
Kit Mutation ◽  
Who Criteria ◽  
Systemic Involvement

Abstract Introduction/Objective Mastocytosis is a rare disease in which there are abnormal mast cell accumulation in one or more tissue sites. Multifocal dense mast cell aggregates with atypical morphology or immunohistochemistry are considered as systemic mastocytosis (SM) based on WHO criteria. SM usually involves bone marrow and majority of them also have KIT mutation. There are rare case reports of atypical enterocolic mast cell aggregates (EMCA) confined to gastrointestinal (GI) only with mild or no symptoms. Here we present a case with extensive atypical mast cell aggregates in lower GI tract yet no evidence of involvement of other organs. Methods/Case Report A 34-year-old woman presented with abdominal bloating, diarrhea along with pruritis but no cutaneous lesion. Biopsies from the ascending and descending colons, caecum and rectum consistently showed increased eosinophils and multifocal infiltrates of atypical spindle shaped mast cells which are positive for CD117/tryptase but negative for CD2 and CD25. This is consistent with SM by WHO criteria based on morphology. Bone marrow biopsy showed normal amount of mast cells with normal morphology. Upper gastrointestinal biopsy was unremarkable. Serum tryptase level was normal. No KIT mutation was detected in exon 9, 11, 13 or 17 from colonic mucosa. Patient has been treated with antihistamine and Montelukast and symptoms resolved. Results (if a Case Study enter NA) N/A Conclusion This case met the criteria of SM based on the presence of multifocal mast cell aggregates and atypical spindle morphology >25%. Johncilla et al. previously reported 16 cases of EMCA with atypical morphology or immunohistochemistry, absent to mild localized symptoms, and negative KIT mutation. Based on lack of generalized disease, the authors preferred using descriptive terminology instead of ‘systemic mastocytosis’ for those cases. Our case has broader involvement of lower gastrointestinal tract than any reported case and the patient needs treatment for the symptoms. However, there is no ‘systemic’ involvement of bone marrow or any other organ. The diagnosis of ‘Systemic Mastocytosis’ would cause potential confusion and/or unnecessary anxiety. Further study of more cases is needed to better characterize and categorize the cases of atypical mast cell aggregates localized only to the GI.

scholarly journals Cutaneous Mastocytosis in a 61-year-old Female from a Dermatological and Histopathological Perspective

2020 ◽  
pp. 01-06
Author(s):  
Erisa Kola ◽  
Jorida Memini ◽  
Ina Kola ◽  
Daniela Nakuci ◽  
John Ekladous ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mast Cell ◽  
Mast Cells ◽  
Lymph Nodes ◽  
Systemic Mastocytosis ◽  
World Health ◽  
Systemic Involvement ◽  
Cutaneous Mastocytosis ◽  
Health Organization ◽  
Cell Disorder

First described by Nettleship et al. in 1869 [1], mastocytoses are a heterogeneous group of disorders characterized by the pathologic accumulation of mast cells in various tissues [2-5]. Mastocytosis can be confined to the skin as in cutaneous mastocytosis (CM), or it can involve extracutaneous tissues such as the liver, spleen, bone marrow and lymph nodes, as in systemic mastocytosis [6]. Mastocytosis is a World Health Organization-defined clonal mast cell disorder characterized by significant clinicopathologic heterogeneity [7]. Keywords: Cutaneous mastocytosis; Systemic mastocytosis; Systemic involvement; Mast cells; Mastocytosis.

Dasatinib (Sprycel™) Therapy for Patients with Systemic Mastocytosis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3627-3627 ◽  
Author(s):  
Srdan Verstovsek ◽  
Hagop Kantarjian ◽  
Jorge Cortes ◽  
Farhad Ravandi-Kashani ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mast Cell ◽  
Mast Cells ◽  
Interferon Alpha ◽  
Systemic Mastocytosis ◽  
Performance Status ◽  
Hypereosinophilic Syndrome ◽  
In Vivo Models ◽  
Recombinant Interferon ◽  
Kit Mutation

Abstract Background Systemic mastocytosis (SM) is characterized by abnormal proliferation and accumulation of neoplastic mast cells. Patients (pts) with SM are treated with recombinant interferon-alpha or cladribine. Responses to these agents are poor. Malignant mast cells in SM carry, in most cases, a mutation involving codon 816 of the c-KIT gene (D816V) resulting in constitutively activated c-kit receptor tyrosine kinase believed to be important for disease progression. Agents that antagonize this mutated form of c-kit may have clinical benefit in SM. Dasatinib is one such agent, proven effective in pre-clinical in vitro and in vivo models of SM. Study Design In pilot Phase II trial for SM, Dasatinib was administered at 70mg PO BID. Response was assessed after minimum of 3 months (3 cycles) of therapy. Therapy was discontinued in pts who showed no response after 6 cycles of therapy. Response was evaluated following guidelines proposed by Valent et al. (Leuk Res. 25;603–625, 2001). In addition, all symptoms related to SM were recorded and monitored. Results Thus far, a total of 30 pts have been treated; 24 are evaluable for response and toxicity, including 6 with aggressive SM (ASM), 4 with SM and associated hematologic non-mast cell disease (SM-AHNMD; 2 with chronic myelomonocytic leukemia and one each with myelofibrosis [SM-MF; JAK2 mutation positive and abnormal cytogenetics] and hypereosinophilic syndrome [SM-HES; FIP1L1-PDGFRa negative]) and 14 with indolent SM (ISM) with uncontrolled symptoms despite optimal supportive care measures. Median age is 57 years (range, 35–73); these were 10 males and 14 females; time from diagnosis to dasatinib therapy 49 months (range, 0–233), performance status 1 in 23 and 2 in 1 pt. Eleven patients were previously treated: imatinib mesylate in 6; denileukin diftitox in 4; and erythropoietin, interferon-alpha, or cladribine in 2 each. One pt, who had undergone splenectomy, had hepatomegaly prior to start of therapy. Median Hb 12.4g/dL (range, 8.5–15.4), WBC 6.7×109/L, (range, 3.5–53.3), and platelets 263×109/L (range, 60–377); no patient was transfusion dependent. Percent bone marrow mast cell varied from <10% in 9 pts, to 60% in 4 pts; blood tryptase level was ≤20ng/mL (not significant) in 7 pts and >200ng/mL (upper limit of the test) in 7 pts. A total of 94 cycles of therapy were administered. The median number of cycles was 4 (range, 1–8). Ten patients stopped therapy: 1 due to progression of AHNMD to acute leukemia, 1 lost a response (symptomatic improvement), 2 had no response after 3 months of therapy, and 6 due to toxicity. No grade 4 toxicity was observed. Twelve patients decreased the dose of dasatinib to 50mg PO BID, of which four to 40mg PO BID. Two patients (8%) achieved complete remission, one with SM-MF, and one with SM-HES. Both were c-KIT mutation negative and had low, not significant tryptase levels. Both were anemic (Hb 9.4g/dL) and failed erythropoietin therapy, and had abnormal WBC differential; one had low platelets (90×109/L). No significant response in % bone marrow mast cells (4 pts are too early in therapy) or blood tryptase levels have been observed in other patients so far. Symptoms related to SM improved significantly in 7 patients (29%). Conclusion Dasatinib is active in SM (overall response rate 37%). Updated clinical and molecular results will be presented.

Imatinib Mesylate in the Treatment of Systemic Mastocytosis, a Phase I/II Trial.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1516-1516 ◽  
Author(s):  
H.J. Droogendijk ◽  
J.C. Kluin-Nelemans ◽  
P.L.A van Daele
Keyword(s):  
Bone Marrow ◽  
Cell Proliferation ◽  
Mast Cell ◽  
Mast Cells ◽  
Imatinib Mesylate ◽  
Systemic Mastocytosis ◽  
Skin Lesions ◽  
Tissue Response ◽  
Serum Tryptase ◽  
Kit Receptor

Abstract Introduction: mastocytosis comprimes a group of diseases characterized by abnormal proliferation and accumulation of mast cells in one or more organs. A cutaneous and systemic form of mastocytosis is distinguished. Systemic mastocytosis defines the disease process in which mast cell proliferation exceeds the skin. The clinical manifestations of systemic mastocytosis depend on the tissues involved and the tissue response to the accumulation of mast cells. Although in general the disease progresses slowly, it may develop into a malignant disease. Currently there is no cure for systemic mastocytosis. Mast cells develop from pluripotent bone marrow progenitor cells that express CD34 antigen and are dispersed as precursors which undergo proliferation and maturation in different tissues. Normal mast cell development involves the action of stam cell growth factor and c-kit receptors, which are expressed by mast cells at their different developmental stages. Deregulation and/or abnormalities of the c-kit receptor are assumed to play a causal role in disordered mast-cell proliferation. In most patients a mutation in the gene for c-kit exists. One of the mutations is the D816V mutation. Aim of the study:imatinib mesylate, formerly called ST1571, is a potent inhibitor of c-kit receptor tyrosine kinase activity. In this study, we evaluate whether imatinib mesylate is safe and effective in the treatment of patients with systemic mastocytosis. Primary end-points of study are reduction in urinary N-methylhistamine excretion, serum tryptase activity, skin lesions, number of mast cells in sections of bone marrow, hepato-and/or splenomegaly and symptoms.Adverse effects on therapy are also considered. Results: up to now, 10 patients with systemic mastocytosis are treated with 400 mg of imatinib mesylate orally once daily. During the first 2 weeks of the study the patients also received 30 mg of prednisolone daily. In general imatinib mesylate is well tolerated. The first results show a 38–80% reduction in urinary N-methylhistamine excretion and 30–66% reduction in serum tryptase activity. Skin lesions diminish in two of the six patients with cutaneous mastocytosis,. Number of mast cells in sections of bone marrow are reduced in 63% (5/8) of the patients. Hepato-and/or splenomegaly is slightly decreased in two of the three patients with organomegaly. Finally 60 % of all patients experiences relief of symptoms. In eight patients the D816V mutation was found. In contrast with former studies imatinib mesylate is also effective in these patients. Further results are to be awaited. Conclusion: imatinib mesylate is safe and seems effective in the treatment of patients with systemic mastocytosis (including patients with the D816V mutation).

Detection of Activated STAT5 in Neoplastic Mast Cells in Patients with Systemic Mastocytosis: Role of c-kit D816V.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3515-3515 ◽  
Author(s):  
Karoline Sonneck ◽  
Matthias Mayerhofer ◽  
Karoline V. Gleixner ◽  
Marc Kerenyi ◽  
Maria-Theresa Krauth ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Systemic Mastocytosis ◽  
Cell Leukemia ◽  
Oncogenic Signaling ◽  
Kit Mutation ◽  
Knock Out ◽  
Mast Cell Leukemia ◽  
Kit D816v

Abstract Recent data suggest that activated STAT5 contributes to growth and differentiation of mast cells (MC) and that STAT5-knock out mice are MC-deficient. We have recently shown that constitutively activated STAT5 acts as a potent oncogenic signaling molecule in hematopoietic progenitor cells (Cancer Cell2005;7:87–99). In the present study, we examined the expression of activated STAT5 in neoplastic MC in systemic mastocytosis (SM) and asked whether the SM-related oncogene c-kit D816V is involved in STAT5-activation. For the immunohistochemical detection of activated tyrosine phosphorylated STAT5 (P-Y-STAT5), we used the specific monoclonal antibody AX1 (Advantex) which does not react with inactive STAT5. In all patients with SM tested (indolent SM, n=11; smouldering SM, n=2; aggressive SM, n=1; mast cell leukemia, n=1; all exhibiting c-kit D816V), MC were found to display P-Y-STAT5. Expression of activated STAT5 was also demonstrable in the c-kit D816V-positive mast cell leukemia-derived cell line HMC-1. The reactivity of HMC-1 cells with AX1 antibody was abrogated by a STAT5-specific blocking-peptide. To define the role of c-kit D816V in STAT5-activation, Ba/F3 cells with doxycycline-inducible expression of c-kit D816V (Ton.kit) were employed. In these cells, induction of c-kit D816V was followed by a massive increase in phosphorylated STAT5 as determined by a specific DNA-binding assay, whereas the total amounts of STAT5-mRNA and of the STAT5-protein showed only a slight increase or remained unchanged. In summary, these data show that neoplastic MC in SM express activated STAT5 (P-Y-STAT5), and that the transforming c-kit mutation D816V leads to persistent activation of STAT5 in these cells.

Kit Signaling Regulates Mitf Expression in Mastocytosis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3601-3601
Author(s):  
Youl-Nam Lee ◽  
Pierre Noel ◽  
Amir Shahlaee ◽  
Melody Carter ◽  
Reuben Kapur ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mast Cell ◽  
Mast Cells ◽  
Systemic Mastocytosis ◽  
Tyrosine Kinase Receptor ◽  
Bone Marrow Biopsies ◽  
Activating Mutations ◽  
Cell Assays ◽  
Mast Cell Disease ◽  
Mitf Expression

Abstract Mastocytosis is a heterogeneous disease arising from abnormal proliferation of mast cells. Activating mutations in codon D816 of the tyrosine kinase receptor, c-kit, are found in the majority of adult patients with systemic mastocytosis, an aggressive form of the disease. Constitutive activation of the Kit signaling pathway is critical to the transformed phenotype, and thus understanding how this pathway regulates downstream events is of great importance. A number of transcription factors are also essential to mast cell development, including the Microphthalmia-associated transcription factor (Mitf). We examined Mitf expression in bone marrow biopsies from nine patients with systemic mastocytosis by immunohistochemistry; we found that Mitf is highly expressed in all cases with the D816V mutation. In contrast, Mitf is not highly expressed in non-malignant mast cells in the bone marrow from patients with aplastic anemia and leukemia, suggesting thatMitf expression is regulated by Kit-dependent signalsMitf may play a role in the transformed phenotype of mastocytosis.We show that in normal mast cells, Kit signaling markedly upregulates Mitf expression. In both normal and malignant mast cells, pharmacologic inhibitors of Kit, and the downstream kinase, PI3K, block Mitf expression. To examine whether Mitf is required for transformed phenotype from constitutive Kit signaling in mast cells, we have used a shRNA-expressing lentivirus to knockdown Mitf expression in mastocytosis cell lines. We found that silencing of Mitf markedly impaired growth in proliferation and colony forming cell assays. This work demonstrates a link between two critical factors, Kit and Mitf, in the development of malignant mast cell disease.

Change In Mast Cell Bone Marrow Burden and In Serum Tryptase Level Are Not Accurate Markers of Response In Patients with Systemic Mastocytosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3073-3073
Author(s):  
Alfonso QuintÁs-Cardama, ◽  
Matjaz Sever ◽  
Jorge E. Cortes ◽  
Hagop M. Kantarjian ◽  
Srdan Verstovsek
Keyword(s):  
Bone Marrow ◽  
Mast Cell ◽  
Mast Cells ◽  
Systemic Mastocytosis ◽  
Median Number ◽  
Response To Therapy ◽  
Serum Tryptase ◽  
Bone Marrow Biopsies ◽  
Tryptase Level ◽  
Bone Marrow Mast Cell

Abstract Abstract 3073 Background: Bone marrow involvement, with or without cutaneous or visceral involvement, is almost universal in patients with systemic mastocytosis (SM). The KITD816V mutation is present in most patients with SM, thus confirming its clonal nature. Patients with ASM are usually managed with cytoreductive agents such as hydroxyurea (HU), cladribine (2CDA), or interferon-alpha (IFN-α), although the activity of these therapies is limited as they do not target specifically the malignant clone. Response assessment in SM relies on symptom improvement and reduction in serum tryptase levels and visceral and/or bone marrow mast cell burden (percent mast cell involvement). We contend that the later two relatively objective metrics may not be appropriate markers of response because serum tryptase levels may vary significantly at different time-points in the same patient in the absence of intervention, do not correlate accurately with mast cell burden, and bone marrow mast cell burden determination is subject to sampling bias given the patchy infiltration observed in many cases of SM. Objectives: To assess the utility of bone marrow mast cell burden reduction and serum tryptase level reduction as criteria for response in patients with SM. Patients and Therapy: We studied a cohort of 50 patients with SM for whom at least 2 sequential bone marrow biopsies and 2 serum tryptase level determinations were available at our center. The KITD816V mutation was present in 20 (59%) of 34 assessable patients. No patient carried the JAK2V617F mutation or the FIP1L1-PDGFRA rearrangement. Patients had a diagnosis of indolent SM (ISM, n=25), aggressive SM (ASM, n=16), or SM-AHNMD (n=9). All but 1 patient received SM-directed therapy (median number of therapies 2, range 1–5), including: imatinib (n=16), dasatinib (n=23), RAD001 (n=8), denileukin diftitox (n=7). The median number of bone marrow biopsies available per patient was 4 (range, 2–14) and the median number of tryptase measurements was 6 (range, 2–18), which were obtained both on and off SM-directed therapies. Results: Four patients had a bone marrow complete response: 1 with imatinib, 2 with dasatinib, and 1 with decitabine (with SM-MDS). However none of the responders normalized their tryptase levels. We used the coefficient of variation (CV) as a normalized measure of dispersion of a probability distribution for the percentage of mast cells in bone marrow biopsies and serum tryptase levels. In this manner, the CV summarizes/describes the variation in tryptase levels and bone marrow mast cell percentage from the baseline (first recorded value) in the patients evaluated. We found that among the 49 treated patients, the percentage of bone marrow mast cells varied significantly with a CV ranging from 6 – 173% and an average of 65%. Forty-four percent of patients had a CV equal or higher to the average. Similar results were observed regarding tryptase levels, with an average CV of 19% that ranged from 0 to 96%. Thirty-six percent of patients had a CV higher than average. Conclusion: While most patients fail to respond to currently available SM-directed therapies, sequential bone marrow biopsies and tryptase level determinations exhibit remarkable variation both during and in the absence of SM-directed therapy. Therefore, it seems that single time point measurements of these values do not represent proper tools to assess accurately response to therapy. Disclosures: No relevant conflicts of interest to declare.

Comprehensive Cytokine Profiling in Systemic Mastocytosis: Prognostic Relevance of Increased Plasma IL-2R Levels.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2836-2836 ◽  
Author(s):  
Animesh Pardanani ◽  
Christy Finke ◽  
Terra L Lasho ◽  
Ayalew Tefferi
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Mast Cell ◽  
Median Survival ◽  
Systemic Mastocytosis ◽  
B Cell Lymphoma ◽  
World Health ◽  
Serum Tryptase ◽  
Who Criteria

Abstract Abstract 2836 Background: The clinical phenotype of systemic mastocytosis (SM) is highly variable; establishing prognosis in terms of overall survival or risk of transformation to aggressive disease for those with non-indolent and indolent disease variants, respectively, is not trivial. Similar to other clonal hemopathies, mast cell (MC) activation and/or stromal response to clonal MC expansion likely results in a dysregulated immuno cellular/cytokine profile; analysis of this aspect of SM may provide additional prognostic information within the context of well established parameters such as the World Health Organization (WHO) SM classification system. Here, we conducted a comprehensive analysis of circulating cytokines/chemokines with clinicopathologic and clinical outcome correlations in a cohort of SM patients seen at our institution. Methods: The diagnosis of SM and its subclassification were established according to WHO criteria. Inclusion in this study required availability of archived plasma, bone marrow biopsy, and cytogenetic information at the time of first referral. Follow up information including data on survival and disease progression were updated in July 2012. Concentrations of plasma cytokines were analyzed in duplicate by using Multiplex Bead-Based Luminex technology (Invitrogen, Carlsbad, CA). Results: Forty six SM patients met the above stipulated criteria; 25 (54%) were male and the median age at referral was 61 years (range 21–85). Subclassification of patients per WHO criteria was: indolent SM (ISM) 23 (50%), aggressive SM (ASM) 8 (17%) and SM with associated clonal hematological non-MC lineage disease (SM-AHNMD) 15 (33%). When the distribution of 30 cytokines was considered across the 3 SM sub groups, only interleukin (IL)-8 was significantly different (SM-AHNMD > ISM/ASM; p=0.0002). For ISM patients, increased levels of sIL-2R were associated with presence of B-findings (p=0.0046) including splenomegaly (p=0.001) and serum tryptase levels >200 ng/mL (p=0.0046), and decreased levels of IL-8 and hepatocyte growth factor (HGF) with MC mediator-release symptoms (p <0.05). Increased levels of sIL-2R (r2=0.6; p<0.0001) and RANTES (r2=0.37; p=0.0013) were correlated with bone marrow MC burden, and sIL-2R (r2=0.34; p=0.004) and MIG (r2=0.42; p=0.0012) with serum tryptase levels in ISM patients; similar findings were noted for the overall cohort. At a median follow up of 28 months (range 0–116), 20 (43%) deaths, and 3 (13%) and 1 (2%) transformations to ASM and mast cell leukemia, respectively, were recorded for the overall cohort. In univariate analysis, increased sIL-2R levels were predictive for inferior overall survival (p=0.005); this prognostic significance was maintained in multivariate analysis after adjusting for other known prognostic variables individually (i.e. WHO SM subtypes, age >65 years, hemoglobin <10 g/dL, thrombocytopenia, weight loss or hypoalbuminemia) (all p <0.05). Increased sIL-2R (>75th percentile) effectively stratified patients in the overall cohort into 2 well-delineated risk groups for overall survival (median survival 109 vs. 26 months; p=0.0004) (Figure). This sIL-2R threshold was also able to risk stratify patients within ISM (median survival not reached vs. 38 months) and non-ISM (median survival 31 vs. 5 months) categories (p <0.0001). Conclusions: The current study demonstrates s-IL2R to be a key inflammatory cytokine in SM; it is significantly correlated with a phenotype of high systemic MC burden and in this regard, is an attractive surrogate for treatment response in clinical practice, if validated. The predictive value of sIL-2R for overall survival is akin to similar observations in primary myelofibrosis and diffuse large B-cell lymphoma; in this study, it was noted to be independent of conventional measures of organopathy from MC infiltration, and thus may reflect a novel pathogenetic process in SM, mediated by dysregulated inflammatory and/or immuno cellular pathways. Disclosures: No relevant conflicts of interest to declare.

scholarly journals AK002, a Novel Humanized Monoclonal Antibody to Siglec-8, Inhibits Mast Cell Activity and Depletes Eosinophils in Ex Vivo Bone Marrow Tissue from Patients with Systemic Mastocytosis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1104-1104 ◽  
Author(s):  
Bradford A Youngblood ◽  
Emily C Brock ◽  
John Leung ◽  
Alan T Chang ◽  
Christopher Bebbington ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Bone Marrow ◽  
Flow Cytometry ◽  
Mast Cell ◽  
Mast Cells ◽  
Ex Vivo ◽  
Systemic Mastocytosis ◽  
Cell Activity ◽  
Receptor Expression ◽  
Long Term Treatment

Abstract INTRODUCTION: Systemic Mastocytosis (SM) is a rare disease characterized by the clonal proliferation and accumulation of mast cells in the bone marrow, respiratory and gastrointestinal tracts, and organs such as the skin, liver, spleen, and brain. Common symptoms include pruritus, flushing, headache, cognitive impairment, fatigue, diarrhea, abdominal pain, hypotension and skin lesions, as well as an increased risk for osteoporosis and anaphylaxis. SM is currently managed with antihistamines, cromolyn sodium, and leukotriene blocking agents, which lack specificity and efficacy. In addition, glucocorticoids can provide temporary relief in some cases; however long-term treatment with steroids is not appropriate due to their many side effects. Siglec-8 is an inhibitory receptor selectively expressed on human mast cells and eosinophils, and therefore represents a novel target for the treatment of SM. Antibodies to Siglec-8 have been shown to inhibit mast cell activity and induce apoptosis of eosinophils. AK002 is a novel, humanized, non-fucosylated IgG1 monoclonal antibody to Siglec-8. This study evaluates the expression of Siglec-8 and ex vivo activity of AK002 on mast cells and eosinophils in bone marrow biopsies from patients with SM. METHODS: Bone marrow aspirates were obtained from patients clinically diagnosed with SM and processed to remove red blood cells. Multi-color flow cytometry was used to quantify eosinophils and mast cells and to evaluate the activation state of mast cells. The ex vivo activity of AK002 against eosinophils and mast cells was evaluated by flow cytometry. The inhibitory activity of AK002 agaist mast cells was also examined by quantifying cytokine levels in cultured bone marrow aspirate supernatants. RESULTS: All mast cells and eosinophils in bone marrow aspirates from SM patients displayed high Siglec-8 receptor expression (Figure 1). These mast cells also expressed the SM specific markers, CD25 (Figure 1) and CD30 and increased levels of cell surface degranulation markers. The expression of CD25 on mast cells significantly decreased following overnight treatment with AK002. AK002 also significantly reduced the level of mast cell-associated cytokines produced in cultured bone marrow supernatants, including IL-6, IL-8, and TNFα (Figure 2A). These changes in mast cell activity after AK002 treatment were not due to a reduction in mast cell numbers. In contrast, overnight incubation of AK002 significantly reduced the number of bone marrow eosinophils compared to an isotype control (Figure 2B). CONCLUSIONS: Bone marrow aspirates from patients with SM had activated mast cells and eosinophils that displayed robust expression of Siglec-8. AK002 demonstrated SM mast cell inhibition in ex vivo bone marrow aspirates. AK002 also had depleting effects on eosinophils, which may be valuable to SM patients with associated eosinophilia. These encouraging results could represent a novel approach for the treatment of SM. Disclosures Youngblood: Allakos, Inc.: Employment. Brock:Allakos, Inc.: Employment. Leung:Allakos, Inc.: Employment. Chang:Allakos, Inc.: Employment. Bebbington:Allakos, Inc.: Employment. Tomasevic:Allakos, Inc.: Employment.

Efficacy and Safety of Cladribine in Adult Systemic Mastocytosis : A French Multicenter Study of 33 Patients.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 661-661 ◽  
Author(s):  
Olivier Lortholary ◽  
Jacques Vargaftig ◽  
Frederic Feger ◽  
Fabienne Palmerini ◽  
Richard Delarue ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mast Cell ◽  
Peripheral Blood ◽  
Systemic Mastocytosis ◽  
Symptomatic Therapy ◽  
Efficacy And Safety ◽  
Cell Leukemia ◽  
Recombinant Interferon ◽  
Kit Mutation ◽  
Mast Cell Leukemia

Abstract Systemic mastocytosis (SM) is a myeloproliferative disabling disorder for which no consensual curative therapy is currently available. Recent preliminary experiences in small groups of patients using cladribine (2-CdA) were encouraging. We thus studied the efficacy and safety of 2-CdA in 33 patients enrolled in a compassionate program in France. Characteristics of patients were as follows: 19 male, 14 female, mean age 55y (17–76y), mean duration of disease 10 y (1m–71y). Treatment consisted in intravenous 2-CdA (1 to 6 cycles of 0.15 mg/kg/d administered in a 2-hour infusion or subcutaneously for 5 d, repeated at 4–12 weeks) for severe SM-related infiltration or symptoms. Patients were classified as having indolent SM (n=6), aggressive SM (n=22) or SM with an associated clonal hematologic non-MC-lineage (AHNMD) (n=4), mast cell leukemia (n=1). C-kit mutation analysis was performed in skin and/or bone marrow in 27 cases (D816V =24; WT=3). All failed previous symptomatic therapy and/or recombinant interferon-a (n=5). Evaluation was based according to consensus criteria (Valent et al. Leuk Research 2003). Major response, partial response and no response were observed in 24, 2, 7 patients, respectively. Mean time to best response was 4 months (1–12m), and mean duration of response was 16m (2–36). In responding patients skin lesions, hepatomegaly/ascitis, splenomegaly, bone involvement, peripheral blood cytopenia, major asthenia, flush, syncope/anaphylaxis, GI tract and pulmonary symptoms improved or disappeared. Treatment was overall well tolerated. Adverse events consisted mainly in peripheral blood cytopenia (n=10) with resolutive opportunistic infections in 2 patients. Although mast cell infiltration persisted in bone marrow, the patient with mast cell leukemia, responded to treatment with disappearance of circulating abnormal mast cells, and resolution of thrombocytopenia. Death was observed in 4 cases related to two disease progression and two acute myeloid leukemia. Therefore, as a single agent, cladribine is an effective and safe treatment in symptomatic and agressive SM. In contrast with interferon, cladribine may induce regression of mast cell tumoral burden. However, cladribine is ineffective to improve AHNMD. Further work is warranted to define the optimal regimen with respect to dose and schedule, and the usefulness of maintenance cladribine therapy.

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