Systemic Mastocytosis with Extensive Polypoid Lesions in the Intestines; Successful Treatment with Interferon-.ALPHA..

Takasaki, Yozo; Tsukasaki, Kunihiro; T, Jubashi; Tomonaga, Masao; Kamihira, Shimeru; Makiyama, Kazuya

doi:10.2169/internalmedicine.37.484

Cited by 31 publications

(29 citation statements)

References 11 publications

(4 reference statements)

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“…In many cases, symptomatic measures are employed first but generally are not successful. Ex vivo studies revealed that IFN could exert inhibitory effects on factor-dependent growth of mast cells from circulating progenitor cells in patients with SM and a number of clinical reports have shown IFN to be useful in the treatment of ASM [3,[7][8][9][10][11][12][21][22][23][24][25]. In the largest series of patients reported, Casassus et al treated 20 consecutive adult SM patients with IFN 1-5 MU/m 2 /day SQ, with progressive dose intensification over the first month of treatment, to a maximum of 6 months [26].…”

Section: Discussionmentioning

confidence: 99%

Management of patients with systemic mastocytosis: Review of M. D. Anderson Cancer Center experience

et al. 2004

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Mastocytosis is characterized by mast cell proliferation that may be limited to the skin (cutaneous mastocytosis) or may involve one or more extracutaneous organs, e.g., the bone marrow (systemic mastocytosis; SM). This study objective is to evaluate the features and outcome of patients referred to M. D. Anderson Cancer Center (MDACC) with SM. A search of the MDACC database from 1944 to 2002 was conducted for patients with SM and review of their clinical charts. Eighteen patients with mastocytosis were identified in the MDACC database; 15 (11 males and 4 females) had SM and available information. Two had associated myelodysplastic syndrome (MDS), and one had acute myeloid leukemia (AML). The median age was 58 years (range 31-80). Nine patients were treated with subcutaneous interferon-alpha, and only 1 experienced temporary control of the disease. Three of these patients were then treated with imatinib mesylate: transient improvement was noted in two patients. One patient underwent stem cell transplantation as first therapy and achieved complete remission; this patient had associated MDS and is now in complete remission for 8 years. The patient with associated AML was treated with high-dose cytarabine and idarubicin; he has been in complete remission for 16 months. One patient was treated with induction chemotherapy consisting of high-dose cytarabine and 2CDA but expired due to sepsis. Three patients received symptomatic therapy only; these were the only 3 patients who presented with normal blood counts. SM is rare and has no effective standard of care. Collaboration among academic centers to accrue enough patients to evaluate novel therapeutic strategies is needed. Am.

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Section: Discussionmentioning

confidence: 99%

Management of patients with systemic mastocytosis: Review of M. D. Anderson Cancer Center experience

et al. 2004

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“…IFN-a is often considered the first-line cytoreductive therapy in symptomatic SM; since the initial report in 1992 [79], several case reports or small series have shown IFN-a (IFN-a2b in most instances) to improve symptoms of MC degranulation, decrease BM MC infiltration, and ameliorate mastocytosis-related ascites/hepatosplenomegaly, cytopenias, skin findings, and osteoporosis [80][81][82][83][84][85][86][87][88][89][90][91][92]. IFN-a treatment is not uniformly effective [93], and the frequency of major response (i.e., complete resolution of one or more baseline 'C' findings) is 20-30%; the optimal dose and duration of IFN-a therapy for SM remain unclear, however concurrent administration of corticosteroids (prednisone) may improve its efficacy (up to 40% major response rate) and tolerability [87,94].…”

Section: Interferon (Ifn)-amentioning

confidence: 99%

Systemic mastocytosis in adults: 2015 update on diagnosis, risk stratification, and management

Pardanani

2015

American J Hematol

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Disease overview: Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MC) in one or more extracutaneous 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 2008 World Health Organization classification of SM has been shown to be prognostically relevant. Classification of SM patients into indolent SM (ISM), 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; there is a role for allogeneic stem cell transplantation in select cases.Investigational Drugs: Recent data confirms midostaurin's significant anti‐MC activity in patients with advanced SM. Am. J. Hematol. 90:251–262, 2015. © 2015 Wiley Periodicals, Inc.

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“…25,[30][31][32][33][34] Systemic mast cell disorders in humans have been treated with interferon-␣, although the effectiveness of this therapy has been variable. [35][36][37][38][39][40][41][42][43] Recent studies suggest that tumors expressing activating mutations in Kit may be amenable to treatment with Kit inhibitors. This has been particularly relevant for gastrointestinal stromal tumors (GISTs), most of which have deletions of various size in exon 11 of c-kit that lead to autophosphorylation of Kit in the absence of ligand binding.…”

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confidence: 99%

Inhibition of constitutively active forms of mutant kit by multitargeted indolinone tyrosine kinase inhibitors

Liao¹,

Chien²,

Shenoy³

et al. 2002

Blood

113

101

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IntroductionThe proto-oncogene c-kit was first identified as the oncogenic component of the acutely transforming Hardy-Zuckerman 4-feline sarcoma virus. 1 It encodes Kit, a type 3 receptor tyrosine kinase (RTK) that binds the ligand stem cell factor (SCF). 2 Structurally, Kit is related to the receptors for platelet-derived growth factor, vascular endothelial growth factor, fibroblast growth factor, and FLT-3 ligand (reviewed in Ashman 3 ). All contain an extracellular ligand-binding domain composed of 3 to 7 immunoglobulinlike regions, a transmembrane domain, a negative regulatory juxtamembrane (JM) domain, and 2 kinase domains in which resides a kinase insert. SCF-Kit interactions promote the development of mast cells from hematopoietic progenitors; mice deficient in either SCF or Kit (Sl or W mutant mice) exhibit a near-complete absence of mast cells, anemia, and thrombocytopenia. 2,4-6 These mice are also sterile and lack skin pigmentation because of the absence of melanocytes. With regard to mast cells, SCF-Kit interactions are intimately involved in several critical processes. Most important, Kit signaling is required for the differentiation and maturation of mast cells in vivo. 2,[7][8][9][10] Other activities attributable to SCF-Kit binding include chemotaxis and haptotaxis of mast cells and the promotion of cell survival and proliferation. 2,7,8,11,12 Several years ago, investigators began to study the potential role of Kit dysfunction in malignant mast cells. Point mutations in c-kit that lead to constitutive activation of Kit in the absence of ligand binding were identified in 3 malignant mast cell lines (human HMC-1, rat RBL, and mouse P815), providing an indication that dysregulation of Kit may promote uncontrolled growth or survival of mast cells. [13][14][15] Following this discovery, similarly activating mutations were identified in the CD34 ϩ hematopoietic precursors from patients with mastocytosis and in cells from patients with urticaria pigmentosa, thus providing the first evidence that c-kit may play a role in spontaneous mast cell disease. 16,17 Recent studies have consistently demonstrated the presence of activating point mutations in the catalytic domain of c-kit in human patients with aggressive mastocytosis, mast cell leukemia, and hematologic disorders with associated mastocytosis. [17][18][19][20][21][22][23] In contrast to the disease in humans, mast cell neoplasms are one of the most common malignant tumors of the dog, representing between 7% and 21% of all canine tumors. 24,25 Given the link between mast cell disorders and dysfunctional Kit, we investigated whether similar mutations in c-kit were present in canine mast cell tumors (MCTs). Although c-kit derived from the canine MCTs did not contain the previously described activating mutations, 30% to 50% of the tumors examined had novel mutations consisting of tandem duplications in exons 11 and 12 of the gene. 26 As is the case with tandem duplications in exons 11 and 12 of Flt-3, these mutations also result in constitutive phosph...

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Systemic Mastocytosis with Extensive Polypoid Lesions in the Intestines; Successful Treatment with Interferon-.ALPHA..

Cited by 31 publications

References 11 publications

Management of patients with systemic mastocytosis: Review of M. D. Anderson Cancer Center experience

Management of patients with systemic mastocytosis: Review of M. D. Anderson Cancer Center experience

Systemic mastocytosis in adults: 2015 update on diagnosis, risk stratification, and management

Inhibition of constitutively active forms of mutant kit by multitargeted indolinone tyrosine kinase inhibitors

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