scholarly journals Mast Cell Leukaemia: c-KIT Mutations Are Not Always Positive

2012 ◽  
Vol 2012 ◽  
pp. 1-6
Author(s):  
Magalie Joris ◽  
Sophie Georgin-Lavialle ◽  
Marie-Olivia Chandesris ◽  
Ludovic Lhermitte ◽  
Jean-François Claisse ◽  
...  
Keyword(s):  
Mast Cell ◽  
Cell Leukaemia ◽  
Therapeutic Approaches ◽  
Kit Mutation ◽  
Short Survival Time ◽  
Therapeutic Choice ◽  
Molecular Abnormality ◽  
Mast Cell Leukemia ◽  
Genotypic Characteristics ◽  
Diagnostic Investigations

Mast cell leukemia (MCL) is a rare and aggressive disease with poor prognosis and short survival time. D816V c-KIT mutation is the most frequent molecular abnormality and plays a crucial role in the pathogenesis and development of the disease. Thus, comprehensive diagnostic investigations and molecular studies should be carefully carried out to facilitate the therapeutic choice. A MCL patient’s case with rare phenotypic and genotypic characteristics is described with review of major clinical biological and therapeutic approaches in MCL.

scholarly journals Chronic mast cell leukaemia with exon 9 KIT mutation A502_Y503dup: a rare imatinib responsive variant

2020 ◽  
Vol 13 (8) ◽  
pp. e236447
Author(s):  
Sukesh Manthri ◽  
Patrick N Costello ◽  
Koyamangalath Krishnan
Keyword(s):  
Mast Cell ◽  
Cell Leukaemia ◽  
Kit Mutation ◽  
Exon 9

t(8;21)-Positive AML with Mutant Kit Is a Novel Therapeutic Target of Imatinib Mesylate.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1164-1164
Author(s):  
Hiroya Asou ◽  
Taiichi Kyo ◽  
Toshiya Inaba
Keyword(s):  
Mast Cell ◽  
Imatinib Mesylate ◽  
Therapeutic Target ◽  
Kinase Domain ◽  
Leukemia Cells ◽  
Human Mast Cell ◽  
Cell Leukemia ◽  
Short Term ◽  
Kit Mutation ◽  
Mast Cell Leukemia

Abstract Point mutations in the kinase domain of c-Kit are frequently associated with t(8;21)-acute myeloid leukemia (AML). In our study, eleven (26 %) of 43 patients had mutations: six Asp816Val, two Asp816Tyr, one Asp816Ala, one Asp816His, and one Asn822Lys. Here, we provide evidences that proliferation of leukemia cells expressing both the AML1-ETO chimera and a c-Kit mutation heavily depends on signals originating from mutated c-Kit, and this mutation is a possible therapeutic target for imatinib mesylate. We initially investigated effects of imatinib on the growth of the Kasumi-1 cell line, which harbors both t(8;21) and a c-Kit kinase domain mutation (Asn822Lys). Imatinib inhibited autophosphorylation of c-Kit at the standard concentration (0.1 μM), and induced cell cycle arrest and apoptosis in an even faster time course than Ph1-positive cell lines treated with this drug. By contrast, growth of SKNO-1, another t(8;21)-positive leukemia cells without c-Kit mutation was not affected by imatinib. To test whether imatinib is effective for Asp816 c-Kit mutants, we isolated t(8;21)-positive fresh leukemia cells from untreated patients. Numbers of cells with an Asp816 mutant from four patients after short-term cultures in the presence of imatinib (0.1 μM, 4 days) were 20–30 % of those in the absence of imatinib, while no significant difference was observed for cells isolated from four patients without c-Kit mutation. (Viability of fresh leukemia cells without imatinib was maintained over 80% during this short-term culture.) Moreover, autophosphorylation of mutated c-Kit in leukemia cells from one patient with an Asp816 mutant was inhibited by imatinib. Our results disagree with those of previous studies, which indicated that cells with c-Kit mutations in the kinase domain are resistant to imatinib in murine IL-3-dependent cells and human mast cell leukemia cells. This discrepancy could be explained by high expression levels of c-Kit mutants in IL-3-dependent cells by powerful ectopic promoters, since overexpression of Bcr-Abl kinase is one of the major causes of resistance to imatinib in the treatment of CML patients. In addition, drug metabolism may be different between human t(8;21)-positive leukemia cells and in murine IL-3-dependent cells or mast cell leukemia cells. Although t(8;21) in AML represents a favorable prognostic indicator for achievement of cure, a substantial number of these patients relapse and eventually die of their disease. Indeed, of five patients harboring both t(8;21) and c-Kit mutations who we identified and followed up for more than five years, four relapsed. Therefore, our results suggest that imatinib would be useful for eliminating minimal residual disease in these patients after achievement of complete remission.

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.

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.

PKC412 Inhibits In Vitro Growth of Neoplastic Mast Cells Expressing the D816V-Mutated Variant of KIT: Comparison with AMN107 and Imatinib, and Evaluation of Drug-Interactions.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3523-3523
Author(s):  
Karoline V. Gleixner ◽  
Matthias Mayerhofer ◽  
Karl J. Aichberger ◽  
Sophia Derdak ◽  
Karoline Sonneck ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Drug Interactions ◽  
Leukemia Cell ◽  
Leukemia Cell Line ◽  
Human Mast Cell ◽  
Cell Leukemia ◽  
Kit Mutation ◽  
Mast Cell Leukemia ◽  
Kit D816v

Abstract In most patients with systemic mastocytosis (SM) including aggressive SM and mast cell leukemia (MCL), neoplastic cells express the oncogenic c-KIT mutation D816V. KIT-D816V is associated with constitutive tyrosine kinase (TK) activity and thus represents an attractive target of drug therapy. However, most available TK inhibitors including STI571=imatinib, fail to block TK-activity of KIT D816V at pharmacologic concentrations. We provide evidence that the novel TK-targeting drugs PKC412 and AMN107 decrease TK-activity of D816V-mutated KIT and counteract growth of Ba/F3 cells with doxycycline-induced expression of KIT D816V as well as growth of the human mast cell leukemia cell line HMC-1 expressing this c-KIT mutation. PKC412 was found to be the superior drug with IC50 values of 50–250 nM and without differences seen between HMC-1 cells exhibiting or lacking KIT D816V. By contrast, AMN107 exhibited potent effects only in the absence of KIT D816V in HMC-1 cells. Corresponding results were obtained with Ba/F3 cells exhibiting wild-type or the D816V-mutated variant of KIT. Moreover, we found that PKC412 and AMN107 inhibit growth of primary neoplastic MC in a patient with KIT D816V+ SM. The growth-inhibitory effects of PKC412 and AMN107 on HMC-1 cells were associated with TK-inhibition of KIT and with induction of apoptosis. In addition, PKC412 was found to downregulate expression of CD2 and CD63, two cell surface antigens upregulated in SM. In co-incubation experiments, PKC412 was found to synergize with AMN107, imatinib, and 2CdA in producing growth inhibition in HMC-1 cells lacking KIT D816V, whereas in KIT D816V+ HMC-1 cells, drug-interactions were additive rather than synergistic. Together, PKC412 and AMN107 alone and in combination counteract growth of neoplastic mast cells. Both drugs may therefore be considered as novel promising agents for targeted therapy in patients with aggressive SM or MCL.

scholarly journals UK Single Institution Experience of Mastocytosis: Guy's and St Thomas' NHS Foundation Trust

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2960-2960
Author(s):  
Clare Oni ◽  
Mufaddal Moonim ◽  
Joana Desterro ◽  
Clive Grattan ◽  
Natalia Curto-Garcia ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mast Cell ◽  
Symptom Control ◽  
Subsequent Development ◽  
Pegylated Interferon ◽  
Rare Disorder ◽  
Cell Leukaemia ◽  
Skin Involvement ◽  
Kit Mutation ◽  
Tryptase Level

Introduction: Systemic mastocytosis (SM) is a heterogeneous disorder of neoplastic mast cells ranging from an indolent to aggressive multi-system disease. We registered our UK Mastocytosis Centre of Excellence with the European Competence Network of Mastocytosis (ECNM) in 2005. Our multidisciplinary team (MDT) includes haematologists, haematopathologists, dermatologist, immunologist and molecular diagnosticians. Over 500 patients have been reviewed in our quarterly SM-MDT. We present a large single centre experience of a rare disorder. Method: We have reviewed prospective and retrospectively collected clinical data for 125 adult patients from 2009. The data captures clinical, laboratory, diagnostic results and management. Local patients with a tryptase level of >20ug/L are offered haematology review and bone marrow investigation with KIT D816V mutation analysis using digital PCR. Patients seen for a second opinion have their diagnostic material reviewed. Since 2018, next generation sequencing (NGS) based myeloid gene panels are carried out on patients with advanced SM (AdvSM). Results: Classification of mastocytosis patients: In 125 patients no gender bias was seen: 56 (44.8%) were male and 69 (55.2%) female. Median age of patients with indolent SM (ISM) was 49 years (range 22-78); and for AdvSM: (aggressive SM, SM with an associated haematological neoplasm and mast cell leukaemia) was 64years (range 5-77). The median serum tryptase level was 48.9ug/L for ISM patients (range 4-682) and 120ug/L for AdvSM patients (range 24-854). 112/125 patients had a bone marrow biopsy. 13 patients chose not to have a biopsy. 88% (110/125) of patients had a mast cell disorder. 4% (5/125) had no marrow involvement. 84% (105/125) met WHO criteria for a diagnosis of SM - Figure 1.These were sub-classified: 71/105 (67%) ISM; 2/105 (2%) smouldering SM (SSM); 3/105 (3%) aggressive SM (ASM); 2/105 (2%) mast cell leukaemia (MCL) and 27/105 (26%) SM with an associated hematologic neoplasm (SM-AHN). The most frequent associated haematological neoplasms were MPN and CMML. Lymphomas (n=3) and plasma cell dyscrasias (n=1) were seen patients. In 10/27 (37%) cases of SM-AHN the SM was the initial diagnosis with subsequent development of an AHN. In 5/27(19%) cases the AHN component preceded the SM and in 12/27 (44%) cases the 2 components were co-diagnosed. Mutation status : 24/32 patients with AdvSM were noted to be positive for an activating KIT mutation (D816V, n=23; D816L, n=1). 15/32 AdvSM patients had NGS myeloid gene panel analysis for the SAR panel (SRSF2, ASXL1 and RUNX1) which confers poor prognosis. 4 of the15 patients harboured at least 2 out of 3 SAR mutations. JAK2 V617F mutation was detected in 7 of 8 classical MPN patients and in 1 of 4 patients with MPNu/MDS overlap. 4 patients had a TET2 mutation. 1 patient with mast cell leukaemia had a GATA2 mutation in addition to all 3 in the SAR panel. Cutaneous involvement: 70% (88/125) of patients had skin involvement: 62% (78/125) urticaria pigments, 3% (4/125) telangiectasia macularis eruptiva perstans and 5% (6/125) having non-specific involvement. Skin involvement was more common in ISM (78%) than AdvSM (54% in SM-AHN, none in the 2 patients with MCL). Management : Treatments in ISM are usually for symptom control. Antihistamines, anti-inflammatory agents, anti-leukotriene agents, mast cell stabilising agents, bisphosphonates, proton-pump inhibitors, PUVA and steroids are used. Various cytoreductive therapies have been used in AdvSM (hydroxycarbamide, pegylated interferon-α, cladrabine, cytarabine, azacitadine alone/combination with midostaurin). Patients with SM-AHN have tailored management depending on the disease component that requires treatment. Access to targeted therapies for AdvSM patients in a trial or compassionate use programme has been successful: 7/32 patients with advanced SM have been enrolled into trials (midostaurin 1; avapritinib 6). Conclusions: Our data reflects the heterogeneous nature of the SM classification spectrum clinically and diagnostically. An experienced MDT provides holistic high standard of care within a comprehensive centre for good patient outcomes (Figure 2). Development of a portfolio of novel therapeutic options in multi-centred, international collaborative trials is beneficial to patients and pivotal for research in this rare disorder. Disclosures Cross: Novartis: Consultancy, Research Funding; Incyte: Consultancy. McLornan:Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Novartis: Honoraria. Radia:Blueprint Medicines: Consultancy; Novartis: Consultancy, Speakers Bureau. OffLabel Disclosure: There are very few medications available in mastocytosis and various off label medications have been used including pegylated interferon alpha.

A case of mast cell leukaemia with exon 9 KIT mutation and good response to imatinib

2011 ◽  
Vol 86 (6) ◽  
pp. 531-535 ◽  
Author(s):  
Andrzej Mital ◽  
Anna Piskorz ◽  
Krzysztof Lewandowski ◽  
Bartosz Wasąg ◽  
Janusz Limon ◽  
...  
Keyword(s):  
Mast Cell ◽  
Cell Leukaemia ◽  
Kit Mutation ◽  
Exon 9

Clinical Course and Prognosis in Mast Cell Proliferative Disorders: A 17 Year Experience in a Single Center.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4741-4741
Author(s):  
Wolfgang R. Sperr ◽  
Friedrich Wimazal ◽  
Alexandra Boehm ◽  
Alexander W. Hauswirth ◽  
Stefan Florian ◽  
...  
Keyword(s):  
Mast Cell ◽  
Clinical Course ◽  
Systemic Mastocytosis ◽  
White Blood Cells ◽  
Latency Period ◽  
Cell Leukaemia ◽  
Event Free Survival ◽  
Serum Tryptase ◽  
Kit Mutation ◽  
Free Survival

Abstract In patients (pts) with mast cell (MC) proliferative disorders, the clinical course, prognosis, and outcome vary depending on age, organ-involvement, and the disease-variant. We have retrospectively analyzed the clinical course and outcome in 56 pts with MC disorders refered to the University of Vienna between 1987 and 2004. Using WHO criteria, pts were found to have cutaneous mastocytosis (CM, n=6), indolent systemic mastocytosis (ISM, n=35), aggressive SM (ASM, n=3), mast cell leukaemia (MCL, n=1), SM with associated clonal hematologic non-MC-lineage disease (SM-AHNMD, n=6), and myelomastocytic leukemia (MML, n=5). These groups differed from each other in serum tryptase levels, hemoglobin, platelet counts, and lactate dehydrogenase (p<0.05). By contrast, no significant differences were found in white blood cells, eosinophils, monocytes, or presence of the c-kit mutation D816V. Most pts with ISM showed a stable clinical course without signs of progression or increase in serum tryptase even when monitored for more than a decade. By contrast, in all pts with ASM, MCL, SM-AHNMD, and MML, the neoplasm progressed after a latency period of several months. The median event-free survival was 3.7 months in pts with ASM/MCL, 22.8 months in SM-AHNMD, and 5.0 months in MML. In CM and ISM, the median survival was not reached. The differences in event-free survival among WHO groups were found to be significant (p<0.05). Apart from high grade WHO categories, adverse prognostic variables concerning survival were i. absence of skin-lesions, ii. high percentage (>5%) of MC in bone marrow smears, and iii. splenomegaly. Polychemotherapy resulted in complete remission in MML, but not in ASM or MCL. Interferon-alpha and 2CdA showed cytoreductive effects in some pts with ASM, but did not work in MCL. For the latter group of pts new therapies need to be developed.

Mast cell leukemia: identification of a new c-Kit mutation, dup(501-502), and response to masitinib, a c-Kit tyrosine kinase inhibitor

2012 ◽  
Vol 89 (1) ◽  
pp. 47-52 ◽  
Author(s):  
Sophie Georgin-Lavialle ◽  
Ludovic Lhermitte ◽  
Felipe Suarez ◽  
Ying Yang ◽  
Sébastien Letard ◽  
...  
Keyword(s):  
Mast Cell ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Kinase Inhibitor ◽  
Cell Leukemia ◽  
Kit Mutation ◽  
Mast Cell Leukemia
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