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.

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.

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.

MAST CELL LEUKEMIA PRESENTING AS URTICARIA PIGMENTOSA

PEDIATRICS ◽  
1957 ◽  
Vol 19 (6) ◽  
pp. 1033-1042
Author(s):  
William J. Waters ◽  
Perpetua S. Lacson
Keyword(s):  
Bone Marrow ◽  
Mast Cell ◽  
Mast Cells ◽  
Peripheral Blood ◽  
The Body ◽  
Urticaria Pigmentosa ◽  
Post Mortem ◽  
Cell Leukemia ◽  
Factors Associated ◽  
Mast Cell Leukemia

The concept of "urticaria pigmentosa" as a benign dermatologic syndrome needs revision. Generalized organ involvement may be present and in this case, with demonstration of the tissue mast cells in the peripheral blood and bone marrow, we chose to classify it as a form of leukemia. The differentiation between tissue mast cells and blood basophils is emphasized. Post-mortem examination revealed generalized infiltration of the body organs with tissue mast cells. "Heparin" and histamine determinations on frozen, post-mortem specimens of liver showed a concentration of approximately 100-times normal. Tissue mast cells were demonstrated in the peripheral blood. The factors associated with the hemorhagic diathesis are reviewed.

scholarly journals Mast Cell Leukemia?—Malignant Mastocytosis with Leukemia-like Manifestations

Blood ◽  
1957 ◽  
Vol 12 (10) ◽  
pp. 869-882 ◽  
Author(s):  
P. EFRATI ◽  
A. KLAJMAN ◽  
H. SPITZ
Keyword(s):  
Bone Marrow ◽  
Mast Cell ◽  
Adult Female ◽  
Gastrointestinal Hemorrhage ◽  
Peripheral Blood ◽  
Clinical Course ◽  
Cell Leukemia ◽  
Tissue Mast Cell ◽  
Massive Gastrointestinal Hemorrhage ◽  
Mast Cell Leukemia

Abstract A case of probable leukemia in an adult female is described which is classified as tissue mast cell leukemia. Clinical course and autopsy findings are analyzed and a detailed morphologic description is given of the different stages of maturation of T.M.C. as found in the peripheral blood and in bone marrow aspirates. The patient succumbed to massive gastrointestinal hemorrhage following cortisone treatment. Histologic examination of spleen and loose areolar tissue suggested origin of T.M.C. from both reticulum cells and fibroblasts. Focal osteosclerosis in the vertebrae probably represents a lesion related to the basic disorder.

Identical Novel C-Kit Transcripts in Two Patients with Mast Cell Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2001-2001 ◽  
Author(s):  
Ozden Ozer ◽  
John Anastasi ◽  
James W. Vardiman ◽  
Lucy A. Godley
Keyword(s):  
Bone Marrow ◽  
Mast Cell ◽  
Amino Acid ◽  
Peripheral Blood ◽  
Leukemia Cell Line ◽  
Single Amino Acid ◽  
Cell Transplant ◽  
Cell Leukemia ◽  
Mast Cell Leukemia ◽  
Peripheral Blood Involvement

Abstract Background: Mutations of c-kit have been well documented in mast cell neoplasms. The most common alterations found in human cutaneous and systemic mastocytosis are V560G and D816V. Mast cell leukemia is the most aggressive mast cell neoplasm, characterized by diffuse bone marrow and peripheral blood involvement. It has not been well studied due to its rarity. To date, no C-KIT mutational analysis of primary mast cell leukemia cells has been reported, although a mast cell leukemia cell line expresses the V560G and D816V mutations. Here we report on C-KIT cDNA analysis on two patients diagnosed with mast cell leukemia at the University of Chicago Hospitals. Both patients had peripheral blood involvement. Their diagnosis was confirmed on bone marrow biopsies with tryptase stains. Patient 1, diagnosed in 1989, died shortly after diagnosis. Patient 2 achieved a complete remission with allogeneic stem cell transplant. Upon relapse, treatment with Gleevec, resulted in an incomplete but significant response. This patient eventually died of sepsis following refractory cytopenias. Methodology: We retrieved liquid nitrogen frozen, pre-treatment bone marrow aspirate samples from both patients. We performed RT-PCR analysis of the entire coding region of C-KIT by amplifying 21 exons in smaller fragments. Each PCR product was cloned and sequenced. A thorough sequencing analysis was performed by screening several clones of each amplification product, with the purpose of being able to identify low abundance transcripts. Results: In both patients, the most abundant transcript was alternatively spliced and lacked exons 12 and 13. In addition, coexisting on the same allele, there were novel but not identical single amino acid deletions: deletion of L521 in patient 1 and of S715 in patient 2. A second novel alteration detected in both patients was the duplication of Q252. Patient 2 also demonstrated two independent, low abundance transcripts, one encoding the point mutation V559G and the other containing a deletion of exon 12. Discussion: Here we describe two novel and identical C-KIT alterations in two patients with mast cell leukemia (deletion of exons 12 and 13 and duplication of Q252). We hypothesize that both are key molecular changes underlying mast cell leukemia. Exons 12 and 13 encode the N-terminus of the kinase domain, which is thought to have modulatory effect on the kinase active site. Amino acid 252 is located in the fourth immunoglobulin-like domain of the extracellular region, which is thought to be critical for receptor dimerization and phosphorylation. We predict that these mutations result in the superactivation of C-KIT, based on the aggressive behaviour of mast cell leukemia. The response to Gleeevec seen in patient 2 indicates that at least some of these transcripts are Gleevec sensitive. Functional assays to test if the encoded C-KIT proteins are constitutively activated and whether Gleevec inhibits the novel C-KIT proteins are in progress.

Porcine Mast Cell Leukemia with Systemic Mastocytosis

1989 ◽  
Vol 26 (1) ◽  
pp. 90-92 ◽  
Author(s):  
D. E. Bean-Knudsen ◽  
C. W. Caldwell ◽  
J. E. Wagner ◽  
H. F. Stills
Keyword(s):  
Mast Cell ◽  
Systemic Mastocytosis ◽  
Cell Leukemia ◽  
Mast Cell Leukemia

Establishment of a murine model of aggressive systemic mastocytosis/mast cell leukemia

2006 ◽  
Vol 34 (3) ◽  
pp. 284-288 ◽  
Author(s):  
Shadmehr Demehri ◽  
Amie Corbin ◽  
Marc Loriaux ◽  
Brian J. Druker ◽  
Michael W. Deininger
Keyword(s):  
Mast Cell ◽  
Murine Model ◽  
Systemic Mastocytosis ◽  
Cell Leukemia ◽  
Mast Cell Leukemia

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.

Mast cell leukemia

Blood ◽  
2013 ◽  
Vol 121 (8) ◽  
pp. 1285-1295 ◽  
Author(s):  
Sophie Georgin-Lavialle ◽  
Ludovic Lhermitte ◽  
Patrice Dubreuil ◽  
Marie-Olivia Chandesris ◽  
Olivier Hermine ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Activation ◽  
De Novo ◽  
Systemic Mastocytosis ◽  
Mast Cell Activation ◽  
Cell Leukemia ◽  
Mast Cell Leukemia ◽  
Kit D816v

Abstract Mast cell leukemia (MCL) is a very rare form of aggressive systemic mastocytosis accounting for < 1% of all mastocytosis. It may appear de novo or secondary to previous mastocytosis and shares more clinicopathologic aspects with systemic mastocytosis than with acute myeloid leukemia. Symptoms of mast cell activation—involvement of the liver, spleen, peritoneum, bones, and marrow—are frequent. Diagnosis is based on the presence of ≥ 20% atypical mast cells in the marrow or ≥ 10% in the blood; however, an aleukemic variant is frequently encountered in which the number of circulating mast cells is < 10%. The common phenotypic features of pathologic mast cells encountered in most forms of mastocytosis are unreliable in MCL. Unexpectedly, non-KIT D816V mutations are frequent and therefore, complete gene sequencing is necessary. Therapy usually fails and the median survival time is < 6 months. The role of combination therapies and bone marrow transplantation needs further investigation.

Sign in / Sign up

Export Citation Format

Share Document