scholarly journals Possible Early Clinical Management of Systemic Mastocytosis Patients with Recently FDA Approved Drug Avapritinib By Molecular Diagnosis Using a Highly Sensitive KIT D816 Mutation Assay

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4622-4622
Author(s):  
Durga Prasad Dash ◽  
David Dinauer ◽  
Michael Janasik
Keyword(s):  
Mast Cell ◽  
Clinical Laboratory ◽  
Systemic Mastocytosis ◽  
Specific Pcr ◽  
Myeloid Neoplasm ◽  
Highly Sensitive ◽  
Allele Specific ◽  
Hematological Neoplasm ◽  
Mast Cell Leukemia ◽  
Mutation Assay

Abstract Recently in June 2021, the Food and Drug Administration approved avapritinib (Ayvakit™) for adult patients with advanced systemic mastocytosis (AdvSM), including patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL). Mastocytosis is a heterogeneous, neoplastic disorder characterized by infiltration of abnormal mast cells in one or more organs. Mastocytosis subtypes are defined by disease distribution and the clinical features include, cutaneous mastocytosis (CM), where mast cell infiltration is confined to the skin, and systemic mastocytosis (SM) in which at least one extracutaneous organ is involved, with or without evidence of skin lesions. CM is most common in pediatric patients whereas SM typically presents in adulthood. The presence of somatic, activating mutations in KIT codon 816, predominantly D816V (A2447T), can be identified in the mast cells of 95% or more of patients with systemic mastocytosis (SM) and represent clonal markers in the disease. KIT is located on chromosome 4q12 and encodes for the mast/stem cell growth factor receptor, a type III receptor tyrosine kinase. Detection of KIT D816 mutations serve as a World Health Organization (WHO) minor criterion for the diagnosis of systematic mastocytosis and appear to confer relative resistance to tyrosine kinase inhibitors. Versiti Blood Center of Wisconsin Diagnostics laboratory which is certified under the Clinical Laboratory Improvement Amendments (CLIA) and qualified to perform high complexity clinical laboratory testing has developed a highly sensitive clinical test for the detection of KIT D816 mutations and molecular diagnosis of systemic mastocytosis patients. The KIT D816 mutation assay is a unique laboratory developed test based on highly sensitive allele specific PCR and its performance characteristics were determined by our laboratory. The sensitivity of the KIT D816 assay is 0.25% allele proportion. The specificity for the D816V mutation is > 99%. Systemic Mastocytosis (SM) is classified as myeloid neoplasm by WHO, however SM may be missed in suspected myeloid neoplasm work up by conventional sequencing technology including NGS which might not be able to achieve higher sensitivity. It is important to have a highly sensitive KIT D816 mutation analysis assay to detect low levels of KIT D816 allele burden that may be present in blood or bone marrow especially at early stage disease. Our highly sensitive laboratory developed KIT D816 assay based on allele specific PCR with a limit of detection of 0.25% could help physicians identify SM patients and clinically manage the disease. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Recently FDA approved Avapritinib for adult patients with advanced systemic mastocytosis (AdvSM), including patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL).

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

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.

Plasma Detection of JAK2 Mutation Is Not Suitable as a Clinical Test

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5231-5231
Author(s):  
Mohamed E Salama ◽  
Sabina Swierczek ◽  
Roberto H Nussenzveig ◽  
Kimberly Hickman ◽  
Andrew Wilson ◽  
...  
Keyword(s):  
Quantitative Assessment ◽  
Jak2 V617f ◽  
Progressive Increase ◽  
Clinical Test ◽  
Jak2 Mutation ◽  
Specific Pcr ◽  
Highly Sensitive ◽  
Allele Specific ◽  
Allele Specific Pcr ◽  
Over Time

Abstract The 1849G>T (V617F) JAK2 gene activating point mutation is identified in a substantial number of chronic myeloproliferative neoplasms (MPN) and the mutant allele burden correlates with some of the complications of MPN, justifying the introduction of quantitative JAK2 assays in clinical practice. Recent reports suggested a higher detection rate of the JAK2 mutation using plasma rather than by cell analysis and even suggested its use to detect zygosity. In this study we questioned the biologic basis of this suggestion and tested its validity by comparing JAK2 mutation allele burden in paired cell and plasma samples over time using a highly sensitive quantitative assay. Peripheral blood samples were collected from known patients with a positive JAK2 mutation as detected in their purified granulocytes. Separation of plasma and granulocytes (GNC) were carried on day 0,3,5,7,9,10 after sample collection. Quantitative assessment of JAK2 was performed on a total of 63 samples from 7 patients using allele-specific PCR amplification of JAK2-exon14 in genomic DNA isolated from the paired purified peripheral blood granulocytes and plasma samples. The detection of wild and mutant JAK2 alleles was achieved by highly sensitive and discriminatory allele-specific PCR utilizing allele specific primers that incorporate a mismatched nucleotide and synthetic ”locked nucleic acid” (Nussenzveig Expl Hemat.35: 32–38, 2007). Quantitative assessment of the sample is achieved by real-time monitoring amplification from each allele (in separate reactions). The values for each reaction are then used to determine the frequency of the T-allele relative to the G-allele in the sample and statistical calculations were performed using SAS software, Version 9.1 of the SAS System Copyright © 2002–2003 SAS Institute Inc, Cary, NC, USA. Quantitative measurements of JAK2 V617F mRNA in these samples were also analyzed. The JAK2 V617F range was (0.2–90%) in GNC and (0–88%) in plasma with no concordance of corresponding values in any patient at any given time point. We identified a progressive increase in plasma JAK2 V617F DNA values accompanied by a progressive reciprocal decrease of JAK2 V617F in paired GNC samples in all cases over time, suggesting preferential lysis of the GNC bearing the JAK2 V617F mutation. Similar data were obtained using in vitro expansion of JAK2 V617F polycythemia vera erythroid progenitors. A repeated-measures ANOVA was calculated to determine whether there was interaction between GNC vs. plasma and time. The rate of change in the value of JAK2 did indicate an interaction and was significantly different (p=.003) between GNC and plasma. In one patient, the JAK2 V617F was detected in GNC (0.7%) but not in plasma sample on day 0. We conclude that detection of JAK2 V617F in plasma is due to decreased viability of the JAK2 bearing cells, which leads to progressive increase in plasma detection. There is no correlation between JAK2 V617F allelic burden values in GNC and plasma at any given point. JAK2 quantitation in plasma is not suitable as a clinical test.

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.

Detection of the c-kit D816V mutation in systemic mastocytosis by allele-specific PCR

2007 ◽  
Vol 61 (1) ◽  
pp. 109-114 ◽  
Author(s):  
J A Schumacher ◽  
K S J Elenitoba-Johnson ◽  
M S Lim
Keyword(s):  
Systemic Mastocytosis ◽  
Specific Pcr ◽  
Allele Specific ◽  
Allele Specific Pcr ◽  
Kit D816v

scholarly journals Myelodysplasia and Mast Cell Leukemia with t(9;22)

2017 ◽  
Vol 2017 ◽  
pp. 1-5
Author(s):  
Kathryn J. Lago ◽  
Matthew P. Shupe ◽  
William N. Hannah ◽  
Gopalrao V. N. Velagaleti ◽  
Christina Mendiola ◽  
...  
Keyword(s):  
Mast Cell ◽  
Poor Prognosis ◽  
Systemic Mastocytosis ◽  
Gastrointestinal Symptoms ◽  
Maculopapular Rash ◽  
Cell Leukemia ◽  
Mast Cell Leukemia ◽  
The Relationship ◽  
Over Time

Introduction. Mast cell leukemia (MCL) is a rare variant of systemic mastocytosis. Most cases of mast cell leukemia do not have cytogenics performed. Furthermore, there is no consistent chromosomal abnormality identified in MCL. This is the first reported case of MCL with a (9;22) translocation. Case Report. An 80-year-old female presented with pancytopenia and was diagnosed with MDS. Over time, she required hospitalizations for platelet transfusions with increased frequency. She developed fatigue and weakness along with gastrointestinal symptoms. On exam, she had diffuse abdominal tenderness and a maculopapular rash. Her lab results revealed a new basophilia. A bone marrow biopsy showed 100% cellularity with many aggregates of mast cells. Chromosomal analysis showed t(9;22) with confirmed BCR/ABL1 fusion by fluorescence in situ hybridization (FISH). Discussion. MCL has a poor prognosis due to the aggressive nature of the disease and ineffective therapies. Translocation (9;22) is known to be associated with MDS transformations to acute leukemia; however, this translocation has never been reported in MCL. Further research on the relationship between t(9;22) and MCL could lead to development of improved therapeutic options.

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.

Aleukemic Mast Cell Leukemia (aMCL) - Clinical Characteristics and Outcomes

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4255-4255 ◽  
Author(s):  
Preetesh Jain ◽  
Sa Wang ◽  
Hagop M. Kantarjian ◽  
Nawid Sarwari ◽  
Keyur P. Patel ◽  
...  
Keyword(s):  
Overall Survival ◽  
Mast Cell ◽  
Mast Cells ◽  
Research Funding ◽  
Median Overall Survival ◽  
Systemic Mastocytosis ◽  
Cell Transplant ◽  
Cell Leukemia ◽  
Mast Cell Leukemia

Abstract ABSTRACT Introduction: Systemic mastocytosis (SM) is a complex and rare disease of clonal mast cells. Mast cell leukemia (MCL) is a very rare form of SM seen in <1% patients. We describe here our experience with MCL patients treated at our institution. Methods: We reviewed the medical records of 218 patients with mastocytosis who presented to our institution between 1994 and 2016. The survival of patients was calculated from the date of initial presentation to the date of last follow up. Kaplan-Meier product limit method was used to estimate the median survival. Results: From the 218 patients with mastocytosis, we identified 13 patients with MCL (6.5%). All 13 had aleukemic variant of MCL (aMCL; no presence of mast cells in blood measured by standard CBC technique but with ≥ 20% atypical mast cells in the marrow aspirate). In addition, in 4 of 13 patients, associated hematologic neoplasm (AHN) was present: 2 with myelodysplastic syndrome, 1 with chronic myelomonocytic leukemia and 1 with multiple myeloma. Median age of 13 patients was 62 years (range 24-75 years). Baseline features are summarized in Table-1. During their initial clinical presentation, 85% had constitutional symptoms, 54% had skin rash and other cutaneous symptoms, 31% gastrointestinal symptoms and 23% had joint pains. Imaging studies were performed in 6 patients: 5/6 had enlarged liver and/or spleen, 3 patients had nodal involvement, 2 had sclerotic bony lesions and 1 pt had adrenal involvement. Serum tryptase was >200 ng/ml in all the patients. Testing for c-KITD816V mutation was performed in 9 patients using mutation-specific quantitative (real-time) PCR, of which mutation was undetectable in 6 and detected in 3 patients. The sensitivity of detection was approximately 1 in 1000 mutation-bearing cells. None had FIP1L1-PDGFRA mutations. Treatments given were heterogeneous. Two patients each received imatinib with no response, 2 received dasatinib (one [positive for KITD816V mutation] had significant improvement in hepatosplenomegaly and pruritus but progressed after 1 year of dasatinib therapy), 2 cladribine based therapy with no response, and 2 with stem cell transplant and progression after it. Overall, median follow up was 111 months (1.4-131); 3 patients were alive and 9 died at the time of last follow up. Interestingly, among our 13 aMCL patients, those 4 with AHN appear to have had worse outcome: Figure-1A, shows the median overall survival (OS) of aMCL vs aMCL-AHN (32 vs 25 months; p=0.22). Overall, the median overall survival (OS) of aMCL without AHN was significantly inferior compared to aggressive systemic mastocytosis (ASM) and indolent systemic mastocytosis (ISM) without AHN: 31 months and not reached respectively (Figure-1B; p<0.001). Conclusions: In this analysis, we have shown that aMCL is very rare and these patients have very poor outcome. Based on the recent data from Gotlib et al NEJM 2016, role of midostaurin in the treatment of MCL should be explored. Further studies to characterize the genomic profile of patients with MCL are needed to identify potential therapeutic targets and disease resistance pathways. Table Survival of patients with aleukemic mast cell leukemia (aMCL) with/without AHN (A) and survival comparison of aMCL to other types of systemic mastocytosis, all without AHN (B) Table. Survival of patients with aleukemic mast cell leukemia (aMCL) with/without AHN (A) and survival comparison of aMCL to other types of systemic mastocytosis, all without AHN (B) Figure Figure. Disclosures Daver: Sunesis: Consultancy, Research Funding; Kiromic: Research Funding; Ariad: Research Funding; Pfizer: Consultancy, Research Funding; Otsuka: Consultancy, Honoraria; Karyopharm: Honoraria, Research Funding; BMS: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Verstovsek:Celgene: Research Funding; Bristol-Myers Squibb: Research Funding; AstraZeneca: Research Funding; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Galena BioPharma: Research Funding; Gilead: Research Funding; CTI BioPharma Corp: Research Funding; Lilly Oncology: Research Funding; NS Pharma: Research Funding; Geron: Research Funding; Promedior: Research Funding; Seattle Genetics: Research Funding; Roche: Research Funding; Pfizer: Research Funding; Genentech: Research Funding.

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