scholarly journals Hypereosinophilic syndromes

2013 ◽  
pp. 129-135
Author(s):  
Giuseppe Civardi ◽  
Luca Zanlari ◽  
Emanuele Bassi ◽  
Roberta Bonassi ◽  
Corrado Ajolfi
Keyword(s):  
Tyrosine Kinase ◽  
Imatinib Mesylate ◽  
Kinase Inhibitors ◽  
Fusion Gene ◽  
Correct Diagnosis ◽  
Hypereosinophilic Syndrome ◽  
Genetic Mutation ◽  
The Body ◽  
International Consensus ◽  
Eosinophilic Cell

Background: The last few years have seen a complete change in the etiopathogenetic features, classification and therapeutic approach of the hypereosinophilic syndrome (HES), a multiorgan targeted blood disease. The discovery of a genetic mutation and the occurrence of a new fusion gene, named FIP1L1-PDGFRA (FIP gene), in some patients allowed the identification of a new myeloproliferative disorder, M-HES: thereafter, the pivotal therapeutic role of the tyrosine kinase inhibitors, particularly, imatinib mesylate, was clearly detected. In the same period a new pathogenetic mechanism has been detected: some authors described the presence of a CD3-CD4 +Tcell clone correlating with the overproduction of IL5, a potent eosinophilic cell line stimulating cytokine. As a consequence an international consensus committee proposed a new classification for these syndromes, in accordance with these new pathogenetic features. The disease is characterized by an extensive tissue and organ damage due to an eosinophilic cell infiltration and leading to the release of toxic cytokines and subsequent organ dysfunction. The heart, lungs, gastrointestinal apparatus, skin and central nervous system are affected. Moreover the released cytokines can induce a thrombophilic status and thromboembolic events can occur throughout the body. Aim of the study: We describe the diagnostic procedures that are necessary in order to obtain a correct diagnosis and classification of the disease and to evaluate the presence of an organ and tissue damage. In particular, bone marrow biopsy and cytogenetic examination of blood and marrow are necessary for detecting M-HES cases that are positive for the FIP gene. In these patients, imatinib mesylate has a leading role for obtaining complete remission of the disease in a high percentage of cases. We also examine the therapeutic options for the other forms of the disease: prednisone, interferon, hydroxiurea are effective therapeutic tools in these patients. Finally, the new therapeutic perspectives, such as monoclonal antibodies directed against IL 5 or IL 5 receptor and novel tyrosine kinase inhibiting drugs, are examined.

scholarly journals Mutations Associated with Imatinib Mesylate Resistance - Review

Folia Medica ◽  
2018 ◽  
Vol 60 (4) ◽  
pp. 617-623 ◽  
Author(s):  
Alexandar J. Linev ◽  
Hristo J. Ivanov ◽  
Ivan G. Zhelyazkov ◽  
Hristina Ivanova ◽  
Veselina S. Goranova-Marinova ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Imatinib Mesylate ◽  
Kinase Inhibitors ◽  
Fusion Gene ◽  
Philadelphia Chromosome ◽  
Point Mutations ◽  
Kinase Domain ◽  
Chromosome Translocation ◽  
New Drugs ◽  
Chromosome 22Q11.2

Abstract Chronic myeloid leukemia (CML) arises from the fusion of the BCR and the ABL1 genes. The BCR gene (chromosome 22q11.2) and the ABL1 gene (chromosome 9q34) fuse together due to reciprocal chromosome translocation forming the Philadelphia chromosome (Ph). This fusion gene codes tyrosine kinase which accelerates the cell division and reduces DNA repair. Imatinib mesylate is a selective inhibitor of this tyrosine kinase. It is the first-line treatment for CML-patients. However, it became clear that Philadelphia-positive (Ph+) cells could evolve to elude inhibition due to point mutations within the BCR-ABL kinase domain. To date more than 40 mutations have been identified and their early detection is important for clinical treatment. With the development of the new tyrosine kinase inhibitors (TKIs), associated with these mutations, the resistance problem seems to diminish, as some of the new drugs are less prone to resistance. The aim of this review is to focus on the diff erent mutations leading to resistance.

scholarly journals Detection of BCR-ABL gene in Chronic Myeloid Leukemia patients treated with Tyrosine Kinase Inhibitors Drugs by Gene Expert System

2019 ◽  
Vol 10 (2) ◽  
Author(s):  
Maysaa Ali Abdul Khaleq ◽  
Hussein Ali Saheb ◽  
Ahmed M Sultan ◽  
Mohsen A. N. Alrodhan
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Fusion Gene ◽  
Philadelphia Chromosome ◽  
Genetic Mutation ◽  
Newly Diagnosed ◽  
High Concentration ◽  
Final Dose ◽  
One Year ◽  
Wbc Count

Chronic myeloid leukaemia (CML) is one of the human fatalities caused by genetic mutation and chromosomal translocation, a BCR-ABL fusion gene and as a result, Philadelphia chromosome is formed. The irregular tyrosine kinase activity of the encoded protein by this gene causes the establishment of the disease. This study was conducted at the period from September 2016 to February 2017,100 Iraqi CML patients were divided into two groups, first group of 50 patients were received Imatinib 400-800 mg/day, second group of another 50 patients were received 800 mg/day Nilotinib, WBC were microscopically counted using improved Neubauer ruled hemocytometer counting chamber. The results of WBC count in different disease duration and stages of treatment in the group of patients treated with Imatinib showed that highest WBC count was observed in newly diagnosed patients while there was a significant reduction in the WBC count after one month, after one year and final dose of treatment were 11.8, 6.4 and 8.1 respectively, on the other hand the results of WBC count  in the group of patients treated with Nilotinib showed that the highest WBC count was observed in newly diagnosed patients 87.54± 8.71 whereas the WBC count after one month, one year and at the final dose of treatment were 7.3, 6.8, 7.9 respectively with significant reduction in the WBC count. The results of the CML patient’s distribution according to BCR-ABL gene analysis in the patient's group treated with Imatinib showed that high concentration in newly diagnosed patients 4.753 as compared with significant reduction with other stages of treatment after one month and after one year 0.94 and 0.09 respectively.

scholarly journals Philadelphia Chromosome-Positive Leukemia in the Lymphoid Lineage—Similarities and Differences with the Myeloid Lineage and Specific Vulnerabilities

2020 ◽  
Vol 21 (16) ◽  
pp. 5776 ◽  
Author(s):  
Lukasz Komorowski ◽  
Klaudyna Fidyt ◽  
Elżbieta Patkowska ◽  
Malgorzata Firczuk
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Great Majority ◽  
Metabolic Reprogramming ◽  
Chromosome 9 ◽  
Treatment Protocols ◽  
Resistant Disease

Philadelphia chromosome (Ph) results from a translocation between the breakpoint cluster region (BCR) gene on chromosome 9 and ABL proto-oncogene 1 (ABL1) gene on chromosome 22. The fusion gene, BCR-ABL1, is a constitutively active tyrosine kinase which promotes development of leukemia. Depending on the breakpoint site within the BCR gene, different isoforms of BCR-ABL1 exist, with p210 and p190 being the most prevalent. P210 isoform is the hallmark of chronic myeloid leukemia (CML), while p190 isoform is expressed in majority of Ph-positive B cell acute lymphoblastic leukemia (Ph+ B-ALL) cases. The crucial component of treatment protocols of CML and Ph+ B-ALL patients are tyrosine kinase inhibitors (TKIs), drugs which target both BCR-ABL1 isoforms. While TKIs therapy is successful in great majority of CML patients, Ph+ B-ALL often relapses as a drug-resistant disease. Recently, the high-throughput genomic and proteomic analyses revealed significant differences between CML and Ph+ B-ALL. In this review we summarize recent discoveries related to differential signaling pathways mediated by different BCR-ABL1 isoforms, lineage-specific genetic lesions, and metabolic reprogramming. In particular, we emphasize the features distinguishing Ph+ B-ALL from CML and focus on potential therapeutic approaches exploiting those characteristics, which could improve the treatment of Ph+ B-ALL.

scholarly journals Mechanisms of Disease Progression and Resistance to Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukemia: An Update

2019 ◽  
Vol 20 (24) ◽  
pp. 6141 ◽  
Author(s):  
Luana Bavaro ◽  
Margherita Martelli ◽  
Michele Cavo ◽  
Simona Soverini
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Disease Progression ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Fusion Gene ◽  
Primary Resistance ◽  
Secondary Resistance ◽  
Dismal Prognosis

Chronic myeloid leukemia (CML) is characterized by the presence of the BCR-ABL1 fusion gene, which encodes a constitutive active tyrosine kinase considered to be the pathogenic driver capable of initiating and maintaining the disease. Despite the remarkable efficacy of tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1, some patients may not respond (primary resistance) or may relapse after an initial response (secondary resistance). In a small proportion of cases, development of resistance is accompanied or shortly followed by progression from chronic to blastic phase (BP), characterized by a dismal prognosis. Evolution from CP into BP is a multifactorial and probably multistep phenomenon. Increase in BCR-ABL1 transcript levels is thought to promote the onset of secondary chromosomal or genetic defects, induce differentiation arrest, perturb RNA transcription, editing and translation that together with epigenetic and metabolic changes may ultimately lead to the expansion of highly proliferating, differentiation-arrested malignant cells. A multitude of studies over the past two decades have investigated the mechanisms underlying the closely intertwined phenomena of drug resistance and disease progression. Here, we provide an update on what is currently known on the mechanisms underlying progression and present the latest acquisitions on BCR-ABL1-independent resistance and leukemia stem cell persistence.

Imatinib Mesylate for Refractory Acute Myeloblastic Leukemia Harboring inv(16) and C-KIT Exon 8 Mutation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4405-4405
Author(s):  
Naofumi Matsuno ◽  
Tomoko Nanri ◽  
Toshiro Kawakita ◽  
Hiroaki Mitsuya ◽  
Norio Asou
Keyword(s):  
Tyrosine Kinase ◽  
Imatinib Mesylate ◽  
Kinase Inhibitors ◽  
Kinase Domain ◽  
Acute Myeloblastic Leukemia ◽  
Tyrosine Kinase Domain ◽  
High Dose ◽  
Term Survival ◽  
Kit Gene

Abstract While approximately 50% of acute myeloblastic leukemia (AML) patients carrying favorable karyotypes show long-term survival, treatment outcome is not universally favorable in such patients. Recently, mutations in the C-KIT and FLT3 genes were frequently found in patients with inv(16) AML. Of 15 patients we examined, 2 had the FLT3-D835 mutations, 1 had a mutation in the second tyrosine kinase domain, 1 in the juxtamembrane domain, and 1 in the exon 8 of the C-KIT gene. These mutations are potential therapeutic targets for specific tyrosine kinase inhibitors. In this study, we present a case of inv(16) AML harboring C-KIT exon 8 mutation that was successfully treated with imatinib mesylate. After treatment with low-dose cytarabine, aclarubicin and granulocyte colony-stimulating factor (CAG) plus vincristine and prednisone (VP), a 58-year-old man with AML M4Eo showed second relapse with left inguinal lymph nodes involvement. The patient was treated with high-dose cytarabine and mitoxantrone only unsuccessfully. However, the following treatment with 400 mg of imatinib mesylate for 2 weeks in combination with CAG plus VP brought about complete hematological remission. This treatment was well tolerated, and no severe adverse events occurred. This observation suggests that imatinib mesylate can be an alternative treatment modality for AML with the mutation in exon 8 of the C-KIT gene, although further studies are required to confirm the efficacy of this approach for refractory AML.

TYROSINE KINASE INHIBITORS AND THE DAWN OF MOLECULAR CANCER THERAPEUTICS

2005 ◽  
Vol 45 (1) ◽  
pp. 357-384 ◽  
Author(s):  
Raoul Tibes ◽  
Jonathan Trent ◽  
Razelle Kurzrock
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Hypereosinophilic Syndrome ◽  
Growth Factor Receptor ◽  
Cancer Therapeutics ◽  
Designer Drugs ◽  
Normal Tissues ◽  
Mast Cell Disease

The clinical application of tyrosine kinase inhibitors for cancer treatment represents a therapeutic breakthrough. The rationale for developing these compounds rests on the observation that tyrosine kinase enzymes are critical components of the cellular signaling apparatus and are regularly mutated or otherwise deregulated in human malignancies. Novel tyrosine kinase inhibitors are designed to exploit the molecular differences between tumor cells and normal tissues. Herein, we will review the current state-of-the-art using agents that target as prototypes Bcr-Abl, platelet-derived growth factor receptor (PDGFR), KIT (stem cell factor receptor), and epidermal growth factor receptor (EGFR). These compounds are remarkably effective in treating diverse cancers that are highly resistant to conventional treatment, including various forms of leukemia, hypereosinophilic syndrome, mast cell disease, sarcomas, and lung cancer. It is now clear that the molecular defects underlying cancer can be targeted with designer drugs that yield striking salutary effects with minimal toxicity.

scholarly journals Targeting Leukemic Stem Cells in Chronic Myeloid Leukemia: Is It Worth the Effort?

2021 ◽  
Vol 22 (13) ◽  
pp. 7093
Author(s):  
Simona Soverini ◽  
Sara De Santis ◽  
Cecilia Monaldi ◽  
Samantha Bruno ◽  
Manuela Mancini
Keyword(s):  
Stem Cell ◽  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Fusion Gene ◽  
Cell Cancer ◽  
Chromosomal Translocation ◽  
Hematopoietic Stem ◽  
Differentiated Cells

Chronic myeloid leukemia (CML) is a classical example of stem cell cancer since it arises in a multipotent hematopoietic stem cell upon the acquisition of the t(9;22) chromosomal translocation, that converts it into a leukemic stem cell (LSC). The resulting BCR-ABL1 fusion gene encodes a deregulated tyrosine kinase that is recognized as the disease driver. Therapy with tyrosine kinase inhibitors (TKIs) eliminates progenitor and more differentiated cells but fails to eradicate quiescent LSCs. Thus, although many patients obtain excellent responses and a proportion of them can even attempt treatment discontinuation (treatment free remission [TFR]) after some years of therapy, LSCs persist, and represent a potentially dangerous reservoir feeding relapse and hampering TFR. Over the past two decades, intensive efforts have been devoted to the characterization of CML LSCs and to the dissection of the cell-intrinsic and -extrinsic mechanisms sustaining their persistence, in an attempt to find druggable targets enabling LSC eradication. Here we provide an overview and an update on these mechanisms, focusing in particular on the most recent acquisitions. Moreover, we provide a critical appraisal of the clinical relevance and feasibility of LSC targeting in CML.

scholarly journals Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia—From Molecular Mechanisms to Clinical Relevance

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4820
Author(s):  
Raquel Alves ◽  
Ana Cristina Gonçalves ◽  
Sergio Rutella ◽  
António M. Almeida ◽  
Javier De Las De Las Rivas ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
De Novo ◽  
Fusion Gene ◽  
Computational Prediction ◽  
Tki Resistance

Resistance to targeted therapies is a complex and multifactorial process that culminates in the selection of a cancer clone with the ability to evade treatment. Chronic myeloid leukemia (CML) was the first malignancy recognized to be associated with a genetic alteration, the t(9;22)(q34;q11). This translocation originates the BCR-ABL1 fusion gene, encoding the cytoplasmic chimeric BCR-ABL1 protein that displays an abnormally high tyrosine kinase activity. Although the vast majority of patients with CML respond to Imatinib, a tyrosine kinase inhibitor (TKI), resistance might occur either de novo or during treatment. In CML, the TKI resistance mechanisms are usually subdivided into BCR-ABL1-dependent and independent mechanisms. Furthermore, patients’ compliance/adherence to therapy is critical to CML management. Techniques with enhanced sensitivity like NGS and dPCR, the use of artificial intelligence (AI) techniques, and the development of mathematical modeling and computational prediction methods could reveal the underlying mechanisms of drug resistance and facilitate the design of more effective treatment strategies for improving drug efficacy in CML patients. Here we review the molecular mechanisms and other factors involved in resistance to TKIs in CML and the new methodologies to access these mechanisms, and the therapeutic approaches to circumvent TKI resistance.

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