-
Molecular Cytogenetics 2016The gain of a second copy of the Philadelphia chromosome is one of the main secondary chromosomal changes related to the clonal evolution of cells with t(9;22) in...
The gain of a second copy of the Philadelphia chromosome is one of the main secondary chromosomal changes related to the clonal evolution of cells with t(9;22) in chronic myelogenous leukemia. This gain causes the acquisition of another copy of the fusion gene. Isochromosomes of the der(22) chromosome or double minute chromosomes are well known to lead an increased copy number of gene. There is no antecedent of Philadelphia chromosome duplication as a ring chromosome. A recent published report contains evidence that strongly suggests that the Philadelphia chromosome was duplicated as a ring chromosome, observation that was overlooked by the authors. The instability inherent to the ring chromosome increases the risk of emergence of clones containing more and more gene copies, which would produce increased fitness for clonal selection, resulting in worsening of the patient's prognosis.
PubMed: 27895712
DOI: 10.1186/s13039-016-0292-2 -
Haematologica May 2016With the deaths of Janet Rowley and John Goldman in December 2013, the world lost two pioneers in the field of chronic myeloid leukemia. In 1973, Janet Rowley, unraveled... (Review)
Review
With the deaths of Janet Rowley and John Goldman in December 2013, the world lost two pioneers in the field of chronic myeloid leukemia. In 1973, Janet Rowley, unraveled the cytogenetic anatomy of the Philadelphia chromosome, which subsequently led to the identification of the BCR-ABL1 fusion gene and its principal pathogenetic role in the development of chronic myeloid leukemia. This work was also of major importance to support the idea that cytogenetic changes were drivers of leukemogenesis. John Goldman originally made seminal contributions to the use of autologous and allogeneic stem cell transplantation from the late 1970s onwards. Then, in collaboration with Brian Druker, he led efforts to develop ABL1 tyrosine kinase inhibitors for the treatment of patients with chronic myeloid leukemia in the late 1990s. He also led the global efforts to develop and harmonize methodology for molecular monitoring, and was an indefatigable organizer of international conferences. These conferences brought together clinicians and scientists, and accelerated the adoption of new therapies. The abundance of praise, tributes and testimonies expressed by many serve to illustrate the indelible impressions these two passionate and affable scholars made on so many people's lives. This tribute provides an outline of the remarkable story of chronic myeloid leukemia, and in writing it, it is clear that the historical triumph of biomedical science over this leukemia cannot be considered without appreciating the work of both Janet Rowley and John Goldman.
Topics: Antineoplastic Agents; Cytogenetic Analysis; Fusion Proteins, bcr-abl; History, 20th Century; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Molecular Targeted Therapy; Mutation; Philadelphia Chromosome; Prognosis; Protein Kinase Inhibitors; Research
PubMed: 27132280
DOI: 10.3324/haematol.2015.139337 -
Hamostaseologie Jun 2021Philadelphia chromosome-negative myeloproliferative neoplasms are hematopoietic stem cell disorders characterized by dysregulated proliferation of mature myeloid blood... (Review)
Review
Philadelphia chromosome-negative myeloproliferative neoplasms are hematopoietic stem cell disorders characterized by dysregulated proliferation of mature myeloid blood cells. They can present as polycythemia vera, essential thrombocythemia, or myelofibrosis and are characterized by constitutive activation of signaling. They share a propensity for thrombo-hemorrhagic complications and the risk of progression to acute myeloid leukemia. Attention has also been drawn to mutant clonal hematopoiesis of indeterminate potential as a possible precursor state of MPN. Insight into the pathogenesis as well as options for the treatment of MPN has increased in the last years thanks to modern sequencing technologies and functional studies. Mutational analysis provides information on the oncogenic driver mutations in , , or in the majority of MPN patients. In addition, molecular markers enable more detailed prognostication and provide guidance for therapeutic decisions. While inhibitors represent a standard of care for MF and resistant/refractory PV, allogeneic hematopoietic stem cell transplantation remains the only therapy with a curative potential in MPN so far but is reserved to a subset of patients. Thus, novel concepts for therapy are an important need, particularly in MF. Novel inhibitors, combination therapy approaches with ruxolitinib, as well as therapeutic approaches addressing new molecular targets are in development. Current standards and recent advantages are discussed in this review.
Topics: Aged; Allografts; Calreticulin; Combined Modality Therapy; DNA Mutational Analysis; Female; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Janus Kinase 2; Janus Kinase Inhibitors; Male; Middle Aged; Mutation; Myeloproliferative Disorders; Nitriles; Philadelphia Chromosome; Polycythemia Vera; Primary Myelofibrosis; Pyrazoles; Pyrimidines; Receptors, Thrombopoietin; Thrombocythemia, Essential
PubMed: 34192778
DOI: 10.1055/a-1447-6667 -
Blood Nov 2015The development of BCR/ABL1 tyrosine kinase inhibitors (TKIs) over the past 20 years has dramatically improved the outcomes for patients with every stage of Philadelphia... (Review)
Review
The development of BCR/ABL1 tyrosine kinase inhibitors (TKIs) over the past 20 years has dramatically improved the outcomes for patients with every stage of Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML). Clinicians now have access to 5 oral, generally well-tolerated, and highly effective TKIs. How should these agents be used for an individual patient to ensure the best possible duration and quality-of-life, to avoid treatment-related complications, and potentially to achieve a cure at an affordable cost? Because CML patients may need to continue TKI therapy indefinitely, the long-term safety of each treatment option must be considered. Evidence-based care requires an understanding of the optimal use of these drugs, their specific early and late toxicities, the prognostic significance of achieving treatment milestones, and the critical importance of molecular monitoring. Efficacy is important, but treatment choice does not depend only on efficacy. Choosing among various treatment options is informed by understanding the distinct benefits and risks of each agent, along with careful consideration of patient-specific factors, such as risk status, age, and comorbidities.
Topics: Animals; Fusion Proteins, bcr-abl; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Philadelphia Chromosome; Protein Kinase Inhibitors
PubMed: 26585806
DOI: 10.1182/blood-2015-06-641043 -
Blood Jun 2021
Topics: COVID-19; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Philadelphia Chromosome; SARS-CoV-2; Vaccination
PubMed: 34110406
DOI: 10.1182/blood.2021011935 -
Biology of Blood and Marrow... Jan 2020Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukemia (ALL) is a relatively new entity characterized by high cytokine receptor and tyrosine kinase... (Review)
Review
Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukemia (ALL) is a relatively new entity characterized by high cytokine receptor and tyrosine kinase signaling resulting in multiple downstream pathway stimulation. The standard diagnostic method, gene expression profiling, is not widely available. Efforts are ongoing to establish easy and clinically applicable diagnostic pathways to facilitate the accurate identification of these patients and thus enable a better understanding of the prognosis and outcomes with different treatment approaches. The rates of complete remission in ALL patients are consistently above 90% with the different induction protocols; however, maintaining remission depends on the risk group of the patient and consolidation therapy. Allogeneic hematopoietic cell transplant (allo-HCT) is particularly beneficial when the risk of relapse is very high and the expected complications with transplant are low. Data on the outcomes of allo-HCT for Ph-like ALL are scarce. In this article we review the published literature on outcomes of Ph-like ALL patients treated using different therapeutic approaches and make recommendations about transplant consideration for these patients.
Topics: Allografts; Hematopoietic Stem Cell Transplantation; Humans; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 31445182
DOI: 10.1016/j.bbmt.2019.08.010 -
Genes Mar 2022The Philadelphia (Ph+) chromosome, t(9;22)(q34;q11.2), originates from a chimeric gene called and is present in more than 90% of CML patients. Most patients with CML...
The Philadelphia (Ph+) chromosome, t(9;22)(q34;q11.2), originates from a chimeric gene called and is present in more than 90% of CML patients. Most patients with CML express the protein p210 and, with a frequency lower than 5%, express rare isoforms, the main one being p190. In the transition from the chronic phase to the blast phase (BP), additional chromosomal abnormalities, such as the presence of the double Ph+ chromosome, are revealed. Of the 1132 patients analyzed via molecular biology in this study, two patients (0.17%) showed the co-expression of the p210 and p190 isoforms for the transcript, with the concomitant presence of a double Ph+ chromosome, which was observed via conventional cytogenetics and confirmed by fluorescent in situ hybridization. The /% p210 and p190 ratio increased in these two patients from diagnosis to progression to blast crisis. To our knowledge, this is the first report in the literature of patients who co-expressed the two main transcript isoforms and concomitantly presented Ph+ chromosome duplication. The evolution from the chronic phase to BP often occurs within 5 to 7 years, and, in this study, the evolution to BP was earlier, since disease-free survival was on average 4.5 months and overall survival was on average 9.5 months. The presence of the p190 transcript and the double Ph+ chromosome in CML may be related to the vertiginous progression of the disease.
Topics: Blast Crisis; Fusion Proteins, bcr-abl; Humans; In Situ Hybridization, Fluorescence; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Philadelphia Chromosome; Protein Isoforms
PubMed: 35456386
DOI: 10.3390/genes13040580 -
International Journal of Molecular... Nov 2021Chronic Myeloid Leukemia (CML) is a rare malignant proliferative disease of the hematopoietic system, whose molecular hallmark is the Philadelphia chromosome (Ph). The... (Review)
Review
Chronic Myeloid Leukemia (CML) is a rare malignant proliferative disease of the hematopoietic system, whose molecular hallmark is the Philadelphia chromosome (Ph). The Ph chromosome originates an aberrant fusion gene with abnormal kinase activity, leading to the buildup of reactive oxygen species and genetic instability of relevance in disease progression. Several genetic abnormalities have been correlated with CML in the blast phase, including chromosomal aberrations and common altered genes. Some of these genes are involved in the regulation of cell apoptosis and proliferation, such as the epidermal growth factor receptor () tumor protein p53 (), or Schmidt-Ruppin A-2 proto-oncogene (); cell adhesion, e.g., catenin beta 1 (); or genes associated to TGF-β, such as SKI like proto-oncogene (), transforming growth factor beta 1 () or transforming growth factor beta 2 (); and TNF-α pathways, such as Tumor necrosis factor () or Nuclear factor kappa B subunit 1 (). The involvement of miRNAs in CML is also gaining momentum, where dysregulation of some critical miRNAs, such as miRNA-451 and miRNA-21, which have been associated to the molecular modulation of pathogenesis, progression of disease states, and response to therapeutics. In this review, the most relevant genomic alterations found in CML will be addressed.
Topics: Biomarkers, Tumor; Blast Crisis; ErbB Receptors; Genomic Instability; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Philadelphia Chromosome; Proto-Oncogene Proteins pp60(c-src); Reactive Oxygen Species; Transforming Growth Factor beta1; Tumor Suppressor Protein p53; beta Catenin
PubMed: 34830398
DOI: 10.3390/ijms222212516 -
The Oncologist Jul 2023Asciminib is an allosteric high-affinity tyrosine kinase inhibitor (TKI) of the BCR-ABL1 protein kinase. This kinase is translated from the Philadelphia chromosome in... (Randomized Controlled Trial)
Randomized Controlled Trial
The EMA Assessment of Asciminib for the Treatment of Adult Patients With Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic Phase Who Were Previously Treated With at Least Two Tyrosine Kinase Inhibitors.
Asciminib is an allosteric high-affinity tyrosine kinase inhibitor (TKI) of the BCR-ABL1 protein kinase. This kinase is translated from the Philadelphia chromosome in chronic myeloid leukemia (CML). Marketing authorization for asciminib was granted on August 25, 2022 by the European Commission. The approved indication was for patients with Philadelphia chromosome-positive CML in the chronic phase which have previously been treated with at least 2 TKIs. Clinical efficacy and safety of asciminib were evaluated in the open-label, randomized, phase III ASCEMBL study. The primary endpoint of this trial was major molecular response (MMR) rate at 24 weeks. A significant difference in MRR rate was shown between the asciminib treated population and the bosutinib control group (25.5% vs. 13.2%, respectively, P = .029). In the asciminib cohort, adverse reactions of at least grade 3 with an incidence ≥ 5% were thrombocytopenia, neutropenia, increased pancreatic enzymes, hypertension, and anemia. The aim of this article is to summarize the scientific review of the application which led to the positive opinion by the European Medicines Agency's Committee for Medicinal Products for Human Use.
Topics: Adult; Humans; Antineoplastic Agents; Drug Resistance, Neoplasm; Fusion Proteins, bcr-abl; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Philadelphia Chromosome; Protein Kinase Inhibitors; Tyrosine Kinase Inhibitors
PubMed: 37141403
DOI: 10.1093/oncolo/oyad119 -
World Journal of Clinical Oncology Feb 2021Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm and was the first neoplastic disease associated with a well-defined genotypic anomaly - the presence of... (Review)
Review
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm and was the first neoplastic disease associated with a well-defined genotypic anomaly - the presence of the Philadelphia chromosome. The advances in cytogenetic and molecular assays are of great importance to the diagnosis, prognosis, treatment, and monitoring of CML. The discovery of the fusion oncogene has revolutionized the treatment of CML patients by allowing the development of targeted drugs that inhibit the tyrosine kinase activity of the BCR-ABL oncoprotein. Tyrosine kinase inhibitors (known as TKIs) are the standard therapy for CML and greatly increase the survival rates, despite adverse effects and the odds of residual disease after discontinuation of treatment. As therapeutic alternatives, the subsequent TKIs lead to faster and deeper molecular remissions; however, with the emergence of resistance to these drugs, immunotherapy appears as an alternative, which may have a cure potential in these patients. Against this background, this article aims at providing an overview on CML clinical management and a summary on the main targeted drugs available in that context.
PubMed: 33680875
DOI: 10.5306/wjco.v12.i2.69