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Hematology. American Society of... Dec 2017Treatment of Philadelphia chromosome positive acute lymphoblastic leukemia exemplifies how the addition of potent targeted agents, directed at the molecular aberrations... (Review)
Review
Treatment of Philadelphia chromosome positive acute lymphoblastic leukemia exemplifies how the addition of potent targeted agents, directed at the molecular aberrations responsible for leukemic transformation, can overcome resistance mechanisms to traditional regimens and lead to improved outcomes. The introduction of targeted tyrosine kinase inhibitors (TKIs) has significantly improved the outcomes not only by allowing more patients to undergo allogeneic hematopoietic cell transplantation (alloHCT) but also by decreasing our reliance on this potentially toxic strategy, particularly in the less fit population. Long-term data using chemotherapy and TKI combinations demonstrate that a proportion of patients treated can achieve durable relapse-free survival without undergoing alloHCT. Furthermore, the availability of sensitive minimal residual disease monitoring assays may allow early detection of the patients who are more likely to relapse and who are likely candidates for early alloHCT. The emergence of more potent TKIs with significant activity against resistant mutations has allowed deintensification of chemotherapy regimens. Available data indicate that complete reliance on TKIs, alone or with minimal additional therapy, and elimination of more intensive chemotherapy or alloHCT is unlikely to achieve long term cure in most patients. However, introduction of other highly effective agents that can be combined with TKIs may allow further minimization of chemotherapy and alloHCT in the future, as we have witnessed in acute promyelocytic leukemia.
Topics: Allografts; Fusion Proteins, bcr-abl; Humans; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase Inhibitors; Stem Cell Transplantation
PubMed: 29222233
DOI: 10.1182/asheducation-2017.1.22 -
Biology of Blood and Marrow... Jan 2007The Philadelphia chromosome (Ph)-negative myeloproliferative disorders (MPDs) include essential thrombocythemia (ET), idiopathic myelofibrosis (IMF), and polycythemia... (Review)
Review
The Philadelphia chromosome (Ph)-negative myeloproliferative disorders (MPDs) include essential thrombocythemia (ET), idiopathic myelofibrosis (IMF), and polycythemia vera (PV). All of these disorders are clonal hematologic malignancies originating at the level of the pluripotent hematopoietic stem cell. Recently, activating mutations of the intracellular cytokine-signaling molecule JAK2 have been identified in > 90% of patients with PV and in 50% of those with IMF and ET. In addition, a mutation of the thrombopoietin receptor, MPLW515L, has been documented in some patients with IMF. Both mutations activate JAK-STAT signaling pathways and likely play a role in disease progression. Both ET and PV are associated with prolonged clinical courses associated with frequent thrombotic and hemorrhagic events, and progression to myelofibrosis and acute leukemia. IMF has a much poorer prognosis and is associated with cytopenias, splenomegaly, extramedullary hematopoiesis, and bone marrow fibrosis. Stratification of risk for the development of complications from Ph-negative MPDs has guided the identification of appropriate therapies for this population. Intermediate/high-risk IMF or myelofibrosis after ET or PV is associated with a sufficiently poor prognosis to justify the use of allogeneic stem cell transplantation, which is capable of curing such patients. Reduced-intensity conditioning in preparation for allogeneic stem cell transplantation has permitted older patients with IMF to undergo transplantation with increasing success.
Topics: Hematopoietic Stem Cell Transplantation; Humans; Janus Kinase 2; Myeloproliferative Disorders; Philadelphia Chromosome; Signal Transduction
PubMed: 17222772
DOI: 10.1016/j.bbmt.2006.11.003 -
Annals of Hematology Jun 2023Philadelphia chromosome-like (Ph-like) ALL is a recent subtype of acute lymphoblastic leukemia. Although it does not express the BCR-ABL fusion gene, it has a behavior... (Review)
Review
Philadelphia chromosome-like (Ph-like) ALL is a recent subtype of acute lymphoblastic leukemia. Although it does not express the BCR-ABL fusion gene, it has a behavior like true BCR/ABL1-positive cases. This subtype harbors different molecular alterations most commonly CRLF2 rearrangements. Most cases of Ph-like ALL are associated with high white blood cell count, high minimal residual disease level after induction therapy, and high relapse rate. Efforts should be encouraged for early recognition of Ph-like ALL to enhance therapeutic strategies. Recently, many trials are investigating the possibility of adding the tyrosine kinase inhibitor (TKI) to chemotherapy to improve clinical outcomes. The role and best timing of allogeneic bone marrow transplant in those cases are still unclear. Precision medicine should be implemented in the treatment of such cases. Here in this review, we summarize the available data on Ph-like ALL.
Topics: Humans; Fusion Proteins, bcr-abl; Bone Marrow Transplantation; Philadelphia Chromosome; Protein Kinase Inhibitors; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 37129698
DOI: 10.1007/s00277-023-05241-2 -
Haematologica Jun 2021
Topics: Acute Disease; Humans; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 34060295
DOI: 10.3324/haematol.2020.270645 -
Hematology (Amsterdam, Netherlands) Dec 2015
Review
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Bone Marrow Cells; Hematopoietic Stem Cell Transplantation; Humans; Immunophenotyping; Molecular Diagnostic Techniques; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Protein Kinase Inhibitors
PubMed: 26574786
DOI: 10.1179/1024533215Z.000000000402 -
Best Practice & Research. Clinical... Dec 2021Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a subset of high-risk B-ALL associated with high relapse risk and inferior clinical outcomes... (Review)
Review
Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a subset of high-risk B-ALL associated with high relapse risk and inferior clinical outcomes across the pediatric-to-adult age spectrum. Ph-like ALL is characterized by frequent IKZF1 alterations and a kinase-activated gene expression profile similar to that of Philadelphia chromosome-positive (Ph+) ALL, yet lacks the canonical BCR-ABL1 rearrangement. Advances in high-throughput sequencing technologies during the past decade have unraveled the genomic landscape of Ph-like ALL, revealing a diverse array of kinase-activating translocations and mutations that may be amenable to targeted therapies that have set a remarkable precision medicine paradigm for patients with Ph + ALL. Collaborative scientific efforts to identify and characterise Ph-like ALL during the past decade has directly informed current precision medicine trials investigating the therapeutic potential of tyrosine kinase inhibitor-based therapies for children, adolescents, and adults with Ph-like ALL, although the most optimal treatment paradigm for this high-risk group of patients has yet to be established. Herein, we describe the epidemiology, clinical features, and biology of Ph-like ALL, highlight challenges in implementing pragmatic and cost-effective diagnostic algorithms in the clinic, and describe the milieu of treatment strategies under active investigation that strive to decrease relapse risk and improve long-term survival for patients with Ph-like ALL as has been successfully achieved for those with Ph + ALL.
Topics: Adolescent; Adult; Child; Fusion Proteins, bcr-abl; Humans; Molecular Targeted Therapy; Mutation; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Translocation, Genetic
PubMed: 34865703
DOI: 10.1016/j.beha.2021.101331 -
Cancer Science Jun 2016Acute lymphoblastic leukemia (ALL) occurs with high frequency in childhood and is associated with high mortality in adults. Recent technical advances in next-generation... (Review)
Review
Acute lymphoblastic leukemia (ALL) occurs with high frequency in childhood and is associated with high mortality in adults. Recent technical advances in next-generation sequencing have shed light on genetic abnormalities in hematopoietic stem/progenitor cells as the precursor to ALL pathogenesis. Based on these genetic abnormalities, ALL is now being reclassified into newly identified subtypes. Philadelphia chromosome-like B-lineage ALL is one of the new high-risk subtypes characterized by genetic alterations that activate various signaling pathways, including those involving cytokine receptors, tyrosine kinases, and epigenetic modifiers. Philadelphia chromosome-like ALL is essentially heterogeneous; however, deletion mutations in the IKZF1 gene encoding the transcription factor IKAROS underlie many cases as a key factor inducing aggressive phenotypes and poor treatment responses. Whole-genome sequencing studies of ALL patients and ethnically matched controls also identified inherited genetic variations in lymphoid neoplasm-related genes, which are likely to increase ALL susceptibility. These findings are directly relevant to clinical hematology, and further studies on this aspect could contribute to accurate diagnosis, effective monitoring of residual disease, and patient-oriented therapies.
Topics: Genetic Predisposition to Disease; Germ-Line Mutation; Humans; Ikaros Transcription Factor; Mutation; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 26991355
DOI: 10.1111/cas.12927 -
Cancer Gene Therapy Jan 2023The Philadelphia (Ph) chromosome was the first translocation identified in leukemia. It is supposed to be generated by aberrant ligation between two DNA double-strand...
The Philadelphia (Ph) chromosome was the first translocation identified in leukemia. It is supposed to be generated by aberrant ligation between two DNA double-strand breaks (DSBs) at the BCR gene located on chromosome 9q34 and the ABL1 gene located on chromosome 22q11. Thus, mimicking the initiation process of translocation, we induced CRISPR/Cas9-mediated DSBs simultaneously at the breakpoints of the BCR and ABL1 genes in a granulocyte-macrophage colony-stimulating factor (GM-CSF) dependent human leukemia cell line. After transfection of two single guide RNAs (sgRNAs) targeting intron 13 of the BCR gene and intron 1 of the ABL1 gene, a factor-independent subline was obtained. In the subline, p210 BCR::ABL1 and its reciprocal ABL1::BCR fusions were generated as a result of balanced translocation corresponding to the Ph chromosome. Another set of sgRNAs targeting intron 1 of the BCR gene and intron 1 of the ABL1 gene induced a factor-independent subline expressing p190 BCR::ABL1. Both p210 and p190 BCR::ABL1 induced factor-independent growth by constitutively activating intracellular signaling pathways for transcriptional regulation of cell cycle progression and cell survival that are usually regulated by GM-CSF. These observations suggested that simultaneous DSBs at the BCR and ABL1 gene breakpoints are initiation events for oncogenesis in Ph+ leukemia. (200/200 words).
Topics: Humans; Philadelphia Chromosome; Fusion Proteins, bcr-abl; Granulocyte-Macrophage Colony-Stimulating Factor; CRISPR-Cas Systems; Translocation, Genetic; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Carcinogenesis
PubMed: 35999358
DOI: 10.1038/s41417-022-00522-w -
The Journal of Clinical Investigation Aug 2007The discovery of the Philadelphia chromosome as a hallmark of chronic myelogenous leukemia in 1960 by Peter Nowell provided evidence for a genetic link to cancer. As... (Review)
Review
The discovery of the Philadelphia chromosome as a hallmark of chronic myelogenous leukemia in 1960 by Peter Nowell provided evidence for a genetic link to cancer. As with most seminal scientific observations, the description of the Philadelphia chromosome posed many more questions than were answered. This Review series includes contributions from individuals who performed critical experiments addressing some of the most important of these questions, reflecting the nearly 50 years of work inspired by Nowell's initial finding. The legacy of the Philadelphia chromosome now serves as a paradigm for how basic science discoveries can lead to effective new approaches for the treatment of human disease.
Topics: Biomedical Research; History, 20th Century; History, 21st Century; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Philadelphia Chromosome
PubMed: 17671635
DOI: 10.1172/JCI33032 -
Biology of Blood and Marrow... Apr 2018
In the Era of BCR-ABL1 Inhibitors, Are We Closing the Survival Gap Between Allogeneic Hematopoietic Cell Transplantation and Chemotherapy for Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia in First Complete Remission?
Topics: Hematopoietic Stem Cell Transplantation; Humans; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein-Tyrosine Kinases; Remission Induction
PubMed: 29474869
DOI: 10.1016/j.bbmt.2018.02.011