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International Journal of Molecular... Sep 2023Tyrosine kinase inhibitors (TKIs) exemplify the success of molecular targeted therapy for chronic myeloid leukemia (CML). However, some patients do not respond to TKI... (Review)
Review
Tyrosine kinase inhibitors (TKIs) exemplify the success of molecular targeted therapy for chronic myeloid leukemia (CML). However, some patients do not respond to TKI therapy. Mutations in the kinase domain of are the most extensively studied mechanism of TKI resistance in CML, but -independent mechanisms are involved in some cases. There are two known types of mechanisms that contribute to resistance: mutations in known cancer-related genes; and Philadelphia-associated rearrangements, a novel mechanism of genomic heterogeneity that occurs at the time of the Philadelphia chromosome formation. Most chronic-phase and accelerated-phase CML patients who were treated with the third-generation TKI for drug resistance harbored one or more cancer gene mutations. Cancer gene mutations and additional chromosomal abnormalities were found to be independently associated with progression-free survival. The novel agent asciminib specifically inhibits the ABL myristoyl pocket (STAMP) and shows better efficacy and less toxicity than other TKIs due to its high target specificity. In the future, pooled analyses of various studies should address whether additional genetic analyses could guide risk-adapted therapy and lead to a final cure for CML.
Topics: Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Oncogenes; Philadelphia Chromosome; Mutation
PubMed: 37762109
DOI: 10.3390/ijms241813806 -
Oncotarget Nov 2017
PubMed: 29212147
DOI: 10.18632/oncotarget.22071 -
Cancers Apr 2022Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL) is the most common subtype of B-ALL in adults and its incidence increases with age. It is... (Review)
Review
Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL) is the most common subtype of B-ALL in adults and its incidence increases with age. It is characterized by the presence of BCR-ABL oncoprotein that plays a central role in the leukemogenesis of Ph+ ALL. Ph+ ALL patients traditionally had dismal prognosis and long-term survivors were only observed among patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1). However, feasibility of allo-HSCT is limited in this elderly population. Fortunately, development of increasingly powerful tyrosine kinase inhibitors (TKIs) from the beginning of the 2000's dramatically improved the prognosis of Ph+ ALL patients with complete response rates above 90%, deep molecular responses and prolonged survival, altogether with good tolerance. TKIs became the keystone of Ph+ ALL management and their great efficacy led to develop reduced-intensity chemotherapy backbones. Subsequent introduction of blinatumomab allowed going further with development of chemo free strategies. This review will focus on these amazing recent advances as well as novel therapeutic strategies in adult Ph+ ALL.
PubMed: 35406576
DOI: 10.3390/cancers14071805 -
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 -
Journal of Hematology & Oncology Apr 2019The Philadelphia (Ph) chromosome, resulting from the t(9;22)(q34;q11) translocation, can be found in chronic myeloid leukemia (CML) as well as in a subset of acute... (Review)
Review
The Philadelphia (Ph) chromosome, resulting from the t(9;22)(q34;q11) translocation, can be found in chronic myeloid leukemia (CML) as well as in a subset of acute lymphoblastic leukemias (ALL). The deregulated BCR-ABL1 tyrosine kinase encoded by the fusion gene resulting from the translocation is considered the pathogenetic driver and can be therapeutically targeted. In both CML and Ph-positive (Ph+) ALL, tyrosine kinase inhibitors (TKIs) have significantly improved outcomes. In the TKI era, testing for BCR-ABL1 transcript levels by real-time quantitative polymerase chain reaction (RQ-PCR) has become the gold standard to monitor patient response, anticipate relapse, and guide therapeutic decisions. In CML, key molecular response milestones have been defined that draw the ideal trajectory towards optimal long-term outcomes. Treatment discontinuation (treatment-free remission, TFR) has proven feasible in a proportion of patients, and clinical efforts are now focused on how to increase this proportion and how to best select TFR candidates. In Ph+ ALL, results of trials with second- and third-generation TKIs are challenging the role of intensive chemotherapy and even that of allogeneic stem cell transplantation. Additional weapons are offered by the recently introduced monoclonal antibodies. In patients harboring mutations in the BCR-ABL1 kinase domain, prompt therapeutic reassessment and individualization based on mutation status are important to regain response and prevent disease progression. Next-generation sequencing is likely to become a precious tool for mutation testing because of the greater sensitivity and the possibility to discriminate between compound and polyclonal mutations. In this review, we discuss the latest advances in treatment and monitoring of CML and Ph+ ALL and the issues that still need to be addressed to make the best use of the therapeutic armamentarium and molecular testing technologies currently at our disposal.
Topics: Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Philadelphia Chromosome
PubMed: 31014376
DOI: 10.1186/s13045-019-0729-2 -
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 -
International Journal of Molecular... Aug 2020Philadelphia chromosome (Ph) results from a translocation between the breakpoint cluster region () gene on chromosome 9 and ABL proto-oncogene 1 () gene on chromosome... (Review)
Review
Philadelphia chromosome (Ph) results from a translocation between the breakpoint cluster region () gene on chromosome 9 and ABL proto-oncogene 1 () gene on chromosome 22. The fusion gene, , is a constitutively active tyrosine kinase which promotes development of leukemia. Depending on the breakpoint site within the 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.
Topics: Cell Lineage; Clinical Trials as Topic; Humans; Leukemia; Lymphocytes; Myeloid Cells; Philadelphia Chromosome; Proto-Oncogene Mas
PubMed: 32806528
DOI: 10.3390/ijms21165776