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Chinese Journal of Cancer May 2016The truncated chromosome 22 that results from the reciprocal translocation t(9;22)(q34;q11) is known as the Philadelphia chromosome (Ph) and is a hallmark of chronic... (Review)
Review
The truncated chromosome 22 that results from the reciprocal translocation t(9;22)(q34;q11) is known as the Philadelphia chromosome (Ph) and is a hallmark of chronic myeloid leukemia (CML). In leukemia cells, Ph not only impairs the physiological signaling pathways but also disrupts genomic stability. This aberrant fusion gene encodes the breakpoint cluster region-proto-oncogene tyrosine-protein kinase (BCR-ABL1) oncogenic protein with persistently enhanced tyrosine kinase activity. The kinase activity is responsible for maintaining proliferation, inhibiting differentiation, and conferring resistance to cell death. During the progression of CML from the chronic phase to the accelerated phase and then to the blast phase, the expression patterns of different BCR-ABL1 transcripts vary. Each BCR-ABL1 transcript is present in a distinct leukemia phenotype, which predicts both response to therapy and clinical outcome. Besides CML, the Ph is found in acute lymphoblastic leukemia, acute myeloid leukemia, and mixed-phenotype acute leukemia. Here, we provide an overview of the clinical presentation and cellular biology of different phenotypes of Ph-positive leukemia and highlight key findings regarding leukemogenesis.
Topics: Carcinogenesis; Cell Proliferation; Fusion Proteins, bcr-abl; Genomic Instability; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Proto-Oncogene Mas
PubMed: 27233483
DOI: 10.1186/s40880-016-0108-0 -
JAMA Oncology Feb 2018The outcome of patients with relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL) is poor. Inotuzumab ozogamicin, a CD22 monoclonal antibody bound to...
Salvage Chemoimmunotherapy With Inotuzumab Ozogamicin Combined With Mini-Hyper-CVD for Patients With Relapsed or Refractory Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia: A Phase 2 Clinical Trial.
IMPORTANCE
The outcome of patients with relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL) is poor. Inotuzumab ozogamicin, a CD22 monoclonal antibody bound to calicheamicin, has single-agent activity in R/R ALL.
OBJECTIVE
To evaluate the efficacy and safety of inotuzumab ozogamicin plus low-intensity chemotherapy in patients with R/R ALL.
DESIGN, SETTING, AND PARTICIPANTS
A single-arm, phase 2 study of adults with R/R B-cell ALL conducted at The University of Texas MD Anderson Cancer Center, Houston.
INTERVENTIONS
The chemotherapy used was lower intensity than hyper-CVAD (cyclophosphamide, vincristine, doxorubicin [trade name, Adriamycin; Pfizer], and dexamethasone) and is referred to as mini-hyper-CVD (mini-HCVD: cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, and cytarabine at 0.5 g/m2 × 4 doses). Inotuzumab was given on day 3 of the first 4 courses at 1.8 to 1.3 mg/m2 for cycle 1 followed by 1.3 to 1.0 mg/m2 for subsequent cycles.
MAIN OUTCOMES AND MEASURES
The primary end points were the overall response rate and overall survival (OS). Secondary end points included safety, relapse-free survival (RFS), the rate of allogeneic stem cell transplantation (ASCT), and the minimal residual disease (MRD) negativity rate.
RESULTS
Fifty-nine patients (30 women and 29 men) with a median age of 35 years (range, 18-87 years) were treated. Overall, 46 patients (78%) responded, 35 of them (59%) achieving complete response. The overall MRD negativity rate among responders was 82%. Twenty-six patients (44%) received ASCT. Grade 3 to 4 toxic effects included prolonged thrombocytopenia (81%; n = 48), infections (73%; n = 43), and hyperbilirubinemia (14%; n = 8). Veno-occlusive disease (VOD) occurred in 9 patients (15%). With a median follow-up of 24 months, the median RFS and OS were 8 and 11 months, respectively. The 1-year RFS and OS rates were 40% and 46%, respectively. The 1-year OS rates for patients treated in salvage 1, salvage 2, and salvage 3 or beyond were 57%, 26%, and 39%, respectively (P = .03).
CONCLUSIONS AND RELEVANCE
The combination of inotuzumab with low-intensity mini-HCVD chemotherapy shows encouraging results in R/R ALL. The risk of VOD should be considered carefully in patients with previous liver damage and among transplant candidates.
TRIAL REGISTRATION
clinicaltrials.gov Identifier: NCT01371630.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Dacarbazine; Dexamethasone; Dose-Response Relationship, Drug; Doxorubicin; Drug Resistance, Neoplasm; Female; Hematopoietic Stem Cell Transplantation; Humans; Inotuzumab Ozogamicin; Male; Middle Aged; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Salvage Therapy; Survival Analysis; Vincristine; Young Adult
PubMed: 28859185
DOI: 10.1001/jamaoncol.2017.2380 -
Hematology. American Society of... Dec 2016Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a newly identified high-risk (HR) B-lineage ALL subtype, accounting for ∼15% of children... (Review)
Review
Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a newly identified high-risk (HR) B-lineage ALL subtype, accounting for ∼15% of children with National Cancer Institute-defined HR B-ALL. It occurs more frequently in adolescents and adults, having been reported in as much as 27% of young adults with ALL between 21 and 39 years of age. It exhibits adverse clinical features, confers a poor prognosis, and harbors a diverse range of genetic alterations that activate cytokine receptor genes and kinase signaling pathways, making it amenable to treatment with tyrosine kinase inhibitor (TKI) therapy. Multiple groups are currently conducting clinical trials to prospectively screen patients with Ph-like ALL and incorporate the relevant TKI for those harboring ABL-class gene rearrangements or those with JAK-STAT pathway alterations. The success of combinatorial treatment of TKI with chemotherapy in the setting of Ph-positive ALL suggests that this approach may similarly improve outcomes for patients with Ph-like ALL. Hence, Ph-like ALL illustrates the modern treatment paradigm of precision medicine and presents unique opportunities for harnessing international collaborations to further improve outcomes for patients with ALL.
Topics: Adolescent; Adult; Child; Child, Preschool; Clinical Trials as Topic; Female; Humans; Male; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase Inhibitors
PubMed: 27913529
DOI: 10.1182/asheducation-2016.1.561 -
Frontiers in Pediatrics 2021Previously, the outcome of paediatric Philadelphia-chromosome-positive (Ph) ALL treated with conventional chemotherapy alone was poor, necessitating the use of... (Review)
Review
Previously, the outcome of paediatric Philadelphia-chromosome-positive (Ph) ALL treated with conventional chemotherapy alone was poor, necessitating the use of haematopoietic stem cell transplantation (HSCT) for the best outcomes. The recent addition of tyrosine kinase inhibitors (TKIs) alongside the chemotherapy regimens for Ph ALL has markedly improved outcomes, replacing the need for HSCT for lower risk patients. An additional poor prognosis group of Philadelphia-chromosome-like (Ph-like) ALL has also been identified. This group also can be targeted by TKIs in combination with chemotherapy, but the role of HSCT in this population is not clear. The impact of novel targeted immunotherapies (chimeric antigen receptor T cells and bispecific or drug-conjugated antibodies) has improved the outcome of patients, in combination with chemotherapy, and made the role of HSCT as the optimal curative therapy for Ph ALL and Ph-like ALL less clear. The prognosis of patients with Ph ALL and persistent minimal residual disease (MRD) at the end of consolidation despite TKI therapy or with additional genetic risk factors remains inferior when HSCT is not used. For such high-risk patients, HSCT using total-body-irradiation-containing conditioning is currently recommended. This review aims to provide an update on the current and future role of HSCT for Ph ALL and addresses key questions related to the management of these patients, including the role of HSCT in first complete remission, MRD evaluation and related actions post HSCT, TKI usage post HSCT, and the putative role of HSCT in Ph-like ALL.
PubMed: 35186828
DOI: 10.3389/fped.2021.807002 -
Clinical Lymphoma, Myeloma & Leukemia Aug 2017Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a recently described B-cell precursor ALL with a gene expression profile and a high frequency... (Review)
Review
Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a recently described B-cell precursor ALL with a gene expression profile and a high frequency of IKZF1 gene alteration similar to that of Ph-positive ALL. Its prevalence is approximately 12% in children, 21% in adolescents (16-20 years of age), and 20% to 24% in adults older than 40 years, with a peak (27%) in young adults 21 to 39 years old. It occurs more often in male individuals and patients with Down syndrome. Ph-like ALL is overrepresented in those with Hispanic ethnicity and is associated with inherited genetic variants in GATA3 (rs3824662). It is a clinically and biologically heterogeneous subtype of B-ALL. Although most patients with Ph-like ALL have positive minimal residual disease after remission induction and poor event-free survival, approximately 40% of pediatric patients responded well to chemotherapy and can be cured with relatively low intensity of treatment. The treatment outcome correlated negatively with increasing age at presentation. Ph-like ALL is characterized by a wide range of genetic alterations that dysregulate several cytokine receptor and kinase signaling pathways, including CRLF2 rearrangement in half of the cases and translocation of nonreceptor tyrosine kinases (predominantly ABL-class and Janus kinases). Patients with ABL-class fusions respond clinically to ABL1 tyrosine kinase inhibitors, whereas mutations activating the JAK-STAT pathway are amendable to treatment with JAK inhibitors in vitro or in preclinical models. Prospective studies are needed to determine if incorporation of tyrosine kinase inhibitor targeting kinase alterations into intensive chemotherapy regimens will improve outcome of patients with Ph-like ALL.
Topics: Animals; Biomarkers, Tumor; Fusion Proteins, bcr-abl; Genetic Variation; Genome-Wide Association Study; Humans; Ikaros Transcription Factor; Molecular Targeted Therapy; Phenotype; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prevalence
PubMed: 28842136
DOI: 10.1016/j.clml.2017.03.299 -
Annals of Laboratory Medicine Nov 2014The Philadelphia chromosome was the first genetic abnormality discovered in cancer (in 1960), and it was found to be consistently associated with CML. The description of... (Review)
Review
The Philadelphia chromosome was the first genetic abnormality discovered in cancer (in 1960), and it was found to be consistently associated with CML. The description of the Philadelphia chromosome ushered in a new era in the field of cancer cytogenetics. Accumulating genetic data have been shown to be intimately associated with the diagnosis and prognosis of neoplasms; thus, karyotyping is now considered a mandatory investigation for all newly diagnosed leukemias. The development of FISH in the 1980s overcame many of the drawbacks of assessing the genetic alterations in cancer cells by karyotyping. Karyotyping of cancer cells remains the gold standard since it provides a global analysis of the abnormalities in the entire genome of a single cell. However, subsequent methodological advances in molecular cytogenetics based on the principle of FISH that were initiated in the early 1990s have greatly enhanced the efficiency and accuracy of karyotype analysis by marrying conventional cytogenetics with molecular technologies. In this review, the development, current utilization, and technical pitfalls of both the conventional and molecular cytogenetics approaches used for cancer diagnosis over the past five decades will be discussed.
Topics: Chromosome Aberrations; Humans; In Situ Hybridization, Fluorescence; Karyotyping; Leukemia; Neoplasms; Prognosis
PubMed: 25368816
DOI: 10.3343/alm.2014.34.6.413 -
Haematologica Nov 2019Advances in our understanding of mechanisms of leukemogenesis and driver mutations in acute lymphoblastic leukemia (ALL) lead to a more precise and informative... (Review)
Review
Advances in our understanding of mechanisms of leukemogenesis and driver mutations in acute lymphoblastic leukemia (ALL) lead to a more precise and informative sub-classification, mainly of B-cell ALL. In parallel, in recent years, novel agents have been approved for the therapy of B-cell ALL, and many others are in active clinical research. Among the newly recognized disease subtypes, Philadelphia-chromosome-like ALL is the most heterogeneous and thus, diagnostically challenging. Given that this subtype of B-cell ALL is associated with a poorer prognosis, improvement of available therapeutic approaches and protocols is a burning issue. Herein, we summarize, in a clinically relevant manner, up-to-date information regarding diagnostic strategies developed for the identification of patients with Philadelphia-chromosome-like ALL. Common therapeutic dilemmas, presented as several case scenarios, are also discussed. It is currently acceptable that patients with B-cell ALL, treated with an aim of cure, irrespective of their age, be evaluated for a Philadelphia-chromosome-like signature as early as possible. Following Philadelphia-chromosome-like recognition, a higher risk of resistance or relapse must be realized and treatment should be modified based on the patient's specific genetic driver and clinical features. However, while active targeted therapeutic options are limited, there is much more to do than just prescribe a matched inhibitor to the identified mutated driver genes. In this review, we present a comprehensive evidence-based approach to the diagnosis and management of Philadelphia-chromosome-like ALL at different time-points during the disease course.
Topics: Biomarkers, Tumor; Chromosome Aberrations; Disease Management; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Outcome Assessment, Health Care; Phenotype; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Symptom Assessment
PubMed: 31582548
DOI: 10.3324/haematol.2018.207506 -
Haematologica Jul 2021
Topics: Humans; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Vincristine
PubMed: 33538156
DOI: 10.3324/haematol.2020.278077 -
Best Practice & Research. Clinical... Sep 2017Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a recently identified high risk disease subtype characterized by a gene expression profile... (Review)
Review
Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a recently identified high risk disease subtype characterized by a gene expression profile similar to that observed in Philadelphia chromosome-positive (Ph-positive) ALL, but without an underlying BCR-ABL1 translocation. Adults and children with Ph-like ALL harbor a diversity of alterations that all lead to activated kinase signaling. Outcomes for patients with Ph-like ALL are poor, which has prompted investigation into the role of tyrosine kinase inhibitor (TKI)-based therapies for this disease. Several clinical trials are now ongoing that include screening for the Ph-like signature and treatment of patients with Ph-like ALL with TKI therapy. This review examines how testing for Ph-like ALL is being incorporated into clinical trials.
Topics: Antineoplastic Agents; Clinical Trials as Topic; Dasatinib; Gene Expression Regulation, Leukemic; Hematopoietic Stem Cell Transplantation; Humans; Imatinib Mesylate; Janus Kinases; Molecular Targeted Therapy; Nitriles; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; STAT Transcription Factors; Signal Transduction; Survival Analysis; Transplantation, Homologous
PubMed: 29050695
DOI: 10.1016/j.beha.2017.06.001 -
ADMET & DMPK 2023The reciprocal translocation of the ABL gene from chromosome 9 to chromosome 22 near the BCR gene gives rise to chronic myelogenous leukemia (CML). The translocation... (Review)
Review
BACKGROUND AND PURPOSE
The reciprocal translocation of the ABL gene from chromosome 9 to chromosome 22 near the BCR gene gives rise to chronic myelogenous leukemia (CML). The translocation results in forming the Philadelphia chromosome (BCR-ABL) tyrosine kinase. CML results in an increase in the number of white blood cells and alteration in tyrosine kinase expression. CML prognosis includes three stages, namely chronic, accelerated, and blast. The diagnosis method involves a CT scan, biopsy, and complete blood count. However, due to certain disadvantages, early diagnosis of CML is not possible by traditional methods. Nanotechnology offers many advantages in diagnosing and treating cancer.
EXPERIMENTAL APPROACH
We searched PubMed, Scopus and Google Scholar using the keywords Philadelphia chromosome, bionanotechnology, tyrosine kinase pathway, half-life, passive targeting, and organic and inorganic nanoparticles. The relevant papers and the classical papers in this field were selected to write about in this review.
KEY RESULTS
The sensitivity and specificity of an assay can be improved by nanoparticles. Utilizing this property, peptides, antibodies, aptamers, etc., in the form of nanoparticles, can be used to detect cancer at a much earlier stage. The half-life of the drug is also increased by nanoformulation. The nanoparticle-coated drugs can easily escape from the immune system.
CONCLUSION
Depending on their type, nanoparticles can be categorized into organic, inorganic and hybrid. Each type has its advantages. Organic nanoparticles have good biocompatibility, inorganic nanoparticles increase the half-life of the drugs. In this review, we highlight the nanoparticles involved in treating CML.
PubMed: 37937247
DOI: 10.5599/admet.2013