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Cancer Mar 2024Philadelphia chromosome (Ph)-like B-acute lymphoblastic leukemia (B-ALL) is a clinically significant, high-risk genetic subtype of B-ALL cases. There are few data on the...
BACKGROUND
Philadelphia chromosome (Ph)-like B-acute lymphoblastic leukemia (B-ALL) is a clinically significant, high-risk genetic subtype of B-ALL cases. There are few data on the incidence, characterization, and treatment outcomes of Ph-like ALL cases from low- and middle-income countries. There is a pressing need to establish a well-organized/cost-effective approach for identifying Ph-like ALL instances.
METHODS
Multiplex reverse transcriptase polymerase chain reaction, nCounter NanoString, and fluorescence in situ hybridization were used to detect and characterize Ph-like ALL cases among recurrent genetic abnormalities (RGA) B-ALL cases. At the end of induction therapy, flow cytometry-minimal residual disease (MRD) assay was used to quantify MRD positivity in Ph-like ALL cases.
RESULTS
Of 130 newly diagnosed B-ALL cases, 25% (BCR::ABL1), 4% (ETV6::RUNX1), 5% (TCF3::PBX1), 2% (KM2TA::AFF1), and 65% RGA B-ALL cases were revealed by multiplex reverse transcriptase polymerase chain reaction. Among RGA B-ALL cases, 24% Ph-like ALL cases using nCounter NanoString were identified, with 48% CRLF2 cases with 45% CRLF2::P2RY8 and 18% CRLF2::IGH rearrangements(∼r) revealed by fluorescence in situ hybridization. In 52% of CRLF2 cases, 17% ABL1 and JAK2∼r 8% EPOR::IGH & PDGRFB∼r were identified. Ph-like ALL cases had higher total leukocyte count (p < .05), male preponderance (p < .05), and high MRD-positivity/induction failure compared with RGA B-ALL cases. Furthermore, in Ph-like ALL cases, 11 significant genes using quantitative polymerase chain reaction were identified and validated. CRLF2, IGJ, CEACAM6, MUC4, SPATS2L and NRXN3 genes were overexpressed and show statistical significance (p < .05) in Ph-like ALL cases.
CONCLUSIONS
This study showed the high incidence of Ph-like ALL cases with kinase activating alterations and treatment outcomes from low- and middle-income region. Furthermore, a surrogate cost-effective multiplex panel of 11 overexpressed genes for the prompt detection of Ph-like ALL cases is proposed.
PLAIN LANGUAGE SUMMARY
Identification of recurrent gene abnormalities (RGA) B-acute lymphoblastic leukemia (B-ALL) cases using multiplex-reverse transcriptase polymerase chain reaction. Identification and characterization of Philadelphia (Ph)-like ALL cases using nCounter NanoString gene expression profiling and fluorescence in situ hybridization. Furthermore, Ph-like ALL cases were characterized according to CRLF2 expression and kinase-activating genomic alterations. Minimal residual disease of Ph-like ALL cases were quantified using flow cytometry-minimal residual disease assay. A surrogate molecular approach was established to detect Ph-like ALL cases from low- and middle-income countries.
Topics: Humans; Male; Philadelphia Chromosome; In Situ Hybridization, Fluorescence; Neoplasm, Residual; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Acute Disease
PubMed: 37819686
DOI: 10.1002/cncr.35051 -
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 -
Hematology (Amsterdam, Netherlands) Dec 2023Venetoclax has shown synergism with BCR-ABL1 tyrosine kinase inhibitors (TKIs) in preclinical studies for patients with Philadelphia chromosome-positive (Ph+) leukemias....
OBJECTIVES
Venetoclax has shown synergism with BCR-ABL1 tyrosine kinase inhibitors (TKIs) in preclinical studies for patients with Philadelphia chromosome-positive (Ph+) leukemias. This combination may suggest a novel treatment strategy for Ph + leukemias.
METHODS
We conducted a retrospective study to summarize the activity of combining venetoclax and BCR-ABL1 TKI-based therapies in Ph + leukemias.
RESULT
A total of 18 patients with Ph + leukemias were enrolled in this study. At the time of venetoclax and TKI-based therapy, 5 patients were initially diagnosed, with Ph + acute myeloid leukemia (AML) (n = 1) and mixed phenotype acute leukemia (MPAL) (n = 4), 7 patients had chronic myeloid leukemia at blastic phase (CML-BP), and the remaining 6 patients had relapsed or refractory to prior therapy. The overall response rate (ORR) was 88.9% (9 CR, 2 CRi, 4 MLFS, 1 PR), and a major molecular response (MMR) (or better) was achieved in 7 (38.8%) of all patients. With a median follow-up of 7.0 months (range, 2.3-15.6), 15 (83.3%) were in continuous CR at the time of this analysis, with a 1-year OS of 85.6%, 1-year LFS of 76.7%, and 1-year CIR of 22.4%. Moreover, 10 of 18 patients were treated with venetoclax, TKI and hypomethylating agent (HMA) regimens, which also associated with a high ORR rate (6 CR, 1 CRi, 3 MLFS), and can be used for induction or salvage therapy.
CONCLUSION
Venetoclax and TKI-based combination regimens may be a feasible approach for Ph + leukemias, and prospective studies are needed to properly assess the safety, tolerability and efficacy of this regimen.
Topics: Humans; Philadelphia Chromosome; Tyrosine Kinase Inhibitors; Retrospective Studies; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Fusion Proteins, bcr-abl; Protein Kinase Inhibitors
PubMed: 37477259
DOI: 10.1080/16078454.2023.2237790 -
Targeting BCR-Abl in the treatment of Philadelphia-chromosome positive chronic myelogenous leukemia.Pharmacological Research Apr 2022Chronic myelogenous leukemia (CML) is an indolent malignant hematological disease that accounts for about 15% of all cases of leukemia. This disorder results from the... (Review)
Review
Chronic myelogenous leukemia (CML) is an indolent malignant hematological disease that accounts for about 15% of all cases of leukemia. This disorder results from the formation of the Philadelphia chromosome that involves a reciprocal translocation that produces a lengthened chromosome 9 and shortened chromosome 22 - the Philadelphia chromosome. As a consequence of the translocation, the dysregulated BCR-Abl fusion oncoprotein is formed and it produces the abnormal proliferation of white blood cells. The treatment of CML with imatinib revolutionized the treatment of this disorder and led to the discovery and development of dozens of effective targeted protein kinase inhibitors. Imatinib (first generation), dasatinib, nilotinib, and bosutinib (second generation) have been FDA-approved for frontline therapy, and ponatinib (third generation) is approved for resistant disease with a T315I mutation. Each of these drugs is orally bioavailable. The BCR-Abl fusion protein lacks the physiological N-terminal myristoyl group that binds to a hydrophobic pocket in the large protein kinase lobe and inhibits enzyme activity. The absence of the myristoyl group leads to enhanced protein kinase catalytic activity. Asciminib was designed to bind to this binding pocket to reduce Abl kinase activity. Asciminib is orally effective and was FDA-approved as a third-line treatment for CML and a first-line treatment in patients with the T315I mutation. It blocks the activity of BCR-Abl by interacting with the myristate-binding site located 23 Å from the ATP-binding site and is the prototype of a type IV inhibitor. Asciminib is a so-called STAMP inhibitor that Specifically Targets the Abl Myristoyl Pocket.
Topics: Antineoplastic Agents; Drug Resistance, Neoplasm; Fusion Proteins, bcr-abl; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Philadelphia Chromosome; Protein Kinase Inhibitors
PubMed: 35257901
DOI: 10.1016/j.phrs.2022.106156 -
Nature Communications Jan 2024Dysregulated hematopoietic niches remodeled by leukemia cells lead to imbalances in immunological mediators that support leukemogenesis and drug resistance. Targeting...
Dysregulated hematopoietic niches remodeled by leukemia cells lead to imbalances in immunological mediators that support leukemogenesis and drug resistance. Targeting immune niches may ameliorate disease progression and tyrosine kinase inhibitor (TKI) resistance in Philadelphia chromosome-positive B-ALL (Ph B-ALL). Here, we show that T helper type 17 (Th17) cells and IL-17A expression are distinctively elevated in Ph B-ALL patients. IL-17A promotes the progression of Ph B-ALL. Mechanistically, IL-17A activates BCR-ABL, IL6/JAK/STAT3, and NF-kB signalling pathways in Ph B-ALL cells, resulting in robust cell proliferation and survival. In addition, IL-17A-activated Ph B-ALL cells secrete the chemokine CXCL16, which in turn promotes Th17 differentiation, attracts Th17 cells and forms a positive feedback loop supporting leukemia progression. These data demonstrate an involvement of Th17 cells in Ph B-ALL progression and suggest potential therapeutic options for Ph B-ALL with Th17-enriched niches.
Topics: Humans; Imatinib Mesylate; Philadelphia Chromosome; Fusion Proteins, bcr-abl; Interleukin-17; Drug Resistance, Neoplasm; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase Inhibitors; Acute Disease
PubMed: 38172124
DOI: 10.1038/s41467-023-44270-3 -
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 -
JAMA Oncology Mar 2020
Topics: Acute Disease; Child; Dasatinib; Humans; Imatinib Mesylate; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 31944218
DOI: 10.1001/jamaoncol.2019.5849 -
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 -
American Journal of Cancer Research 2022Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) is a high-risk disease subtype with a dismal prognosis. Inhibiting BCR-ABL kinase alone is...
Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) is a high-risk disease subtype with a dismal prognosis. Inhibiting BCR-ABL kinase alone is insufficient to eradicate Ph+ALL clones, and alternative BCR-ABL-dependent and -independent pathways need to be targeted as an effective strategy. Our study revealed that the combination of dasatinib and interferon-α showed synergistic activity against Ph+ALL, inducing mitochondrial dysfunction and causing necrosis-like cell lysis. Mechanistic studies showed that the induced cell death was caspase-3-independent. Canonical necroptosis signals, such as RIP1 and MLKL, were not activated; instead, the pyroptosis executor Gasdermin D was upregulated expression and activated. The expression levels of extracellular ATP and IL-1β were also upregulated, both of which are markers of pyroptotic cell death. In a murine Ph+ALL model, the dual drug treatment prolonged the survival of tumor-bearing mice. More importantly, we incorporated the dual drugs to maintenance therapy in 39 patients who were unfit for allogeneic stem cell transplantation (allo-HSCT). The median follow-up was 28.5 months, the 4-year disease-free survival and overall survival rates were 52.2% and 65.2%, respectively. Our data suggest that the combination of dasatinib and interferon-α has potential synergistic activity against Ph+ALL and shows promise as a maintenance therapy for Ph+ALL patients who are unfit for allo-HSCT.
PubMed: 35812060
DOI: No ID Found