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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 -
Haematologica Sep 2023The BCR::ABL1 gene fusion initiates chronic myeloid leukemia (CML); however, evidence has accumulated from studies of highly selected cohorts that variants in other...
The BCR::ABL1 gene fusion initiates chronic myeloid leukemia (CML); however, evidence has accumulated from studies of highly selected cohorts that variants in other cancer-related genes are associated with treatment failure. Nevertheless, the true incidence and impact of additional genetic abnormalities (AGA) at diagnosis of chronic phase (CP)-CML is unknown. We sought to determine whether AGA at diagnosis in a consecutive imatinib-treated cohort of 210 patients enrolled in the TIDEL-II trial influenced outcome despite a highly proactive treatment intervention strategy. Survival outcomes including overall survival, progression-free survival, failure-free survival, and BCR::ABL1 kinase domain mutation acquisition were evaluated. Molecular outcomes were measured at a central laboratory and included major molecular response (MMR, BCR::ABL1 ≤0.1%IS), MR4 (BCR::ABL1 ≤0.01%IS), and MR4.5 (BCR::ABL1 ≤0.0032%IS). AGA included variants in known cancer genes and novel rearrangements involving the formation of the Philadelphia chromosome. Clinical outcomes and molecular response were assessed based on the patient's genetic profile and other baseline factors. AGA were identified in 31% of patients. Potentially pathogenic variants in cancer-related genes were detected in 16% of patients at diagnosis (including gene fusions and deletions) and structural rearrangements involving the Philadelphia chromosome (Ph-associated rearrangements) were detected in 18%. Multivariable analysis demonstrated that the combined genetic abnormalities plus the EUTOS long-term survival clinical risk score were independent predictors of lower molecular response rates and higher treatment failure. Despite a highly proactive treatment intervention strategy, first-line imatinib-treated patients with AGA had poorer response rates. These data provide evidence for the incorporation of genomically-based risk assessment for CML.
Topics: Humans; Imatinib Mesylate; Antineoplastic Agents; Philadelphia Chromosome; Fusion Proteins, bcr-abl; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Chronic-Phase; Protein Kinase Inhibitors
PubMed: 36951160
DOI: 10.3324/haematol.2022.282184 -
Current Hematologic Malignancy Reports Oct 2017The prognosis for patients with Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs) is highly variable. All Ph-negative MPNs carry an increased... (Review)
Review
PURPOSE OF REVIEW
The prognosis for patients with Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs) is highly variable. All Ph-negative MPNs carry an increased risk for thrombotic complications, bleeding, and leukemic transformation. Several clinical, biological, and molecular prognostic factors have been identified in recent years, which provide important information in guiding management of patients with Ph-negative MPNs. In this review, we critically evaluate the recent published literature and discuss important new developments in clinical and molecular factors that impact survival, disease transformation, and thrombosis in patients with polycythemia vera, essential thrombocythemia, and primary myelofibrosis.
RECENT FINDINGS
Recent studies have identified several clinical factors and non-driver mutations to have prognostic impact on Ph-negative MPNs independent of conventional risk stratification and prognostic models. In polycythemia vera (PV), leukocytosis, abnormal karyotype, phlebotomy requirement on hydroxyurea, increased bone marrow fibrosis, and mutations in ASXL1, SRSF2, and IDH2 were identified as additional adverse prognostic factors. In essential thrombocythemia (ET), JAK2 V617F mutation, splenomegaly, and mutations in SH2B3, SF3B1, U2AF1, TP53, IDH2, and EZH2 were found to be additional negative prognostic factors. Bone marrow fibrosis and mutations in ASXL1, SRSF2, EZH2, and IDH1/2 have been found to be additional prognostic factors in primary myelofibrosis (PMF). CALR mutations appear to be a favorable prognostic factor in PMF, which has not been clearly demonstrated in ET. The prognosis for patients with PV, ET, and PMF is dependent upon the presence or absence of several clinical, biological, and molecular risk factors. The significance of additional risk factors identified in these recent studies will need further validation in prospective studies to determine how they may be best utilized in the management of these disorders.
Topics: Disease-Free Survival; Hematologic Neoplasms; Humans; Mutation; Myeloproliferative Disorders; Neoplasm Proteins; Philadelphia Chromosome; Survival Rate
PubMed: 28948488
DOI: 10.1007/s11899-017-0401-2 -
American Society of Clinical Oncology... 2016Acute lymphoblastic leukemia (ALL) remains an important cause of morbidity in children and adults. In this article, we highlight advances in the genetics and therapy of... (Review)
Review
Acute lymphoblastic leukemia (ALL) remains an important cause of morbidity in children and adults. In this article, we highlight advances in the genetics and therapy of three key subtypes of ALL: T-cell ALL, BCR-ABL1 (Philadelphia [Ph] chromosone-positive), and Ph-like ALL. T-ALL is an aggressive disease that accounts for about 15% and 25% of ALL among pediatric and adult cohorts, respectively, and exhibits a multistep nature of cancer initiation and progression. The integration of cytogenetics, molecular biology, and immunophenotype analyses has led to the identification of defined T-ALL subgroups, such as early T-cell precursor ALL and novel lesions with a prognostic role, for which specific inhibitors are being developed. Ph-positive ALL was historically regarded as a subtype of ALL with a poor prognosis, and allogeneic stem cell transplant was recommended for all patients who could undergo this procedure. The deep complete responses seen with combination tyrosine kinase inhibitors (TKIs) and chemotherapy in Ph-positive ALL, and the reports of long-term survival among some patients not undergoing allogeneic stem cell transplant, has raised the question of whether there is a subset of patients who could be cured without this intervention. Ph-like ALL is a subtype of B-progenitor ALL common among older children and adults and associated with a diverse range of genetic alterations that activate kinase signaling. Ph-like ALL is also associated with poor outcome, for which precision medicine trials identifying kinase alterations and testing TKI therapy are being developed.
Topics: Adult; Child; Hematopoietic Stem Cell Transplantation; Humans; Philadelphia Chromosome; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Protein Kinase Inhibitors; Remission Induction
PubMed: 27249738
DOI: 10.1200/EDBK_156628 -
International Journal of Hematologic... Sep 2016The outcome of adult patients with Philadelphia chromosome-positive (Ph) acute lymphoblastic leukemia (ALL) has improved substantially with the introduction of tyrosine... (Review)
Review
The outcome of adult patients with Philadelphia chromosome-positive (Ph) acute lymphoblastic leukemia (ALL) has improved substantially with the introduction of tyrosine kinase inhibitors (TKIs). TKIs are now integral components of therapy for Ph ALL. The current consensus is that they improve patient outcomes compared with historical control patients treated with chemotherapy alone, and increase the number of patients able to receive stem cell transplant. New challenges have emerged with respect to induction of resistance mainly via Abelson tyrosine kinase mutations. Several novel kinase inhibitors with significantly more potent antileukemic activity are currently being developed. Furthermore novel immune therapies, which recruit or modify patient's own T cells to fight leukemic cells, are being developed and could find an important place in Ph ALL therapy by few years. In this article, we reviewed treatment approaches in adults with Ph ALL with a focus on TKIs and combined chemotherapy regimens.
PubMed: 30302206
DOI: 10.2217/ijh-2016-0009 -
American Journal of Hematology Feb 2018Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukemia (ALL) is a biologically, clinically, and genetically distinct subtype of precursor-B ALL. The... (Review)
Review
Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukemia (ALL) is a biologically, clinically, and genetically distinct subtype of precursor-B ALL. The Ph chromosome, results from a reciprocal translocation of the ABL1 kinase gene on chromosome 9 to the breakpoint cluster region (BCR) gene on chromosome 22. Depending on the translocation breakpoint, typically a p210 BCR-ABL1 or a p190 BCR-ABL onc protein are generated; both are constitutively active tyrosine kinases that play a central role to alter signaling pathways of cell proliferation, survival, and self-renewal, leading to leukemogenesis. In Ph-positive ALL, the p190-BCR-ABL (minor [m]-bcr) subtype is more frequent than the p210-BCR-ABL (major [M]-bcr) subtype, commonly found in chronic myeloid leukemia. The Philadelphia chromosome is the most frequent recurrent cytogenetic abnormality in elderly patients with ALL. Its incidence increases with age, reaching ∼50% in patients with ALL aged 60 years and over. Patients traditionally had a very poor outcome with chemotherapy, particularly if they do not undergo allogeneic hematopoietic cell transplantation (allo-HCT) in first complete remission (CR1). With the availability of multiple tyrosine kinase inhibitors (TKI), the therapeutic armamentarium is expanding quickly. However, there is no consensus on how to best treat Ph-positive ALL. With modern therapy, improved outcomes have led to the emergence of a number of controversies, including the need for intensive chemotherapy, the ideal TKI, and whether all eligible patients should receive an allo-HSCT, and if so, what type. Here, we discuss these controversies in light of the available literature.
Topics: Adult; Disease Management; Fusion Proteins, bcr-abl; Humans; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 28971501
DOI: 10.1002/ajh.24926 -
Journal of Cellular and Molecular... Sep 2022Chronic myelogenous leukaemia (CML) has a special phenomenon of chromosome translocation, which is called Philadelphia chromosome translocation. However, the detailed...
Chronic myelogenous leukaemia (CML) has a special phenomenon of chromosome translocation, which is called Philadelphia chromosome translocation. However, the detailed connection of this structure is troublesome and expensive to be identified. Low-coverage whole genome sequencing (LCWGS) could not only detect the previously unknown chromosomal translocation, but also provide the breakpoint candidate small region (with an accuracy of ±200 bases). Importantly, the sequencing cost of LCWGS is about US$300. Then, with the Sanger DNA sequencing, the precise breakpoint can be determined at a single base level. In our project, with LCWGS, BCR and ABL1 are successfully identified to be disrupted in three CML patients (at chr22:23,632,356 and chr9:133,590,450; chr22:23,633,748 and chr9:133,635,781; chr22: 23,631,831 and chr9:133,598,513, respectively). Due to the reconnection after chromosome breakage, classical fusion gene (BCR::ABL1) was found in bone marrow and peripheral blood. The precise breakpoints were helpful to investigate the pathogenic mechanism of CML and could better guide the classification of CML subtypes. This LCWGS method is universal and can be used to detect all diseases related to chromosome variation, such as solid tumours, liquid tumours and birth defects.
Topics: Bone Marrow; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Philadelphia Chromosome; Translocation, Genetic
PubMed: 35903038
DOI: 10.1111/jcmm.17500 -
Frontiers in Oncology 2022Incidence rates of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) are lower but more aggressive in children... (Review)
Review
Incidence rates of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) are lower but more aggressive in children than in adults due to different biological and host factors. After the clinical application of tyrosine kinase inhibitor (TKI) blocking BCR/ABL kinase activity, the prognosis of children with CML and Ph+ ALL has improved dramatically. Yet, off-target effects and drug tolerance will occur during the TKI treatments, contributing to treatment failure. In addition, compared to adults, children may need a longer course of TKIs therapy, causing detrimental effects on growth and development. In recent years, accumulating evidence indicates that drug resistance and side effects during TKI treatment may result from the cellular metabolism alterations. In this review, we provide a detailed summary of the current knowledge on alterations in metabolic pathways including glucose metabolism, lipid metabolism, amino acid metabolism, and other metabolic processes. In order to obtain better TKI treatment outcomes and avoid side effects, it is essential to understand how the TKIs affect cellular metabolism. Hence, we also discuss the relevance of cellular metabolism in TKIs therapy to provide ideas for better use of TKIs in clinical practice.
PubMed: 36561525
DOI: 10.3389/fonc.2022.1072806 -
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 -
Clinical Lymphoma, Myeloma & Leukemia Aug 2016Currently, prognostication in primary myelofibrosis (PMF) relies on the International Prognostic Scoring System (IPSS), dynamic IPSS (DIPSS), and DIPSS-plus, which... (Review)
Review
Currently, prognostication in primary myelofibrosis (PMF) relies on the International Prognostic Scoring System (IPSS), dynamic IPSS (DIPSS), and DIPSS-plus, which incorporate age, blood counts, constitutional symptoms, circulating blasts, red cell transfusion need, and karyotype. Although the JAK2 V617F mutation was discovered a decade ago and MPL mutations shortly thereafter, it was the recent discovery of CALR mutations in the vast majority of JAK2/MPL-unmutated patients and recognition of the powerful impact of CALR mutations and triple-negative (JAK2/MPL/CALR-negative) status on outcome that set the stage for revision of traditional prognostic models to include molecular information. Additionally, the advent of next-generation sequencing has identified a host of previously unrecognized somatic mutations across hematologic malignancies. As in the myelodysplastic syndromes, the majority of common and prognostically informative mutations in PMF affect epigenetic regulation and mRNA splicing. Thus, a need has arisen to incorporate mutational information on genes such as ASXL1 and SRSF2 into risk stratification systems. Mutations in yet other genes appear to be important players in leukemic transformation, and new insights into disease pathogenesis are emerging. Finally, the number of prognostically detrimental mutations may affect both survival and response to ruxolitinib, which has significant implications for clinical decision making. In this review, we briefly summarize the prognostic models in use today and discuss in detail the somatic mutations commonly encountered in patients with PMF, along with their prognostic implications and role in leukemic transformation. Emerging prognostic models that incorporate new molecular information into existing systems or exclude clinical variables are also presented.
Topics: Cell Transformation, Neoplastic; Epigenesis, Genetic; Gene Expression Profiling; Gene Expression Regulation; Genetic Association Studies; Genetic Predisposition to Disease; Genomics; Humans; Mutation; Myeloproliferative Disorders; Philadelphia Chromosome; Primary Myelofibrosis; Prognosis; RNA Splicing; Risk Factors
PubMed: 27521306
DOI: 10.1016/j.clml.2016.02.031