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Philadelphia-chromosome positive acute lymphoblastic leukemia

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https://www.readbyqxmd.com/read/29152059/gzd824-suppresses-the-growth-of-human-b-cell-precursor-acute-lymphoblastic-leukemia-cells-by-inhibiting-the-src-kinase-and-pi3k-akt-pathways
#1
Wei Ye, Zhiwu Jiang, Xiaoyun Lu, Xiaomei Ren, Manman Deng, Shouheng Lin, Yiren Xiao, Simiao Lin, Suna Wang, Baiheng Li, Yi Zheng, Peilong Lai, Jianyu Weng, Donghai Wu, Yuguo Ma, Xudong Chen, Zhesheng Wen, Yaoyu Chen, Xiaoyan Feng, Yangqiu Li, Pentao Liu, Xin Du, Duanqing Pei, Yao Yao, Bing Xu, Ke Ding, Peng Li
Available therapeutic options for advanced B cell precursor acute lymphoblastic leukemia (pre-B ALL) are limited. Many lead to neutropenia, leaving patients at risk of life-threatening infections and result in bad outcomes. New treatment options are needed to improve overall survival. We previously showed that GZD824, a novel BCR-ABL tyrosine kinase inhibitor, has anti-tumor activity in Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia cells and tumor models. Here, we show that GZD824 decreases cell viability, induces cell-cycle arrest, and causes apoptosis in pre-B ALL cells...
October 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/29140408/philadelphia-chromosome-like-mixed-phenotype-acute-leukemia-demonstrating-p2ry8-crlf2-fusion-and-jak1-mutation
#2
Sarah M Choi, John K Frederiksen, Charles W Ross, Dale L Bixby, Lina Shao
Objectives: Philadelphia chromosome-like (Ph-like) genetic alterations define a subset of B lymphoblastic leukemia/lymphoma (B-ALL), which represents a separate provisional entity in the World Health Organization 2016 updated classification. However, these alterations have not been described outside the context of B-ALL. Methods: Cytogenomic array and molecular analysis identified a Ph-like signature in a mixed-phenotype acute leukemia (MPAL), B/myeloid, confirmed using conventional immunophenotypic and cytochemical analysis...
November 11, 2017: American Journal of Clinical Pathology
https://www.readbyqxmd.com/read/29132472/-research-progress-in-ph-like-childhood-acute-lymphoblastic-leukemia
#3
Xue Tang, Xia Guo
Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a subtype of B-lineage ALL (B-ALL) that displays a gene expression profile (GEP) similar to Philadelphia chromosome-positive ALL (Ph(+) ALL). It has a diverse range of genetic alterations that activate cytokine receptor genes and kinase signaling pathways, frequently accompanied by abnormal transcription factors related to lymphatic development. Children with Ph-like ALL account for 15% of children with high-risk B-ALL. It has adverse clinical features and a poor prognosis...
November 2017: Zhongguo Dang Dai Er Ke za Zhi, Chinese Journal of Contemporary Pediatrics
https://www.readbyqxmd.com/read/29082835/efficacy-and-safety-of-bispecific-t-cell-engager-blinatumomab-and-the-potential-to-improve-leukemia-free-survival-in-b-cell-acute-lymphoblastic-leukemia
#4
Josep-Maria Ribera
Immunotherapy is a promising modality of treatment of neoplastic diseases, including acute lymphoblastic leukemia (ALL). The CD19/CD3-bispecific T cell-engaging (BiTE®) monoclonal antibody blinatumomab can transiently bind cytotoxic T cells to CD19(+) target B cells of ALL inducing their serial lysis. Areas covered: This review focuses on the efficacy and safety of blinatumomab used for the treatment of relapsed/refractory (R/R) ALL and minimal residual disease (MRD)-positive B-cell precursor (BCP) ALL in adults and children, as well as the future prospects of this drug in the treatment of ALL...
October 30, 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/29058281/decitabine-for-relapsed-acute-lymphoblastic-leukemia-after-allogeneic-hematopoietic-stem-cell-transplantation
#5
Jie-Ke Cui, Yin Xiao, Yong You, Wei Shi, Qing Li, Yi Luo, Lin Jiang, Zhao-Dong Zhong
Relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a main question on treatment failure. Current strategies for management that usually include salvage chemotherapy, donor lymphocytic infusion and second transplantation. Our study assessed the efficacy of decitabine (DAC) for treating patients with acute lymphoblastic leukemia (ALL) who relapsed after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We retrospectively analyzed the outcomes of 12 patients with relapsed ALL after allo-HSCT who received DAC therapy...
October 2017: Journal of Huazhong University of Science and Technology. Medical Sciences
https://www.readbyqxmd.com/read/29050695/how-is-the-ph-like-signature-being-incorporated-into-all-therapy
#6
REVIEW
Luke Maese, Sarah K Tasian, Elizabeth A Raetz
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...
September 2017: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/29050694/the-biology-of-philadelphia-chromosome-like-all
#7
REVIEW
Kathryn G Roberts
Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a recently described subtype of B-cell precursor ALL with a gene expression profile similar to Ph-positive ALL and a high frequency of IKZF1 alterations. The prevalence of Ph-like ALL increases with age, ranging from 10-15% of children to over 25% of young adults with ALL. It occurs more frequently in males and is associated with adverse clinical features including elevated minimal residual disease levels and poor survival in both children and adults...
September 2017: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/29050693/how-should-we-treat-older-adults-with-ph-adult-all-and-what-novel-approaches-are-being-investigated
#8
REVIEW
Matthew J Wieduwilt
Treatment of older patients with Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukemia presents unique challenges. Advanced age, comorbidities, high treatment-related death rates with traditional chemotherapy, and relapse combine to yield poor survival. Reduced-intensity induction with BCR-ABL1 targeted tyrosine kinase inhibitors (TKIs) and corticosteroids yields CR rates 96-100% with no induction mortality but relapse is nearly certain without effective consolidation. Few clinical trials provide guidance on optimal consolidation for older Ph+ ALL...
September 2017: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/29050692/which-tyrosine-kinase-inhibitor-should-we-use-to-treat-philadelphia-chromosome-positive-acute-lymphoblastic-leukemia
#9
REVIEW
Nicholas J Short, Hagop Kantarjian, Elias Jabbour, Farhad Ravandi
The incorporation of tyrosine kinase inhibitors (TKIs) into chemotherapy regimens has significantly improved the long-term survival of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Successive generations of TKIs with increased potency against BCR-ABL and broader spectrum of activity against ABL kinase domain mutations have led to incremental improvements in the outcomes of patients with this disease. In particular, ponatinib, a potent pan-BCR-ABL TKI capable of overcoming the T315I mutation, holds significant promise in the treatment of Ph+ ALL, although the potential cardiovascular toxicity of this agent remains a concern...
September 2017: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/29050691/philadelphia-chromosome-negative-b-cell-acute-lymphoblastic-leukemia-in-older-adults-current-treatment-and-novel-therapies
#10
REVIEW
Kristen M O'Dwyer, Jane L Liesveld
Older adults with Philadelphia chromosome negative (Ph-),-B-cell acute lymphoblastic leukemia (ALL) have the highest rates of treatment failure and treatment complications with current therapy, and, thus, there is no standard treatment for these patients. Approximately 16 percent of patients with newly diagnosed Ph- B-cell ALL are aged 60 years or older [1]. The five-year overall survival for this older cohort of patients is approximately 20 percent, and there has been no improvement in their survival in decades [2]...
September 2017: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/29046900/us-intergroup-study-of-chemotherapy-plus-dasatinib-and-allogeneic-stem-cell-transplant-in-philadelphia-chromosome-positive-all
#11
Farhad Ravandi, Megan Othus, Susan M O'Brien, Stephen J Forman, Chul S Ha, Jeffrey Y C Wong, Martin S Tallman, Elisabeth Paietta, Janis Racevskis, Geoffrey L Uy, Mary Horowitz, Naoko Takebe, Richard Little, Uma Borate, Partow Kebriaei, Laura Kingsbury, Hagop M Kantarjian, Jerald P Radich, Harry P Erba, Frederick R Appelbaum
This multicenter trial was conducted to determine whether the addition of dasatinib to chemotherapy followed by an allogeneic hematopoietic cell transplant (HCT) in patients with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) was feasible. Patients ≥ 18 and ≤ 60 years of age with newly diagnosed Ph+ ALL received up to 8 cycles of alternating hyperCVAD and high dose cytarabine and methotrexate with dasatinib. Patients with an available matched sibling or unrelated donor underwent an allogeneic HCT in first complete remission (CR1) followed by daily dasatinib starting from day 100...
December 27, 2016: Blood Advances
https://www.readbyqxmd.com/read/29046392/nutlin-3-plus-tanshinone-iia-exhibits-synergetic-anti-leukemia-effect-with-imatinib-by-reactivating-p53-and-inhibiting-akt-mtor-pathway-in-ph-all
#12
Yong Guo, Yi Li, Bing Xiang, Xiao-Ou Huang, Hong-Bing Ma, Fang-Fang Wang, Yu-Ping Gong
Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is triggered by BCR/ABL kinase. Recent efforts focused on the development of more potent tyrosine kinase inhibitors (TKI) that also inhibit mutant tyrosine kinases such as nilotinib and dasatinib. Although major advances in the treatment of this aggressive disease with potent inhibitors of the BCR/ABL kinases, patients in remission frequently relapse due to drug resistance possibly mediated, at least in part, by compensatory activation of growth-signaling pathways and protective feedback signaling of leukemia cells in response to TKI-treatment...
October 18, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/29043880/concurrent-therapy-of-chronic-lymphocytic-leukemia-and-philadelphia-chromosome-positive-acute-lymphoblastic-leukemia-utilizing-cd19-targeted-car-t-cells
#13
Mark B Geyer, Shwetha H Manjunath, Andrew G Evans, Jae H Park, Marco L Davila, Corey S Cutler, Xiuyan Wang, Yongzeng Wang, Brigitte Senechal, Isabelle Rivière, Michel Sadelain, Jane L Liesveld, Renier J Brentjens
No abstract text is available yet for this article.
October 18, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/29042995/overexpression-of-dominant-negative-ikaros-6-isoform-is-associated-with-resistance-to-tkis-in-patients-with-philadelphia-chromosome-positive-acute-lymphoblastic-leukemia
#14
Changfeng Shao, Jie Yang, Yirong Kong, Cong Cheng, Wei Lu, Hongzai Guan, Haiyan Wang
The clinical significance of the dominant-negative Ikaros 6 (DN-IK6) in the treatment of patients with Philadelphia-positive acute lymphoblastic leukemia (Ph(+)-ALL) with tyrosine kinase inhibitors (TKIs) remains elusive. In the present study, it was demonstrated that DN-IK6 was overexpressed in B-cell (B)-ALL cases compared with T cell-ALL cases at the mRNA and protein levels. Furthermore, nucleotide sequencing revealed that DN-IK6 was due to the deletion of IKAROS family zinc finger 1 exons 4-7. The outcome of patients with Ph(+)-B-ALL with DN-IK6, and treated with TKIs and hyper-cyclophosphamide/vincristine/doxorubicin/dexamethasone regimen were restrospectively evaluated in a 2 year follow-up...
October 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/29025593/prognostic-significance-of-recurrent-additional-chromosomal-abnormalities-in-adult-patients-with-philadelphia-chromosome-positive-acute-lymphoblastic-leukemia
#15
Chang Ahn Seol, Young-Uk Cho, Seongsoo Jang, Chan-Jeoung Park, Jung-Hee Lee, Je-Hwan Lee, Kyoo Hyung Lee, Eul-Ju Seo
In Philadelphia (Ph) chromosome-positive acute lymphoblastic leukemia (ALL), additional chromosomal abnormalities (ACAs) are frequently observed. We investigated the cytogenetic characteristics and prognostic significance of ACAs in Ph-positive ALL. We reviewed the clinical data and bone marrow cytogenetic findings of 122 adult Ph-positive ALL patients. The ACAs were examined for partial or whole chromosomal gains or losses, and structural aberrations. The overall survival (OS) and disease-free survival (DFS) of patients who received hematopoietic cell transplantation were compared between the isolated Ph group and ACA group...
October 2017: Cancer Genetics
https://www.readbyqxmd.com/read/28978840/current-treatment-of-adult-acute-lymphoblastic-leukemia
#16
Shin Fujisawa
The survival outcomes for children with acute lymphoblastic leukemia (ALL) have dramatically improved over recent years, and improved outcomes in adolescents and young adults patients have been achieved by applying regimens based on pediatric protocols. The treatment strategies for adult ALL are similar to those for pediatric ALL. T-cell ALL is less common than B-cell ALL. Therefore, there are only few reports of investigations in a large group of adult T-ALL patients. In Japan, nelarabine-combined chemotherapy has been tested in a phase II study in patients with newly diagnosed T-ALL...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/28978065/the-pan-bcl-2-blocker-obatoclax-gx15-070-and-the-pi3-kinase-mtor-inhibitor-bez235-produce-cooperative-growth-inhibitory-effects-in-all-cells
#17
Gabriele Stefanzl, Daniela Berger, Sabine Cerny-Reiterer, Katharina Blatt, Gregor Eisenwort, Wolfgang R Sperr, Gregor Hoermann, Karin Lind, Alexander W Hauswirth, Peter Bettelheim, Heinz Sill, Junia V Melo, Ulrich Jäger, Peter Valent
Acute lymphoblastic leukemia (ALL) is characterized by leukemic expansion of lymphoid blasts in hematopoietic tissues. Despite improved therapy only a subset of patients can be cured. Therefore, current research is focusing on new drug-targets. Members of the BCL-2 family and components of the PI3-kinase/mTOR pathway are critically involved in the regulation of growth and survival of ALL cells. We examined the effects of the pan-BCL-2 blocker obatoclax and the PI3-kinase/mTOR-inhibitor BEZ235 on growth and survival of ALL cells...
September 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28973362/cd20-positivity-and-white-blood-cell-count-predict-treatment-outcomes-in-philadelphia-chromosome-negative-acute-lymphoblastic-leukemia-patients-ineligible-for-pediatric-inspired-chemotherapy
#18
Yusuke Isshiki, Chikako Ohwada, Emiko Sakaida, Masahiro Onoda, Nobuyuki Aotsuka, Hiroaki Tanaka, Motoharu Fukazawa, Ryuko Cho, Takeaki Sugawara, Takeharu Kawaguchi, Satoru Hara, Akira Yokota
Background: The efficacy of conventional chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been controversial as post-remission therapies for adult Philadelphia chromosome-negative acute lymphoblastic leukemia patients. Methods: We retrospectively analyzed 96 adolescent and adult cases of Philadelphia chromosome-negative acute lymphoblastic leukemia to evaluate whether allo-HSCT should be performed after first complete remission (1CR)...
November 1, 2017: Japanese Journal of Clinical Oncology
https://www.readbyqxmd.com/read/28972016/philadelphia-chromosome-like-acute-lymphoblastic-leukemia
#19
REVIEW
Sarah K Tasian, Mignon L Loh, Stephen P Hunger
Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL), also referred to as BCR-ABL1-like ALL, is a high-risk subset with a gene expression profile that shares significant overlap with that of Ph-positive (Ph(+)) ALL and is suggestive of activated kinase signaling. Although Ph(+) ALL is defined by BCR-ABL1 fusion, Ph-like ALL cases contain a variety of genomic alterations that activate kinase and cytokine receptor signaling. These alterations can be grouped into major subclasses that include ABL-class fusions involving ABL1, ABL2, CSF1R, and PDGFRB that phenocopy BCR-ABL1 and alterations of CRLF2, JAK2, and EPOR that activate JAK/STAT signaling...
November 9, 2017: Blood
https://www.readbyqxmd.com/read/28971501/current-paradigms-in-the-management-of-philadelphia-chromosome-positive-acute-lymphoblastic-leukemia-in-adults
#20
REVIEW
Riad El Fakih, Elias Jabbour, Farhad Ravandi, Mona Hassanein, Farhan Anjum, Syed Ahmed, Hagop Kantarjian
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...
October 3, 2017: American Journal of Hematology
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