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Ph+ acute lymphoblastic leukemia

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https://www.readbyqxmd.com/read/27913531/treatment-of-older-patients-with-acute-lymphoblastic-leukemia
#1
Nicola Gökbuget
The treatment of older patients with acute lymphoblastic leukemia (ALL) is an unmet medical need. With increasing age, ALL patients have a significantly lower clinical remission rate, higher early mortality, higher relapse rate, and poorer survival compared with younger patients. This is only partly explained by a higher incidence of poor prognostic factors in the older age group. Most importantly, intensive chemotherapy with or without stem cell transplantation (SCT) is less well tolerated in older patients...
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/27913529/ph-like-acute-lymphoblastic-leukemia
#2
Thai Hoa Tran, Mignon L Loh
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...
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/27899971/the-targetable-role-of-herpes-virus-associated-ubiquitin-specific-protease-hausp-in-p190-bcr-abl-leukemia
#3
Giovanna Carrà, Cristina Panuzzo, Sabrina Crivellaro, Deborah Morena, Riccardo Taulli, Angelo Guerrasio, Giuseppe Saglio, Alessandro Morotti
Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL) is driven by the p190 breakpoint cluster region (BCR)-ABL isoform. Although effectively targeted by BCR-ABL tyrosine kinase inhibitors (TKIs), ALL is associated with a less effective response to TKIs compared with chronic myeloid leukemia. Therefore, the identification of additional genes required for ALL maintenance may provide possible therapeutic targets to aid the eradication of this cancer. The present study demonstrated that p190 BCR-ABL is able to interact with the deubiquitinase herpesvirus-associated ubiquitin-specific protease (HAUSP), which in turn affects p53 protein stability...
November 2016: Oncology Letters
https://www.readbyqxmd.com/read/27894622/a-case-of-philadelphia-chromosome-positive-acute-lymphoblastic-leukemia-with-partial-trisomy-of-chromosome-1q-involving-chromosome-13-as-the-acceptor-a-novel-cytogenetic-finding
#4
Mohit Bharadwaj, Anurag Sharma, Rahul Katara, Dinesh Pradhan, Raman Arora, Reena Mittal, Sambit K Mohanty
The Philadelphia (Ph) chromosome is infrequently found in acute lymphoblastic leukemia and is associated with poor prognosis. We present a case of Ph chromosome positive B cell-acute lymphoblastic leukemia with the partial trisomy of chromosome 1q involving chromosome 13 as the acceptor which has never been reported in the English literature. Jumping translocation (JT) of chromosome 1 is rare and is associated with disease progression and poor prognosis. Herein, we report the first case of Ph chromosome positive B cell-acute lymphoblastic leukemia with coexisting jumping translocation of chromosome 1 leading to trisomy of chromosome 1q...
September 4, 2016: Pathology, Research and Practice
https://www.readbyqxmd.com/read/27894117/t-1-9-p34-q34-sfpq-abl1-fusion-in-a-patient-with-ph-like-common-b-cell-acute-lymphoblastic-leukemia
#5
Guangying Sheng, Zhao Zeng, Jinlan Pan, Qinrong Wang, Hong Yao, Lijun Wen, Liang Ma, Depei Wu, Suning Chen
No abstract text is available yet for this article.
November 29, 2016: Acta Haematologica
https://www.readbyqxmd.com/read/27890258/should-anyone-with-philadelphia-chromosome-positive-all-who-is-negative-for%C3%A2-minimal-residual-disease-receive-a-hematopoietic-stem-cell-transplant-in-first-remission
#6
REVIEW
Mark R Litzow
Outcomes for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in the pre-imatinib era were poor, particularly if patients did not receive an allogeneic hematopoietic stem cell transplant. This led to the recommendation that all patients with Ph+ ALL, if they were transplant candidates, should be transplanted. With the introduction of imatinib and subsequently other tyrosine kinase inhibitors, patient outcomes improved dramatically, raising the question of whether transplant in first complete molecular remission for these patients is really necessary...
December 2016: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/27880933/immunological-effects-of-nilotinib-prophylaxis-after-allogeneic-stem-cell-transplantation-in-patients-with-advanced-chronic-myeloid-leukemia-or-philadelphia-chromosome-positive-acute-lymphoblastic-leukemia
#7
Nira Varda-Bloom, Ivetta Danylesko, Roni Shouval, Shiran Eldror, Atar Lev, Jacqueline Davidson, Esther Rosenthal, Yulia Volchek, Noga Shem-Tov, Ronit Yerushalmi, Avichai Shimoni, Raz Somech, Arnon Nagler
Allogeneic stem cell transplantation remains the standard treatment for resistant advanced chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. Relapse is the major cause of treatment failure in both diseases. Post-allo-SCT administration of TKIs could potentially reduce relapse rates, but concerns regarding their effect on immune reconstitution have been raised. We aimed to assess immune functions of 12 advanced CML and Ph+ ALL patients who received post-allo-SCT nilotinib...
November 18, 2016: Oncotarget
https://www.readbyqxmd.com/read/27873237/estimating-long-term-survival-of-adults-with-philadelphia-chromosome-negative-relapsed-refractory-b-precursor-acute-lymphoblastic-leukemia-treated-with-blinatumomab-using-historical-data
#8
Arie Barlev, Vincent W Lin, Aaron Katz, Kuolung Hu, Ze Cong, Beth Barber
INTRODUCTION: Blinatumomab is a bispecific T cell-engaging antibody construct indicated for adult patients with relapsed/refractory (R/R) Ph(-) B-precursor acute lymphoblastic leukemia (ALL), an aggressive disease with poor prognosis. A phase 2 single-arm clinical study showed that 43% of patients achieved CR/CRh within two cycles and approximately 20% of patients receiving blinatumomab were still alive after 2 years. METHODS: The objective of the current analysis was to estimate long-term survival of patients receiving blinatumomab beyond the observed time period in the clinical study using a large historical observational dataset...
November 21, 2016: Advances in Therapy
https://www.readbyqxmd.com/read/27870571/high-frequency-and-poor-outcome-of-philadelphia-chromosome-like-acute-lymphoblastic-leukemia-in-adults
#9
Kathryn G Roberts, Zhaohui Gu, Debbie Payne-Turner, Kelly McCastlain, Richard C Harvey, I-Ming Chen, Deqing Pei, Ilaria Iacobucci, Marcus Valentine, Stanley B Pounds, Lei Shi, Yongjin Li, Jinghui Zhang, Cheng Cheng, Alessandro Rambaldi, Manuela Tosi, Orietta Spinelli, Jerald P Radich, Mark D Minden, Jacob M Rowe, Selina Luger, Mark R Litzow, Martin S Tallman, Peter H Wiernik, Ravi Bhatia, Ibrahim Aldoss, Jessica Kohlschmidt, Krzysztof Mrózek, Guido Marcucci, Clara D Bloomfield, Wendy Stock, Stephen Kornblau, Hagop M Kantarjian, Marina Konopleva, Elisabeth Paietta, Cheryl L Willman, Charles G Mullighan
Purpose Philadelphia chromosome (Ph) -like acute lymphoblastic leukemia (ALL) is a high-risk subtype of childhood ALL characterized by kinase-activating alterations that are amenable to treatment with tyrosine kinase inhibitors. We sought to define the prevalence and genomic landscape of Ph-like ALL in adults and assess response to conventional chemotherapy. Patients and Methods The frequency of Ph-like ALL was assessed by gene expression profiling of 798 patients with B-cell ALL age 21 to 86 years. Event-free survival and overall survival were determined for Ph-like ALL versus non-Ph-like ALL patients...
November 21, 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/27870151/ph-like-acute-lymphoblastic-leukemia-with-a-novel-pax5-kidins220-fusion-transcript
#10
Kenichi Sakamoto, Toshihiko Imamura, Takuyo Kanayama, Mio Yano, Daisuke Asai, Takao Deguchi, Yoshiko Hashii, Akihiko Tanizawa, Yusei Ohshima, Nobutaka Kiyokawa, Keizo Horibe, Atsushi Sato
Although "paired box 5" (PAX5)-related fusion genes are well documented in childhood B-cell precursor acute lymphoblastic leukemia (ALL), these types of fusion with the exception of PAX5-JAK2 are rarely seen in patients with gene expression profiles similar to those of BCR-ABL1 (Philadelphia)-positive ALL (Ph-like ALL). We report a novel fusion of the genes PAX5 and "kinase D-interacting substrate of 220 kDa" (KIDINS220, also known as ARMS) in a Ph-like ALL. As PAX5 is a master regulator of B-lymphocyte differentiation, PAX5 rearrangements induce a differentiation block in B lymphocytes...
November 7, 2016: Genes, Chromosomes & Cancer
https://www.readbyqxmd.com/read/27865806/ikaros-exploiting-and-targeting-the-hematopoietic-stem-cell-niche-in-b-progenitor-acute-lymphoblastic-leukemia
#11
REVIEW
Michelle L Churchman, Charles G Mullighan
Genetic alterations of IKZF1 encoding the lymphoid transcription factor IKAROS are a hallmark of high risk B-progenitor ALL such as BCR-ABL1 positive (Ph+) and Ph-like ALL, and are associated with poor outcome, even in the era of contemporary chemotherapy incorporating tyrosine kinase inhibitors in the treatment of Ph+ ALL. Recent experimental mouse modeling of B-progenitor ALL has shown that IKZF1 alterations have multiple effects, including arresting differentiating, skewing lineage of leukemia from myeloid to lymphoid, and in Ph+ leukemia, conferring resistance to TKI therapy without abrogating ABL1 inhibition...
November 16, 2016: Experimental Hematology
https://www.readbyqxmd.com/read/27855558/diagnostic-evaluation-of-rna-sequencing-for-the-detection-of-genetic-abnormalities-associated-with-ph-like-acute-lymphoblastic-leukemia-all
#12
Kai Lee Yap, Larissa V Furtado, Kazuma Kiyotani, Emily Curran, Wendy Stock, Jennifer L McNeer, Sabah Kadri, Jeremy P Segal, Yusuke Nakamura, Michelle M Le Beau, Sandeep Gurbuxani, Gordana Raca
Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) is a molecular subtype of high-risk B-cell ALL characterized by formation of abnormal gene fusions involving tyrosine kinase (TK) and cytokine receptor genes and activation of TK signaling. Because of the diversity of associated genetic changes, the detection of Ph-like ALL cases currently requires multiple cytogenetic and molecular assays; thus, our goal was to develop a consolidated workflow for detecting genetic abnormalities in Ph-like ALL. We found that total and targeted RNA sequencing (RNAseq)-based approach allowed the detection of abnormal fusion transcripts (EBF1-PDGFRB, P2RY8-CRLF2, RCSD1-ABL1, and RCSD1-ABL2)...
November 17, 2016: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/27821800/synergistic-effects-of-selective-inhibitors-targeting-the-pi3k-akt-mtor-pathway-or-nup214-abl1-fusion-protein-in-human-acute-lymphoblastic-leukemia
#13
Carolina Simioni, Simona Ultimo, Alberto M Martelli, Giorgio Zauli, Daniela Milani, James A McCubrey, Silvano Capitani, Luca M Neri
Philadelphia chromosome-positive (Ph+) Acute Lymphoblastic Leukemia (ALL) accounts for 25-30% of adult ALL and its incidence increases with age in adults >40 years old. Irrespective of age, the ABL1 fusion genes are markers of poor prognosis and amplification of the NUP214-ABL1 oncogene can be detected mainly in patients with T-ALL. T cell malignancies harboring the ABL1 fusion genes are sensitive to many cytotoxic agents, but up to date complete remissions have not been achieved. The PI3K/Akt/mTOR signaling pathway is often activated in leukemias and plays a crucial role in leukemogenesis...
November 3, 2016: Oncotarget
https://www.readbyqxmd.com/read/27799606/successful-reintroduction-of-blinatumomab-in-a-patient-with-relapsed-refractory-acute-lymphoblastic-leukemia-following-grade-4-cytokine-release-syndrome
#14
Bernard L Marini, Yihan Sun, Patrick W Burke, Anthony J Perissinotti
Relapsed/refractory acute lymphoblastic leukemia poses a clinical challenge due to its poor prognosis and lack of effective treatment. Blinatumomab, a novel immunotherapy, has demonstrated excellent efficacy in relapsed/refractory acute lymphoblastic leukemia; however, life-threatening toxicities such as cytokine release syndrome have been reported in pivotal clinical trials. In this report, we describe the safe reintroduction of blinatumomab in an adult patient with relapsed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia after experiencing grade 4 blinatumomab-induced cytokine release syndrome using a unique dosing strategy and a very diligent monitoring approach...
October 31, 2016: Journal of Oncology Pharmacy Practice
https://www.readbyqxmd.com/read/27795512/how-has-the-management-of-ph-acute-lymphoblastic-leukemia-all-changed-over-the-years
#15
Sabina Chiaretti, Robin Foà
For decades, Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) has been considered the ALL subgroup with the worse outcome. It represents the most frequent genetic subtype of adult ALL and, in the elderly, it accounts for approximately 50% of cases. The introduction of tyrosine kinase inhibitors (TKIs) has led to obtain complete hematologic remissions (CHR) in virtually all patients, to improve disease-free survival and overall survival, and to increase the percentage of patients who can undergo an allogeneic stem cell transplant (allo-SCT)...
2016: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/27792701/-long-term-destiny-of-adolescents-and-young-adults-with-de-novo-acute-lymphoblastic-leukemia-treated-with-a-pediatric-protocol-type
#16
Manuel Antonio López-Hernández, Martha Alvarado-Ibarra, José Luis Álvarez-Veral, Maricela Ortiz-Zepeda, Martha Lilia Guajardo-Leal, Xochitl Cota-Range
INTRODUCTION: The prognosis, in the long term, of adolescents and young adults with acute de novo lymphoblastic leukemia, treated with a pediatric type protocol. OBJECTIVE: To analyze the efficacy and tolerability of a chemotherapy regimen of pediatric type on patients 15-35 years old with de novo acute lymphoblastic leukemia, Ph(-). METHODS: A retrospective study of patients received from 2001 to 2013, without initial infiltration of the central nervous system...
September 2016: Gaceta Médica de México
https://www.readbyqxmd.com/read/27786412/initial-testing-of-vs-4718-a-novel-inhibitor-of-focal-adhesion-kinase-fak-against-pediatric-tumor-models-by-the-pediatric-preclinical-testing-program
#17
Raushan T Kurmasheva, Richard Gorlick, E Anders Kolb, Stephen T Keir, John M Maris, Richard B Lock, Hernan Carol, Min Kang, C Patrick Reynolds, Jianrong Wu, Peter J Houghton, Malcolm A Smith
VS-4718, a novel inhibitor of focal adhesion kinase (FAK), was tested against the Pediatric Preclinical Testing Program's (PPTP's) in vitro cell line panel and showed a median relative IC50 of 1.22 μM. VS-4718 was tested in vivo against the PPTP xenograft models using a dose of 50 mg/kg administered by the oral route twice daily for 21 days. VS-4718 induced significant differences in an event-free survival distribution compared with control in 18 of 36 of the evaluable solid tumor xenografts and in 0 of 8 acute lymphoblastic leukemia (ALL) xenografts, but no xenograft lines showed tumor regression...
October 27, 2016: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/27784350/-establishment-and-identification-of-mouse-model-of-philadelphia-chromosome-positive-acute-lymphoblastic-leukemia
#18
Xue Wang, Na Qi, Sha Ma, Xu-Guang Song, Zhi-Ling Yan, Qing-Yun Wu, Lin Wang, Chong Chen, Kai-Lin Xu
OBJECTIVE: To establish a mouse model of Ph(+) acute lymphoblastic leukemia (ALL) for providing a valuable tool to facilitate the researches on Ph(+) ALL. METHODS: CML-like mice were generated by transfection to bone marrow cells of BABL/c with Mig190 retrovirus. The Ph(+) ALL mouse model was established by infusion of sorted CML like mouse-derived BCR-ABL(+) B cells into the mice of same linege. Immonophenotypes, BCR-ABL transcription and expression of these leukemic cells were detected by flow cytometry, RT-PCR and Western blot respectively...
October 2016: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/27781393/t-cell-rich-hla-haploidentical-hematopoietic-stem-cell-transplantation-for-relapsed-refractory-pediatric-philadelphia-chromosome-positive-acute-lymphoblastic-leukemia-without-posttransplant-tyrosine-kinase-inhibitor-therapy
#19
Hideki Sano, Kazuhiro Mochizuki, Mitsuko Akaihata, Shogo Kobayashi, Hitoshi Ohto, Atsushi Kikuta
Intensive chemotherapy with tyrosine kinase inhibitor (TKI) improves the prognosis of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-ALL). However, the prognosis of cases of relapsed or refractory Ph-ALL remains poor. Here, we aimed to assess the efficacy of T-cell-rich HLA-haploidentical hematopoietic stem cell transplantation (TCR-haplo-HSCT) in eight patients with relapsed or refractory pediatric Ph-ALL. Transplant-related mortality was observed in two patients. All patients discontinued TKI after receiving TCR-haplo-HSCT...
October 26, 2016: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/27777238/potent-efficacy-of-combined-pi3k-mtor-and-jak-or-abl-inhibition-in-murine-xenograft-models-of-ph-like-acute-lymphoblastic-leukemia
#20
Sarah K Tasian, David T Teachey, Yong Li, Feng Shen, Richard C Harvey, I-Ming Chen, Theresa Ryan, Tiffaney L Vincent, Cheryl L Willman, Alexander E Perl, Stephen P Hunger, Mignon L Loh, Martin Carroll, Stephan A Grupp
Philadelphia chromosome-like B-cell lymphoblastic leukemia (BCR-ABL1-like or Ph-like ALL) is associated with activated JAK/STAT, SRC/ABL, and/or PI3K/Akt/mTOR signaling and poor clinical outcomes. Inhibitors of PI3K pathway signaling (PI3Ki) have been minimally investigated in Ph-like ALL to date. We hypothesized that targeted inhibition of PI3Kα, PI3Kδ, PI3K/mTOR, or TORC1/TORC2 would decrease leukemia proliferation and abrogate aberrant kinase signaling. We further hypothesized that combined PI3K pathway and JAK inhibition or PI3K pathway and SRC/ABL inhibition would have superior efficacy compared to inhibitor monotherapy...
October 24, 2016: Blood
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