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Relapsed acute lymphoblastic leukemia

Charlotte V Cox, Paraskevi Diamanti, John P Moppett, Allison Blair
A significant number of children with T-lineage acute lymphoblastic leukemia (T-ALL) fail to respond to therapy and experience early relapse. CD99 has been shown to be overexpressed on T-ALL cells and is considered to be a reliable detector of the disease. However, the relevance of CD99 overexpression in ALL has not been investigated in a functional context. The aim of this study was to investigate the functional capacity of CD99+ cells in childhood ALL and determine the suitability of CD99 as a therapeutic target...
2016: PloS One
Amita Trehan, Deepak Bansal, Neelam Varma, Ajay Vora
BACKGROUND: The outcome of malignancies in low- and middle-income countries (LMICs) is hampered owing to numerous factors. Current protocols are complex, demanding supportive care, often not optimally available. We de-escalated the UKALL 2003 protocol to improve the outcome of acute lymphoblastic leukemia (ALL) at our center. METHODS: In 2007-2009, children were treated as per the UKALL 2003 protocol (protocol 1). In 2010 and 2011, a modified version of the UKALL 2003 (protocol 2) was followed...
October 20, 2016: Pediatric Blood & Cancer
Jolanta Skalska-Sadowska, Małgorzata Dawidowska, Bronisława Szarzyńska-Zawadzka, Małgorzata Jarmuż-Szymczak, Joanna Czerwińska-Rybak, Ludomiła Machowska, Katarzyna Derwich
We report a pediatric case of acute T-lymphoblastic leukemia (T-ALL) with NOTCH1(wt) , FBXW7(wt) , STIL/TAL1, and PTEN (exons 2, 3, 4, 5) monoallelic deletions, biallelic CDKN2A/B deletion, and a minor t(8;14)(q24;q11)-positive subclone. Undetectable by a flow cytometric minimal residual disease assay, the t(8;14)(q24;q11) subclone expanded as detected by fluorescence in situ hybridization from 5% at diagnosis to 26% before consolidation and 100% at relapse bearing a monoallelic deletion (exons 2, 3) with a new frameshift mutation of PTEN and the same set of remaining molecular alterations...
October 19, 2016: Pediatric Blood & Cancer
Jinghua Wu, Shan Jia, Changxi Wang, Wei Zhang, Sixi Liu, Xiaojing Zeng, Huirong Mai, Xiuli Yuan, Yuanping Du, Xiaodong Wang, Xueyu Hong, Xuemei Li, Feiqiu Wen, Xun Xu, Jianhua Pan, Changgang Li, Xiao Liu
Acute B lymphoblastic leukemia (B-ALL) is one of the most common types of childhood cancer worldwide and chemotherapy is the main treatment approach. Despite good response rates to chemotherapy regiments, many patients eventually relapse and minimal residual disease (MRD) is the leading risk factor for relapse. The evolution of leukemic clones during disease development and treatment may have clinical significance. In this study, we performed immunoglobulin heavy chain (IGH) repertoire high throughput sequencing (HTS) on the diagnostic and post-treatment samples of 51 pediatric B-ALL patients...
2016: Frontiers in Immunology
Aleš Hnízda, Jana Škerlová, Milan Fábry, Petr Pachl, Martina Šinalová, Lukáš Vrzal, Petr Man, Petr Novák, Pavlína Řezáčová, Václav Veverka
BACKGROUND: Relapsed acute lymphoblastic leukemia (ALL) is one of the main causes of mortality in childhood malignancies. Previous genetic studies demonstrated that chemoresistant ALL is driven by activating mutations in NT5C2, the gene encoding cytosolic 5´-nucleotidase (cN-II). However, molecular mechanisms underlying this hyperactivation are still unknown. Here, we present kinetic and structural properties of cN-II variants that represent 75 % of mutated alleles in patients who experience relapsed ALL (R367Q, R238W and L375F)...
October 19, 2016: BMC Biology
Marcin Braun, Agata Pastorczak, Wojciech Fendler, Joanna Madzio, Bartlomiej Tomasik, Joanna Taha, Marta Bielska, Lukasz Sedek, Tomasz Szczepanski, Michal Matysiak, Katarzyna Derwich, Monika Lejman, Jerzy Kowalczyk, Bernarda Kazanowska, Wanda Badowska, Jan Styczynski, Nina Irga-Jaworska, Joanna Trelinska, Beata Zalewska-Szewczyk, Filip Pierlejewski, Iwona Wlodarska, Wojciech Młynarski
The inactivation of tumor suppressor genes located within 9p21 locus (CDKN2A, CDKN2B) occurs in up to 30% of children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL), but its independent prognostic significance remains controversial. In order to investigate the prognostic impact of deletions and promoter methylation within 9p21, 641 children with newly diagnosed BCP-ALL using methylation specific multiplex ligation-dependent probe amplification (MS-MLPA) were investigated. A total of 169 (26.4%) microdeletions in 9p21 were detected, of which 71 were homozygous...
October 18, 2016: Leukemia & Lymphoma
Yu Mi Seo, Seok Hwang-Bo, Seong Koo Kim, Seung Beom Han, Nack-Gyun Chung, Jin Han Kang
BACKGROUND: Although adenovirus (ADV) infection usually causes self-limiting respiratory disorders in immune competent children; severe and systemic ADV infection in children undergoing chemotherapy for leukemia has been continuously reported. Nevertheless, there has been no consensus on risk factors and treatment strategies for severe ADV infection in children undergoing chemotherapy. CASE SUMMARY: We report a case of a 15-year-old boy with a fatal systemic ADV infection...
October 2016: Medicine (Baltimore)
Mervi Taskinen, Trausti Oskarsson, Mette Levinsen, Matteo Bottai, Marit Hellebostad, Olafur Gisli Jonsson, Päivi Lähteenmäki, Kjeld Schmiegelow, Mats Heyman
BACKGROUND: Central nervous system irradiation (CNS-RT) has played a central role in the cure of acute lymphoblastic leukemia (ALL), but due to the risk of long-term toxicity, it is now considered a less-favorable method of CNS-directed therapy. PROCEDURES: Retrospectively, we estimated the effect of CNS involvement and CNS-RT on events and overall survival (OS) in 835 children treated for high-risk ALL in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL-92 and ALL-2000 trials...
October 17, 2016: Pediatric Blood & Cancer
Noelle V Frey, David L Porter
Chimeric antigen receptors (CARs) are engineered molecules that can be introduced into T cells to enable them to target specific tumor antigens. CAR T cells targeting CD19 have shown promise in patients with relapsed and refractory B-cell neoplasms, including those with acute lymphoblastic leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphomas. Notably, durable responses have been observed in patients who had not undergone consolidative stem cell transplant, a finding that correlates with reports of T-cell persistence and B-cell aplasia in studies of anti-CD19 treatment in vivo...
October 15, 2016: Oncology (Williston Park, NY)
Eva Rettinger, Michael Merker, Emilia Salzmann-Manrique, Hermann Kreyenberg, Thomas Krenn, Matthias Dürken, Jörg Faber, Sabine Huenecke, Claudia Cappel, Melanie Bremm, Andre Willasch, Shahrzad Bakhtiar, Andrea Jarisch, Jan Soerensen, Thomas Klingebiel, Peter Bader
Monitoring of minimal residual disease (MRD) or chimerism may help guide pre-emptive immunotherapy (IT) with a view to preventing relapse in childhood acute lymphoblastic leukemia (ALL) post-transplant. ALL-patients consecutively transplanted in Frankfurt/Main, Germany between January 1(st), 2005, and July 1(st), 2014, were included in this retrospective study. Chimerism monitoring was performed in all, MRD assessment in 58 of 89 patients. IT was guided in 19 of 24 patients with mixed chimerism (MC) and MRD and by MRD only in another 4 patients with complete chimerism (CC)...
October 11, 2016: Biology of Blood and Marrow Transplantation
Deena Samir Eissa, Eman Zaghloul Kandeel, Mohamed Ghareeb
The prognosis of acute myeloid leukemia (AML) is poor because of relapses occurring on conventional chemotherapy. The distinction between leukemic and normal stem cells relies on the expression of antigen combinations defining leukemia-associated immunophenotypes (LAIPs), which are absent or extremely infrequent in normal bone marrow. However, LAIPs are very different from patient to patient and are not necessarily stable over the course of the disease. Accordingly, we addressed the applicability of human myeloid inhibitory C-lectin (hMICL) by flow cytometry as a specific leukemic myeloid stem cell marker for the diagnosis of AML in CD34(+) and CD34(-) cases and evaluated the stability of hMICL during the course of the disease...
October 13, 2016: Hematological Oncology
Leylagul Kaynar, Koray Demir, Esra Ermiş Turak, Çiğdem Pala Öztürk, Gökmen Zararsız, Zeynep Burçin Gönen, Selma Gökahmetoğlu, Serdar Şıvgın, Bülent Eser, Yavuz Köker, Musa Solmaz, Ali Ünal, Mustafa Çetin
INTRODUCTION: The use of αβ+ T-cell-depleted grafts is a novel approach to prevent graft failure, graft-versus-host disease (GVHD), and non-relapse mortality (NRM) in patients undergoing haploidentical hematopoietic stem cell transplantation. PATIENT AND METHOD: Thirty-four patients with acute leukemia and lacking a match donor were treated with αβ T-cell-depleted allografts from haploidentical family donors. A total of 24 patients had acute myeloid leukemia (AML) and 10 had acute lymphoblastic leukemia...
October 10, 2016: Hematology (Amsterdam, Netherlands)
Ashley Rosko, Hai-Lin Wang, Marcos de Lima, Brenda Sandmaier, H Jean Khoury, Andrew Artz, Johnathan Brammer, Christopher Bredeson, Sherif Farag, Mohamed Kharfan-Dabaja, Hillard M Lazarus, David I Marks, Rodrigo Martino Bufarull, Joseph McGuirk, Mohamed Mohty, Taiga Nishihori, Ian Nivison-Smith, Armin Rashidi, Olle Ringden, Matthew Seftel, Daniel Weisdorf, Veronika Bachanova, Wael Saber
: Older adults with B-cell acute lymphoblastic leukemia (B-ALL) have poor survival. We examined the effectiveness of reduced intensity conditioning (RIC) hematopoietic cell transplant (HCT) in adults with B-ALL age 55 years and older and explored prognostic factors associated with long-term outcomes. METHODS: Using CIBMTR registry data, we evaluated 273 patients (median age 61, range 55-72) with B-ALL with disease status in CR1 (71%), >CR2 (17%) and Primary Induction Failure (PIF)/Relapse (11%), who underwent RIC HCT between 2001-2012 using mostly unrelated donor (59%) or HLA-matched sibling (32%)...
October 6, 2016: American Journal of Hematology
Judith Feucht, Simone Kayser, David Gorodezki, Mohamad Hamieh, Michaela Döring, Franziska Blaeschke, Patrick Schlegel, Hans Bösmüller, Leticia Quintanilla-Fend, Martin Ebinger, Peter Lang, Rupert Handgretinger, Tobias Feuchtinger
T-cell immunotherapies are promising options in relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL). We investigated the effect of co-signaling molecules on T-cell attack against leukemia mediated by CD19/CD3-bispecific T-cell engager. Primary CD19+ ALL blasts (n≥10) and physiologic CD19+CD10+ bone marrow precursors were screened for 20 co-signaling molecules. PD-L1, PD-1, LAG-3, CD40, CD86, CD27, CD70 and HVEM revealed different stimulatory and inhibitory profiles of pediatric ALL compared to physiologic cells, with PD-L1 and CD86 as most prominent inhibitory and stimulatory markers...
September 30, 2016: Oncotarget
Lisa M Greene, Seema M Nathwani, Daniela M Zisterer
T-cell acute lymphoblastic leukemia (T-ALL) is a rare and aggressive hematopoietic malignancy prone to relapse and drug resistance. Half of all T-ALL patients exhibit mutations in Notch1, which leads to aberrant Notch1 associated signaling cascades. Notch1 activation is mediated by the γ-secretase cleavage of the Notch1 receptor into the active intracellular domain of Notch1 (NCID). Clinical trials of γ-secretase small molecule inhibitors (GSIs) as single agents for the treatment of T-ALL have been unsuccessful...
October 2016: Oncology Letters
M Kato, S Ishimaru, M Seki, K Yoshida, Y Shiraishi, K Chiba, N Kakiuchi, Y Sato, H Ueno, H Tanaka, T Inukai, D Tomizawa, D Hasegawa, T Osumi, Y Arakawa, T Aoki, M Okuya, K Kaizu, K Kato, Y Taneyama, H Goto, T Taki, M Takagi, M Sanada, K Koh, J Takita, S Miyano, S Ogawa, A Ohara, M Tsuchida, A Manabe
In the treatment of childhood acute lymphoblastic leukemia (ALL), excess shortening of maintenance therapy resulted in high relapse rate, as shown by our previous trial, TCCSG L92-13, in which maintenance therapy was terminated at one year from initiation of treatment. In this study, we aimed to confirm the long-term outcome of L92-13, and to identify who can or cannot be cured by shorter duration of maintenance therapy. To obtain sentinel cytogenetics information which had been missed before, we performed genetic analysis with genomic microarray and target intron-capture sequencing from diagnostic bone marrow smear...
October 4, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Meng-Ju Li, Hsi-Che Liu, Hsiu-Ju Yen, Tang-Her Jaing, Dong-Tsamn Lin, Chao-Ping Yang, Kai-Hsin Lin, Iou-Jih Hung, Shiann-Tarng Jou, Meng-Yao Lu, Chih-Cheng Hsiao, Ching-Tien Peng, Tai-Tsung Chang, Shih-Chung Wang, Ming-Tsan Lin, Jiann-Shiuh Chen, Te-Kau Chang, Giun-Yi Hung, Kang-Hsi Wu, Yung-Li Yang, Hsiu-Hao Chang, Shih-Hsiang Chen, Ting-Chi Yeh, Chao-Neng Cheng, Pei-Chin Lin, Shyh-Shin Chiou, Jiunn-Ming Sheen, Shin-Nan Cheng, Shu-Huey Chen, Yu-Hsiang Chang, Wan-Ling Ho, Yu-Hua Chao, Rong-Long Chen, Bow-Wen Chen, Jinn-Li Wang, Yuh-Lin Hsieh, Yu-Mei Liao, Shang-Hsien Yang, Wan-Hui Chang, Yu-Mei Y Chao, Der-Cherng Liang
BACKGROUND: Reinduction therapy has improved the outcomes in children with acute lymphoblastic leukemia (ALL). We sought to determine the optimal course(s) of reinduction therapy for standard-risk (SR, or "low-risk" in other groups) patients. Also, we evaluated outcomes using triple intrathecal therapy without cranial radiation (CrRT) for central nervous system (CNS) preventive therapy. PROCEDURE: From 2002 to 2012, all newly diagnosed children with ALL in Taiwan were enrolled in Taiwan Pediatric Oncology Group ALL-2002 protocol...
October 3, 2016: Pediatric Blood & Cancer
Ghayas C Issa, Hagop M Kantarjian, C Cameron Yin, Wei Qiao, Farhad Ravandi, Deborah Thomas, Nicholas J Short, Koji Sasaki, Guillermo Garcia-Manero, Tapan M Kadia, Jorge E Cortes, Naval Daver, Gautam Borthakur, Nitin Jain, Marina Konopleva, Issa Khouri, Partow Kebriaei, Richard E Champlin, Sherry Pierce, Susan M O'Brien, Elias Jabbour
BACKGROUND: The introduction of novel prognostic factors such as minimal residual disease (MRD) and genomic profiling has led to the reevaluation of the role of cytogenetics and other conventional factors in risk stratification for acute lymphoblastic leukemia (ALL). METHODS: This study assessed the impact of baseline cytogenetics on the outcomes of 428 adult patients with Philadelphia chromosome-negative ALL who were receiving frontline chemotherapy. Three hundred thirty patients (77%) were treated with hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone-based regimens, and 98 (23%) were treated with the augmented Berlin-Frankfurt-Munster regimen...
October 3, 2016: Cancer
Nikolaos Papadantonakis, Anjali S Advani
This is an exciting time in the treatment of acute lymphoblastic leukemia (ALL) given the advances in the relapsed/refractory setting. The development of antibody treatments (including antibody drug conjugates with toxins) offers a different treatment approach compared with conventional chemotherapy regimens. Moreover, the use of bispecific T-cell-engager antibodies (BiTEs) such as blinatumomab harness the cytotoxic activity of T cells against CD19-positive lymphoblasts. Another strategy involves the use of chimeric antigen receptor (CAR) T cells...
October 2016: Therapeutic Advances in Hematology
Sebastian Giebel, Myriam Labopin, Gerard Socie', Dietrich Beelen, Paul Browne, Liisa Volin, Slawomira Kyrcz-Krzemien, Ibrahim Yakoub-Agha, Mahmoud Aljurf, Depei Wu, Mauricette Michallet, Renate Arnold, Mohamad Mohty, Arnon Nagler
Allogeneic hematopoietic cell transplantation is widely used to treat adults with high risk acute lymphoblastic leukemia. The aim of this study was to analyze whether the results changed over time and to identify prognostic factors. Adult patients treated between year 1993 and 2012 with myeloablative allogeneic hematopoietic cell transplantation from HLA matched sibling (n=2681) or unrelated donors (n=2178) in first complete remission were included. For transplantations from sibling donors performed between 2008-2012, the following two-year probabilities of the overall survival were obtained: 76% (18-25 years old group), 69% (26-35 and 36-45 years old groups) and 60% (46-55 years old group)...
September 29, 2016: Haematologica
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