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Acute T Lymphoblastic Leukemia

Boaz Nachmias, Adir Shaulov, Moshe E Gatt, Michael Shapira, Alexander Gural
The treatment of relapsed/refractory acute lymphoblastic leukemia (RR-ALL) presents a true clinical challenge. In 2012, a protocol combining bortezomib, dexamethasone, asparaginase, doxorubicin, and vincristine administered to children with RR-ALL was published with encouraging results. Over the past 5 years, we have implemented this protocol in the adult RR-ALL population (> 18 years) and addressed its feasibility in terms of remission rate and toxicity. Here, we present the results of our experience in 9 patients, all of whom received multiple previous chemotherapy protocols, two of them relapsing after an allogeneic bone marrow transplantation...
October 19, 2018: Acta Haematologica
Benjamin Neveu, Maxime Caron, Karine Lagacé, Chantal Richer, Daniel Sinnett
Genetic alterations in the transcriptional repressor ETV6 are associated with hematological malignancies. Notably, the t(12;21) translocation leading to an ETV6-AML1 fusion gene is the most common genetic alteration found in childhood acute lymphoblastic leukemia. Moreover, most of these patients also lack ETV6 expression, suggesting a tumor suppressor function. To gain insights on ETV6 DNA-binding specificity and genome wide transcriptional regulation capacities, we performed chromatin immunoprecipitation experiments coupled to deep sequencing in a t(12;21)-positive pre-B leukemic cell line...
October 19, 2018: Scientific Reports
Jose L Lepe-Zuniga, Virginia Ramirez-Nova
Childhood Lymphoblastic leukemia's (ALL) early mortality (EM) is an undesirable treatment outcome for a disease for which >90% long term success is achievable. In the Western world EM constitutes no >3%; yet, in Chiapas, Mexico, remains around 15%. With the objective of improving on EM, we determined associated elements in 28 ALL who died within 60 days of arriving at Hospital de Especialidades Pediátricas in Chiapas (HEP), by comparing them to those in 84 controls who lived beyond the first 90 days...
October 18, 2018: Journal of Pediatric Hematology/oncology
Jing-Wen Zhang, Yun-Xin Zeng, Jia-Yin Liang, Ling Zhang, Xin-Bao Zhao, Jian-Hua Pan, Ruo-Zhi Xiao
BACKGROUND: We herein report a fatal case of fulminant septicemia caused by Bacillus cereus in a 49-year-old female with T-cell acute lymphoblastic leukemia receiving chemotherapy. METHODS: Her two blood culture sets were positive for Gram-positive, rod-shaped bacterium. Bacillus cereus was identified by high-throughput MALDI-TOF mass spectrometry and 16S ribosomal RNA gene sequencing. RESULTS: The patient died within 12 hours from the onset of B cereus infection...
October 1, 2018: Clinical Laboratory
T Jiang, J Chen, X Huang, Y Li, L Zhong
Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) is the most fatal leukemia due to the BCR/ABL fusion protein. This fusion protein could induce the interleukin 6 (IL-6) expression in leukemia stem cells (LSCs), which sustain the stemness by binding IL-6R and activating Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. IL-6R was one of the targets of miR-451a, which was downregulated in LSCs by BCR/ABL. We aimed to investigate the relationship between miR-451a, IL-6R, and BCR/ABL in Ph+ ALL and create a strategy to treat this disease...
September 4, 2018: Neoplasma
Ufuk Ateş, Nil Yaşam Taştekin, Fuad Mammadov, Ergun Ergün, Gülnur Göllü, Özlem Selvi Can, Tayfun Uçar, Meltem Bingöl-Koloğlu, Aydın Yağmurlu, Tanju Aktuğ
Ateş U, Taştekin NY, Mammadov F, Ergün E, Göllü G, Can ÖS, Uçar T, Bingöl-Koloğlu M, Yağmurlu A, Aktuğ T. Stuck tunneled central venous catheters in children: Four cases removed by angiography assistance. Turk J Pediatr 2018; 60: 221-224. Adherent tunneled catheters can usually be removed by a surgical cut down, but in some cases the line can become stuck to the wall of the central veins. In such cases, forceful traction can cause vascular injury, or fracture of the catheter. We present four cases of fixated cuffed tunneled catheters...
2018: Turkish Journal of Pediatrics
Lindsey Hathaway, Jeremy Michael Sen, Michael Keng
Relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) is associated with a poor prognosis in both children and adults. Traditionally, there were limited options for salvage therapy, which consisted mostly of conventional chemotherapy. However, in the past 5 years, novel agents have changed our treatment strategies in this population. Blinatumomab, a bispecific CD19 directed CD3 T-cell engager, has shown to be effective in both minimal residual disease and R/R B-cell ALL. In R/R B-cell ALL, blinatumomab was associated with an improved median overall survival of 7...
2018: Patient related Outcome Measures
Wei Zhang, Kimberly R Jordan, Brian Schulte, Enkhtsetseg Purev
Background: Chimeric antigen receptor (CAR) T-cell therapy is highly effective for treating acute lymphoblastic leukemia and non-Hodgkin's lymphoma with high rate complete responses. However, the broad clinical application of CAR T-cell therapy has been challenging, largely due to the lack of widespread ability to produce and high cost of CAR T-cell products using traditional methods of production. Automated cell processing in a closed system has emerged as a potential method to increase the feasibility of producing CAR T cells locally at academic centers due to its minimal reliance on experienced labor, thereby making the process less expensive and more consistent than traditional methods of production...
2018: Drug Design, Development and Therapy
Hexiu Su, Juncheng Hu, Liang Huang, Yang Yang, Morgan Thenoz, Anna Kuchmiy, Yufeng Hu, Peng Li, Hui Feng, Yu Zhou, Tom Taghon, Pieter Van Vlierberghe, Guoliang Qing, Zhichao Chen, Hudan Liu
T-acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with complicated heterogeneity. Although expression profiling reveals common elevated genes in distinct T-ALL subtypes, little is known about their functional role(s) and regulatory mechanism(s). We here show that SHQ1, an H/ACA snoRNP assembly factor involved in snRNA pseudouridylation, is highly expressed in T-ALL. Mechanistically, oncogenic NOTCH1 directly binds to the SHQ1 promoter and activates its transcription. SHQ1 depletion induces T-ALL cell death in vitro and prolongs animal survival in murine T-ALL models...
October 15, 2018: Nature Communications
Xia Xiao, Xiaoyuan He, Qing Li, Huan Zhang, Juanxia Meng, Yanyu Jiang, Qi Deng, Mingfeng Zhao
BACKGROUND: Tumor immunotherapy with chimeric antigen receptor T cells (CAR-T) is a promising new treatment for B-cell malignancies and has produced exciting results. However, cytokine release syndrome (CRS) is the most significant toxicity associated with this treatment and can be life-threatening. CASE PRESENTATION: A 23-year-old male patient had been diagnosed with relapsed and refractory B-cell acute lymphocytic leukemia. The patient was recruited into our CAR-T clinical trial, and 1×106 /kg of engineered anti-CD19 CAR-T cells was administered...
October 15, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Zhu Xiufeng, Zhao Haijun, Bi Silei, Deng Manman, Zhou Yong, Yu Lian, Fang Zhihong, Xu Bing
T-cell acute lymphoblastic leukemia (T-ALL) is a high-risk subtype of acute lymphoblastic leukemia with limited therapeutic options available. Here, we evaluated the therapeutic potential of the combination of the Bcl-2 antagonist ABT-199 and cytotoxic agent gemcitabine in T-ALL cell lines. Our results showed that the combination of ABT-199 and gemcitabine exhibited synergistic cytotoxicity and induced significant apoptosis in human T-ALL cell lines (Jurkat and Molt4). The augmented apoptosis induced by combination treatment was accompanied by the greater extent of mitochondrial depolarization and enhanced DNA damage...
October 12, 2018: Anti-cancer Drugs
Dongmei Wang, Rui Shi, Qinglong Wang, Jianqiang Li
Philadelphia chromosome-positive (Ph-positive) acute leukemia (ALL) accounts for around one quarter of adult cases of ALL and is usually associated with poor prognosis. The patients still encounter a high rate of relapse even after they receive hematopoietic stem cell transplantation (HSCT). HSCT is considered the established therapy and best option for many malignant ALL cases, however, disease relapse remains the main reason of failure. In recent years, chimeric antigen receptor (CAR) T-cell therapy has become a promising treatment for patients with advanced blood cancers...
2018: OncoTargets and Therapy
Areesha Alam, Archana Kumar
BACKGROUND: Treatment refusal or abandonment are among the major causes of the survival gap between developed and developing countries. METHODS: This retrospective observational study analyzed records of children aged <18 years with acute lymphoblastic leukemia (ALL) registered for treatment at a tertiary-care teaching hospital, North India, between 1995 and 2012. Children who refused or abandoned therapy were tracked, and reasons for refusal/abandonment were recorded by telephone interviews or by surface mail...
October 10, 2018: Cancer Epidemiology
Ping Wang, Xian'gui Peng, Xiaojuan Deng, Li Gao, Xi Zhang, Yimei Feng
RATIONALE: The diagnosis of hematological malignancies depends on laboratory analysis and often requires multiple experimental methods to judge, otherwise misdiagnosis is apt to happen. Lymph node biopsy immunohistochemistry (IHC) for T-lymphoblastic lymphoma (T-LBL) requires the establishment of antibody set screening. For identifying T-LBL and early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) by lymph node biopsy and IHC, WHO has not yet proposed a better IHC antibody combination...
October 2018: Medicine (Baltimore)
Yaping Wang, Xiaoyun Yang, Xiaoyan Sun, Liucheng Rong, Meiyun Kang, Peng Wu, Xiaohui Ji, Rufeng Lin, Jie Huang, Yao Xue, Yongjun Fang
Immune escape due to immunosuppressive microenvironments, such as those associated with regulatory T (Treg) cells is highly associated with initial occurrence and development of solid tumors or hematologic malignancies. Here, we employed high-throughput transcriptome screening to demonstrate immunosuppression-associated increases in the long noncoding (lnc) RNA lnc-insulin receptor precursor (INSR), which was corrected with INSR expression in CD4+ T cells extracted from the bone marrow of patients with childhood acute T lymphoblastic leukemia...
October 11, 2018: Cell Death & Disease
Maura C O'Leary, Xiaobin Lu, Ying Huang, Xue Lin, Iftekhar Mahmood, Donna Przepiorka, Denise Gavin, Shiowjen Lee, Ke Liu, Bindu George, Wilson Bryan, Marc R Theoret, Richard Pazdur
Tisagenlecleucel (Kymriah, Novartis Pharmaceuticals, East Hanover, NJ) is a CD19-directed genetically-modified autologous T-cell immunotherapy. On August 30, 2017, the U.S. Food and Drug Administration approved tisagenlecleucel for treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. Approval was based on the complete remission (CR) rate, durability of CR and minimal residual disease (MRD) < 0.01% in a cohort of 63 children and young adults with relapsed or refractory ALL treated on a single-arm trial (CCTL019B2202)...
October 11, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Norimitsu Kadowaki
Bispecific antibodies comprise two antigen-binding sites that recognize different antigens or epitopes. Blinatumomab, a bispecific T-cell engager (BiTE) that lacks the Fc portion, recognizes CD19 on B tumor cells and CD3 on T cells and induces the T cell-mediated killing of the B tumor cells. The Food and Drug Administration has approved the use of blinatumomab for the treatment of precursor B-cell acute lymphoblastic leukemia (ALL) with minimal residual disease and relapsed/refractory ALL. Various bispecific antibodies have been developed, including BiTEs that target surface molecules on myeloma cells or intracellular antigens presented on the major histocompatibility complex and Fc portion-containing bispecific antibodies that have a potent T cell-activating capacity and a long half-life...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Valeria Tosello, Gloria Milani, Annalisa Martines, Nadia Macri, Wouder Van Loocke, Filip Matthijssens, Barbara Buldini, Sonia Minuzzo, Deborah Bongiovanni, Richard Fabian Schumacher, Alberto Amadori, Pieter Van Vlierberghe, Erich Piovan
MYC -translocated T-lineage acute lymphoblastic leukemia (T-ALL) is a rare subgroup of T-ALL associated with CDKN2A/B deletions, PTEN inactivation, and absence of NOTCH1 or FBXW7 mutations. This subtype of T-ALL has been associated with induction failure and aggressive disease. Identification of drug targets and mechanistic insights for this disease are still limited. Here, we established a human NOTCH1-independent MYC -translocated T-ALL cell line that maintains the genetic and phenotypic characteristics of the parental leukemic clone at diagnosis...
October 9, 2018: Cells
Melanie D Whittington, R Brett McQueen, Daniel A Ollendorf, Varun M Kumar, Richard H Chapman, Jeffrey A Tice, Steven D Pearson, Jonathan D Campbell
Importance: Among children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia, the rate of 5-year disease-free survival is 10% to 20%. Approval of tisagenlecleucel, a chimeric antigen receptor T-cell therapy, represents a new and potentially curative treatment option. However, tisagenlecleucel is expensive, with a current list price of $475 000 per one-time administration. Objective: To estimate the long-term survival and value of tisagenlecleucel for children and young adults with B-cell acute lymphoblastic leukemia...
October 8, 2018: JAMA Pediatrics
Kathrin Rothfelder, Ilona Hagelstein, Malte Roerden, Gunnar Blumenstock, Martin Hofmann, Tina Nuebling, Gundram Jung, Helmut Rainer Salih, Daniela Dörfel
OX40 and its ligand are members of the TNF/TNF receptor superfamily, which includes various molecules influencing cellular signaling and function of both tumor and immune cells. The ability of OX40 to promote proliferation and differentiation of activated T cells fueled present attempts to modulate this immune checkpoint to reinforce antitumor immunity. While we recently found evidence for the involvement of OX40 in pathophysiology of acute myeloid leukemia including natural killer (NK) cell immunosurveillance, less is known on its role in acute lymphoblastic leukemia (ALL)...
October 6, 2018: Neoplasia: An International Journal for Oncology Research
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