2,015 results on '"Myeloid leukaemia"'
Search Results
252. A prophylactic and a therapeutic against AML
- Author
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Zhen Gu and Guojun Chen
- Subjects
0301 basic medicine ,Myeloid ,Injectable biomaterial ,medicine.medical_treatment ,Biomedical Engineering ,Medicine (miscellaneous) ,Bioengineering ,Biocompatible Materials ,Disease ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,hemic and lymphatic diseases ,medicine ,Humans ,business.industry ,medicine.disease ,Biocompatible material ,Computer Science Applications ,Leukemia ,Leukemia, Myeloid, Acute ,030104 developmental biology ,medicine.anatomical_structure ,Cancer research ,Myeloid leukaemia ,business ,Adjuvant ,030217 neurology & neurosurgery ,Biotechnology - Abstract
An injectable biomaterial vaccine encapsulating antigens associated with acute myeloid leukaemia, dendritic-cell-targeting pro-inflammatory cytokines and an adjuvant protects mice from the disease.
- Published
- 2020
253. Expression and Clinical Significance of Large Tumour Suppressor Kinase 2 (LATS2) Gene in Acute Myeloid Leukaemia: An Egyptian Study
- Author
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Doaa Sayed Saleh Sayed, Rehab Muhammad Abdelkareem, Shereen Mohamed El-Hoseiny, Thoraya Aly, Raafat Mohamed Abd El Fattah, Rasha Abd El Razek Khattab, and Heba Hamdy El Demellawy
- Subjects
Large tumour ,Kinase ,Clinical Biochemistry ,lcsh:R ,biomarkers ,lcsh:Medicine ,General Medicine ,Biology ,law.invention ,reverse transcriptase polymerase chain reaction ,LATS2 Gene ,law ,Cancer research ,Suppressor ,Clinical significance ,tumour suppressor proteins ,Myeloid leukaemia ,myeloid - Abstract
Introduction: Large Tumour Suppressor (LATS) family proteins were discovered for the first time in Drosophila in 1995. Since that date, LATS proteins have been considered tumour suppressors. The family includes two members, LATS1 and LATS2, which have a chief function in the control of tumour growth and cell cycles through several mechanisms and signalling pathways, including those of p53, Hippo, and Wnt. LATS2 gene was involved in many types of haematological malignancies as it plays a role in the leukaemogenesis of AML and also in the clinical outcome of the disease. Aim: The current study was an attempt to clarify the relation of LATS2 gene expression and clinical manifestations of Acute Myeloid Leukaemia (AML). Materials and Methods: The present case-control study included 60 adult denovo AML patients and 60 age and sex matched healthy controls for analysis of LATS2 mRNA gene expression level by Real Time-Quantitative Polymerase Chain Reaction (RT-QPCR) technique. Data were analysed using IBM SPSS advanced statistics version 22.0 (SPSS Inc., Chicago, IL). Results: The expression level of LATS2 gene was significantly higher in AML patients compared to controls (p
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- 2020
254. Performance of prognostic scoring systems in elderly patients with acute myeloid leukaemia on intensive chemotherapy: A PETHEMA registry study
- Author
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A. I. Espadana, Isabel Cano, Eliana Aguilar, Belén Vidriales-Vicente, Mar Tormo, Mercedes Colorado-Araujo, David Martínez-Cuadrón, Jorge Labrador Gómez, Pau Montesinos Fernandez, Celina Benavente, José A. Pérez-Simón, Raimundo García-Boyero, Cristina Gil, María Teresa López, María del Pilar Martínez-Sánchez, Jose Luis López-Lorenzo, Teresa Bernal del Castillo, Juan M. Bergua-Burgues, Rosa Fernández, MªJose Sayas-Lloris, Ma Luz Amigo, Esperanza Lavilla-Rubira, Pilar Herrera-Puente, Claudia Lucia Sossa-Melo, Josefina Serrano-López, María García-Fortes, Carlos Rodríguez-Medina, and Gabriela Rodríguez
- Subjects
Cancer Research ,medicine.medical_specialty ,Registry study ,Intensive chemotherapy ,03 medical and health sciences ,0302 clinical medicine ,Elderly ,Internal medicine ,medicine ,Overall survival ,Acute myeloid leukemia ,business.industry ,Cancer ,Hematology ,medicine.disease ,Prognosis ,Confidence interval ,Oncology ,030220 oncology & carcinogenesis ,Cohort ,Myeloid leukaemia ,business ,Acute myeloblastic leukaemia ,030215 immunology - Abstract
Selection of elderly patients (aged =60 years) for intensive chemotherapy treatment of acute myeloblastic leukaemia (AML) remains challenging. Several cooperative groups such as Acute Leukaemia French Association (ALFA), Haematological Oncology Clinical Studies Group (HOCSG) and MD Anderson Cancer Center (MDACC) have developed predictive models to select those patients who can benefit from intensive chemotherapy. Our purpose is to validate and compare these three models in a cohort of patients treated in real-life setting. For this, a total of 1724 elderly AML patients and treated with intensive chemotherapy regimens were identified in the PETHEMA registry. Median age was 67.2 years (range, 60-84,9) and median overall survival [OS] 9 months (95 % confidence interval [CI], 8.2-9.7). Taking into account the ALFA group's model, patients likely to benefit from intensive chemotherapy had longer OS (14 months, 95 % CI 12.3-15.7) than those unlikely to benefit (5 months, 95 % CI 4.1-5.9; p
- Published
- 2020
255. Laboratory quality assessment of candidate gene panel testing for acute myeloid leukaemia: a joint ALLG / RCPAQAP initiative
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Purvi M. Kakadia, Anoop K Enjeti, William Stevenson, Harry J. Iland, Alison Louw, Anna L. Brown, Hamish S. Scott, Piers Blombery, Adam Ivey, Cheryl L. Paul, Martin Horan, Rishu Agarwal, Chun Fong, Jad Othman, Carolyn S. Grove, Stefan K. Bohlander, Linda Lee, Greg Corboy, Andrew H. Wei, Corboy, Greg, Othman, Jad, Lee, Linda, Wei, Andrew, Ivey, Adam, Blombery, Piers, Agarwal, Rishu, Fong, Chun, Brown, Anna, Scott, Hamish, Grove, Carolyn, Louw, Alison, Enjeti, Anoop, Iland, Harry, Paul, Cheryl, Bohlander, Stefan, Kakadia, Purvi, Horan, Martin, and Stevenson, William
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0301 basic medicine ,medicine.medical_specialty ,Candidate gene ,Quality Assurance, Health Care ,Concordance ,Pathology and Forensic Medicine ,Australia and New Zealand ,03 medical and health sciences ,0302 clinical medicine ,Bone marrow aspirate ,Bone Marrow ,Humans ,Medicine ,Genetic Testing ,Intensive care medicine ,Massive parallel sequencing ,Australasia ,Virulence ,business.industry ,Quality assessment ,blood cancer ,High-Throughput Nucleotide Sequencing ,Genomics ,Hematology ,Sequence Analysis, DNA ,Leukemia, Myeloid, Acute ,Dry lab ,030104 developmental biology ,massively parallel sequencing (MPS) ,030220 oncology & carcinogenesis ,Mutation ,acute myeloid leukaemia (AML) ,Myeloid leukaemia ,Laboratories ,business ,Quality assurance - Abstract
Accurate classification of acute myeloid leukaemia (AML) has become increasingly reliant on molecular characterisation of this blood cancer. Throughout Australia and New Zealand massively parallel sequencing (MPS) is being adopted by diagnostic laboratories for the routine evaluation of patients with AML. This technology enables the surveying of many genes simultaneously, with many technical advantages over single gene testing approaches. However, there are many variations in wet and dry lab MPS procedures, which raises the prospect of discordant results between laboratories. This study compared the results obtained from MPS testing of ten diagnostic AML bone marrow aspirate samples sent to eight participating laboratories across Australasia. A reassuringly high concordance of 94% was observed with regard to variant detection and characterisation of pathogenicity. The level of discordance observed, although low, demonstrates the need for ongoing assessment of concordance between diagnostic testing laboratories through quality assurance programs. Refereed/Peer-reviewed
- Published
- 2020
256. PU.1 subcellular localization in acute myeloid leukaemia with mutated NPM1
- Author
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Riccardo Rossi, Camilla Betti, Lorenzo Brunetti, Giulia Pianigiani, and Barbara Bigerna
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NPM1 ,Myeloid ,business.industry ,Hematology ,medicine.disease ,Subcellular localization ,Leukemia ,medicine.anatomical_structure ,Text mining ,Mutation (genetic algorithm) ,medicine ,Cancer research ,Myeloid leukaemia ,business - Published
- 2020
257. Outcome of children relapsing after first allogeneic haematopoietic stem cell transplantation for acute myeloid leukaemia : a retrospective I-BFM analysis of 333 children
- Author
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Arjan C. Lankester, Alice Bertaina, Andrew S. Moore, Birgitta Versluys, Jacek Wachowiak, Theodor Uden, Ian Nivison-Smith, Marc Ansari, Franco Locatelli, Kirsten Mischke, Martin Zimmermann, Henrik Hasle, Corinne Gerhardt, Jerry Stein, Leen Willems, Marc Bierings, Christina Peters, Martin Sauer, Jonas Abrahamsson, Dirk Reinhardt, Petr Sedlacek, Anna Pieczonka, Jean-Pierre Bourquin, Adriana Balduzzi, University of Zurich, Sauer, Martin G, Uden, T, Bertaina, A, Abrahamsson, J, Ansari, M, Balduzzi, A, Bourquin, J, Gerhardt, C, Bierings, M, Hasle, H, Lankester, A, Mischke, K, Moore, A, Nivison-Smith, I, Pieczonka, A, Peters, C, Sedlacek, P, Reinhardt, D, Stein, J, Versluys, B, Wachowiak, J, Willems, L, Zimmermann, M, Locatelli, F, and Sauer, M
- Subjects
Male ,Oncology ,Transplantation Conditioning ,2720 Hematology ,Medizin ,Disease ,Transplantation Conditioning / methods ,0302 clinical medicine ,Transplantation, Homologous / methods ,Relapse ,Child ,Children ,Leukemia, Myeloid, Acute / mortality ,relapse ,ddc:618 ,Hematopoietic Stem Cell Transplantation ,Hematology ,Leukemia, Myeloid, Acute ,Haematopoiesis ,medicine.anatomical_structure ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,Leukemia, Myeloid, Acute / therapy ,second hematopoietic stem cell transplantation ,030220 oncology & carcinogenesis ,Allogeneic hematopoietic stem cell transplantation ,Female ,Stem cell ,Myeloid leukaemia ,medicine.medical_specialty ,610 Medicine & health ,acute myeloid leukemia ,Peripheral Blood Stem Cells ,allogeneic hematopoietic stem cell transplantation ,children ,03 medical and health sciences ,Hematopoietic Stem Cell Transplantation / methods ,Leukemia, Myeloid, Acute / pathology ,Internal medicine ,medicine ,Transplantation, Homologous ,Humans ,Retrospective Studies ,Acute myeloid leukemia ,business.industry ,Second hematopoietic stem cell transplantation ,Matched Unrelated Donor ,Survival Analysis ,Transplantation ,10036 Medical Clinic ,Bone marrow ,business ,030215 immunology - Abstract
Outcome of 333 children with acute myeloid leukaemia relapsing after a first allogeneic haematopoietic stem cell transplantation was analyzed. Four-year probability of overall survival (4y-pOS) was 14%. 4y-pOS for 122 children receiving a second haematopoietic stem cell transplantation was 31% and 3% for those that did not (P= 
- Published
- 2020
258. Live cell detection of chromosome 2 deletion and Sfpi1/PU1 loss in radiation-induced mouse acute myeloid leukaemia.
- Author
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Olme, C.-H., Finnon, R., Brown, N., Kabacik, S., Bouffler, S.D., and Badie, C.
- Subjects
- *
CHROMOSOMES , *LABORATORY mice , *MYELOID leukemia , *DELETION mutation , *CYTOGENETICS , *X-rays - Abstract
Abstract: The CBA/H mouse model of radiation-induced acute myeloid leukaemia (rAML) has been studied for decades to bring to light the molecular mechanisms associated with multistage carcinogenesis. A specific interstitial deletion of chromosome 2 found in a high proportion of rAML is recognised as the initiating event. The deletion leads to the loss of Sfpi, a gene essential for haematopoietic development. Its product, the transcription factor PU.1 acts as a tumour suppressor in this model. Although the deletion can be detected early following ionising radiation exposure by cytogenetic techniques, precise characterisation of the haematopoietic cells carrying the deletion and the study of their fate in vivo cannot be achieved. Here, using a genetically engineered C57BL/6 mouse model expressing the GFP fluorescent molecule under the control of the Sfpi1 promoter, which we have bred onto the rAML-susceptible CBA/H strain, we demonstrate that GFP expression did not interfere with X-ray induced leukaemia incidence and that GFP fluorescence in live leukaemic cells is a surrogate marker of radiation-induced chromosome 2 deletions with or without point mutations on the remaining allele of the Sfpi1 gene. This study presents the first experimental evidence for the detection of this leukaemia initiating event in live leukemic cells. [Copyright &y& Elsevier]
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- 2013
- Full Text
- View/download PDF
259. Down syndrome-associated transient abnormal myelopoiesis with placental involvement.
- Author
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Daneshbod Y and Raghavan R
- Abstract
Competing Interests: The authors have declared no conflict of interest.
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- 2022
- Full Text
- View/download PDF
260. Safety and efficacy of vismodegib in relapsed/refractory acute myeloid leukaemia: results of a phase Ib trial
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Dale L. Bixby, Bruno C. Medeiros, Alwin Krämer, Todd Riehl, Sarit Assouline, Richard Noppeney, Walter Fiedler, Tara L. Lin, Jorge E. Cortes, Natalie Dimier, Karen Yee, B. Simmons, Jürgen Krauter, and Dawn Colburn
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business.industry ,Medizin ,Vismodegib ,Hematology ,03 medical and health sciences ,Hedgehog signalling ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Relapsed refractory ,medicine ,Cancer research ,Myeloid leukaemia ,Stem cell ,business ,030215 immunology ,medicine.drug - Published
- 2018
261. The potential for clinical translation of antibody-targeted nanoparticles in the treatment of acute myeloid leukaemia
- Author
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Jianfeng Guo, Mary R. Cahill, Caitriona M. O'Driscoll, Sharon L. McKenna, Yao Sun, Limei Wang, Zhongcheng Cong, and Xue Luan
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0301 basic medicine ,Immunoconjugates ,Pharmaceutical Science ,Antineoplastic Agents ,Malignancy ,Translational Research, Biomedical ,03 medical and health sciences ,Drug Delivery Systems ,Targeted nanoparticles ,hemic and lymphatic diseases ,medicine ,Animals ,Humans ,neoplasms ,Drug Carriers ,biology ,business.industry ,Antibodies, Monoclonal ,Treatment options ,Translation (biology) ,medicine.disease ,Leukemia, Myeloid, Acute ,Haematopoiesis ,030104 developmental biology ,biology.protein ,Cancer research ,Nanoparticles ,Antibody ,Myeloid leukaemia ,business - Abstract
Acute myeloid leukaemia (AML) is a heterogeneous haematopoietic malignancy. Currently, treatment options offer a 5 year survival of60%. In elderly patients, where the incidence is highest, the survival is much lower. Current standard treatments have significant toxicity and are least well tolerated in older adults, where the need is greatest. Therefore, alternatives are required. Monoclonal antibodies (mAbs), due to the specific targeting to cell surface proteins (i.e. antigens), represent a promising strategy for drug delivery to malignant cells. This concept favours the therapeutic ratio simultaneously by reducing toxicity and increasing efficacy. Although delivery of chemotherapeutics, genes and imaging agents using multifunctional nanoparticles has been substantially explored in treating solid cancers, less information on this approach is available in the case of AML. This review describes the development of antibody-targeted nanoparticulate drug delivery systems, and discusses the barriers to clinical translation in the treatment of AML.
- Published
- 2018
262. Decreasing early mortality in acute myeloid leukaemia in Sweden 1997-2014: improving performance status is a major contributing factor
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Petar Antunovic, Sören Lehmann, Åsa Derolf, Anders Wahlin, Vladimir Lazarevic, Lina Benson, Gunnar Juliusson, Yngvar Fløisand, Lars Möllgård, Bertil Uggla, Stefan Deneberg, and Martin Höglund
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Oncology ,Male ,medicine.medical_specialty ,Disease free survival ,Myeloid ,Disease-Free Survival ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,hemic and lymphatic diseases ,Internal medicine ,Medicine ,Humans ,Registries ,Survival rate ,Aged ,Retrospective Studies ,Sweden ,Hematology ,Performance status ,business.industry ,Retrospective cohort study ,Middle Aged ,medicine.disease ,Survival Rate ,Leukemia ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Female ,Myeloid leukaemia ,business ,030215 immunology - Abstract
Decreasing early mortality in acute myeloid leukaemia in Sweden 1997-2014 : improving performance status is a major contributing factor
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- 2019
263. Evaluating sixty years of UK trials research in acute myeloid leukaemia: lessons for trial design, past, present and future
- Author
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Robert Kerrin Hills
- Subjects
Male ,medicine.medical_specialty ,Guiding Principles ,Disease ,History, 21st Century ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,medicine ,Humans ,Intensive care medicine ,Randomized Controlled Trials as Topic ,business.industry ,Hematology ,Disease monitoring ,History, 20th Century ,Medical research ,United Kingdom ,Clinical trial ,Leukemia, Myeloid, Acute ,030220 oncology & carcinogenesis ,Practice Guidelines as Topic ,Female ,Myeloid leukaemia ,business ,030215 immunology - Abstract
Since the launch of their first trial in Acute myeloid leukaemia (AML) in 1959, the Medical Research Council (and latterly National Cancer Research Institute) has conducted randomised trials in AML uninterrupted for six decades. These sixty years have seen a transformation in the way we diagnose, characterise and treat the disease, (and indeed a sea change in clinical trial regulations) and a continuing improvement in outcomes. The increasing refinement of diagnosis, leading to the advent of tailored therapies, and the use of disease monitoring both have the potential to improve outcomes further, but the associated complexities will require an evolution in our approach to trial design. This article looks at the extent to which the guiding principles of the first AML trials remain relevant today, and the challenges facing the next generation of trials methodologists.
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- 2019
264. Longitudinal trajectory patterns of plasma albumin and C-reactive protein levels around diagnosis, relapse, bacteraemia, and death of acute myeloid leukaemia patients
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Henrik Frederiksen, Thøger Gorm Jensen, Pernille Just Vinholt, Stig Lønberg Nielsen, Pedro Póvoa, Pernille Sanberg Ljungdalh, Ram Benny Dessau, Ming Chen, Olav Sivertsen Garvik, Annmarie Touborg Lassen, John E. Coia, Kim Oren Gradel, Jens Kjølseth Møller, NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM), and Centro de Estudos de Doenças Crónicas (CEDOC)
- Subjects
Male ,Cancer Research ,Denmark ,Bacteremia ,Gastroenterology ,0302 clinical medicine ,Surgical oncology ,hemic and lymphatic diseases ,030212 general & internal medicine ,Longitudinal Studies ,Aged, 80 and over ,biology ,Middle Aged ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Plasma albumin ,Leukemia, Myeloid, Acute ,C-Reactive Protein ,Oncology ,030220 oncology & carcinogenesis ,Biomarker (medicine) ,Female ,Myeloid leukaemia ,Plasma Albumin ,medicine.symptom ,Infection ,Research Article ,Adult ,medicine.medical_specialty ,Adolescent ,Down-Regulation ,Inflammation ,lcsh:RC254-282 ,Acute myeloid leukaemia ,C-reactive protein ,03 medical and health sciences ,Young Adult ,SDG 3 - Good Health and Well-being ,Internal medicine ,medicine ,Genetics ,Biomarkers, Tumor ,Humans ,In patient ,Serum Albumin ,Aged ,Retrospective Studies ,Adult patients ,business.industry ,Survival Analysis ,biology.protein ,Neoplasm Recurrence, Local ,business - Abstract
Background No study has evaluated C-reactive protein (CRP) and plasma albumin (PA) levels longitudinally in patients with acute myeloid leukaemia (AML). Methods We studied defined events in 818 adult patients with AML in relation to 60,209 CRP and PA measures. We investigated correlations between CRP and PA levels and daily CRP and PA levels in relation to AML diagnosis, AML relapse, or bacteraemia (all ±30 days), and death (─30–0 days). Results On the AML diagnosis date (D0), CRP levels increased with higher WHO performance score (PS), e.g. patients with PS 3/4 had 68.1 mg/L higher CRP compared to patients with PS 0, adjusted for relevant covariates. On D0, the PA level declined with increasing PS, e.g. PS 3/4 had 7.54 g/L lower adjusted PA compared to PS 0. CRP and PA levels were inversely correlated for the PA interval 25–55 g/L (R = − 0.51, p p = 0.57). CRP increases and PA decreases were seen prior to bacteraemia and death, whereas no changes occurred up to AML diagnosis or relapse. CRP increases and PA decreases were also found frequently in individuals, unrelated to a pre-specified event. Conclusions PA decrease is an important biomarker for imminent bacteraemia in adult patients with AML.
- Published
- 2019
265. Prolonged administration of low-dose cytarabine and thioguanine in elderly patients with acute myeloid leukaemia (AML) achieves high complete remission rates and prolonged survival
- Author
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Anoop K Enjeti, Naomi Mackinlay, Eva Yip, Luke Coyle, William Stevenson, Vicki Katsioulas, Christopher Arthur, Jake Shortt, Keith Fay, Matthew Greenwood, Anastasios Nalpantidis, Anthony Jeffrey, and Ian Kerridge
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Low dose cytarabine ,03 medical and health sciences ,0302 clinical medicine ,Low-dose chemotherapy ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Thioguanine ,Aged ,Retrospective Studies ,Chemotherapy ,business.industry ,Remission Induction ,Complete remission ,Cytarabine ,Hematology ,Leukemia, Myeloid, Acute ,Treatment Outcome ,030220 oncology & carcinogenesis ,Myeloid leukaemia ,Neoplasm Recurrence, Local ,business ,030215 immunology ,medicine.drug - Abstract
The prognosis of AML in elderly patients is poor and research into novel therapeutic approaches is urgently needed. This study examined the use of low-dose chemotherapy with cytarabine and thioguanine administered in repetitive cycles in 62 elderly patients with newly diagnosed or relapsed/refractory AML. The overall response rate was 58% in the total cohort. Response rates (CR/CRi) were significantly higher in patients with newly diagnosed AML (74%) compared to patients with relapsed/refractory disease (25%
- Published
- 2019
266. Epigenetics of paediatric acute myeloid leukaemia
- Author
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Luke Jones, Peter McCarthy, and Jonathan Bond
- Subjects
Adolescent ,business.industry ,Hematology ,Normal haematopoiesis ,Bioinformatics ,Epigenesis, Genetic ,Hematopoiesis ,03 medical and health sciences ,Leukemia, Myeloid, Acute ,0302 clinical medicine ,Drug Resistance, Neoplasm ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,Mutation ,Medicine ,Humans ,Epigenetics ,Treatment resistance ,Myeloid leukaemia ,business ,Child ,030215 immunology - Abstract
Comprehensive cataloguing of the acute myeloid leukaemia (AML) genome has revealed a high frequency of mutations and deletions in epigenetic factors that are frequently linked to treatment resistance and poor patient outcome. In this review, we discuss how the epigenetic mechanisms that underpin normal haematopoiesis are subverted in AML, and in particular how these processes are altered in childhood and adolescent leukaemias. We also provide a brief summary of the burgeoning field of epigenetic-based therapies, and how AML treatment might be improved through provision of better conceptual frameworks for understanding the pleiotropic molecular effects of epigenetic disruption.
- Published
- 2019
267. A Case of Acute Myeloid Leukaemia Presenting as Subacute Intracranial Hypertension in a Young Adult
- Author
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William Stevenson, Francis Carr, Kimberley Tan, and Kate Ahmad
- Subjects
Chemotherapy ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Case Reports ,Disease ,medicine.disease ,Gastroenterology ,Ophthalmology ,Cerebrospinal fluid ,Internal medicine ,medicine ,Neurology (clinical) ,Young adult ,Myeloid leukaemia ,business ,Pleocytosis ,Acetazolamide ,Infiltration (medical) ,medicine.drug - Abstract
We report a case of an 18-year-old woman presenting with headache, papilloedema, and cerebrospinal fluid (CSF) pleocytosis. She was subsequently diagnosed with acute myeloid leukaemia, which is to date the only reported case manifesting as central nervous system-localised disease in an adult. The intracranial hypertension was treated successfully with chemotherapy, acetazolamide, and CSF drainage, with no permanent visual impairment. The mechanism by which haematological malignancy causes intracranial hypertension is not fully elucidated, but we hypothesise that in our case, blast infiltration interfered with CSF reabsorption at the arachnoid granulations.
- Published
- 2018
268. <scp>JAK</scp> 2 double minutes with resultant simultaneous amplification of <scp>JAK</scp> 2 and <scp>CD</scp> 274 in a therapy‐related myelodysplastic syndrome evolving into an acute myeloid leukaemia
- Author
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Eric D. Hsi, John A. Thorson, Huan You Wang, Rafael Bejar, Zeljko Dvanajscak, H. Elizabeth Broome, Sarah S. Murray, and Marie Dell'Aquila
- Subjects
0301 basic medicine ,medicine.medical_specialty ,business.industry ,Cytogenetics ,Hematology ,Therapy-related myelodysplastic syndrome ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,medicine ,Cancer research ,Myeloid leukaemia ,business - Published
- 2018
269. FLT3 Mutations: Significance in Paediatric AML
- Author
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Salma M. Aldalal
- Subjects
Haematopoiesis ,Allogeneic transplantation ,business.industry ,Flt3 mutation ,Fms-Like Tyrosine Kinase 3 ,Cancer research ,Medicine ,General Medicine ,Myeloid leukaemia ,business - Published
- 2018
270. Acute myeloid leukaemia
- Author
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Michael Rytting, Jorge E. Cortes, and Nicholas J. Short
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Myeloid ,medicine.medical_treatment ,Antineoplastic Agents ,Disease ,Hematopoietic stem cell transplantation ,Antibodies, Monoclonal, Humanized ,Risk Assessment ,Article ,03 medical and health sciences ,0302 clinical medicine ,Recurrence ,Risk Factors ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Intensive care medicine ,business.industry ,Patient Selection ,Remission Induction ,Cytarabine ,Hematopoietic Stem Cell Transplantation ,Consolidation Chemotherapy ,Genomics ,General Medicine ,Staurosporine ,medicine.disease ,Gemtuzumab ,Clinical trial ,Leukemia, Myeloid, Acute ,Leukemia ,Aminoglycosides ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Myeloid leukaemia ,Risk assessment ,business - Abstract
Summary For several decades, few substantial therapeutic advances have been made for patients with acute myeloid leukaemia. However, since 2017 unprecedented growth has been seen in the number of drugs available for the treatment of acute myeloid leukaemia, with several new drugs receiving regulatory approval. In addition to advancing our therapeutic armamentarium, an increased understanding of the biology and genomic architecture of acute myeloid leukaemia has led to refined risk assessment of this disease, with consensus risk stratification guidelines now incorporating a growing number of recurrent molecular aberrations that aid in the selection of risk-adapted management strategies. Despite this promising recent progress, the outcomes of patients with acute myeloid leukaemia remain unsatisfactory, with more than half of patients ultimately dying from their disease. Enrolment of patients into clinical trials that evaluate novel drugs and rational combination therapies is imperative to continuing this progress and further improving the outcomes of patients with acute myeloid leukaemia.
- Published
- 2018
271. Prognostic hallmarks in AML
- Author
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Jasmin Fisher and Matthew A. Clarke
- Subjects
0301 basic medicine ,Proteomics ,Databases, Factual ,Biomedical Engineering ,Medicine (miscellaneous) ,Bioengineering ,Context (language use) ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Biomarkers, Tumor ,Medicine ,Humans ,In patient ,Hypoxia ,business.industry ,Gene Expression Profiling ,Computational Biology ,Prognosis ,Computer Science Applications ,Leukemia, Myeloid, Acute ,030104 developmental biology ,Cancer research ,Myeloid leukaemia ,business ,Transcriptome ,030217 neurology & neurosurgery ,Biotechnology - Abstract
A data-clustering method that incorporates prior knowledge of biological context reveals prognostic signatures of proteomic expression in patients with acute myeloid leukaemia.
- Published
- 2019
272. Response to erythropoiesis-stimulating agents in patients with WHO-defined myelodysplastic syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T)
- Author
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Megan Melody, Christy Finke, Ayalew Tefferi, Ajinkya Buradkar, Martin E. Fernandez-Zapico, Naseema Gangat, Abhishek A. Mangaonkar, Giacomo Coltro, William J. Hogan, Aref Al-Kali, Rebecca L. King, Matthew T. Howard, Michelle A. Elliott, Moritz Binder, Rami S. Komrokji, Terra L. Lasho, Mark R. Litzow, Guadalupe Belen Antelo, Mrinal M. Patnaik, and Ryan M. Carr
- Subjects
Thrombocytosis ,medicine.medical_specialty ,Leukemia ,business.industry ,Sideroblastic anaemia ,Hematology ,Ring sideroblasts ,MDS/MPN-RS-T ,medicine.disease ,World Health Organization ,Gastroenterology ,Anemia, Sideroblastic ,Internal medicine ,Neoplasms ,medicine ,Hematinics ,Erythropoiesis ,Humans ,In patient ,Myeloid leukaemia ,business ,Myeloproliferative neoplasm - Published
- 2019
273. Nitroreductase-Mediated Release of Inhibitors of Lysine-Specific Demethylase 1 (LSD1) from Prodrugs in Transfected Acute Myeloid Leukaemia Cells
- Author
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Christoph Cornelius Miething, Desiree Melanie Redhaber, Mirjam Hau, Eva-Maria Herrlinger, Gabriele Greve, Manfred Jung, Michael Lübbert, Michael Müller, Dominica Willmann, Roland Schüle, and Simon Steimle
- Subjects
animal structures ,Cell Survival ,drug design ,010402 general chemistry ,Transfection ,chemistry ,01 natural sciences ,Biochemistry ,Nitroreductase ,prodrugs ,Cell Line, Tumor ,inhibitors ,Cytotoxic T cell ,Humans ,Enzyme Inhibitors ,Molecular Biology ,Histone Demethylases ,biology ,Full Paper ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Prodrug ,Nitroreductases ,Full Papers ,3. Good health ,0104 chemical sciences ,oxidoreductases ,Drug Liberation ,Leukemia, Myeloid, Acute ,Cell culture ,Cancer research ,biology.protein ,Molecular Medicine ,Demethylase ,LYSINE-SPECIFIC DEMETHYLASE 1 ,Myeloid leukaemia ,luminescence medicinal - Abstract
Lysine‐specific demethylase 1 (LSD1) has evolved as a promising therapeutic target for cancer treatment, especially in acute myeloid leukaemia (AML). To approach the challenge of site‐specific LSD1 inhibition, we developed an enzyme‐prodrug system with the bacterial nitroreductase NfsB (NTR) that was expressed in the virally transfected AML cell line THP1‐NTR+. The cellular activity of the NTR was proven with a new luminescent NTR probe. We synthesised a diverse set of nitroaromatic prodrugs that by design do not affect LSD1 and are reduced by the NTR to release an active LSD1 inhibitor. The emerging side products were differentially analysed using negative controls, thereby revealing cytotoxic effects. The 2‐nitroimidazolyl prodrug of a potent LSD1 inhibitor emerged as one of the best prodrug candidates with a pronounced selectivity window between wild‐type and transfected THP1 cells. Our prodrugs are selectively activated and release the LSD1 inhibitor locally, proving their suitability for future targeting approaches., Site‐specific targeting: Nitroaromatic prodrugs were activated by the bacterial nitroreductase NfsB (NTR) to selectively inhibit lysine‐specific demethylase 1 (LSD1) in transfected leukaemic cells. The effects of LSD1 inhibition and cytotoxicity of the side products were distinguished by negative controls. This system may be applied in targeting approaches to reach site‐specific LSD1 inhibition.
- Published
- 2019
274. A retrospective study of myeloid leukaemia in children with Down syndrome in Ireland
- Author
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David R. Betts, Aoife Sills, Melanie Cotter, Andrea Malone, Gavin P Dowling, Pamela Evans, Owen P Smith, Andrea Piccin, Katherine T Gavin, and Aengus O' Marcaigh
- Subjects
Male ,Pediatrics ,medicine.medical_specialty ,Down syndrome ,030204 cardiovascular system & hematology ,Malignancy ,03 medical and health sciences ,0302 clinical medicine ,Transient Myeloproliferative Disorder ,Medicine ,Humans ,030212 general & internal medicine ,Acute megakaryoblastic leukaemia ,Survival analysis ,Retrospective Studies ,business.industry ,Infant, Newborn ,Infant ,Retrospective cohort study ,General Medicine ,medicine.disease ,Leukemia, Myeloid ,Child, Preschool ,Cohort ,Female ,Myeloid leukaemia ,Down Syndrome ,business ,Ireland - Abstract
Acute megakaryoblastic leukaemia (AMKL) is a subtype of myeloid leukaemia and is the most common leukaemia type in children with Down syndrome (DS) under 4 years of age. AMKL is often preceded by a transient neonatal pre-leukaemic syndrome, transient myeloproliferative disorder (TMD). Although TMD often spontaneously resolves, 20–30% of these patients subsequently develop AMKL within the first 4 years of life. To perform a retrospective consecutive national audit of all documented cases of childhood TMD and AMKL-DS from 1990 to 2018 at Our Lady’s Children’s Hospital, Crumlin (OLCHC), Ireland. All patients with a diagnosis of AMKL treated consecutively at (OLCHC) between 1990 and 2018 were reviewed. Kaplan-Meier survival curves were constructed. Twenty-seven patients with AMKL-DS were identified. A prior neonatal diagnosis of TMD was described in 10 patients (37%). Nineteen patients (70%) are alive and well, in complete remission, at a median follow-up of 11.4 years. Overall survival (OS) of this cohort has risen from 54% from those treated between the years 1990 and 2004 (n = 13) to 93% for those treated between the years 2005 and 2018 (n = 14). High cure rates are observed in AMKL-DS using current polychemotherapy protocols. The finding of a low platelet count at time of diagnosis is in keeping with the knowledge that AMKL-DS is a malignancy of platelet progenitor cells.
- Published
- 2019
275. TP53 mutations and relevance of expression of TP53 pathway genes in paediatric acute myeloid leukaemia
- Author
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Costa Bachas, Sander Huttenhuis, Christian M. Zwaan, David G. J. Cucchi, Kim Klein, Gert J. Ossenkoppele, Jeroen Janssen, Jacqueline Cloos, Gertjan L. Kaspers, Pediatrics, Erasmus MC other, Hematology laboratory, Pediatric surgery, CCA - Cancer biology and immunology, Hematology, and CCA - Imaging and biomarkers
- Subjects
Male ,Adolescent ,endocrine system diseases ,Disease-Free Survival ,03 medical and health sciences ,Exon ,0302 clinical medicine ,stomatognathic system ,Complex Karyotype ,medicine ,Humans ,Missense mutation ,Child ,Gene ,neoplasms ,Gene Expression Regulation, Leukemic ,business.industry ,Effector ,Incidence (epidemiology) ,Infant, Newborn ,Infant ,Hematology ,Survival Rate ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,Child, Preschool ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,Female ,Bone marrow ,Chromosome Deletion ,Smith-Magenis Syndrome ,Tumor Suppressor Protein p53 ,Myeloid leukaemia ,business ,Chromosomes, Human, Pair 17 ,Signal Transduction ,030215 immunology - Abstract
Limited data are available on the incidence and impact of TP53 alterations and TP53 pathway deregulation in paediatric acute myeloid leukaemia (AML). We analysed TP53 alterations in bone marrow samples of 229 patients with de novo paediatric AML, and detected heterozygous missense exon mutations in two patients (1%) and 17p deletions of the TP53 gene in four patients (2%). These patients more frequently had complex karyotype (50% vs. 4%, P = 0·002) or adverse cytogenetic abnormalities, including complex karyotype (67% vs. 17%, P = 0·013), compared to TP53 wild-type. Differential expression of TP53 pathway genes was associated with poor survival, indicating a role for TP53 regulators and effector genes.
- Published
- 2019
276. Measurable residual disease assessment by qPCR in peripheral blood is an informative tool for disease surveillance in childhood acute myeloid leukaemia
- Author
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Jonas Abrahamsson, Hans Beier Ommen, Helen Vålerhaugen, Kirsi Jahnukainen, Birgitte Lausen, Linda Fogelstrand, Sofie Johansson Alm, Christiane Walter, Bernward Zeller, Veli Kairisto, Nils von Neuhoff, Dirk Reinhardt, Henrik Hasle, Charlotte Guldborg Nyvold, and Kristian Løvvik Juul-Dam
- Subjects
Oncology ,Male ,Neoplasm, Residual ,medicine.medical_treatment ,Medizin ,Disease ,Biochemistry ,0302 clinical medicine ,hemic and lymphatic diseases ,Medicine ,Child ,Neoadjuvant therapy ,relapse ,0303 health sciences ,Disease surveillance ,Childhood Acute Myeloid Leukemia ,Hematology ,fusion transcripts ,3. Good health ,Leukemia ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Child, Preschool ,Disease Progression ,Female ,Disease assessment ,Myeloid leukaemia ,measurable residual disease ,medicine.medical_specialty ,Adolescent ,Immunology ,Real-Time Polymerase Chain Reaction ,03 medical and health sciences ,Internal medicine ,Biomarkers, Tumor ,Humans ,acute myeloid leukaemia ,MRD Persistence ,paediatric haematology ,030304 developmental biology ,business.industry ,Complete remission ,Infant, Newborn ,Infant ,Cell Biology ,medicine.disease ,Peripheral blood ,body regions ,Bone marrow ,business ,030215 immunology - Abstract
Background: Relapse remains a serious event and main obstacle to permanent cure in childhood acute myeloid leukemia (AML). Reduction of measurable/minimal residual disease (MRD) assessed by real-time quantitative PCR (qPCR) during therapy is predictive of outcome in adults but persistent MRD positivity may be observed despite long-term remission and hamper accurate risk assignment. Sequential MRD determinations, rather than analysis at single landmark time points, may better capture the dynamics of leukemia eradication and identify relapse at molecular levels when applied in the post-therapy setting. We investigated the post-induction qPCR MRD kinetics in peripheral blood (PB) and bone marrow (BM) in a large cohort of childhood AML patients and demonstrate the utility of serial assessments for disease surveillance after therapy completion. Methods: We collected the results from qPCR MRD analyses of 774 samples (BM 347, PB 427) from 75 children with AML harboring recurrent fusion transcripts (32 RUNX1-RUNX1T1, 24 CBFB-MYH11, 16 KMT2A-MLLT3 and 3 KMT2A-ELL). Patients were treated according to The Nordic Society for Paediatric Haematology and Oncology (NOPHO)-AML 2004 or NOPHO-DBH AML 2012 protocols (2004 - 2016), or AML-BFM 2012 protocol (2014 - 2016). Only patients who achieved complete remission (CR) during induction therapy and received standard-risk consolidation without allografting were eligible for the study. Risk of relapse as a function of time of MRD positivity in sequential samples from BM or PB during consolidation therapy was modeled using restricted cubic splines. Considering shifting from MRD negative to positive in PB and MRD increments in BM above 5x10-4 as time-dependent variables, the Mantel-Byar method was applied to evaluate the prognostic impact of MRD kinetics during follow-up. Results: Risk of relapse was independent of MRD persistence in BM during therapy, but showed a strong correlation with time of MRD positivity in PB where 8/8 patients with detectable MRD after first consolidation course relapsed (Figure 1A and 1B). At therapy completion, MRD level in BM did not correlate to outcome, HR=0.64/MRD log reduction, 95% confidence interval (CI):0.32 - 1.26 (P=0.19), and there was no difference in 3-year cumulative incidence of relapse (CIR) according to MRD status (P=0.51, Figure 2A). Four patients remained MRD positive throughout consolidation therapy and all subsequently relapsed, whereas 7/28 patients who were MRD negative in PB at the end of therapy suffered relapse, 3-year CIR=27%, CI:14% - 49% (P Shifting from negative to positive in PB during follow-up predicted subsequent relapse in 10/10 patients. All 253 PB samples collected during follow-up from 36 patients in continuous CR were MRD negative. In core binding factor (CBF) AML, persistent low-level MRD positivity in BM was frequent (detected in 38% of patients tested within six months of therapy completion) but an increment to above 5x10-4 heralded subsequent relapse in 12/12 patients. Pre-relapse MRD kinetics were delineated in 16 patients and revealed a median log increment/30 days of 0.8 (range:0.4 - 1.5) in CBF patients versus 2.2 (range:1.1 - 3.7) in patients with KMT2A-MLLT3 (P=0.008). Perspectives: This study demonstrates that qPCR MRD monitoring in PB, rather than BM, represents an accurate discriminator of prognosis and is a highly informative tool for disease surveillance in childhood AML. Early relapse detection during follow-up may facilitate preemptive therapy strategies of molecular relapse, possibly improving relapse treatment outcomes. Disclosures No relevant conflicts of interest to declare.
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- 2019
277. Alisertib: a new option for acute myeloid leukaemia
- Author
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Xavier Thomas
- Subjects
Oncology ,medicine.medical_specialty ,Myeloid ,business.industry ,Treatment outcome ,MEDLINE ,Antineoplastic Agents ,Hematology ,Azepines ,medicine.disease ,Prognosis ,chemistry.chemical_compound ,Leukemia ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,Pyrimidines ,Treatment Outcome ,chemistry ,Internal medicine ,Alisertib ,Medicine ,Humans ,Myeloid leukaemia ,business ,Protein Kinase Inhibitors - Published
- 2019
278. The concept of leukaemic stem cells in acute myeloid leukaemia 25 years on:hitting a moving target
- Author
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Peter Hokland, Marie Bill, Marcus Celik Hansen, and Petter S. Woll
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leukaemic stem cells ,business.industry ,Genome, Human ,clinical targeting ,Hematology ,History, 20th Century ,Hematopoietic Stem Cells ,History, 21st Century ,03 medical and health sciences ,Haematopoiesis ,Leukemia, Myeloid, Acute ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Cancer research ,Neoplastic Stem Cells ,Medicine ,Humans ,identification ,acute myeloid leukaemia ,Progenitor cell ,Myeloid leukaemia ,Stem cell ,business ,critical re-evaluation ,030215 immunology - Abstract
The concept of leukaemic stem cells (LSCs) was experimentally suggested 25 years ago through seminal data from John Dick's group, who showed that a small fraction of cells from acute myeloid leukaemia (AML) patients were able to be adoptively transferred into immunodeficient mice. The initial estimation of the frequency was 1:250 000 leukaemic cells, clearly indicating the difficulties ahead in translating knowledge on LSCs to the clinical setting. However, the field has steadily grown in interest, expanse and importance, concomitantly with the realisation of the molecular background for AML culminating in the sequencing of hundreds of AML genomes. The literature is now ripe with contributions describing how different molecular aberrations are more or less specific for LSCs, as well as reports showing selectivity in targeting LSCs in comparison to normal haematopoietic stem and progenitor cells. However, we argue here that these important data have not yet been fully realised within the clinical setting. In this clinically focused review, we outline the difficulties in identifying and defining LSCs at the individual patient level, with special emphasis on intraclonal heterogeneity. In addition, we suggest areas of future focus in order to realise the concept as real-time benefit for AML patients.
- Published
- 2019
279. Targeting Apoptotic Pathways in Acute Myeloid Leukaemia
- Author
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Anoop K Enjeti and Jonathan R. Sillar
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,bcl-2 ,Disease ,Review ,mcl-1 ,lcsh:RC254-282 ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Clinical work ,Internal medicine ,hemic and lymphatic diseases ,medicine ,acute myeloid leukaemia ,B-cell lymphoma ,programmed cell death ,business.industry ,Venetoclax ,apoptosis ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Clinical trial ,030104 developmental biology ,chemistry ,Apoptosis ,030220 oncology & carcinogenesis ,bh3 mimetic ,Myeloid leukaemia ,business ,Early phase - Abstract
Acute Myeloid Leukaemia is a devastating disease that continues to have a poor outcome for the majority of patients. In recent years, however, a number of drugs have received FDA approval, following on from successful clinical trial results. This parallels the characterization of the molecular landscape of Acute Myeloid Leukaemia (AML) over the last decade, which has led to the development of drugs targeting newly identified recurring mutations. In addition, basic biological research into the pathobiology of AML has identified aberrant programmed cell death pathways in AML. Following on from successful outcomes in lymphoid malignancies, drugs targeting the B Cell Lymphoma 2 (BCL-2) family of anti-apoptotic proteins have been explored in AML. In this review, we will outline the preclinical and clinical work to date supporting the role of drugs targeting BCL-2, with Venetoclax being the most advanced to date. We will also highlight rationale combinations using Venetoclax, ongoing clinical trials and biomarkers of response identified from the early phase clinical trials performed.
- Published
- 2019
280. PD-1 blockade potentially enhances adoptive cytotoxic T cell potency in a human acute myeloid leukaemia animal model
- Author
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Fang Liu, Guang-Cui He, Yi Su, Fangyi Fan, Hai Yi, Hao-Ping Sun, and Rui Deng
- Subjects
0301 basic medicine ,Programmed Cell Death 1 Receptor ,Mice, Nude ,Disease ,CD8-Positive T-Lymphocytes ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Animal model ,Infusion therapy ,Cell Line, Tumor ,hemic and lymphatic diseases ,Animals ,Humans ,Cytotoxic T cell ,Potency ,Medicine ,Mice, Inbred BALB C ,business.industry ,Hematology ,Adoptive Transfer ,Xenograft Model Antitumor Assays ,Leukemia, Myeloid, Acute ,CTL ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer research ,Heterografts ,Pd 1 blockade ,Female ,Myeloid leukaemia ,business ,Neoplasm Transplantation - Abstract
Acute myeloid leukaemia (AML) is a malignant haematological disease that remains difficult to cure. Cytotoxic T cell (CTL) adoptive infusion therapy may be conducive to tumour remission by boosting physical immunity. Furthermore, programmed death receptor-1 (PD-1) blockade immunotherapy has shown tremendous success in many cancer therapies.We attempted to combine these two immunotherapy strategies to intervene in AML by generating AML cellspecific cytotoxic T lymphocytes in vitro and in vivo with an AML cell strain expressing specific antigens.First, we observed that peripheral blood mononuclear cells (PBMCs) could be induced to generate large numbers of CD8This finding suggested the potential application of PD-1 blockade in AML. The present work demonstrated an excellent synergistic tumour therapeutic effect of PD-1 blockade and CTL therapy compared with either treatment alone.
- Published
- 2018
281. Octamer-binding transcription factor 4 correlates with complex karyotype, FLT3-ITD mutation and poorer risk stratification, and predicts unfavourable prognosis in patients with acute myeloid leukaemia
- Author
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Yongsheng Xiang and Xiaofen Zhou
- Subjects
Adult ,Male ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,Abnormal Karyotype ,Malignancy ,Risk Assessment ,Disease-Free Survival ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Complex Karyotype ,medicine ,Humans ,In patient ,Prospective Studies ,Prospective cohort study ,Transcription factor ,Gene Expression Regulation, Leukemic ,business.industry ,Hematology ,Middle Aged ,medicine.disease ,Survival Rate ,Leukemia, Myeloid, Acute ,030104 developmental biology ,fms-Like Tyrosine Kinase 3 ,030220 oncology & carcinogenesis ,Mutation ,embryonic structures ,Risk stratification ,Biomarker (medicine) ,Female ,Myeloid leukaemia ,business ,Octamer Transcription Factor-3 - Abstract
Objective To investigate the correlation of octamer-binding transcription factor 4 (OCT4) expression with clinicopathological features and its predictive value for treatment response as well as survival profiles in de novo acute myeloid leukaemia (AML) patients. Method One hundred fifty-two de novo AML patients and 52 non-hematologic malignancy patients were recruited in this prospective cohort study. OCT4 expression was determined in bone marrow sample collected before treatment. Complete response (CR), event free survival (EFS) and overall survival (OS) were evaluated. Results Compared with the controls, OCT4 mRNA expression was higher in AML patients (P
- Published
- 2018
282. Phase I dose-escalation trial investigating volasertib as monotherapy or in combination with cytarabine in patients with relapsed/refractory acute myeloid leukaemia
- Author
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Tilmann Bochtler, Tillmann Taube, Oliver G. Ottmann, Florian Voss, Alwin Krämer, Pilar Garin-Chesa, Hartmut Döhner, Dan Liu, Utz Krug, Gesine Bug, Carsten Müller-Tidow, Richard F. Schlenk, and Michael Lübbert
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,business.industry ,Volasertib ,Hematology ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,chemistry ,Pharmacokinetics ,030220 oncology & carcinogenesis ,Internal medicine ,Relapsed refractory ,medicine ,Dose escalation ,Cytarabine ,In patient ,Myeloid leukaemia ,business ,medicine.drug - Published
- 2018
283. Allogeneic haematopoietic cell transplantation for adult acute myeloid leukaemia in second remission: a retrospective study of the Adult Acute Myeloid Leukaemia Working Group of the Japan Society for Haematopoietic Cell Transplantation (JSHCT)
- Author
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Takeshi Kobayashi, Takaaki Konuma, Yukiyasu Ozawa, Yoshiko Atsuta, Shingo Yano, Minoko Takanashi, Tatsuo Ichinohe, Satoshi Yamasaki, Yoshinobu Kanda, Takumi Hoshino, Junya Kanda, Takahiro Fukuda, Shuichi Ota, Masamitsu Yanada, Satoshi Takahashi, Yachiyo Kuwatsuka, Naoyuki Uchida, and Yasunori Ueda
- Subjects
Adult ,Male ,Oncology ,medicine.medical_specialty ,Adolescent ,Graft vs Host Disease ,chemical and pharmacologic phenomena ,Disease-Free Survival ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Recurrence ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Overall survival ,Humans ,Transplantation, Homologous ,Cumulative incidence ,Aged ,Retrospective Studies ,business.industry ,Hematopoietic Stem Cell Transplantation ,Complete remission ,Cytogenetics ,Haematopoietic cell transplantation ,Allogeneic hct ,Retrospective cohort study ,Hematology ,Middle Aged ,Leukemia, Myeloid, Acute ,Treatment Outcome ,030220 oncology & carcinogenesis ,Female ,Myeloid leukaemia ,business ,030215 immunology - Abstract
To evaluate the outcomes and prognostic factors following allogeneic haematopoietic cell transplantation (HCT) for adult acute myeloid leukaemia (AML) in second complete remission (CR2), we retrospectively analysed the Japanese registration data of 1080 adult AML patients in CR2 who had received allogeneic HCT. The probability of overall survival and the cumulative incidence of relapse at 3 years was 66% and 19%, respectively. In multivariate analysis, older age, poor cytogenetics and shorter duration of first complete remission were significantly associated with a higher overall mortality. Our data demonstrated the significant efficacy of allogeneic HCT for adult AML in CR2.
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- 2018
284. AETIOLOGICAL AND CLINICAL PROFILE OF ACUTE MYELOID LEUKAEMIA IN A TERTIARY CARE HOSPITAL
- Author
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Anza Khader and Mohamed Shaan
- Subjects
0301 basic medicine ,03 medical and health sciences ,medicine.medical_specialty ,030104 developmental biology ,0302 clinical medicine ,business.industry ,030220 oncology & carcinogenesis ,Internal medicine ,Etiology ,Medicine ,Tertiary care hospital ,Myeloid leukaemia ,business - Published
- 2018
285. Features of treatment-related myelodisplastic syndrome and treatment-related acute myeloid leukaemia in children treated for acute lymphoblastic leukaemia: own observations
- Author
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O.І. Dorosh, L.L. Skoropad, O.I. Kozlova, A.I. Stepanyuk, I.P. Tsymbalyuk-Voloshyn, L.P. Seredych, and A.M. Myh
- Subjects
Oncology ,medicine.medical_specialty ,treatment-related myelodisplastic syndrome ,acute lymphoblastic leukaemia ,secondary neoplasia ,business.industry ,lcsh:RJ1-570 ,lcsh:Pediatrics ,treatment-related acute myeloid leukaemia ,children ,Internal medicine ,hemic and lymphatic diseases ,medicine ,Lymphoblastic leukaemia ,Myeloid leukaemia ,business - Abstract
The article presents two clinical cases of secondary treatment-related haemoblastosis – treatment-related myelodisplastic syndrome (t-MDS)/treatment-related acute myeloid leukaemia (AML) – t-MDS/t-AML, compared to the data of other world's investigators. Two boys with primary diagnosed acute lymphoblastic leukaemia (ALL) were treated according to the program ALL IC-BFM-2002, depending upon their belonging to intermediate (IRTG) and high-risk treatment groups (HRTG). The secondary MDS associated with monosomy 7 developed in the patient of the intermediate risk group, which was subsequently transformed to secondary AML. After allogenic transplantation of haemopoetic cells of umbilical cord blood, it appeared that the post-transplant complications developed, which caused death of the patient. In another boy from the high-risk group, the secondary AML associated with translocation t(9.11) (p22; q23) was diagnosed. He was provided with allogenic transplantation of haemopoetic cells as well. The patient has been in clinical-haematological remission of ALL for 77 months and clinical-haematological remission of t-AML — 49 months. The t-MDS/t-AML are registered amid supportive chemotherapy of ALL after 20 months in males with chromosome anomalies, predisposed to progress during standard chemotherapy and severe infectious toxic complications associated with cytopenia. The transplantation of haemopoetic cells presents the only treatment regimen for patients with t-MDS/t-AML.
- Published
- 2018
286. Intra-oral noma-like lesion associated with acute myeloid leukaemia: a case report
- Author
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P. A. Atkin and A. Chatzipantelis
- Subjects
Pathology ,medicine.medical_specialty ,business.industry ,030206 dentistry ,medicine.disease ,Lesion ,Noma ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Intra oral ,medicine ,Surgery ,Oral Surgery ,medicine.symptom ,Myeloid leukaemia ,business - Published
- 2018
287. Genital ulcers as diagnostic clue for acute myeloid leukaemia
- Author
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Sina D Schröder, Stefan W. Krause, and Cornelia Erfurt-Berge
- Subjects
medicine.medical_specialty ,business.industry ,Case Report ,Clinical appearance ,Dermatology ,Myeloid Neoplasm ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,Medicine ,Surgery ,Sex organ ,Genital ulcerations ,Myeloid leukaemia ,business ,Skin lesion - Abstract
Acute myeloid leukaemia is a myeloid neoplasm with an extremely varying clinical appearance. Skin lesions are common for specific subtypes of acute myeloid leukaemia but are often misinterpreted. Here, we present a case of acute myeloid leukaemia in a young woman exhibiting genital ulcerations and gingival erosions.
- Published
- 2018
288. Transplants for аcute myeloid leukaemia in 1st remission: standard of care or something else?
- Author
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Ivan S. Moiseev and Robert Peter Gale
- Subjects
Transplantation ,Pediatrics ,medicine.medical_specialty ,Standard of care ,business.industry ,medicine ,Molecular Medicine ,Myeloid leukaemia ,business - Published
- 2018
289. Vav1 is necessary for <scp>PU</scp> .1 mediated upmodulation of miR‐29b in acute myeloid leukaemia‐derived cells
- Author
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Roberta Piva, Federica Brugnoli, Elisabetta Lambertini, Simone Patergnani, Silvia Grassilli, Ervin Nika, Paolo Pinton, Federica Vezzali, Silvano Capitani, and Valeria Bertagnolo
- Subjects
0301 basic medicine ,VAV1 ,Consensus site ,Socio-culturale ,Chromosomal rearrangement ,MiR-29b ,Acute myeloid leukaemia ,03 medical and health sciences ,Leukemia, Promyelocytic, Acute ,Transcription (biology) ,Cell Line, Tumor ,Proto-Oncogene Proteins ,microRNA ,Humans ,Medicine ,Promoter Regions, Genetic ,Proto-Oncogene Proteins c-vav ,neoplasms ,Gene Expression Regulation, Leukemic ,business.industry ,miR‐29b ,PU.1 ,Cell Differentiation ,Promoter ,Original Articles ,Cell Biology ,Acute myeloid leukaemia, MiR-29b, PU.1, Vav1, Molecular Medicine, Cell Biology ,Leukemia, Myeloid, Acute ,MicroRNAs ,030104 developmental biology ,Hypomethylating agent ,Vav1 ,Trans-Activators ,Cancer research ,Molecular Medicine ,Original Article ,Myeloid leukaemia ,business - Abstract
It has been recently demonstrated that high pre‐treatment levels of miR‐29b positively correlated with the response of patients with acute myeloid leukaemia (AML) to hypomethylating agents. Upmodulation of miR‐29b by restoring its transcriptional machinery appears indeed a tool to improve therapeutic response in AML. In cells from acute promyelocytic leukaemia (APL), miR‐29b is regulated by PU.1, in turn upmodulated by agonists currently used to treat APL. We explored here the ability of PU.1 to also regulate miR‐29b in non‐APL cells, in order to identify agonists that, upmodulating PU.1 may be beneficial in hypomethylating agents‐based therapies. We found that PU.1 may regulate miR‐29b in the non‐APL Kasumi‐1 cells, showing the t(8;21) chromosomal rearrangement, which is prevalent in AML and correlated with a relatively low survival. We demonstrated that the PU.1‐mediated contribution of the 2 miR‐29b precursors is cell‐related and almost completely dependent on adequate levels of Vav1. Nuclear PU.1/Vav1 association accompanies the transcription of miR‐29b but, at variance with the APL‐derived NB4 cells, in which the protein is required for the association of PU.1 with both miRNA promoters, Vav1 is part of molecular complexes to the PU.1 consensus site in Kasumi‐1. Our results add new information on the transcriptional machinery that regulates miR‐29b expression in AML‐derived cells and may help in identifying drugs useful in upmodulation of this miRNA in pre‐treatment of patients with non‐APL leukaemia who can take advantage from hypomethylating agent‐based therapies.
- Published
- 2018
290. Acute myeloid leukaemia: A guide for practice nurses
- Author
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Margaret Perry
- Subjects
Pediatrics ,medicine.medical_specialty ,business.industry ,Excessive Bruising ,Chest pain ,Rare cancer ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Weight loss ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,medicine ,030212 general & internal medicine ,medicine.symptom ,Myeloid leukaemia ,business ,General Nursing ,Nose - Abstract
Acute myeloid leukaemia is a rare cancer of the white blood cells. Margaret Ann Perry provides an overview of the signs, symptoms and treatment for practice nurses This article is part two of a series on types of leukaemia and focuses on acute myeloid leukaemia. Acute myeloid leukaemia is the most common leukaemia in adults, and although it can occur at any age, it is more commonly seen in older adults. Approximately 3000 new cases are diagnosed each year in the UK. Acute myeloid leukaemia develops rapidly, unlike other types of leukaemia. Practice nurses who run minor illness clinics may see patients who present complaining of fever, fatigue, weight loss, excessive bruising and nose bleeds, and anaemia-related symptoms, such as shortness of breath or chest pain.
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- 2018
291. Treatment of relapsed/refractory acute myeloid leukaemia in adults
- Author
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Nelli Bejanyan, Daniel J. Weisdorf, and Armin Rashidi
- Subjects
Adult ,Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Refractory ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Chemotherapy ,business.industry ,Remission Induction ,Hematopoietic Stem Cell Transplantation ,Hematology ,Immunotherapy ,Allografts ,Clinical trial ,Leukemia, Myeloid, Acute ,030220 oncology & carcinogenesis ,Relapsed refractory ,Fatal disease ,Myeloid leukaemia ,business ,030215 immunology - Abstract
The prognosis of relapsed acute myeloid leukaemia (AML) is poor and treatment is challenging. While the most potent treatment modality for patients who achieve a complete remission after relapse is still allogeneic haematopoietic cell transplantation (allo-HCT), both transplant-related mortality and relapse rates are high and many patients are not candidates for this approach. After a few decades of relative stasis in this field, a large number of novel approaches have become available to tackle this highly fatal disease. This is mostly due to our improved understanding of disease pathogenesis (including targetable mutations) and the anti-leukaemia potential of the immune system. Several small-molecule inhibitors and immunotherapeutic options are being explored in clinical trials and many more are in pre-clinical phase. Future studies will focus on novel and mechanistically driven combinations, sequential treatments, and low-toxicity maintenance strategies. While cure of relapsed/refractory AML without allo-HCT is currently unlikely, treatments are becoming less toxic and remissions are lasting longer.
- Published
- 2018
292. CD56 and CD11b Positivity with Low Smac/DIABLO Expression as Predictors of Chemoresistance in Acute Myeloid Leukaemia: Flow Cytometric Analysis
- Author
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Abeer Ibrahim, Asmaa M Zahran, Mohammed H. Hassan, Ahmed Refaat, and Sanaa Shaker Aly
- Subjects
0301 basic medicine ,Oncology ,Male ,medicine.medical_treatment ,Smac/DIABLO ,0302 clinical medicine ,AML ,Antineoplastic Combined Chemotherapy Protocols ,CD11b Antigen ,medicine.diagnostic_test ,biology ,Intracellular Signaling Peptides and Proteins ,General Medicine ,Middle Aged ,Flow Cytometry ,Prognosis ,CD56 Antigen ,Gene Expression Regulation, Neoplastic ,Survival Rate ,Leukemia, Myeloid, Acute ,Integrin alpha M ,030220 oncology & carcinogenesis ,Female ,CD56 ,Myeloid leukaemia ,Chemoresistance ,medicine.drug ,Research Article ,Adult ,medicine.medical_specialty ,Adolescent ,Flow cytometry ,Mitochondrial Proteins ,03 medical and health sciences ,Young Adult ,Antigen ,Internal medicine ,Smac diablo ,medicine ,Biomarkers, Tumor ,Humans ,Mitoxantrone ,Chemotherapy ,business.industry ,CD11b ,030104 developmental biology ,Cross-Sectional Studies ,Drug Resistance, Neoplasm ,biology.protein ,Cytarabine ,business ,Apoptosis Regulatory Proteins ,Follow-Up Studies - Abstract
Background: Resistance to chemotherapy is a major obstacle to curing acute myeloid leukaemia (AML), and several antigens are claimed to play primary roles in this resistance. Purpose: The aim of this study was to evaluate the roles of CD56, CD11b and Smac/DIABLO gene expression levels as prognostic markers of the clinical outcome, response to chemotherapy and survival of AML patients. Materials and Methods: A cross-sectional observational study was conducted on 60 naive-AML patients who received induction therapy with mitoxantrone and cytarabine combined with a high dose of cytarabine. The CD56,CD11b and Smac/DIABLO expression levels were assessed using flow cytometry at diagnosis and were analysed for correlation with the possible associated risk factors, response to chemotherapy, and median duration of disease-free survival (DFS) and overall survival (OS). Results: The overall results revealed that AML patients who exhibited positive expression for CD56 and CD11b had short median durations of DFS and OS.(P = 0.019, 0.006, 0.029 and 0.024, respectively). Additionally, low Smac/DIABLO expression had a negative impact on treatment outcome in terms of CR rate (p=0.012) and reduced DFS (p=0.000) and OS(p=0.000) values. Conclusions: CD56 and CD11b positivity and low Smac/DIABLO expression are important predictive factors for the occurrence of chemoresistance, in addition to other risk factors, among AML patients.
- Published
- 2018
293. Initial presentation of acute myeloid leukaemia as collision intradermal melanocytic naevus and myeloid leukaemia cutis mimicking naevoid melanoma
- Author
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Christopher Mow, Peter I A McQuillan, Chin-Guan Tan, Sant Khan, and Laurence A. Galea
- Subjects
medicine.medical_specialty ,Myeloid ,business.industry ,Cutis ,medicine.disease ,Dermatology ,Pathology and Forensic Medicine ,Naevoid melanoma ,Leukemia ,medicine.anatomical_structure ,medicine ,Intradermal melanocytic naevus ,Nevus ,Presentation (obstetrics) ,Myeloid leukaemia ,business - Published
- 2019
294. Unilateral Ptosis - An Unusual Initial Presentation of Acute Myeloid Leukaemia in an Adolescent Girl
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Satish Kuma
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Pediatrics ,medicine.medical_specialty ,business.industry ,media_common.quotation_subject ,medicine ,Girl ,Myeloid leukaemia ,Presentation (obstetrics) ,business ,Unilateral ptosis ,media_common - Published
- 2019
295. Acute myeloid leukaemia niche regulates response to L‐asparaginase
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Bernhard Gentner, Ilaria M. Michelozzi, Carmelo Rizzari, Chiara Tomasoni, Marta Serafini, Francesco Dazzi, Tiziana Coliva, Valentina Granata, Giada De Ponti, Andrea Biondi, Carlo Gambacorti-Passerini, Laura Antolini, Alice Pievani, Gaia Alberti, Pediatric surgery, CCA - Cancer biology and immunology, Michelozzi, I, Granata, V, DE PONTI, G, Alberti, G, Tomasoni, C, Antolini, L, GAMBACORTI PASSERINI, C, Gentner, B, Dazzi, F, Biondi, A, Coliva, T, Rizzari, C, Pievani, A, and Serafini, M
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Asparaginase ,Myeloid ,cathepsin B ,CD34 ,Biology ,CD38 ,Cathepsin B ,Cell Line ,L asparaginase ,Precursor Cell Lymphoblastic Leukemia Lymphoma ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,hemic and lymphatic diseases ,medicine ,Humans ,Cytotoxic T cell ,acute myeloid leukaemia ,ASNS expression ,acute myeloid leukaemia, asparaginase, leukaemic stem cells, bone marrow microenvironment, cathepsin B ,bone marrow microenvironment ,leukaemic stem cell ,business.industry ,Mesenchymal stem cell ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,AML: heterogeneity ,cathepsin‐B expression ,medicine.disease ,Leukemia, Myeloid, Acute ,Leukemia ,medicine.anatomical_structure ,chemistry ,030220 oncology & carcinogenesis ,Cancer research ,Bone marrow ,Stem cell ,Myeloid leukaemia ,business ,Editorial Comment ,030215 immunology - Abstract
Eradicating the malignant stem cell is the ultimate challenge in the treatment of leukaemia. Leukaemic stem cells (LSC) hijack the normal haemopoietic niche, where they are mainly protected from cytotoxic drugs. The anti-leukaemic effect of L-asparaginase (ASNase) has been extensively investigated in acute lymphoblastic leukaemia, but only partially in acute myeloid leukaemia (AML). We explored the susceptibility of AML-LSC to ASNase as well as the role of the two major cell types that constitute the bone marrow (BM) microenvironment, i.e., mesenchymal stromal cells (MSC) and monocytes/macrophages. Whilst ASNase was effective on both CD34+ CD38+ and CD34+ CD38- LSC fractions, MSC and monocytes/macrophages partially counteracted the effect of the drug. Indeed, the production of cathepsin B, a lysosomal cysteine protease, by BM monocytic cells and by AML cells classified as French-American-British M5 is related to the inactivation of ASNase. Our work demonstrates that, while MSC and monocytes/macrophages may provide a protective niche for AML cells, ASNase has a cytotoxic effect on AML blasts and, importantly, LSC subpopulations. Thus, these features should be considered in the design of future clinical studies aimed at testing ASNase efficacy in AML patients.
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- 2019
296. Rapidly progressing bilateral proptosis in a young boy as initial manisfestation of acute myeloid leukemia
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Neha Singh, S.K. Satsangi, and Himanshu Kumar
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medicine.medical_specialty ,business.industry ,Myeloid leukemia ,Disease ,Peripheral blood ,Ophthalmic pathology ,Neuro-ophthalmology ,hemic and lymphatic diseases ,Medicine ,Pediatric ophthalmology ,Radiology ,Differential diagnosis ,Myeloid leukaemia ,business - Abstract
We present a case of 10 year old boy who came to us with rapidly progressing bilateral proptosis. Computed tomography showed ill defined homogenous mass in bilateral orbits. Total leucocyte count was raised and peripheral smear showed presence of blasts confirming diagnosis of acute myeloid leukaemia. This case of ours highlights that leukaemia is an important differential diagnosis in children presenting with bilateral proptosis. Along with orbital imaging peripheral blood smear is a useful and inexpensive tool to aid in early diagnosis of the disease and for eventual favourable outcome. Keywords: Proptosis, Acute myeloid leukemia, Peripheral smear.
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- 2019
297. A novel entity of acute myeloid leukaemia with recurrent RARG-rearrangement resembling acute promyelocytic leukaemia
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Hui-Yang Yu, Hong Luo, Xing-Hua Chen, Yan-Chun Li, Li-Feng Liu, Ke Li, Yuan Sun, Suo Zhang, and Hong-Hu Zhu
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Cancer Research ,Oncology ,business.industry ,Cancer research ,Medicine ,Hematology ,Acute promyelocytic leukaemia ,Myeloid leukaemia ,business - Published
- 2019
298. Gilteritinib for Relapsed Acute Myeloid Leukaemia with FLT3 Mutation during the COVID-19 Pandemic: Real World Experience from the UK National Health Service
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Vana Katsomitrou, Jad Othman, Justin Loke, Sylvie D. Freeman, Duncan Murray, Manish Jain, Behnaz Mobashwera, Renuka Palanicawandar, David Taussig, Michael J Austin, Anjum Bashir Khan, Charlotte Kallmeyer, Annie Latif, Alex Sternberg, Tom Taylor, Johnathon Elliot, Alex Bashford, Jamie Saunders, Seye Kolade, Michael Lim, Pramila Krishnamurthy, Edward Belsham, Sebastian Francis, John Laurie, Sreetharan Munisamy, Paolo Gallipoli, Charles Craddock, Cara Manson, Richard Dillon, Matthew Smith, Raymond Dang, Saniya Dhawan, Vidhya Murthy, Scott Marshall, Jennifer Byrne, Usman Afzal, Thomas Coats, Katherine Hodgson, Asim Khwaja, Michael Dennis, Ruebina Amofa, and Katherine Smith
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medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,business.industry ,615.Acute Myeloid Leukemias: Commercially Available Therapies, Excluding Transplantation and Cellular Immunotherapies ,Immunology ,education ,Gilteritinib ,Cell Biology ,Hematology ,National health service ,Biochemistry ,Family medicine ,Flt3 mutation ,Pandemic ,Medicine ,Myeloid leukaemia ,business ,health care economics and organizations - Abstract
Background Early data suggest that patients undergoing salvage chemotherapy for relapsed or refractory (R/R) acute myeloid leukaemia (AML) have poor outcomes if infected with SARS-CoV-2, and nosocomial transmission has been a major problem worldwide. Gilteritinib is effective in R/R FLT3 mutated AML, is significantly less immunosuppressive and does not require hospital admission, however at the start of the pandemic this was not yet approved for routine use in all countries. In the United Kingdom, the National Health Service (NHS) made gilteritinib available as an emergency measure from late April 2020 to patients aged >16y with R/R FLT3 mutated AML, with the aim of reducing both mortality and healthcare resource use. We report a health-system-wide real world data collection for toxicity and patient outcomes across 27 NHS Hospitals. Methods Each patient was registered on a central NHS database, with clinicians certifying that their patient met the above criteria. Anonymised data were retrospectively collected by treating physicians. Gilteritinib dose, duration and toxicity information was requested for the first 4 cycles of therapy. Response definitions were as per European Leukaemia Network (ELN) guidelines. A total of 81 patients have been registered on the scheme, with outcomes reported here for those with follow-up information at a data cut on 1st August 2021. Results Fifty patients were included with a median age of 59y (range 19 - 77) and 50% male. The majority (83%) had an ECOG performance status of 0-1. AML was secondary to a previous haematological disorder in 12%, therapy-related in 4% and de novo in the remaining 84%. The disease was refractory to the last therapy in 38%. Most patients had previously received 1 (65%) or 2 (33%) lines of therapy, including intensive chemotherapy in a majority (86%). A FLT3 inhibitor had previously been administered to 45% and 35% were post allogeneic transplant. The FLT3 mutation was an internal tandem duplication (ITD) in 80% and tyrosine kinase domain (TKD) mutation in 22%. NPM1 mutations were detected in 34%. Next-generation sequencing results were available for 94% of patients, with mutations in IDH1 or IDH2 in 12.5%, ASXL1 in 2%, RUNX1 in 21% and no TP53 mutations. Patients spent a median 3.5 days in hospital in cycle 1, 0 days in cycles 2 and 3 and 1 day in cycle 4. In cycles 1, 2, 3 and 4, the median number of days of grade 4 neutropenia was 18, 7, 7.5, and 6.5 respectively, and the grade 4 thrombocytopenia was 2, 7, 0.5 and 0.5. The composite complete remission (CR) / CR with incomplete haematological recovery (CRi) rate was 27%. MRD data is being collected. The best response was morphological leukaemia free state (MLFS) in 4%, partial remission (PR) in 25% and refractory disease in 38%. The rate of combined CR/CRi did not differ in those with previous exposure to FLT3 inhibitors (23% vs 32%, p=0.6) or with past allogeneic transplant (29% vs 27%, p=0.3). There were no CR/CRi in patients with adverse cytogenetic risk. Median follow-up was 10.5 months (95%CI 7.3 - 12.3) with median overall survival (OS) 6.7 months (95%CI 4.5 - not reached). Mortality at day 30 was 0% and day 60 was 14%. 12-month overall survival was 38%. Patients who achieved a CR/CRi had a 12-month OS of 83%, and for PR this was 35%. Survival did not differ in those with previous FLT3 inhibitor exposure (HR 1.0, p>0.9) or allogeneic transplant (HR 0.63, p=0.3). Seven patients (14%) so far have been bridged with gilteritinib to allogeneic transplant. Conclusion Our data demonstrate that gilteritinib is well tolerated and clinically active in adults with relapsed FLT3 mutated AML. Importantly, during the COVID-19 pandemic, its availability has permitted the great majority of treatment to be delivered as an outpatient with significant resource saving at a time of critically constrained inpatient resources. Patients who achieve CR/CRi have good short-term outcomes and are able to proceed to a potentially curative allogeneic stem cell transplant. Figure 1 Figure 1. Disclosures Belsham: Celgene: Other: meeting attendance; Abbvie: Other: meeting attendance. Byrne: Incyte: Honoraria. Khan: Abbvie: Honoraria; Astellas: Honoraria; Takeda: Honoraria; Jazz: Honoraria; Gilead: Honoraria; Novartis: Honoraria. Khwaja: Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Latif: Kite: Consultancy, Honoraria, Speakers Bureau; Jazz: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Speakers Bureau; Takeda UK: Speakers Bureau. Loke: Amgen: Honoraria; Daichi Sankyo: Other: Travel Support; Janssen: Honoraria; Novartis: Other: Travel Support; Pfizer: Honoraria. Munisamy: Jazz Pharmaceuticals: Speakers Bureau; Roche: Speakers Bureau. Murthy: Abbvie: Other: support to attend educational conferences.. Smith: Daiichi Sankyo: Speakers Bureau; Pfizer: Speakers Bureau; ARIAD: Honoraria. Craddock: Novartis Pharmaceuticals: Other: Advisory Board ; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dillon: Amgen: Other: Research support (paid to institution); Astellas: Consultancy, Other: Educational Events , Speakers Bureau; Menarini: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Session chair (paid to institution), Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: educational events; Jazz: Other: Education events; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research Support, Educational Events.
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- 2021
299. A Randomised Evaluation of Low-Dose Ara-C Plus BCT-100 Versus Low Dose Ara-C in Older Patients with Acute Myeloid Leukaemia: Results from the LI-1 Trial
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Mary Frances McMullin, Ian Thomas, Priyanka Mehta, Francis Mussai, Nigel H. Russell, Cono Ariti, Laura Upton, Mhairi Copland, Robert Kerrin Hills, Steve Knapper, Alan K. Burnett, and Mia Sydenham
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medicine.medical_specialty ,business.industry ,Immunology ,Low dose ,Cell Biology ,Hematology ,Biochemistry ,Gastroenterology ,Older patients ,Internal medicine ,medicine ,Myeloid leukaemia ,business ,health care economics and organizations - Abstract
Background: Among patients with Acute Myeloid Leukaemia (AML) over the age of 60, a considerable number are not considered suitable for intensive remission-induction chemotherapy. Survival in these patients is poor, whether they are treated using hypomethylating agents or low-dose ara-C (LDAC). The possibility of combination therapy with additional agents represents an attractive option. Arginine metabolism plays a key role in AML pathogenesis (Mussai et al. Blood 2013); BCT-100 is a pegylated recombinant human arginase that leads to a rapid depletion in extracellular and intracellular arginine concentrations resulting in G0/G1 arrest, and subsequent death by necrosis. BCT-100 demonstrates significant activity as single-agent against AML cell lines, AML xenografts and primary AML blasts from newly diagnosed or relapsed patients (Mussai et al. Blood 2015). Importantly BCT-100 is synergistic in combination with cytarabine. Aims: To assess the efficacy of LDAC+BCT100 versus LDAC alone in patients aged 60+ unsuitable for intensive therapy, in a "pick a winner" design. This design allows several treatments to be assessed simultaneously in a randomised fashion, with the aim of doubling 2-year survival from 11% to 22% (HR 0.69), with interim assessments after 50 and 100 patients per arm are recruited. Methods: LDAC was given at 20mg BD SC on days 1-10 of each course. Patients randomised to the combination received LDAC as above with BCT-100 1600U/kg on Days 1, 8, 15 and 22 as a 1-hour intravenous infusion. Courses occurred at 4-6 week intervals. Toxicities were recorded using CTCAE version 3. Pharmacokinetic and biomarker samples were assessed in BCT-100 patients. Results here are based upon median follow-up of 3.8 months (range: 0.1 - 20.6 months) Results: Between September 2018 and December 2020, 83 patients were randomised. The trial was prematurely closed due to the COVID pandemic and did not reach the pre-planned first evaluation. Median age was 76.7 years (range 62-88). Overall, 65% were male; 70% de novo AML, 23% secondary AML, and 6% high risk MDS; 2% favourable, 59% intermediate, 23% adverse and 15% unknown/unreported cytogenetics. Median of 2 courses was delivered in either arm (mean 2 LDAC, 2 LDAC+BCT, range for both: 1-12). BCT-100 leads to a depletion of arginine from baseline in the majority of patients. Overall response (CR/CRi) was achieved in 12/81 patients (15%), (LDAC+BCT-100 15%, LDAC 15%, R 1.03 (0.30, 3.51),P=0.963). Thirty-day mortality was not significantly increased (18% vs 11%, HR 1.71 (0.50, 5.84), P=0.393; and 1-year survival showed no evidence of a difference (31% vs 30%, HR 1.28 (0.72, 2.25). Median overall survival time was 3.8 vs 6.4months; overall survival HR 1.11 (0.64, 1.90), P=0.715. The most common cause of death was resistant/recurrent disease: 12(46%) vs 16(59%). BCT-100 was not associated with any haematological toxicity; although rare grade 3/4 cardiac and hepatic events were reported, these were not significantly increased with BCT-100. Summary: The addition of BCT-100 to LDAC did not improve response rate or survival. BCT-100 was well tolerated with an acceptable toxicity profile. Further clinical evaluation of BCT-100 induced arginase depletion continues in a variety of malignancies. Acknowledgements: We are grateful to Blood Cancer UK for funding the trial and Bio-Cancer Treatment International for providing drug and additional support for this Investigator Initiated Study. Figure 1. OS All patients Figure 1 Figure 1. Disclosures Knapper: Jazz: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Astellas: Ended employment in the past 24 months, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. McMullin: Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: clinical trial support, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AOP Orphan: Research Funding, Speakers Bureau. Copland: Incyte: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Cyclacel Ltd: Research Funding; Astellas: Honoraria, Speakers Bureau; Jazz: Honoraria, Speakers Bureau. Russell: Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees; Jazz: Research Funding, Speakers Bureau.
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- 2021
300. Genetic Landscape and Clonal Evolution Patterns of CEBPA-Mutated Acute Myeloid Leukaemia Based on Next-Generation Sequencing: A Retrospective Analysis
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Rosa Greco, Silvio Veronese, Alessandro Beghini, Roberto Cairoli, Michele Nichelatti, Laura Pezzetti, Valentina Motta, Valentina Mancini, Marco Montillo, Livia Leuzzi, Giambattista Bertani, Leuzzi, L, Mancini, V, Veronese, S, Pezzetti, L, Motta, V, Nichelatti, M, Greco, R, Bertani, G, Montillo, M, Beghini, A, and Cairoli, R
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Genetics ,Immunology ,CEBPA ,Retrospective analysis ,Acute Myeloid Leukemias ,Cell Biology ,Hematology ,Myeloid leukaemia ,Biology ,Biochemistry ,Somatic evolution in cancer ,DNA sequencing - Abstract
Introduction Although CCAAT/enhancer binding protein alpha double mutated (CEBPADM) acute myeloid leukemia (AML) is considered a low-risk form of AML according to 2017 ELN recommendations, relapse remains a major cause of death. To assess the broader prognostic impact of other cancer-associated genes, we sequenced a panel of 40 myeloid disorders-related genes in a 25 patient cohort. Methods 16 CEBPADM AML diagnosis samples along with 9 CEBPAsingle mutated (SM) were analyzed by targeted next-generation sequencing (Ion Torrent) using Oncomine Myeloid Research Assay. 4 CEBPADM and 2 CEBPASM AML relapse samples were analyzed as well. All patients received intensive chemotherapy according to 2017 ELN recommendations. Results With a median follow-up of 3.2 years (range 0.4-12) 5y OS was 61% and 14% for CEBPADM and CEBPASM patients respectively. Overall, a median of 3 concurrent mutations were present at diagnosis, slightly more in CEBPA SM patients (4 vs 3 in CEBPA DMpatients). The number of somatic mutations influenced both PFS and OS (p = 0.04 and p < 0.01 respectively) independently of CEBPA mutational status. Each single unitary increase in the number of mutations increased the hazard for death of 27.7% (95% CI: -1.4-+65; p = 0.064) while passing from 4 to 5 mutations increased the odds of death by 367%. 5y OS in patients with 5 or more concurrent mutation was 14.3% vs 61.8% in patients with less than 5 co-mutated genes; 5y PFS was 0% vs 38.6%. Mutational landscape of CEBPADMand CEBPASMAML differed significantly, with GATA2, FLT3, DNMT3A and TET2 being the most frequently mutated genes in CEBPADM vs NPM1, FLT3, DNMT3A and WT1 in CEBPASM patients. NPM1(77.8% vs 6.7%; p < 0.01) and ASXL1 mutations (44.4% vs 0%; p = 0.02) were more frequent in CEBPASM patients, confirming they are mutually exclusive with CEBPA biallelic lesions. DNA methylation was the most frequently mutated pathway in biallelic patients (87%) while chromatin/cohesin complex (88%) was the most frequently mutated one in CEBPA monoallelic patients. Mutations of CEBPA, NPM1, DNMT3A, WT1, STAG2, TET2, ASXL1, IDH2, SRSF2, CALR, PRPF8, NF1, TP53, RUNX1 had the highest median variant allele frequency (VAF), more often representing founding mutations. GATA2, IDH1, KRAS, BCOR, MPL, IKZ2F1 and PTPN11 had a more borderline median VAF, variably being clonal or subclonal. Mutations in the 3 tyrosine kinases genes FLT3-ITD , CSF3R, NRAS were only subclonal. Mutations in WT1 and FLT3 were associated with increased relapse rate (p = 0.02 and p = 0.01 respectively), while patients with GATA2 mutations had a strong trend towards better 5y OS (83% vs 32%, p = 0.053). We also identified a not previously described allelic variant in the SH2B3 gene (ATGGGG/A INDEL) with an overall prevalence in our population of 58.3% (46.7% of CEBPA DM and 77.8% of CEBPA SMpatients). Patients with the SH2B3allelic variant had a significantly lower bone marrow blast percentage at diagnosis (p = 0.014) and a strong trend towards a higher number of concurrent mutations (p = 0.056). Moreover, when present at diagnosis, SH2B3 variant persisted at relapse with the same VAF. By real time PCR we demonstrated that this SH2B3 allelic variant leads to a dramatic reduction of the corresponding transcript. This gene encodes for a negative regulator of many crucial signaling pathways (SCF/c-KIT, erythropoietin/JAK2, thrombopoietin/MPL WT/ W515L, JAK2 WT/ V617F, GM-CSFR and FLT3-WT/ITD) of the hematopoietic stem cell. Matched diagnosis and relapse samples analysis suggested different features of clonal evolution: while mutations of SH2B3, WT1, DNMT3A, NPM1, and IDH1 consistently persisted at relapse, CEBPA and GATA2 mutations were unstable during disease course. ZRSR2 and PRPF8 mutations were found in relapse samples only. Summary Our study offers insights into the genetic landscape of CEBPADM mutated AML as compared to CEBPASM AML, highlighting the contribution of NGS to risk stratification. In fact, our data show that the number and the type of concurrent mutation has a prognostic impact, possibly identifying patients eligible to first line allogeneic stem cell transplantation. We identified an allelic variant of SH2B3 that had never been functionally characterized nor associated with AML and that could represent a marker for genetic instability and a potential new target in AML treatment strategies. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
- Published
- 2021
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