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acute refractory myeloid leukemia

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https://www.readbyqxmd.com/read/28211885/the-novel-bmi-1-inhibitor-ptc596-downregulates-mcl-1-and-induces-p53-independent-mitochondrial-apoptosis-in-acute-myeloid-leukemia-progenitor-cells
#1
Y Nishida, A Maeda, M J Kim, L Cao, Y Kubota, J Ishizawa, A AlRawi, Y Kato, A Iwama, M Fujisawa, K Matsue, M Weetall, M Dumble, M Andreeff, T W Davis, A Branstrom, S Kimura, K Kojima
Disease recurrence is the major problem in the treatment of acute myeloid leukemia (AML). Relapse is driven by leukemia stem cells, a chemoresistant subpopulation capable of re-establishing disease. Patients with p53 mutant AML are at an extremely high risk of relapse. B-cell-specific Moloney murine leukemia virus integration site 1 (BMI-1) is required for the self-renewal and maintenance of AML stem cells. Here we studied the effects of a novel small molecule inhibitor of BMI-1, PTC596, in AML cells. Treatment with PTC596 reduced MCL-1 expression and triggered several molecular events consistent with induction of mitochondrial apoptosis: loss of mitochondrial membrane potential, BAX conformational change, caspase-3 cleavage and phosphatidylserine externalization...
February 17, 2017: Blood Cancer Journal
https://www.readbyqxmd.com/read/28207808/autologous-hematopoietic-stem-cell-transplantation-in-lymphoma-patients-is-associated-with-a-decrease-in-the-double-strand-break-repair-capacity-of-peripheral-blood-lymphocytes
#2
Sandrine Lacoste, Smita Bhatia, Yanjun Chen, Ravi Bhatia, Timothy R O'Connor
Patients who undergo autologous hematopoietic stem cell transplantation (aHCT) for treatment of a relapsed or refractory lymphoma are at risk of developing therapy related- myelodysplasia/acute myeloid leukemia (t-MDS/AML). Part of the risk likely resides in inherent interindividual differences in their DNA repair capacity (DRC), which is thought to influence the effect chemotherapeutic treatments have on the patient's stem cells prior to aHCT. Measuring DRC involves identifying small differences in repair proficiency among individuals...
2017: PloS One
https://www.readbyqxmd.com/read/28187034/detection-of-novel-t-12-17-p12-p13-in-relapsed-refractory-acute-myeloid-leukemia-by-anchored-multiplex-pcr-amp-based-next-generation-sequencing
#3
Talha Badar, Laura Johnson, Katelyn Trifilo, Helen Wang, Brian A Kudlow, Eric Padron, Peter R Pappenhausen, Mohammad O Hussaini
Although several technologies can be used to detect gene fusions, anchored multiplex PCR next-generation sequencing (AMP-NGS) offers the advantage of novel fusion detection and the ability to multiplex multitudinous genes. We applied AMP-NGS technology in the evaluation of a 56-year-old gentleman with myelodysplastic syndrome transformed acute myeloid leukemia (AML). Patient was initially diagnosed with low-risk myelodysplastic syndrome-refractory cytopenias and multilineage dysplasia (MDS-RCMD), progressed to AML after failing hypomethylating agent therapy...
February 9, 2017: Applied Immunohistochemistry & Molecular Morphology: AIMM
https://www.readbyqxmd.com/read/28159598/predictive-value-of-pretransplantation-molecular-minimal-residual-disease-assessment-by-wt1-gene-expression-in-flt3-positive-acute-myeloid-leukemia
#4
Anna Candoni, Federico De Marchi, Francesca Zanini, Maria Elena Zannier, Erica Simeone, Eleonora Toffoletti, Alexsia Chiarvesio, Michela Cerno, Carla Filì, Francesca Patriarca, Renato Fanin
The FMS-like tyrosine kinase 3 (FLT3) mutation in acute myeloid leukemia (AML) is a negative prognostic factor and, in these cases, allogeneic stem cell transplantation (allo-SCT) can represent an important therapeutic option, especially if performed in complete remission (CR). However, it is increasingly clear that not all cytological CRs (cCRs) are the same and that minimal residual disease (MRD) before allo-SCT could have an impact on AML outcome. Unfortunately, FLT3, due its instability of expression, is still not considered a good molecular MRD marker...
February 1, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28143565/disulfiram-overcomes-bortezomib-and-cytarabine-resistance-in-down-syndrome-associated-acute-myeloid-leukemia-cells
#5
Ranjan Bista, David W Lee, Oliver B Pepper, David O Azorsa, Robert J Arceci, Eiman Aleem
BACKGROUND: Children with Down syndrome (DS) have increased risk for developing AML (DS-AMKL), and they usually experience severe therapy-related toxicities compared to non DS-AMKL. Refractory/relapsed disease has very poor outcome, and patients would benefit from novel, less toxic, therapeutic strategies that overcome resistance. Relapse/resistance are linked to cancer stem cells with high aldehyde dehydrogenase (ALDH) activity. The purpose of the present work was to study less toxic alternative therapeutic agents for relapsed/refractory DS-AMKL...
February 1, 2017: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/28138829/metabolism-and-disposition-of-the-anticancer-quinolone-derivative-vosaroxin-a-novel-inhibitor-of-topoisomerase-ii
#6
C M Nijenhuis, L Lucas, H Rosing, A D R Huitema, M Mergui-Roelvink, G C Jamieson, J A Fox, D R Mould, J H M Schellens, J H Beijnen
Background Vosaroxin is a first-in-class anticancer quinolone derivative that is being investigated for patients with relapsed or refractory acute myeloid leukemia (AML). The primary objective of this study was to quantitatively determine the pharmacokinetics of vosaroxin and its metabolites in patients with advanced solid tumors. Methods This mass balance study investigated the pharmacokinetics (distribution, metabolism, and excretion) of vosaroxin in cancer patients after a single dose of 60 mg/m(2 14)C-vosaroxin, administered as short intravenous injection...
January 31, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28138160/impact-of-salvage-regimens-on-response-and-overall-survival-in-acute-myeloid-leukemia-with-induction-failure
#7
M Wattad, D Weber, K Döhner, J Krauter, V I Gaidzik, P Paschka, M Heuser, F Thol, T Kindler, M Lübbert, H R Salih, A Kündgen, H-A Horst, P Brossart, K Götze, D Nachbaur, C-H Köhne, M Ringhoffer, G Wulf, G Held, H Salwender, A Benner, A Ganser, H Döhner, R F Schlenk
We evaluated the impact of salvage regimens and allogeneic hematopoietic cell transplantation (allo-HCT) in acute myeloid leukemia (AML) with induction failure. Between 1993 and 2009, 3324 patients with newly diagnosed AML were enrolled in 5 prospective treatment trials of the German-Austrian AML Study Group. After first induction therapy with idarubicin, cytarabine and etoposide (ICE), 845 patients had refractory disease. In addition, 180 patients, although responding to first induction, relapsed after second induction therapy...
February 10, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28137265/targeting-acute-myeloid-leukemia-stem-cell-signaling-by-natural-products
#8
REVIEW
Kodappully Sivaraman Siveen, Shahab Uddin, Ramzi M Mohammad
Acute myeloid leukemia (AML) is the most commonly diagnosed leukemia in adults (25%) and comprises 15-20% in children. It is a genetically heterogeneous aggressive disease characterized by the accumulation of somatically acquired genetic changes, altering self-renewal, proliferation, and differentiation of hematopoietic progenitor cells, resulting in uncontrolled clonal proliferation of malignant progenitor myeloid cells in the bone marrow, peripheral blood, and occasionally in other body tissues. Treatment with modern chemotherapy regimen (cytarabine and daunorubicin) usually achieves high remission rates, still majority of patients are found to relapse, resulting in only 40-45% overall 5 year survival in young patients and less than 10% in the elderly AML patients...
January 30, 2017: Molecular Cancer
https://www.readbyqxmd.com/read/28119224/clinical-significance-of-isolated-del-7p-in-myeloid-neoplasms
#9
Hatice Deniz Gur, Sa A Wang, Zhenya Tang, Shimin Hu, Shaoying Li, L Jeffrey Medeiros, Guilin Tang
Sole del(7p) is a rare finding in myeloid neoplasms and its clinical significance is largely unknown. Here we report 10 patients with isolated del(7p), 4 had acute myeloid leukemia (AML), 2 myelodysplastic syndromes (MDS), 1 chronic myelomonocytic leukemia (CMML), 1 primary myelofibrosis (PMF), and 2 AML in remission. Seven patients had large and 3 had small del(7p) clone. For patients with AML, 3 acquired del(7p) either at disease relapse or disease progression, then became refractory to therapy and died shortly thereafter (median 5 months)...
January 16, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28100265/allogeneic-stem-cell-transplantation-in-adult-patients-with-acute-myeloid-leukaemia-and-17p-abnormalities-in-first-complete-remission-a-study-from-the-acute-leukemia-working-party-alwp-of-the-european-society-for-blood-and-marrow-transplantation-ebmt
#10
Xavier Poiré, Myriam Labopin, Johan Maertens, Ibrahim Yakoub-Agha, Didier Blaise, Norbert Ifrah, Gérard Socié, Tobias Gedde-Dhal, Nicolaas Schaap, Jan J Cornelissen, Stéphane Vigouroux, Jaime Sanz, Lucienne Michaux, Jordi Esteve, Mohamad Mohty, Arnon Nagler
BACKGROUND: Acute myeloid leukaemia (AML) with 17p abnormalities (abn(17p)) carries a very poor prognosis due to high refractoriness to conventional chemotherapy, and allogeneic stem cell transplantation (allo-SCT) appears as the only potential curative option. METHODS: To address outcomes after allo-SCT in patients with abn(17p), we retrospectively analysed de novo or secondary AML undergoing SCT between 2000 and 2013 from the EBMT registry. RESULTS: One hundred thirty-nine patients with confirmed abn(17p) have been selected...
January 18, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28098170/targeting-the-pi3k-akt-pathway-via-gli1-inhibition-enhanced-the-drug-sensitivity-of-acute-myeloid-leukemia-cells
#11
Hui Liang, Qi-Li Zheng, Peng Fang, Jian Zhang, Tuo Zhang, Wei Liu, Min Guo, Christopher L Robinson, Shui-Bing Chen, Xiao-Ping Chen, Fang-Ping Chen, Hui Zeng
Combination targeted therapy is commonly used to treat acute myeloid leukemia (AML) patients, particularly in refractory/relapse (RR) population. However, concerns have been raised regarding the safety and patient tolerance of combination chemotherapy. It is critical to choose the appropriate treatment for precision therapy. We performed genome-wide RNA profiling using RNA-Seq to compare the RR group and the complete remission (CR) group (a total of 42 adult AML patients). The Hedgehog (Hh) and PI3K/AKT pathways were upregulated in the RR population, which was further confirmed by western blot and/or qPCR...
January 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28088971/-eltrombopag-for-refractory-thrombocytopenia-in-patients-with-allogeneic-hematopoietic-stem-cell-transplantation
#12
Y R Ma, X J Huang, X D Mo, W Han, C H Yan, Y Chen, Y Ji, Y Y Chen, Y Wang, X H Zhang, K Y Liu, L P Xu
Objective: To evaluate the efficacy and safety of eltrombopag in post-HSCT thrombocytopenia. Methods: A total of 10 patients who underwent post-HSCT thrombocytopenia at Peking University center, who had been treated with eltrombopag, were retrospectively evaluated. Results: Of the 10 cases, 5 males and 5 females with a median of 34 years old (range, 17-54 years), 5 patients were acute myeloid leukemia, 3 with acute lymphoid leukemia and 2 with severe aplastic anemia. Nine patients had undergone haplo-identical donor transplantation, and one patient was a matched related recipient...
December 14, 2016: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/28088962/-efficacy-and-safety-of-sorafenib-as-monotherapy-to-flt3-itd-positive-acute-myeloid-leukemia
#13
J S Jia, H H Zhu, H X Fu, L Z Gong, J Kong, X J Huang, H Jiang
Objective: To explore the efficacy and safety of Sorafenib as monotherapy to FLT3 positive acute myeloid leukemia (AML). Methods: From April 2014 to December 2015, fourteen AML patients with FLT3 positive, 7 males and 7 females with a median age of 42 (range: 14-81) years old, were enrolled in this study. Of the 14 cases, 4 were de novo cases, 9 refractory cases and 1 relapsed case, including 78.6% patients with severe complications and 57.1% patients with KPS score less than 60 [the median KPS score was 45 (20-70) ]...
December 14, 2016: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/28088961/-the-clinical-and-prognostic-significance-of-acute-myeloid-leukemia-with-flt3-itd
#14
D Lin, H Wei, Y Wang, C L Zhou, B C Liu, K Q Liu, B F Gong, S N Wei, G J Zhang, Y T Liu, X Y Gong, S W Qiu, Y C Mi, J X Wang
Objective: To investigate the clinical significance and prognosis factors of acute myeloid leukemia (AML) with FLT3 mutation-internal tandem duplication (FLT3-ITD) and provide more evidence for prognosis evaluation in AML with FLT3-ITD. Methods: The clinical characteristics and outcomes of 98 AML with FLT3-ITD were analyzed. Results: In patients with FLT3-ITD positive AML, the median of WBC and peripheral blood blast at initial diagnosis were 58.2 (0.3-461.8) ×10(9)/L and 42.2 (0-397.1) ×10(9)/L, respectively...
December 14, 2016: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/28067875/factors-predicting-outcome-after-allogeneic-transplant-in-refractory-acute-myeloid-leukemia-a-retrospective-analysis-of-gruppo-italiano-trapianto-di-midollo-osseo-gitmo
#15
E Todisco, F Ciceri, C Boschini, F Giglio, A Bacigalupo, F Patriarca, I Donnini, E P Alessandrino, W Arcese, A P Iori, P Marenco, I Cavattoni, P Chiusolo, E Terruzzi, L Castagna, A Santoro, A Bosi, E Oldani, B Bruno, F Bonifazi, A Rambaldi
The clinical outcome of primary refractory (PRF) AML patients is poor and only a minor proportion of patients is rescued by allogenic hematopoietic stem cell transplantation (HSCT). The identification of pre-HSCT variables may help to determine PRF AML patients who can most likely benefit from HSCT. We analyzed PRF AML patients transplanted between 1999 and 2012 from a sibling, unrelated donor or a cord blood unit. Overall, 227 patients from 26 Gruppo Italiano Trapianto di Midollo Osseo e Terapia cellulare centers were included in the analysis...
January 9, 2017: Bone Marrow Transplantation
https://www.readbyqxmd.com/read/28058490/second-line-azacitidine-for-elderly-or-infirmed-patients-with-acute-myeloid-leukemia-aml-not-eligible-for-allogeneic-hematopoietic-cell-transplantation-a-retrospective-national-multicenter-study
#16
Ron Ram, Moshe Gatt, Drorit Merkel, Ilana Helman, Tsofia Inbar, Arnon Nagler, Irit Avivi, Yishai Ofran
Elderly and infirm patients with acute myeloid leukemia (AML) with either induction refractory or relapse disease may benefit from treatment with azacitidine. We retrospectively reviewed the data from five tertiary centers in Israel, treated between 2009 and 2015. Thirty-four patients (median age 74 years) were identified. Sixty-two percent of the patients had relapsed disease and 38% had refractory disease. Median time of follow-up was 12.1 months. Out of a total of 327 courses, incidence of infectious episodes was 6%...
January 5, 2017: Annals of Hematology
https://www.readbyqxmd.com/read/28024959/clinicopathologic-immunophenotyping-and-cytogenetic-analysis-of-sweet-syndrome-in-egyptian-patients-with-acute-myeloid-leukemia
#17
Mohamed El-Khalawany, Soha Aboeldahab, Al-Sadat Mosbeh, Aida Thabet
BACKGROUND: Sweet syndrome (SS) is an uncommon dermatologic disorder that could be associated with hematologic malignancies. OBJECTIVE: To describe the clinicopathologic, immunophenotyping and cytogenetic characteristics of SS in Egyptian patients with acute myeloid leukemia (AML). METHODS: The study was conducted during the period from April 2011 to March 2015. For each patient, a clinical evaluation and histological assessment of cutaneous lesions were recorded...
October 26, 2016: Pathology, Research and Practice
https://www.readbyqxmd.com/read/28013105/the-effects-of-azacitidine-on-the-response-and-prognosis-of-myelodysplastic-syndrome-and-acute-myeloid-leukemia-involving-a-bone-marrow-erythroblast-frequency-of-50
#18
Tomoyuki Uchida, Masao Hagihara, Jian Hua, Morihiro Inoue
We reviewed the cases of 68 consecutive patients who were diagnosed with myelodysplastic syndrome (MDS, n=61) or acute erythroleukemia (AEL, n=7) according to the World Health Organization (WHO) 2008 criteria and had previously been treated with azacitidine, a hypomethylating agent. Fifteen MDS patients had bone marrow erythroblast frequencies of ≥50%, and 6 out of the 7 AEL patients were reclassified as MDS (refractory anemia with excess blasts [RAEB]-1: 1, RAEB-2: 5) according to the revised WHO 2016 criteria...
November 25, 2016: Leukemia Research
https://www.readbyqxmd.com/read/28011984/fractionated-gemtuzumab-ozogamicin-combined-with-intermediate-dose-cytarabine-and-daunorubicin-as-salvage-therapy-in-very-high-risk-aml-patients-a-bridge-to-reduced-intensity-conditioning-transplant
#19
Etienne Paubelle, Sophie Ducastelle-Leprêtre, Hélène Labussière-Wallet, Franck Emmanuel Nicolini, Fiorenza Barraco, Adriana Plesa, Gilles Salles, Eric Wattel, Xavier Thomas
Outcome of patients with primary refractory/relapsed (R/R) acute myeloid leukemia (AML) remains dismal. Herein, we present a retrospective monocentric study of 24 very high-risk AML patients who received a combination of fractionated gemtuzumab ozogamicin (GO) with intermediate-dose cytarabine and daunorubicin as salvage therapy. Median age was 55.3 years. Diagnostic was secondary AML for 33% of them. Seven patients had favorable risk, 8 had intermediate-1 or intermediate-2, and 6 had unfavorable risk of AML according to the European LeukemiaNet prognostic index...
March 2017: Annals of Hematology
https://www.readbyqxmd.com/read/27991919/samhd1-is-a-biomarker-for-cytarabine-response-and-a-therapeutic-target-in-acute-myeloid-leukemia
#20
Constanze Schneider, Thomas Oellerich, Hanna-Mari Baldauf, Sarah-Marie Schwarz, Dominique Thomas, Robert Flick, Hanibal Bohnenberger, Lars Kaderali, Lena Stegmann, Anjali Cremer, Margarethe Martin, Julian Lohmeyer, Martin Michaelis, Veit Hornung, Christoph Schliemann, Wolfgang E Berdel, Wolfgang Hartmann, Eva Wardelmann, Federico Comoglio, Martin-Leo Hansmann, Alexander F Yakunin, Gerd Geisslinger, Philipp Ströbel, Nerea Ferreirós, Hubert Serve, Oliver T Keppler, Jindrich Cinatl
The nucleoside analog cytarabine (Ara-C) is an essential component of primary and salvage chemotherapy regimens for acute myeloid leukemia (AML). After cellular uptake, Ara-C is converted into its therapeutically active triphosphate metabolite, Ara-CTP, which exerts antileukemic effects, primarily by inhibiting DNA synthesis in proliferating cells. Currently, a substantial fraction of patients with AML fail to respond effectively to Ara-C therapy, and reliable biomarkers for predicting the therapeutic response to Ara-C are lacking...
February 2017: Nature Medicine
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