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Relapsed acute myeloid leukemia

Michael Medinger, Claudia Lengerke, Jakob Passweg
Acute myeloid leukemia (AML) is a biologically complex and molecularly and clinically heterogeneous disease, and its incidence is increasing as the population ages. Cytogenetic anomalies and mutation testing remain important prognostic tools for tailoring treatment after induction therapy. Despite major advances in understanding the genetic landscape of AML and its impact on the pathophysiology and biology of the disease, as well as the rapid development of new drugs, standard treatment options have not experienced major changes during the past three decades...
2016: Leukemia Research Reports
Elisabetta Zappone, Marzia Defina, Lara Aprile, Alessandro Gozzetti, Giulia Bartalucci, Monica Bocchia
In recent years there has been a great improvement in molecular characterization of acute myeloid leukemia (AML) allowing the stratification of patients in different rate of risk. Patients with FLT3 mutated AML have poor prognosis because of resistance to induction chemotherapy or early relapse. Several first and second generation molecules, able to inhibit FLT3 signaling have been developed and many single agent or combination studies are ongoing. Of these, quizartinib seems to have the best clinical activity...
October 10, 2016: Anti-cancer Agents in Medicinal Chemistry
Patrice Chevallier, Myriam Labopin, Regis Peffault de La Tour, Bruno Lioure, Claude-Eric Bulabois, Anne Huynh, Didier Blaise, Pascal Turlure, Etienne Daguindau, Natacha Maillard, Ibrahim Yakoub-Agha, Gaelle Guillerm, Jeremy Delage, Nathalie Contentin, Jacques-Olivier Bay, Florence Beckerich, Jean-Henri Bourhis, Marie Detrait, Stéphane Vigouroux, Sylvie François, Faezeh Legrand, Thierry Guillaume, Mohamad Mohty
We have retrospectively compared survivals between acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) patients who received either a clofarabine/busulfan (CloB2A2) or a fludarabine/busulfan (FB2A2) RIC regimen for allogeneic stem cell transplantation. Between 2009 and 2014, 355 allotransplanted cases were identified from the SFGM-TC registry as having received either the FB2A2 (n = 316, 56% males, median age: 59.2 years, AML 78.5%, first complete remission [CR1] 72%, median follow-up: 20 months) or the CloB2A2 (n = 39, 62% males, median age: 60...
October 17, 2016: Cancer Medicine
Savitha Varatharajan, John C Panetta, Ajay Abraham, Sreeja Karathedath, Ezhilpavai Mohanan, Kavitha M Lakshmi, Nancy Arthur, Vivi M Srivastava, Sandeep Nemani, Biju George, Alok Srivastava, Vikram Mathews, Poonkuzhali Balasubramanian
PURPOSE: Chemotherapy drug resistance and relapse of the disease have been the major factors limiting the success of acute myeloid leukemia (AML) therapy. Several factors, including the pharmacokinetics (PK) of Cytarabine (Ara-C) and Daunorubicin (Dnr), could contribute to difference in treatment outcome in AML. METHODS: In the present study, we evaluated the plasma PK of Dnr, the influence of genetic polymorphisms of genes involved in transport and metabolism of Dnr on the PK, and also the influence of these factors on clinical outcome...
October 13, 2016: Cancer Chemotherapy and Pharmacology
Beejal R Ganti, Bernard L Marini, Jerod Nagel, Dale Bixby, Anthony J Perissinotti
PURPOSE: This study evaluated the impact of antibacterial prophylaxis with levofloxacin in relapsed/refractory acute myeloid leukemia (AML) patients. METHODS: This was a retrospective, single-center, cohort study. Adult patients with relapsed/refractory AML admitted for reinduction chemotherapy between November 1, 2006 and June 15, 2015 were screened for inclusion. A protocol initiating levofloxacin prophylaxis was implemented on December 1, 2013. Patients receiving hypomethylating agents (decitabine/azacitidine) were not administered antibacterial prophylaxis and thus not included in this analysis...
October 14, 2016: Supportive Care in Cancer: Official Journal of the Multinational Association of Supportive Care in Cancer
Xiang Wang, Dongjian Zuo, Yufang Yuan, Xiaochun Yang, Ze Hong, Rongrong Zhang
PURPOSE: The aim of this study was to investigate roles of microRNA (miR)-183 in pediatric acute myeloid leukemia (AML). METHODS: miR-183 expression in bone marrow and patients' sera of childhood AML was detected by real-time quantitative PCR. Functions of miR-183 in malignant phenotypes of two leukemia cell lines were then evaluated. Additionally, putative targets of miR-183 were predicted using three miRNA target prediction algorithms and validated by luciferase reporter assay...
October 13, 2016: Journal of Cancer Research and Clinical Oncology
Chantal Fridle, Michael Medinger, Matthias C Wilk, Katja Seipel, Jakob Passweg, Markus G Manz, Thomas Pabst
BACKGROUND: The prognosis for relapsing AML patients is disappointing and the preferred salvage chemotherapy is unclear. Among other regimens, cladribine, cytarabine, and idarubicin (CLA-Ida) is used. METHODS: We analyzed relapsing AML patients receiving CLA-Ida chemotherapy between July 2012 and April 2015 at three academic centers in Switzerland. RESULTS: Thirty-four patients underwent at least one cycle of CLA-Ida chemotherapy, with 6 patients having two cycles...
October 13, 2016: Leukemia & Lymphoma
Gregory A Reed, Gary J Schiller, Suman Kambhampati, Martin S Tallman, Dan Douer, Mark D Minden, Karen W Yee, Vikas Gupta, Joseph Brandwein, Yulia Jitkova, Marcela Gronda, Rose Hurren, Aisha Shamas-Din, Andre C Schuh, Aaron D Schimmer
Acute myeloid leukemia (AML) cells meet the higher energy, metabolic, and signaling demands of the cell by increasing mitochondrial biogenesis and mitochondrial protein translation. Blocking mitochondrial protein synthesis through genetic and chemical approaches kills human AML cells at all stages of development in vitro and in vivo. Tigecycline is an antimicrobial that we found inhibits mitochondrial protein synthesis in AML cells. Therefore, we conducted a phase 1 dose-escalation study of tigecycline administered intravenously daily 5 of 7 days for 2 weeks to patients with AML...
October 13, 2016: Cancer Medicine
Deena Samir Eissa, Eman Zaghloul Kandeel, Mohamed Ghareeb
The prognosis of acute myeloid leukemia (AML) is poor because of relapses occurring on conventional chemotherapy. The distinction between leukemic and normal stem cells relies on the expression of antigen combinations defining leukemia-associated immunophenotypes (LAIPs), which are absent or extremely infrequent in normal bone marrow. However, LAIPs are very different from patient to patient and are not necessarily stable over the course of the disease. Accordingly, we addressed the applicability of human myeloid inhibitory C-lectin (hMICL) by flow cytometry as a specific leukemic myeloid stem cell marker for the diagnosis of AML in CD34(+) and CD34(-) cases and evaluated the stability of hMICL during the course of the disease...
October 13, 2016: Hematological Oncology
Xiao-Su Zhao, Ya-Zhen Qin, Yan-Rong Liu, Ying-Jun Chang, Lan-Ping Xu, Xiao-Hui Zhang, Xiao-Jun Huang
The minimal residual disease (MRD) before and after a haploidentical hematopoietic stem cell transplantation (HSCT) of 86 patients with acute myeloid leukemia (AML) in complete remission (CR) was measured using flow cytometry (FCM) and Wilms tumor 1 (WT1). In all, 18 patients met the criteria of pre-MRD + before HSCT. The FCM + (p = .028) and the combinative criteria for positive MRD (MRDco+) (p = .022) post-transplantation were significantly correlated to relapse in univariate analysis. A multivariate analysis showed that only MRDco + post-transplantation was an independent risk factor of leukemia relapse (p = ...
October 12, 2016: Leukemia & Lymphoma
Takahiro Yamauchi
Standard induction chemotherapy regimens achieve complete remission rates of 80% in younger adult patients with acute myeloid leukemia (AML). However, because of disease relapse only 40-50% of patients achieve long-term survival. Five-year survival rates in older patients are only one third of those achieved in younger cases. The adverse prognostic impact of advanced age is attributable to the chemotherapy-resistant nature of the blasts and the limited tolerability these patients have for intensive chemotherapy...
2016: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Norio Asou
Current treatment of acute myeloid leukemia (AML) still relies on intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT). AML is a heterogeneous neoplasm characterized by distinct chromosomal and genetic abnormalities. Recent comprehensive gene analyses have highlighted distinct genetic subgroups that are associated with different responses to chemotherapy. Therefore, the molecular landscape of AML is fundamental to the development of novel therapeutic approaches and provides opportunities for individualization of therapy...
2016: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Jie Xu, Wu Zhang, Xiao-Jing Yan, Xue-Qiu Lin, Wei Li, Jian-Qing Mi, Jun-Min Li, Jiang Zhu, Zhu Chen, Sai-Juan Chen
BACKGROUND: DNMT3A mutations are frequently discovered in acute myeloid leukemia (AML), associated with poor outcome. Recently, a relapse case report of AML extramedullary disease has showed that AML cells harboring DNMT3A variation were detected in the cerebral spinal fluid. However, whether a causal relationship exists between DNMT3A mutation (D3Amut) and extramedullary infiltration (EMI) is unclear. METHODS: We took advantage of DNMT3A (R882C) mutation-carrying AML cell strain, that is, OCI-AML3, assessing its migration ability in vitro and in vivo...
October 10, 2016: Journal of Hematology & Oncology
Leylagul Kaynar, Koray Demir, Esra Ermiş Turak, Çiğdem Pala Öztürk, Gökmen Zararsız, Zeynep Burçin Gönen, Selma Gökahmetoğlu, Serdar Şıvgın, Bülent Eser, Yavuz Köker, Musa Solmaz, Ali Ünal, Mustafa Çetin
INTRODUCTION: The use of αβ+ T-cell-depleted grafts is a novel approach to prevent graft failure, graft-versus-host disease (GVHD), and non-relapse mortality (NRM) in patients undergoing haploidentical hematopoietic stem cell transplantation. PATIENT AND METHOD: Thirty-four patients with acute leukemia and lacking a match donor were treated with αβ T-cell-depleted allografts from haploidentical family donors. A total of 24 patients had acute myeloid leukemia (AML) and 10 had acute lymphoblastic leukemia...
October 10, 2016: Hematology (Amsterdam, Netherlands)
Hyojeong Kim, Young Mi Seol, Moo-Kon Song, Young Jin Choi, Ho-Jin Shin, Sang Hyuk Park, Eun Yup Lee, Joo-Seop Chung
BACKGROUND: It is widely known that the prognosis of acute myeloid leukemia (AML) depends on chromosomal abnormalities. The majority of AML patients relapse and experience a dismal disease course despite initial remission. METHODS: We reviewed the medical records and laboratory findings of 55 AML patients who had relapsed between 2004 and 2013 and who had been treated at the Division of Hematology of the Pusan National University Hospital. RESULTS: The event-free survival (EFS) was related to prognostic karyotype classification at the time of diagnosis and relapse (unfavorable vs...
September 2016: Blood Research
B C Medeiros, A T Fathi, C D DiNardo, D A Pollyea, S M Chan, R Swords
Alterations to genes involved in cellular metabolism and epigenetic regulation are implicated in the pathogenesis of myeloid malignancies. Recurring mutations in isocitrate dehydrogenase (IDH) genes are detected in approximately 20% of adult patients with acute myeloid leukemia (AML) and 5% of adults with myelodysplastic syndromes (MDS). IDH proteins are homodimeric enzymes involved in diverse cellular processes, including adaptation to hypoxia, histone demethylation, and DNA modification. The IDH2 protein is localized in the mitochondria and is a critical component of the tricarboxylic acid (TCA, also called the 'citric acid' or Krebs) cycle...
October 10, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Silke Heidenreich, Dimitris Ziagkos, Liesbeth C de Wreede, Anja van Biezen, Jürgen Finke, Uwe Platzbecker, Dietger Niederwieser, Hermann Einsele, Wolfgang Bethge, Michael Schleuning, Dietrich W Beelen, Johanna Tischer, Arnon Nagler, Bertram Glass, Johan Maertens, Lucrecia Yáñez, Yves Beguin, Heinz Sill, Christof Scheid, Matthias Stelljes, Arnold Ganser, Pierre Zachée, Dominik Selleslag, Theo de Witte, Marie Robin, Nicolaus Kröger
In this retrospective analysis we evaluated the outcome of 313 patients aged 70 years or older in the registry of the European Society for Blood and Marrow Transplantation (EBMT) with MDS (n=221) and secondary acute myeloid leukemia (sAML) (n= 92) who underwent allogeneic hematopoietic stem cell transplantation (HSCT) from related (n=79) or unrelated donors (n=234). Median age at HSCT was 72 years (70-78 years). Conditioning regimen was non-myeloablative (NMA, n=54), reduced-intensity (RIC, n=207) or standard-intensity (MAC, n=52)...
October 5, 2016: Biology of Blood and Marrow Transplantation
Maël Heiblig, Mohamed Elhamri, Caroline Le Jeune, Marie-Charlotte Laude, Alexandre Deloire, Eric Wattel, Gilles Salles, Xavier Thomas
OBJECTIVE: Little data exist regarding long-term survival in elderly patients with acute myeloid leukemia (AML). METHODS: In view of the fact that most deaths occurred during the first 3 yr, this study examined long-term survival in this patient population, defined as overall survival for at least 3 yr with the aim to determine the number of long-term survivors and to identify factors that might impact on longer survival. RESULTS: The criterion for entry into this cohort was fulfilled by 57 patients among 302 seen over a 14-yr period (19%): 12 patients who never achieved complete remission (CR), 21 patients who relapsed after CR achievement, and 24 patients who achieved CR and did not relapse, including three patients who died while in CR and 21 patients still alive in first CR at the time of analysis...
September 26, 2016: European Journal of Haematology
Christoph Schliemann, Joachim Gerss, Stefanie Wiebe, Jan-Henrik Mikesch, Nicola Knoblauch, Tim Sauer, Linus Angenendt, Tobias Kewitz, Marc Urban, Trude Butterfass-Bahloul, Sabine Edemir, Kerstin Vehring, Carsten Müller-Tidow, Wolfgang E Berdel, Utz Krug
: Nintedanib (BIBF 1120), a potent multikinase inhibitor of VEGFR-1/-2/-3, FGFR-1/-2/-3 and PDGFR-α/-β, exerts growth inhibitory and pro-apoptotic effects in myeloid leukemic cells, especially when used in combination with cytarabine. This phase I study evaluated nintedanib in combination with low-dose cytarabine (LDAC) in elderly patients with untreated or relapsed/refractory acute myeloid leukemia (AML) ineligible for intensive chemotherapy in a 3+3 design. Nintedanib (dose levels 100, 150, and 200 mg orally twice daily) and LDAC (20 mg subcutaneous injection twice daily for 10 days) were administered in 28-day cycles...
2016: PloS One
Stephen S Y Lam, Eric S K Ho, Bai-Liang He, Wui-Wing Wong, Chae-Yin Cher, Nelson K L Ng, Cheuk-Him Man, Harinder Gill, Alice M S Cheung, Ho-Wan Ip, Chi-Chiu So, Jerome Tamburini, Chi Wai Eric So, Dona N Ho, Chun-Hang Au, Tsun-Leung Chan, Edmond S K Ma, Raymond Liang, Yok-Lam Kwong, Anskar Y H Leung
An in vitro drug-screening platform on patient samples was developed and validated to design personalized treatment for relapsed/refractory acute myeloid leukemia (AML). Unbiased clustering and correlation showed that homoharringtonine (HHT), also known as omacetaxine mepesuccinate, exhibited preferential antileukemia effect against AML carrying internal tandem duplication of fms-like tyrosine kinase 3 (FLT3-ITD). It worked synergistically with FLT3 inhibitors to suppress leukemia growth in vitro and in xenograft mouse models...
October 5, 2016: Science Translational Medicine
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