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secondary acute myeloid leukemia

Guillermo Garcia-Manero, Yasmin Abaza, Koichi Takahashi, Bruno C Medeiros, Martha Arellano, Samer K Khaled, Mrinal Patnaik, Olatoyosi Odenike, Hamid Sayar, Mohan Tummala, Prapti Patel, Lori Maness-Harris, Robert Stuart, Elie Traer, Kasra Karamlou, Abdulraheem Yacoub, Richard Ghalie, Ruben Giorgino, Ehab Atallah
Pracinostat, a potent oral pan-histone deacetylase inhibitor with modest single-agent activity in acute myeloid leukemia (AML), has shown synergistic antitumor activity when combined with azacitidine. This single-group, multicenter phase 2 study assessed the safety and efficacy of pracinostat combined with azacitidine in patients who were at least 65 years old with newly diagnosed AML and who were ineligible for standard induction chemotherapy. Patients received pracinostat 60 mg/d, 3 d/wk, for 3 consecutive weeks, plus azacitidine 75 mg/m2 daily for 7 days in a 28-day cycle...
February 26, 2019: Blood Advances
Peter Valent, Wolfgang Kern, Gregor Hoermann, Jelena D Milosevic Feenstra, Karl Sotlar, Michael Pfeilstöcker, Ulrich Germing, Wolfgang R Sperr, Andreas Reiter, Dominik Wolf, Michel Arock, Torsten Haferlach, Hans-Peter Horny
The development of leukemia is a step-wise process that is associated with molecular diversification and clonal selection of neoplastic stem cells. Depending on the number and combinations of lesions, one or more sub-clones expand/s after a variable latency period. Initial stages may develop early in life or later in adulthood and include premalignant (indolent) stages and the malignant phase, defined by an acute leukemia. We recently proposed a cancer model in which the earliest somatic lesions are often age-related early mutations detectable in apparently healthy individuals and where additional oncogenic mutations will lead to the development of an overt neoplasm that is usually a preleukemic condition such as a myelodysplastic syndrome...
February 12, 2019: International Journal of Molecular Sciences
Jonas Samuel Jutzi, Titiksha Basu, Maximilian Pellmann, Sandra Kaiser, Doris Steinemann, Mathijs A Sanders, Adil S A Hinai, Annelieke Zeilemaker, Sarolta Bojtine Kovacs, Christoph Koellerer, Jenny Ostendorp, Konrad Aumann, Wei Wang, Emmanuel Raffoux, Bruno Cassinat, Lars Bullinger, Brigitte Schlegelberger, Peter J M Valk, Heike Luise Pahl
In acute myeloid leukemia (AML), acquired genetic aberrations carry prognostic implications and guide therapeutic decisions. Clinical algorithms have been improved by the incorporation of novel aberrations. Here, we report the presence and functional characterization of mutations in the transcription factor NFE2 in AML patients and in a patient with myelosarcoma. We previously described NFE2 mutations in patients with myeloproliferative neoplasms and demonstrated that expression of mutant NFE2 in mice causes a myeloproliferative phenotype...
February 12, 2019: Blood
Marie Sébert, Aline Renneville, Cécile Bally, Pierre Peterlin, Odile Beyne-Rauzy, Laurence Legros, Marie-Pierre Gourin, Laurence Sanhes, Eric Wattel, Emmanuel Gyan, Sophie Park, Aspasia Stamatoullas, Anne Banos, Kamel Laribi, Simone Jueliger, Luke Bevan, Fatiha Chermat, Rosa Sapena, Olivier Nibourel, Cendrine Chaffaut, Sylvie Chevret, Claude Preudhomme, Lionel Adès, Pierre Fenaux
High-risk myelodysplastic syndrome/acute myeloid leukemia patients have a very poor survival after azacitidine failure. Guadecitabine (SGI-110) is a novel subcutaneous hypomethylating agent, which results in extended decitabine exposure. This multicenter phase II study evaluated the efficacy and safety of guadecitabine in high-risk myelodysplastic syndrome and low blast count acute myeloid leukemia patients refractory or relapsing after azacitidine. We included 56 patients with a median age of 75 years (IQR 69-76)...
February 7, 2019: Haematologica
Florian Huemer, Thomas Melchardt, Bettina Jansko, Adam Wahida, Stefanie Jilg, Philipp J Jost, Eckhard Klieser, Steiger Katja, Teresa Magnes, Lisa Pleyer, Sigrun Greil-Ressler, Christof Rass, Richard Greil, Alexander Egle
Secondary acute myeloid leukemia (sAML) evolving from an antecedent hematological disorder and therapy-related sAML represent high-risk subsets of AML and are associated with poor clinical outcome. The hypomethylating agents (HMA), azacitidine and decitabine represent treatment options for elderly AML patients including sAML patients unfit for intensive chemotherapy. This article is protected by copyright. All rights reserved.
February 6, 2019: European Journal of Haematology
Geetanjali R Kamath, Douglas Tremblay, Alexander Coltoff, Jessica Caro, Guido Lancman, Sheena Bhalla, Vesna Najfeld, John Mascarenhas, Emanuela Taioli
Acute promyelocytic leukemia (APL) is a particularly aggressive subtype of acute myeloid leukemia (AML), with high rates of early death. It is important to examine how epidemiologic characteristics, clinical and treatment factors, cytogenetic and genetic data affect survival and differ between APL and non-APL AML patients. We analyzed population data from the New York State Cancer Registry to characterize AML including APL incidence rates by demographics. APL incidence rates were higher among Hispanics than non-Hispanics (Incidence rate ratio=1...
January 23, 2019: Carcinogenesis
Marco Picardi, Roberta Della Pepa, Claudio Cerchione, Novella Pugliese, Chiara Mortaruolo, Fabio Trastulli, Claudia Giordano, Francesco Grimaldi, Irene Zacheo, Marta Raimondo, Federico Chiurazzi, Fabrizio Pane
BACKGROUND: The incidence of peripherally inserted central catheter (PICC)-related adverse events has been uncertain in the setting of acute myeloid leukemia (AML) compared with the incidence of centrally inserted central catheter (CICC) adverse events. PATIENTS AND METHODS: We conducted a monocentric, randomized trial of patients with previously untreated AML. Of the 93 patients, 46 had received a PICC and 47 had received a CICC as frontline intravascular device...
December 20, 2018: Clinical Lymphoma, Myeloma & Leukemia
N Naganna, Clement Opoku-Temeng, Eun Yong Choi, Elizabeth Larocque, Elizabeth T Chang, Brandon A Carter-Cooper, Modi Wang, Sandra E Torregrosa-Allen, Bennett D Elzey, Rena G Lapidus, Herman O Sintim
BACKGROUND: Acute myeloid leukemia (AML) remains one of the most lethal, rarely cured cancers, despite decades of active development of AML therapeutics. Currently, the 5-year survival of AML patients is about 30% and for elderly patients, the rate drops to <10%. About 30% of AML patients harbor an activating mutation in the tyrosine kinase domain (TKD) of Fms-Like Tyrosine kinase 3 (FLT3) or a FLT3 internal tandem duplication (FLT3-ITD). Inhibitors of FLT3, such as Rydapt that was recently approved by the FDA, have shown good initial response but patients often relapse due to secondary mutations in the FLT3 TKD, like D835Y and F691 L mutations...
January 24, 2019: EBioMedicine
Juan Eduardo Megías-Vericat, David Martínez-Cuadrón, Miguel Ángel Sanz, José Luis Poveda, Pau Montesinos
Induction chemotherapy based on anthracyclines and cytarabine (Ara-C) combination remains the standard of care for acute myeloid leukemia (AML) patients who are considered candidate for intensive and curative approaches. However, the toxicity of this regimen is high, with disappointing clinical outcomes among the so-called poor-prognosis AML subsets, which generally refer to patients with adverse cytogenetic risk, secondary AML including therapy-related AML, poor-prognosis mutations, especially FLT3-ITD, and relapse/refractory AML...
January 23, 2019: Expert Review of Clinical Pharmacology
Tiffany N Tanaka, Rafael Bejar
Myelodysplastic syndromes (MDS) are clonal diseases defined by clinical, morphologic and genetic features often shared by related myeloid disorders. The diagnostic boundaries between these diseases can be arbitrary and not necessarily reflective of underlying disease biology or outcomes. In practice, measures that distinguish MDS from related disorders may be difficult to quantify and can vary as disease progression occurs. Patients may harbor findings that are not consistent with a single diagnostic category...
January 22, 2019: Blood
Adélia Mendes, Birthe Fahrenkrog
NUP214 is a component of the nuclear pore complex (NPC) with a key role in protein and mRNA nuclear export. Chromosomal translocations involving the NUP214 locus are recurrent in acute leukemia and frequently fuse the C-terminal region of NUP214 with SET and DEK, two chromatin remodeling proteins with roles in transcription regulation. SET-NUP214 and DEK-NUP214 fusion proteins disrupt protein nuclear export by inhibition of the nuclear export receptor CRM1, which results in the aberrant accumulation of CRM1 protein cargoes in the nucleus...
January 21, 2019: Cells
Jan Philipp Bewersdorf, Maximilian Stahl, Amer M Zeidan
The 5-year overall survival rate of AML patients remains 25-40%. The prognosis is even more dismal for older patients who are ineligible for intensive chemotherapy and patients with secondary or relapsed/refractory AML. In 2017, 4 new drugs were approved by the US Food and Drug Administration for AML treatment: The FLT3 inhibitor midostaurin, the isocitrate dehydrogenase (IDH)-2 inhibitor enasidenib, a liposomal formulation of cytarabine and daunorubicin (CPX-351), and the anti-CD33 antibody gemtuzumab ozogamicin...
January 17, 2019: Leukemia & Lymphoma
Naval Daver, Richard F Schlenk, Nigel H Russell, Mark J Levis
Genomic investigations of acute myeloid leukemia (AML) have demonstrated that several genes are recurrently mutated, leading to new genomic classifications, predictive biomarkers, and new therapeutic targets. Mutations of the FMS-like tyrosine kinase 3 (FLT3) gene occur in approximately 30% of all AML cases, with the internal tandem duplication (ITD) representing the most common type of FLT3 mutation (FLT3-ITD; approximately 25% of all AML cases). FLT3-ITD is a common driver mutation that presents with a high leukemic burden and confers a poor prognosis in patients with AML...
January 16, 2019: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Haijiao Zhang, Samantha Savage, Anna Reister Schultz, Daniel Bottomly, Libbey White, Erik Segerdell, Beth Wilmot, Shannon K McWeeney, Christopher A Eide, Tamilla Nechiporuk, Amy Carlos, Rachel Henson, Chenwei Lin, Robert Searles, Hoang Ho, Yee Ling Lam, Richard Sweat, Courtney Follit, Vinay Jain, Evan Lind, Gautam Borthakur, Guillermo Garcia-Manero, Farhad Ravandi, Hagop M Kantarjian, Jorge Cortes, Robert Collins, Daelynn R Buelow, Sharyn D Baker, Brian J Druker, Jeffrey W Tyner
FLT3 mutations are prevalent in AML patients and confer poor prognosis. Crenolanib, a potent type I pan-FLT3 inhibitor, is effective against both internal tandem duplications and resistance-conferring tyrosine kinase domain mutations. While crenolanib monotherapy has demonstrated clinical benefit in heavily pretreated relapsed/refractory AML patients, responses are transient and relapse eventually occurs. Here, to investigate the mechanisms of crenolanib resistance, we perform whole exome sequencing of AML patient samples before and after crenolanib treatment...
January 16, 2019: Nature Communications
Mohamad Jawhar, Konstanze Döhner, Sebastian Kreil, Juliana Schwaab, Khalid Shoumariyeh, Manja Meggendorfer, Lambert L F Span, Stephan Fuhrmann, Nicole Naumann, Hans-Peter Horny, Karl Sotlar, Boris Kubuschok, Nikolas von Bubnoff, Karsten Spiekermann, Michael Heuser, Georgia Metzgeroth, Alice Fabarius, Stefan Klein, Wolf-Karsten Hofmann, Hanneke C Kluin-Nelemans, Torsten Haferlach, Hartmut Döhner, Nicholas C P Cross, Wolfgang R Sperr, Peter Valent, Andreas Reiter
KIT D816 mutations (KIT D816mut ) are strongly associated with systemic mastocytosis (SM) but are also detectable in acute myeloid leukemia (AML), where they represent an adverse prognostic factor in combination with core binding factor (CBF) fusion genes. Here, we evaluated the clinical and molecular features of KIT D816mut /CBF-negative (CBFneg ) AML, a previously uncharacterized combination. All KIT D816mut /CBFneg cases (n = 40) had histologically proven SM with associated AML (SM-AML). Molecular analyses revealed at least one additional somatic mutation (median, n = 3) beside KIT D816 (e...
January 11, 2019: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Gerwin Huls, Dana A Chitu, Violaine Havelange, Mojca Jongen-Lavrencic, Arjan A van de Loosdrecht, Bart J Biemond, Harm Sinnige, Beata Hodossy, Carlos Graux, Rien van Marwijk Kooy, Okke de Weerdt, Dimitri Breems, Saskia Klein, Jürgen Kuball, Dries Deeren, Wim Terpstra, Marie-Christiane Vekemans, Gert J Ossenkoppele, Edo Vellenga, Bob Löwenberg
The prevention of relapse is the major therapeutic challenge in older patients with acute myeloid leukemia (AML) who have obtained a complete remission (CR) on intensive chemotherapy. In this randomized phase III study (HOVON97) in older patients (≥ 60 years) with AML or MDS-RAEB, in CR/CRi after at least 2 cycles of intensive chemotherapy, we assessed the value of azacitidine as post remission therapy with respect to the disease free survival (DFS; primary endpoint) and overall survival (OS; secondary endpoint)...
January 10, 2019: Blood
Maximilian Doppelhammer, Alessia Fraccaroli, Dusan Prevalsek, Veit Bücklein, Sarah Häbe, Christoph Schulz, Max Hubmann, Andreas Hausmann, Rainer Claus, Andreas Rank, Christoph Schmid, Johanna Tischer
In acute myeloid leukemia (AML), primary refractory or relapsed disease, secondary AML, and leukemia with unfavorable genetics are considered high-risk AML (hrAML), with allogeneic stem cell transplantation (SCT) representing the standard treatment. Sequential conditioning has been successfully used for SCT in hrAML in HLA-matched transplants, and found its way into HLA-haploidentical SCT (haplo-SCT) later on. Hence, sequential conditioning had become standard for all patients with hrAML in our two centers, regardless of donor type...
January 8, 2019: Annals of Hematology
Tomasz Wojdyla, Hrishikesh Mehta, Taly Glaubach, Roberto Bertolusso, Marta Iwanaszko, Rosemary Braun, Seth J Corey, Marek Kimmel
Cancer development is driven by series of events involving mutations, which may become fixed in a tumor via genetic drift and selection. This process usually includes a limited number of driver (advantageous) mutations and a greater number of passenger (neutral or mildly deleterious) mutations. We focus on a real-world leukemia model evolving on the background of a germline mutation. Severe congenital neutropenia (SCN) evolves to secondary myelodysplastic syndrome (sMDS) and/or secondary acute myeloid leukemia (sAML) in 30-40%...
January 2019: PLoS Computational Biology
Umit Y Malkan, Ibrahim C Haznedaroglu
We aim to report a CML case that had fluid retention and serum creatinine increase under long-term imatinib mesylate (IM) treatment. A 68-year-old woman was diagnosed with chronic myeloid leukemia, and IM was started in 2002 with a dose of 400 mg/day. She had achieved complete hematological, molecular and cytogenetic remission under IM treatment. In September 2015, her creatinine level was 1.7 mg/dl. In May 2016, she was admitted to our hospital with dyspnea. Hypervolemia secondary to fluid retention was detected in our patient...
2019: Open Medicine (Warsaw, Poland)
Johannes Schetelig, Liesbeth C de Wreede, Michel van Gelder, Linda Koster, Jürgen Finke, Dietger Niederwieser, Dietrich Beelen, G J Mufti, Uwe Platzbecker, Arnold Ganser, Silke Heidenreich, Johan Maertens, Gerard Socié, Arne Brecht, Matthias Stelljes, Guido Kobbe, Liisa Volin, Arnon Nagler, Antonin Vitek, Thomas Luft, Per Ljungman, Ibrahim Yakoub-Agha, Marie Robin, Nicolaus Kröger
The causes and rates of late patient-mortality following alloHCT for myelodysplastic syndromes or secondary acute myeloid leukemia were studied, to assess the contribution of relapse-related, treatment-related, and population factors. Data from EBMT on 6434 adults, who received a first alloHCT from January 2000 to December 2012, were retrospectively studied using combined land-marking, relative-survival methods and multi-state modeling techniques. Median age at alloHCT increased from 49 to 58 years, and the number of patients aged ≥65 years at alloHCT increased from 5 to 17%...
December 20, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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