Journal ArticleDOI
Multicenter, Phase II Study of Decitabine for the First-Line Treatment of Older Patients With Acute Myeloid Leukemia
TLDR
Decitabine given in a low-dose, 5-day regimen has activity as upfront therapy in older patients with AML, and it has acceptable toxicity and 30-day mortality.Abstract:
Purpose Older patients with acute myeloid leukemia (AML) have limited treatment options because of the lack of effectiveness and the toxicity of available therapies. We investigated the efficacy and toxicity of the hypomethylating agent decitabine as initial therapy in older patients with AML. Patients and Methods In this multicenter, phase II study, patients older than 60 years who had AML (ie, > 20% bone marrow blasts) and no prior therapy for AML were treated with decitabine 20 mg/m2 intravenously for 5 consecutive days of a 4-week cycle. Response was assessed by weekly CBC and bone marrow biopsy after cycle 2 and after each subsequent cycle. Patients continued to receive decitabine until disease progression or an unacceptable adverse event occurred. Results Fifty-five patients (mean age, 74 years) were enrolled and were treated with a median of three cycles (range, one to 25 cycles) of decitabine. The expert-reviewed overall response rate was 25% (complete response rate, 24%). The response rate was co...read more
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Journal ArticleDOI
DNMT3A Mutations in Acute Myeloid Leukemia
Timothy J. Ley,Li Ding,Matthew J. Walter,Michael D. McLellan,Tamara Lamprecht,David E. Larson,Cyriac Kandoth,Jacqueline E. Payton,Jack Baty,John S. Welch,Chris Harris,Cheryl F. Lichti,R. Reid Townsend,Robert S. Fulton,David J. Dooling,Daniel C. Koboldt,Heather Schmidt,Qunyuan Zhang,John R. Osborne,Ling Lin,Michelle O'Laughlin,Joshua F. McMichael,Kim D. Delehaunty,Sean McGrath,Lucinda Fulton,Vincent Magrini,Tammi L. Vickery,Jasreet Hundal,Lisa Cook,Joshua J. Conyers,Gary W. Swift,Jerry P. Reed,Patricia A. Alldredge,Todd Wylie,Jason Walker,Joelle Kalicki,Mark A. Watson,Sharon Heath,William D. Shannon,Nobish Varghese,Rakesh Nagarajan,Peter Westervelt,Michael H. Tomasson,Daniel C. Link,Timothy A. Graubert,John F. DiPersio,Elaine R. Mardis,Richard K. Wilson +47 more
TL;DR: DNMT3A mutations are highly recurrent in patients with de novo AML with an intermediate-risk cytogenetic profile and are independently associated with a poor outcome in Cox proportional-hazards analysis.
Journal ArticleDOI
Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia.
Courtney D. DiNardo,Keith W. Pratz,Vinod Pullarkat,Brian A. Jonas,Martha Arellano,Pamela S. Becker,Pamela S. Becker,Olga Frankfurt,Marina Konopleva,Andrew H. Wei,Hagop M. Kantarjian,Tu Xu,Wan Jen Hong,Brenda Chyla,Jalaja Potluri,Daniel A. Pollyea,Anthony Letai +16 more
TL;DR: The novel combination of venetoclax with decitabine or azacitidine was effective and well tolerated in elderly patients with AML and achieved complete remission (CR) + CR with incomplete count recovery (CRi).
Journal ArticleDOI
Multicenter, Randomized, Open-Label, Phase III Trial of Decitabine Versus Patient Choice, With Physician Advice, of Either Supportive Care or Low-Dose Cytarabine for the Treatment of Older Patients With Newly Diagnosed Acute Myeloid Leukemia
Hagop M. Kantarjian,Xavier Thomas,Anna Dmoszynska,Agnieszka Wierzbowska,Grzegorz Mazur,Jiri Mayer,Jyh Pyng Gau,Wen-Chien Chou,Rena Buckstein,Jaroslav Cermak,Ching Yuan Kuo,Albert Oriol,Farhad Ravandi,Stefan Faderl,Jacques Delaunay,Daniel Lysák,Mark D. Minden,Christopher Arthur +17 more
TL;DR: In older patients with AML, decitabine improved response rates compared with standard therapies without major differences in safety, and an unplanned survival analysis showed a benefit for decit abine, which was not observed at the time of the primary analysis.
Journal ArticleDOI
TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes
John S. Welch,Allegra A. Petti,Christopher A. Miller,Catrina Fronick,Michelle O'Laughlin,Robert S. Fulton,Richard K. Wilson,Jack Baty,Eric J. Duncavage,Bevan Tandon,Yi-Shan Lee,Lukas D. Wartman,Geoffrey L. Uy,Armin Ghobadi,Michael H. Tomasson,Iskra Pusic,Rizwan Romee,Todd A. Fehniger,Keith Stockerl-Goldstein,Ravi Vij,Stephen T. Oh,Camille N. Abboud,Amanda F. Cashen,Mark A. Schroeder,Meagan A. Jacoby,Sharon Heath,Kierstin Luber,Megan Janke,Andrew Hantel,Niloufer Khan,Madina Sukhanova,Randall W. Knoebel,Wendy Stock,Timothy A. Graubert,Matthew J. Walter,Peter Westervelt,Daniel C. Link,John F. DiPersio,Timothy J. Ley +38 more
TL;DR: Patients with AML and MDS who had cytogenetic abnormalities associated with unfavorable risk, TP53 mutations, or both had favorable clinical responses and robust (but incomplete) mutation clearance after receiving serial 10-day courses of decitabine.
Journal ArticleDOI
Transient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells.
Hsing-Chen Tsai,Huili Li,Leander Van Neste,Yi Cai,Carine Robert,Feyruz V. Rassool,James Shin,Kirsten Harbom,Robert Beaty,Emmanouil P. Pappou,James C. Harris,Ray Whay Chiu Yen,Nita Ahuja,Malcolm V. Brock,Vered Stearns,David Feller-Kopman,Lonny Yarmus,Yi Chun Lin,Alana L. Welm,Jean Pierre J. Issa,Il Minn,William Matsui,William Matsui,Yoon Young Jang,Saul J. Sharkis,Stephen B. Baylin,Stephen B. Baylin,Cynthia A. Zahnow +27 more
TL;DR: It is shown that transient exposure of cultured and primary leukemic and epithelial tumor cells to clinically relevant nanomolar doses produce an antitumor "memory" response, including inhibition of subpopulations of cancer stem-like cells.
References
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Journal ArticleDOI
Revised Recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia
Bruce D. Cheson,John M. Bennett,Kenneth J. Kopecky,Thomas Büchner,Cheryl L. Willman,Elihu H. Estey,Charles A. Schiffer,Hartmut Doehner,Martin S. Tallman,T. Andrew Lister,Francesco Lo-Coco,Roel Willemze,Andrea Biondi,Wolfgang Hiddemann,Richard A. Larson,Bob Löwenberg,Miguel A. Sanz,David R. Head,Ryuzo Ohno,Clara D. Bloomfield +19 more
TL;DR: An International Working Group met to revise the diagnostic and response criteria for acute myelogenous leukemia originally published in 1990, as well as to provide definitions of outcomes and reporting standards to improve interpretability of data and comparisons among trials as mentioned in this paper.
Journal ArticleDOI
Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group study
Marilyn L. Slovak,Kenneth J. Kopecky,Peter A. Cassileth,David H. Harrington,Karl S. Theil,Anwar Mohamed,Elizabeth Paietta,Cheryl L. Willman,David R. Head,Jacob M. Rowe,Stephen J. Forman,Frederick R. Appelbaum +11 more
TL;DR: Cytogenetic risk status is a significant factor in predicting response of AML patients to therapy; however, to tighten treatment correlates within genetically defined AML subsets, a significantly larger leukemia cytogenetic database is warranted.
Journal ArticleDOI
Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study.
Hagop Kantarjian,J. Issa,Craig S. Rosenfeld,John M. Bennett,Maher Albitar,John DiPersio,Virginia Klimek,James Slack,Carlos de Castro,Farhad Ravandi,Richard Helmer,Lanlan Shen,Stephen D. Nimer,Richard Leavitt,Azra Raza,Hussain Saba +15 more
TL;DR: Aberrant DNA methylation, which results in leukemogenesis, is frequent in patients with myelodysplastic syndromes (MDS) and is a potential target for pharmacologic therapy.
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5-Azacytidine and 5-aza-2'-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy.
TL;DR: The current status of the understanding of the mechanism(s) by which 5-azacytosine residues in DNA inhibit DNA methylation is reviewed with an emphasis on the interactions of these residues with bacterial and mammalian DNA (cytosines-C5) methyltransferases.
Journal ArticleDOI
The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial.
David Grimwade,Helen Walker,G Harrison,Fiona Oliver,S Chatters,Christine J. Harrison,Keith Wheatley,Alan Kenneth Burnett,Anthony H. Goldstone +8 more
TL;DR: This study suggests that hierarchical cytogenetic classification identifies biologically distinct subsets of AML that are represented in all age groups, and highlights the importance of karyotype as a critical independent determinant of outcome in older patients with AML.
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