Current challenges in clinical development of "targeted therapies": the case of acute myeloid leukemia.

Blood
Elihu EsteyBob Löwenberg

Abstract

A fundamental difficulty in testing "targeted therapies" in acute myeloid leukemia (AML) is the limitations of preclinical models in capturing inter- and intrapatient genomic heterogeneity. Clinical trials typically focus on single agents despite the routine emergence of resistant subclones and experience in blast-phase chronic myeloid leukemia and acute promyelocytic leukemia arguing against this strategy. Inclusion of only relapsed-refractory, or unfit newly diagnosed, patients risks falsely negative results. There is uncertainty as to whether eligibility should require demonstration of the putative target and regarding therapeutic end points. Although use of in vivo preclinical models employing primary leukemic cells is first choice, newer preclinical models including "organoids" and combinations of pharmacologic and genetic approaches may better align models with human AML. We advocate earlier inclusion of combinations ± chemotherapy and of newly diagnosed patients into clinical trials. When a drug plausibly targets a pathway uniquely related to a specific genetic aberration, eligibility should begin with this subset, including patients with other malignancies, with subsequent extension to other patients. In other cases, a ...Continue Reading

References

Feb 1, 2003·Blood·Elihu H Estey, Peter F Thall
Dec 16, 2003·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Bruce D ChesonUNKNOWN International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards
Aug 3, 2005·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·André RogatkoGary Hudes
Aug 13, 2008·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Dimitri A BreemsBob Löwenberg
May 5, 2010·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Boglarka GyurkoczaBrenda M Sandmaier
Feb 15, 2011·Statistical Science : a Review Journal of the Institute of Mathematical Statistics·Peter F Thall
Jul 8, 2011·Blood·Robert K Hills, Alan K Burnett
May 9, 2012·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Jan J CornelissenBob Löwenberg
May 9, 2012·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Kevin Kalinsky, Dawn L Hershman
Jul 24, 2012·Cell·John S WelchRichard K Wilson
May 3, 2013·The New England Journal of Medicine·UNKNOWN Cancer Genome Atlas Research NetworkGreg Eley
May 25, 2013·Blood·Jan KrönkeKonstanze Döhner
Jun 8, 2013·Nature Medicine·Cassandra Willyard
Jul 11, 2013·Blood·Alan K BurnettUNKNOWN UK National Cancer Research Institute AML Working Group
Jul 12, 2013·The New England Journal of Medicine·Francesco Lo-CocoUNKNOWN Study Alliance Leukemia
Nov 5, 2013·The New England Journal of Medicine·J E CortesUNKNOWN PACE Investigators
Nov 20, 2013·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Prashant KapoorMorie A Gertz
Dec 7, 2013·Best Practice & Research. Clinical Haematology·Jeffrey E Lancet
Jan 17, 2014·The New England Journal of Medicine·Jesvin SamuelMartin J S Dyer
Feb 15, 2014·World Journal of Clinical Cases·Raj GopalVikram Kate
Mar 22, 2014·Cancer Cell·Jesús Duque-Afonso, Michael L Cleary
Mar 25, 2014·Current Opinion in Genetics & Development·Norman Sachs, Hans Clevers
Oct 22, 2014·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Edith A PerezNorman Wolmark
Dec 4, 2014·The New England Journal of Medicine·Benjamin J SolomonUNKNOWN PROFILE 1014 Investigators
Dec 4, 2014·The New England Journal of Medicine·Dan L Longo

❮ Previous
Next ❯

Citations

Feb 20, 2016·Blood·Guido Marcucci, Ling Li
Dec 15, 2015·Blood·Eytan M Stein, Martin S Tallman
Nov 23, 2015·Best Practice & Research. Clinical Haematology·Jacob M Rowe
Mar 24, 2016·Annals of Oncology : Official Journal of the European Society for Medical Oncology·L DangE C Attar
Jun 24, 2015·Journal of Experimental & Clinical Cancer Research : CR·Patricia A AssisEduardo M Rego
Jun 10, 2015·Cancer Cell·Karilyn Larkin, John C Byrd
Oct 2, 2015·BMC Bioinformatics·Erich A PetersonDonald J Johann
May 2, 2015·Blood·Christian Recher
Nov 3, 2016·Bone Marrow Transplantation·A M BrunnerY B Chen
Jul 16, 2016·American Journal of Hematology·Elihu Estey
Aug 16, 2016·Clinical Lymphoma, Myeloma & Leukemia·Thomas Prebet, Amer Zeidan
Oct 25, 2016·Future Oncology·Maliha KhanTapan M Kadia
Nov 12, 2016·Leukemia·E Estey, R P Gale
Oct 11, 2016·Leukemia·B C MedeirosR Swords
Jan 5, 2017·Blood·Bob LöwenbergUNKNOWN Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON) and Swiss Group for Clinical Cancer Research (SAKK)
Jun 6, 2018·International Immunology·Nathaniel J ButeynSusheela Tridandapani
Sep 22, 2018·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Renato BassanSabina Chiaretti
Jan 10, 2019·Current Opinion in Hematology·Shyam K PoudelLeland Metheny
Dec 7, 2018·Hematology·Laura C Michaelis
Apr 20, 2017·Journal of Hematology & Oncology·Caner Saygin, Hetty E Carraway
Aug 31, 2019·Annual Review of Medicine·Brian T Emmer, David Ginsburg
Jul 27, 2018·Oncotarget·Shelley M HerbrichPatrick A Zweidler-McKay
Oct 27, 2016·The Journal of Biological Chemistry·Kavin FatehchandSusheela Tridandapani
Mar 16, 2017·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Erel JoffeAnas Younes
Dec 1, 2016·International Journal of Hematologic Oncology·Germana CastelliUgo Testa
May 18, 2019·American Society of Clinical Oncology Educational Book·Heidi D KlepinTapan Kadia
Oct 18, 2018·American Journal of Hematology·Elihu H Estey
Dec 14, 2016·The New England Journal of Medicine·Elihu Estey
Jul 1, 2017·Targeted Oncology·Maximilian StahlAmer M Zeidan
Oct 25, 2020·Biometals : an International Journal on the Role of Metal Ions in Biology, Biochemistry, and Medicine·Miguel Mendivil-PerezMarlene Jimenez-Del-Rio
Mar 4, 2020·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Govardhan AnandeJohn E Pimanda
May 25, 2021·Blood Cancer Discovery·Emily Schwenger, Ulrich Steidl
Jul 8, 2021·Cancer Discovery·Emily Schwenger, Ulrich Steidl

❮ Previous
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