leukemia research reports acceptance rate

Leukemia Research Reports

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The set of journals have been ranked according to their SJR and divided into four equal groups, four quartiles. Q1 (green) comprises the quarter of the journals with the highest values, Q2 (yellow) the second highest values, Q3 (orange) the third highest values and Q4 (red) the lowest values.

The SJR is a size-independent prestige indicator that ranks journals by their 'average prestige per article'. It is based on the idea that 'all citations are not created equal'. SJR is a measure of scientific influence of journals that accounts for both the number of citations received by a journal and the importance or prestige of the journals where such citations come from It measures the scientific influence of the average article in a journal, it expresses how central to the global scientific discussion an average article of the journal is.

Evolution of the number of published documents. All types of documents are considered, including citable and non citable documents.

This indicator counts the number of citations received by documents from a journal and divides them by the total number of documents published in that journal. The chart shows the evolution of the average number of times documents published in a journal in the past two, three and four years have been cited in the current year. The two years line is equivalent to journal impact factor ™ (Thomson Reuters) metric.

Evolution of the total number of citations and journal's self-citations received by a journal's published documents during the three previous years. Journal Self-citation is defined as the number of citation from a journal citing article to articles published by the same journal.

Evolution of the number of total citation per document and external citation per document (i.e. journal self-citations removed) received by a journal's published documents during the three previous years. External citations are calculated by subtracting the number of self-citations from the total number of citations received by the journal’s documents.

International Collaboration accounts for the articles that have been produced by researchers from several countries. The chart shows the ratio of a journal's documents signed by researchers from more than one country; that is including more than one country address.

Not every article in a journal is considered primary research and therefore "citable", this chart shows the ratio of a journal's articles including substantial research (research articles, conference papers and reviews) in three year windows vs. those documents other than research articles, reviews and conference papers.

Ratio of a journal's items, grouped in three years windows, that have been cited at least once vs. those not cited during the following year.

Evolution of the percentage of female authors.

Evolution of the number of documents cited by public policy documents according to Overton database.

Evoution of the number of documents related to Sustainable Development Goals defined by United Nations. Available from 2018 onwards.

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Leukemia Research Reports : Guide for authors

Leukemia Research Reports is an open access, international journal which delivers timely information online to all health care professionals involved in basic and/or applied clinical research in leukemias, lymphomas, multiple myeloma and other hematologic malignancies. It does this by rapidly publishing a range of peer-reviewed short form papers, including brief communications, case reports, letters to the Editors, images, and debate articles. The Editors encourage the submission of articles relevant to normal and leukemic hemopoiesis, biochemistry, cell biology, immunology and molecular biology as well as epidemiologic and clinical studies. Leukemia Research Reports ' coverage encompasses the application of oncogenes, genomics (gene expression profiles and microRNAs), proteomics, growth factors, cell markers, cell cycle and differentiation agents, novel therapeutics and clinical trials in both the acute and chronic leukemias as well as the myelodysplastic syndromes. In addition articles are solicited on the rapidly growing specialty of marrow or stem cell reconstitution after high dose therapy with curative attempt in patients with a wide range of neoplasms.

Publishing policy —All articles will be peer reviewed and if accepted for publication in the Journal, Authors will be notified of this decision and at the same time requested to pay an Article Processing Fee of US$ 600/EUR 458/JPY 46,638 (exclusive of VAT/Sales Tax). Following payment of this fee, articles will be made universally available at no further charge through ScienceDirect and through the Journal's own website www.lrreports.com .

Submission of Manuscripts – All Manuscripts and Material should be submitted on-line via EES→ http://ees.elsevier.com/lrr/

Please refer to the ‘Tutorial for Authors’ located on the EES site for guidance on the electronic submission process.

All published papers containing research data are subject to peer-review. Submission of an article implies that the work described has not been published previously and will not be simultaneously submitted or published elsewhere (except in the form of an abstract or as part of a published lecture or academic thesis), that it is not under consideration for publication elsewhere, that its publication is approved by all authors and tacitly or explicitly by the responsible authorities where the work was carried out, and that, if accepted, it will not be published elsewhere in the same form, in English or in any other language, without the written consent of the Publisher.

These guidelines generally follow the ‘Uniform Requirements for Manuscripts Submitted to Biomedical Journals’. The complete document appears at → http://www.icmje.org .

Submitting an Article —Articles should be submitted online at → http://ees.elsevier.com/lrr/ and the instructions on the site should be closely followed. Authors may submit manuscripts and track their progress to final decision.

Types of Contribution —All articles are limited by word count and the number of references. Word count limits do not include the abstract, references, acknowledgment, figures or tables, or their captions.

Brief Communications include an abstract; the total word count should not exceed 1200 words, a maximum of 10 references and up to 4 figures and/or tables.

Case Reports include an abstract; they should not exceed 1200 words, a maximum of 10 references and an optional 1–2 figures and/or tables.

Letters to the Editor should clearly indicate the purpose of the letter by a brief striking title; they should include an abstract and should not exceed 1200 words, up to 5 references and an optional 1–2 figures and/or tables.

Debate and Controversies —the journal welcomes opinion pieces on research and clinical topics in leukemia. Debate & Controversies articles should include an abstract, should not exceed 1200 words, plus a maximum of 5 references and 1 figure or table.

Images —authors are encouraged to submit images for publication. These should be accompanied by a title and a caption that explains the significance of the image. In addition to ‘still life ‘ images, authors may submit video files. For full details of artwork formats see below.

Meeting Perspectives are reports on one or several sessions of Congress, Workshops or Symposia (also closed ones). Such papers should not exceed 1200 words, 5 references and up to 2 figures and/or tables.

Comments on Published Papers are comments on a prior published paper. Mention the title in both the Cover Letter and the References. This paper does not have an abstract and should not exceed 1200 words; limit 3 references and optional 1–2 figures and/or tables. Comments that seek to address an error in a previous paper are exempt from the Article Processing Fee if accepted for publication.

Preparation of Manuscripts

1. Covering letter : This is a letter stating that you wish to submit your paper to Leukemia Research Reports . Please include the title, and signature of corresponding author. Also include details of any previous version.

2. All contributions must be 1.5 spaced except the references which are single spaced with a space between each reference.

3. Manuscripts submitted for publication should be written concisely and clearly. Manuscripts will only be accepted when they are written in an acceptable standard of English (American or British usage is accepted, but not a mixture of these). Authors whose native language is not English are strongly advised to have their manuscripts be checked by an English-speaking colleague prior to submission or to submit them for language editing (see below for more details). Either the Concise Oxford Dictionary or Webster's New International Dictionary may be used as a standard for English spelling.

4. The manuscript should be organized in the following sequence: All manuscripts must have a title page which is Page 1 of your manuscript. Note the Title should be clear, descriptive and less than 20 words long. Avoid non-specific phrases such as ‘A study of…’ or ‘The effects of…’. Do not give the title a numbered subtitle or series number.

The title page is the first page of the paper and must contain the following: title name of authors (listed as, first name last name academic degree then superscript the institutional code); institutional has superscript code (1, 2, 3,…), Department of…, institution, city and country; the Corresponding Author. Note : No positions like Dr., Professor, or Faculty of, we use academic degrees only.

Role of Corresponding Author : Please note there is only one corresponding author of the manuscript. The corresponding author is the one that submits the manuscript and is displayed on the Title Page of the manuscript. They have the duty to ensure that all of the named authors have seen and approved the original manuscript and subsequent revisions. Each author should have participated sufficiently in the work to take public responsibility for the content. The corresponding author should also ensure that those who have contributed to the research are acknowledged appropriately either as a co-author or in the Acknowledgments. In addition, the corresponding author has the prime responsibility for ensuring the paper is correctly prepared according to the Guide for Authors. Submitted manuscripts not complying with the Guide for Authors may be returned to the authors for revision.

Word Count : does not include the references, acknowledgment, figures and tables.

Abstract : The abstract should be clear, descriptive and less than 100 words.

Keywords —Keywords are index terms or descriptions for information retrieval systems, and a maximum of five should be provided. Words selected should reflect the essential topics of the article and may be taken from both the title and the text.

Abbreviations and units : Generally, avoid abbreviations in the Title and abbreviating single words. Otherwise explain all abbreviations at first mention in the abstract and text, except for: DNA, RNA, AIDS, and HIV. Standard SI abbreviations for units do not need to be spelled out.

Brief Communications should include an Introduction, Materials and Methods, Results and Discussion sections. Case Reports and Letters to the Editor do not need to include these divisions.

Introduction : This should give the reasons for doing the work. As this is a specialist journal a detailed review of the literature is not necessary. The introduction should preferably conclude with a final paragraph stating concisely and clearly the aims and objectives of the investigation.

Materials and Methods : A full technical description of a method should be given in detail only when the method is new.

Results : This need only report results of representative experiments illustrated by tables and figures. Use well-known statistical tests in preference to obscure ones. Consult a statistician or a statistics text for detailed advice.

Discussion (including Conclusions) : This section must not recapitulate results but should relate the authors' experiments to other work and give their conclusions, which may be given in a subsection headed after called Conclusions.

References : References are numbered. All publications cited in the text should be presented in a list of references following the text of the manuscript. In the text refer to references by a number in square brackets on the line (e.g. Since Peterson [1]), and the full reference should be given in a numerical list at the end of the paper. References should be given in the following form: 1. Latagliata R, Concetta Petti M, Mandelli F. Acute myeloid leukemia in the elderly: ‘per aspera ad astra’? Leukemia Res 1999;23:603–613. 2. Alfrey V. The isolation of subcellular components. In: Brachet J, Mirsky AE, editors. The cell, biochemistry, physiology, morphology I. New York: Academic Press, 1959. p. 200.

Note : Authors are strongly encouraged to check the accuracy of each reference against its original source. Work accepted for publication but not yet published should be referred to as ‘in press’. Authors should provide evidence (such as a copy of the letter of acceptance). References concerning unpublished data, theses, and ‘personal communications’ should not be cited in the reference list but may be mentioned in the text. Do not only put the first author et al. list all authors.

5. Acknowledgments should be organized in the following sequence.

Acknowledgments —All contributors who do not meet the criteria for authorship as defined above should be listed in an acknowledgments section. E.g. those who might be acknowledged include a person who provided purely technical help, writing assistance, or a department chair that provided only general support. Authors should disclose whether they had any writing assistance and identify the entity that paid for this assistance.

Role of the funding source— All sources of funding should be declared. Authors should declare the role of study sponsors, if any, in the study design, collection, analysis and interpretation of data; in the writing of the manuscript; and in the decision to submit the manuscript for publication. If the study sponsors had no such involvement, the authors should so state.

Authors' Contributions —All authors should have made substantial contributions to the following: (1) the conception and design of the study, or acquisition of data, or analysis and interpretation of data. (2) drafting the article or revising it critically for important intellectual content. (3) final approval of the version to be submitted. For authors we use initials and if there is more than one author that does the same function put them together. Note: If there is more than one author that contributed equally to the work it goes in this section not on the title page.

Conflict of Interest —All authors must disclose any financial and personal relationships with other people or organizations that could inappropriately influence (bias) their work. E.g. potential conflicts of interest include employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants or other funding. If there no conflicts of interest exist this must be stated. Please see the Elsevier website for further information http://www.elsevier.com/wps/find/authorsview.authors/conflictsofinterest .

6. Figures and Figure Legends —Figures should be cited consecutively in the text. Full details for the electronic submission of artwork can be obtained from http://www.elsevier.com/artworkinstructions . All figures have to be uploaded in EES separately.

For further information on the preparation of electronic artwork, please see http://www.elsevier.com/artworkinstructions .

Type the figure legends in order in one word document and starting with the words figure legends; limit 40 words or less. Spacing is 1.5 and if more than one page put a page number in the footer.

7. Table and Table Legends —Tables should be cited consecutively in the text. Type tables on separate pages with a title. Avoid white spaces in the table by using footnotes, and ensure all symbols or abbreviation are explained. Take care to distinguish between ‘zero’ and ‘not done’ as an entry in the table. Tables are uploaded separately.

Type the table legends in order in one word document and starting with the words table legends. Spacing is 1.5 and if more than one page put a page number in the footer.

Footnotes : Footnotes should only be used to provide addresses of authors or to provide explanations essential to the understanding of Tables.

8. Supplementary Data —As Leukemia Research Reports focuses on short papers, Supplementary Data files are not accepted.

Ethics —Identifying information, including patients images, names, initials, or hospital numbers, should not be included in videos, recordings, written descriptions, photographs, and pedigrees unless the information is essential for scientific purposes and you have obtained written informed consent for publication in print and electronic form from the patient (or parent, guardian or next of kin where applicable). If such consent is made subject to any conditions, Elsevier must be made aware of all such conditions. Written consents must be provided to Elsevier on request.

Even where consent has been given, identifying details should be omitted if they are not essential. If identifying characteristics are altered to protect anonymity, such as in genetic pedigrees, authors should provide assurance that alterations do not distort scientific meaning and editors should so note.

If such consent has not been obtained, personal details of patients included in any part of the paper and in any supplementary materials (including all illustrations and videos) must be removed before submission.

Drug names —Use generic names for drugs. Commercial names may be included in parentheses at first mention in the text. Complicated drug names or regimens may be abbreviated, with the abbreviation in parentheses after first mention.

Revised Manuscript —All manuscripts are peer-reviewed. On receipt of the first decision letter authors should send their revised manuscript as soon as possible in order to ensure that the scientific content of their manuscript is timely and up to date.

The revised paper must be submitted without tracking or highlights and 1.5 spaced. A Revision Letter must contain detailed responses to the reviewers and indicate where in the letter you changed the text.

Author Names —This policy concerns the addition, deletion, or rearrangement of author names in the authorship of accepted manuscripts: Before the accepted manuscript is published in an online issue: Requests to add or remove an author, or to rearrange the author names, must be sent to the Journal Manager from the corresponding author of the accepted manuscript and must include the following: (a) the reason the name should be added or removed, or the author names rearranged and (b) written confirmation (e-mail, fax, and letter) from all authors that they agree with the addition, removal or rearrangement. In the case of addition or removal of authors, this includes confirmation from the author being added or removed. Requests that are not sent by the corresponding author will be forwarded by the Journal Manager to the corresponding author, who must follow the procedure as described above. Note that (1) Journal Managers will inform the Journal Editors of any such requests and (2) publication of the accepted manuscript in an online issue is suspended until authorship has been agreed. After the accepted manuscript is published in an online issue: Any requests to add, delete, or rearrange author names in an article published in an online issue will follow the same policies as noted above and result in a corrigendum.

Copyright —Upon acceptance of an article, authors will be asked to sign a Journal Publishing Agreement. This includes details of the rights that you retain as author (for more information on this and copyright see http://www.elsevier.com/wps/find/authorsview.authors/authorsrights ). An e-mail will be sent to the corresponding author confirming receipt of the manuscript together with a Journal Publishing Agreement form. Following signature of this form and payment of the Author Fee, case reports will be made universally accessible through →ScienceDirect and through the Journal's own website, www.lrreports.com .

If excerpts from other copyrighted works are included, the author(s) must obtain written permission from the copyright owners and credit the source(s) in the article. Elsevier has preprinted forms for use by authors in these cases; contact Elsevier s Rights Department, Philadelphia, PA, USA: Tel. (+1) 215 238 7869; Fax (+1) 215 238 2239; e-mail [email protected]. Requests may also be completed online via the Elsevier homepage ( http://www.elsevier.com/locate/permissions ).

Proofs —One set of page proofs in PDF format will be sent by e-mail to the corresponding author. Elsevier now sends PDF proofs which can be annotated; for this you will need to download Adobe Reader version 7 available free from → http://www.adobe.com/products/acrobat/readstep2.html . Instructions on how to annotate PDF files will accompany the proofs. The exact system requirements are given at the Adobe site: → http://www.adobe.com/products/acrobat/acrrsystemreqs.html#70win . If you do not wish to use the PDF annotations function, you may list the corrections (including replies to the Query Form) and return to Elsevier in an e-mail. Please list your corrections quoting line number. If, for any reason, this is not possible, then mark the corrections and any other comments (including replies to the Query Form) on a printout of your proof and return by fax, or scan the pages and e-mail, or by post.

Please use this proof only for checking the typesetting, editing, completeness and correctness of the text, tables and figures. Significant changes to the article as accepted for publication will only be considered at this stage with permission from the Editor. We will do everything possible to get your article published quickly and accurately. Therefore, it is important to ensure that all of your corrections are sent back to us in one communication: please check carefully before replying, as inclusion of any subsequent corrections cannot be guaranteed. Proofreading is solely your responsibility. Note that Elsevier may proceed with the publication of your article if no response is received.

Language services —Authors who require information about language editing and copyediting services pre- and post-submission should visit → http://webshop.elsevier.com/languageservices or our customer support site at → http://support.elsevier.com for more information.

Enquiries —Authors can keep a track on the progress of their accepted article, and set up e-mail alerts informing them of changes to their manuscript's status, by using the ‘Track a Paper’ feature at: http://www.elsevier.com/trackarticle . For privacy, information on each article is password-protected. The author should key in the ‘Our Reference’ code (which is in the letter of acknowledgment sent by the publisher on receipt of the accepted article) and the name of the corresponding author. In case of problems or questions, authors may contact the Author Service Department, E-mail: [email protected]

Offprints —The corresponding author, at no cost, will be provided with a PDF file of the article via e-mail. The PDF file is a watermarked version of the published article and includes a cover sheet with the journal cover image and a disclaimer outlining the terms and conditions of use.

© 2012 Elsevier Ltd. All rights reserved —This journal and the individual contributions contained in it are protected under copyright by Elsevier Ltd. Please click on User Rights for a summary of how articles published in Leukemia Research Reports can be utilized.

Notice —No responsibility is assumed by the Publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. Although all advertising material is expected to conform to ethical (medical) standards, inclusion in this publication does not constitute a guarantee or endorsement of the quality or value of such product or of the claims made of it by its manufacturer.

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• Review Article
• Open access
• Published: 22 February 2021

Acute myeloid leukemia: current progress and future directions

• Hagop Kantarjian   ORCID: orcid.org/0000-0002-1908-3307 1 ,
• Tapan Kadia   ORCID: orcid.org/0000-0002-9892-9832 1 ,
• Courtney DiNardo   ORCID: orcid.org/0000-0001-9003-0390 1 ,
• Naval Daver   ORCID: orcid.org/0000-0001-7103-373X 1 ,
• Gautam Borthakur   ORCID: orcid.org/0000-0001-7679-6453 1 ,
• Elias Jabbour 1 ,
• Guillermo Garcia-Manero   ORCID: orcid.org/0000-0002-3631-2482 1 ,
• Marina Konopleva   ORCID: orcid.org/0000-0002-9347-2212 1 &
• Farhad Ravandi 1  

Blood Cancer Journal volume  11 , Article number:  41 ( 2021 ) Cite this article

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• Health services

Progress in the understanding of the biology and therapy of acute myeloid leukemia (AML) is occurring rapidly. Since 2017, nine agents have been approved for various indications in AML. These included several targeted therapies like venetoclax, FLT3 inhibitors, IDH inhibitors, and others. The management of AML is complicated, highlighting the need for expertise in order to deliver optimal therapy and achieve optimal outcomes. The multiple subentities in AML require very different therapies. In this review, we summarize the important pathophysiologies driving AML, review current therapies in standard practice, and address present and future research directions.

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Emerging agents and regimens for treatment of relapsed and refractory acute myeloid leukemia

Two decades of targeted therapies in acute myeloid leukemia

FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm

Introduction.

Progress in understanding the pathophysiology and improving the therapy of acute myeloid leukemia (AML) is now occurring at a rapid pace. The discovery of the activity of cytarabine (ara-C) and of anthracyclines in AML, and combining them in the 1970’s, into what is known as the “3 + 7 regimen” (3 days of daunorubicin + 7 days of cytarabine), has long been considered the standard of care, resulting in long-term cures of 30 to 40% among younger patients with AML 1 , 2 , 3 , 4 , 5 . The earlier studies focused on patients usually up to the age of 50–55 years, and reported 5-year survival rates of 40–45%. Later studies including patients up to the age of 60 years reported 5-year survival rates of 30–35%. These intensive chemotherapy regimens, applied commonly in older patients (age 60 years and older), resulted in 5-year survival rates of <10–15% 6 , 7 . Figure 1 shows the MD Anderson outcomes in AML in younger and older patients from 1970 to 2018.

Survival of de novo acute myeloid leukemia at MD Anderson (1970–2017) by Age and Treatment Era: Left panel: age<60 years; Right panel: age 60+ years.

Unraveling the heterogeneity of AML at the clinical, cytogenetic, and molecular levels allowed improved prognostic and predictive abilities and led to the development of selected therapies for AML subsets. Chemotherapy-free regimens consisting of all trans-retinoic acid (ATRA) and arsenic trioxide in acute promyelocytic leukemia (APL) resulted in cure rates of 90% 8 , 9 , 10 , 11 , 12 . In core-binding factor (CBF) AML, adding gemtuzumab ozogamicin (CD33-targeted monoclonal antibody conjugated to the calicheamicin payload) to high-dose cytarabine-based chemotherapy increased the long-term survival rate from 50% to 75+% 13 , 14 , 15 , 16 , 17 .

Research efforts in the last decade have expanded the pathophysiologic-molecular subsets of AML, through identification of prognostic, predictive, and targetable molecular abnormalities 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 . Ongoing studies and recently approved agents in AML of particular interest include: (1) Combinations of epigenetic therapy with hypomethylating agents (HMAs; azacitidine, decitabine) and venetoclax in older patients (or patients unfit for intensive chemotherapy); and combinations of intensive chemotherapy and venetoclax in younger/fit patients. (2) The addition of fms-like tyrosine kinase 3 (FLT3) inhibitors (gilteritinib, midostaurin, sorafenib, quizartinib, crenolanib, others) to intensive chemotherapy, or to HMA/low-intensity therapy in FLT3 -mutated AML. (3) The addition of IDH inhibitors (IDH1 inhibitor ivosidenib; IDH2 inhibitor enasidenib) and/or venetoclax in IDH1/2- mutated AML. (4) Investigations of the roles of APR246 (TP53 modulator) and of magrolimab (anti-CD47 monoclonal antibody enhancing the macrophage-mediated phagocytosis) in TP53 -mutated AML. (5) Exploring the role of menin inhibitors in mixed-lineage leukemia ( MLL1 )-rearranged acute leukemia. (6) Investigations of combined small-molecule targeted therapies, with or without standard intensive chemotherapy or HMAs (+/− venetoclax; at the expense of worsening myelosuppression), in order not only to prolong survival, but also to improve the potential cure rates in previously incurable AML subsets. (7) Establishing maintenance therapy as an important strategy in AML (as it is in acute lymphoblastic leukemia [ALL]). (8) Developing oral anti-AML therapy (e.g., oral decitabine, oral azacitidine) to replace and improve upon the effects of parenteral therapies. (9) Approaches to enhance T-cell immune responses to AML (as done in ALL) with T-cell engagers (BiTEs), checkpoint inhibitors, and chimeric antigen receptor (CAR)-T-cell approaches.

Many AML experts ascribe to the 3 + 7 regimen as the AML standard of care today; others may not. We will discuss the results with 3 + 7 and put them into context with the more recent combined modality regimens, which may be superior. The nihilistic mood that prevailed in the AML community until 2015 has lifted, particularly with research resulting in the FDA approvals of multiple agents for AML since 2017 (Table 1 ). It is interesting to compare this AML review to the one published in 2016 1 , to appreciate the previous “bare cupboard” in AML research and the tremendous progress over such a short period of time. Prior to 2017, some decisions may have temporarily slowed progress in AML. One example is the voluntary withdrawal of gemtuzumab ozogamicin (GO) by the manufacturer (June 2010) from clinical use in the United States based on a negative trial by the Southwest Oncology Group (SWOG) 16 . This was remedied with the GO re-approval in 2017 at a lower dose to minimize toxicity, based on a meta-analysis of five randomized frontline trials in AML clearly demonstrating benefit 17 . The use of GO is now particularly important in the therapy of CBF AML and APL. The second example was the non-approval of decitabine in the US for frontline therapy of older patients with AML (approved in Europe) 26 , 27 . Low-intensity HMA therapy with decitabine and azacitidine-based regimens is now the most common form of treatment among older (or unfit for intensive chemotherapy) patients with AML 26 , 30% blasts. Blood 126, 291–299 (2015)." href="/articles/s41408-021-00425-3#ref-CR28" id="ref-link-section-d52434916e565">28 . A third possible example is the non-submission of vosaroxin for FDA approval for the therapy of AML first salvage 29 . Vosaroxin may have offered a non-cardiotoxic form of topoisomerase-II inhibitor therapy.

In this review, we discuss progress in AML research, outline the MD Anderson approaches in 2020, and explore investigational strategies over the coming years.

Cytogenetic and molecular abnormalities

Acute myeloid leukemia has diverged from being considered as one acute leukemia entity to become a heterogeneous constellation of AML subentities characterized by diverse pathophysiologic, clinical, cytogenetic, and molecular profiles that benefit from individualized selective therapies and have vastly different outcomes.

The cytogenetic-molecular entities in AML are outlined in Table 2 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 . These include APL with its characteristic translocation 15;17 [t(15;17) (q22,q21)]; inversion 16 [inv 16(p13; q22)] or t(16;16) (p13;q22) and t(8;21)(q22;q22,), together referred to as CBF AML; diploid karyotype (about 40–50% of patients); complex karyotype (three or more chromosomal abnormalities); others.

Molecular subsets also define prognosis and are therapeutically targetable. Among patients with a diploid karyotype, single mutations and mutation combinations interact differently, in sometimes intricate balancing acts. For example, a mutation of nucleophosmin-1 ( NPM1 ) without a FLT3 mutation is associated with a more favorable outcome. If a FLT3 mutation, particularly FLT3 internal tandem duplication (FLT3- ITD ) , is present (about 50% of patients with a diploid karyotype and NPM1 mutation), then the outcome was worse historically, and largely dependent on the FLT3 allelic ratio (AR). In newly diagnosed FLT3- mutated AML, the AR of FLT3- ITD to FLT3 - wild type strongly influenced outcome in several studies of chemotherapy-based therapies that did not include FLT3 inhibitors 34 , 35 , 36 . The FLT3- ITD AR is defined as the ratio of the area under the curve of “ FLT3- ITD” divided by the area under the curve of “FLT3 - wildtype” using a semi-quantitative DNA fragment analysis 30 . A higher FLT3- ITD AR (generally defined as ⩾ 0.5) is associated with worse survival than lower ratios, likely reflecting increased FLT3 dependency in cases with high ARs. This may change with the incorporation of FLT3 inhibitors into AML chemotherapy and into post stem cell transplantation (SCT) maintenance. Mutations, including ASXL1, RUNX1, TP53 , and others may also associate with outcome differences. Several molecular mutations are potentially targetable (Table 3 ) 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 .

Next-generation sequencing identified multiple recurrent somatic mutations in >90% of patients with AML 21 , 52 . Frequently mutated genes (frequency >5%) are FLT3, NPM1, DNMT3A, IDH1, IDH2, TET2, RUNX1, p53, NRAS, CEBPA, WT1 21 , 24 , 52 . Based on functional analysis and known pathways, these are routinely grouped into biologic- functional categories: myeloid transcription-factor fusions or mutations; NPM1 mutations; tumor-suppressor gene mutations; epigenome-modifying gene mutations; activated signaling-pathway gene mutations; cohesin-complex gene mutations; and spliceosome-complex gene mutations. These mutations exhibit shared co-occurrences or exclusive dissociations that help identify AML pathways of clonal dominance and shifts that would result into more rational targeting therapies.

Translating to clinical practice, the important molecular subsets are based on the identification of a FLT3 mutation (30% of AML), NPM1 mutation (40–50% of normal karyotype AML), isocitrate dehydrogenase 1 or 2 ( IDH1/2 ) mutations (20% of AML), and TP53 mutations (2 to 20% of AML).

Patients with NPM1 -mutated AML have a more favorable prognosis; those with FLT3- ITD mutations have a poor prognosis, especially among patients with high FLT3 ARs and in the absence of NPM1 mutation. Patients with diploid karyotype AML (without adverse mutations such as TP53 , or ASXL1 ) and biallelic CEBPA mutations (2% or less of AML) have a favorable prognosis 5 .

The FLT3 mutations, including FLT3- ITD and FLT3- tyrosine kinase domain (TKD) point mutations (D835 most common), can now be targeted with FLT3 inhibitors. Midostaurin and gilteritinib are type I FLT3 inhibitors and suppress both FLT3- ITD and FLT3- TKD mutations. Sorafenib and quizartinib are type II FLT3 inhibitors that target only FLT3- ITD.

The IDH1/2 mutations can be targeted with novel IDH inhibitors, ivosidenib, which targets IDH1 mutations, and enasidenib, which targets IDH2 mutations. The IDH1/2 mutations also generate AML dependence on BCL-2 for survival, rendering them responsive to venetoclax-based therapy 53 .

Mutations of epigenetically related molecular events ( DNMT3A , IDH1/2 , TET2, ASXL1 , and MLL1 ) may suggest the possible benefit of epigenetic-targeted therapy.

In CBF AML, mutations in c-KIT may be associated with worse outcome in some studies 47 , 48 , 49 , 50 , but not with fludarabine-cytarabine-GO-based regimens 12 , 13 , 14 . Investigating the addition of a potent c-KIT inhibitor (avapritinib, dasatinib) to chemotherapy in c-KIT -mutated CBF AML is of interest 50 , 51 .

Mutations and/or deletions of the tumor-suppressor gene TP53 (located on the short arm of chromosome 17) occur in 2–20%, are more common in older patients and patients with secondary or therapy-related AML, and are associated with complex cytogenetics 38 , 39 , 40 , 41 . In a study of 293 patients, 53 (18%) had TP53 mutations; these were associated with complex karyotype ( p  < 0.001) and with abnormalities of chromosomes 17 and 5 and/or 7, and with a low CR rate and short survival 39 . Most patients with TP53 mutations may not benefit from intensive chemotherapy and may have similar or improved outcomes and less toxicity with lower intensity approaches 40 , 54 . The variant allelic frequency (VAF; percent mutated/total) of TP53 mutations may help select patients who would not benefit from intensive induction therapy. Novel strategies like APR-246 or magrolimab have shown promise.

Patients with the cytogenetic-molecular subset of “mixed-lineage leukemia” (translocations involving 11q23; MLL1 , KMT2A rearrangement) may respond well to the novel menin inhibitors (SNDX-5613, KO-539, others) 55 .

Translocations involving chromosome 3q26.2 ( EVI1 ), location of the MECOM ( M DS1 and E VI1 com plex locus) gene, have an extremely poor outcome with standard chemotherapy 46 . Additional mutations associated with adverse outcomes are DNMT3A 42 , 43 , ASXL1 , RUNX1 44 , 45 , and others 40 , 41 , 42 , 43 , 44 .

Measurable residual disease in complete remission

Measuring residual disease in AML in complete remission (CR) is now part of the standard of care in AML 56 , 57 , 58 , 59 , 60 , 61 , 62 . The detection of measurable residual disease (MRD) at the time of morphologic CR is associated with a higher relapse rate and with worse survival in AML. Measurable residual disease has been commonly investigated using two methodologies, multi-color flow-cytometric measurements of MRD (MFC-MRD), and molecular quantification of residual disease 56 , 57 , 58 , 59 , 60 , 61 .

Polymerase chain reaction (PCR) measure of residual molecular disease is routinely used to monitor quantitatively unique AML-defining translocations and mutations in APL, CBF AML, NPM1- mutated AML, and now expanding to other molecular subsets ( IDH1/2 and FLT3 mutations). In APL, PCR quantification of promyelocytic leukemia-retinoic receptor alpha ( PML-RAR alpha ) may detect early molecular relapse 63 . The same is true for CBF AML. Inversion 16 and t (16; 16) result in the formation of the CBF beta/myosin heavy chain 11 ( CBFB/MYH11 ) fusion gene. The t (8; 21) leads to the formation of the Runt-related transcription factor 1 [ RUNX1 ]/ RUNX1T1 ( RUNX1 / RUNX1T1 ) fusion gene. Detection of molecular fusion genes MRD by quantitative PCR in CBF AML (especially AML with inversion 16) predicts for relapse 64 , 65 . Interestingly, patients with t (8; 21) may have persistent MRD at levels below 0.1%, but still remain in durable complete remissions and possibly cured. Among patients with non-CBF non-APL AML, monitoring mutations by next-generation sequencing is informative when possible, for example in patients with NPM1 mutations 66 , 67 . Combining MFC and molecular PCR studies may improve on the capability of MRD studies to predict for relapse 56 . Better outcomes are reported in FLT3 -mutated and IDH -mutated AML with molecular MRD clearance.

Measurable residual disease in CR indicates worse prognosis due to a higher risk of relapse. This should lead to consideration of therapeutic interventions. In APL, therapy at the time of molecular relapse improved survival compared with therapy at the time of hematologic relapse 63 . Allogeneic SCT for persistent MRD in CR in CBF AML improved survival compared with continuation of standard therapy 65 . Important interventions in AML with MRD in CR may include allogeneic SCT; investigational approaches with more intensified chemotherapy regimens, or with HMAs (parenteral or newly approved oral formulations) plus venetoclax; targeted therapy combinations when indicated for particular molecular abnormalities (FLT3 or IDH inhibitors); antibody therapies (e.g., CD123 or CD33 monoclonal or BiTEs); or immune therapies (e.g., checkpoint inhibitors). However, the persistence of DTA mutations in CR (mutations in DNMT3A, TET2, ASXL1 ) does not predict for relapse 56 .

Treatment of AML

The heterogeneous group of AML disorders requires different selective therapies. Next, we will discuss the treatment of the highly curable leukemias, APL and CBF AML; the different therapeutic approaches in younger and older patients with AML; and the addition of the novel targeted therapies (venetoclax, FLT3 inhibitors, and IDH inhibitors) to standard therapies.

Acute promyelocytic leukemia

Acute promyelocytic leukemia represents 5–10% of AML and is defined by the cytogenetic abnormality t (15; 17), which results in the PML-RAR alpha fusion oncogene and its encoded oncoprotein. The PML-RAR α oncoprotein acts as a dominant negative inhibitor of wild-type RAR α, causing a maturation block and the clinical-pathologic picture of APL.

Combinations of anthracyclines and cytarabine first established the potential cure rate of 30–40% in APL 68 , 69 . The early mortality from disseminated intravascular coagulopathy (DIC) and bleeding with anthracyclines-cytarabine was significant, about 10–20%. The added anti-APL efficacy of high-dose cytarabine and maintenance chemotherapy (POMP) was modest at best 69 .

In the late 1980s and early 1990s, the major anti-APL efficacies of ATRA and arsenic trioxide were discovered. Gemtuzumab ozogamicin was also highly effective in APL 70 . The most potent anti-APL drugs are arsenic trioxide, followed by ATRA, GO, and anthracyclines.

Based on the single-agent anti-APL efficacies of ATRA and arsenic trioxide 71 , ATRA was initially added to chemotherapy during both induction and/or consolidation 72 , 73 , 74 , and arsenic trioxide was investigated initially in APL relapse and later as consolidation therapy 75 . Comparative studies showed that the addition of ATRA to chemotherapy during induction and/or consolidation improved survival 71 , 72 , 73 , and that the addition of arsenic trioxide during consolidation in CR also improved event-free survival (EFS). In the late 1990’s, the combination of idarubicin (or other anthracyclines) and ATRA (AIDA regimen) became standard of care in APL 76 .

Chemotherapy-free regimens: ATRA and arsenic trioxide

The MD Anderson group first investigated the use of non-chemotherapy regimens including ATRA, arsenic trioxide and GO, and demonstrated the high efficacy of this strategy 8 . Randomized studies confirmed the superiority of ATRA plus arsenic trioxide over AIDA in low and intermediate risk APL 11 , 77 . A SWOG study also demonstrated the efficacy and safety of ATRA with arsenic trioxide and GO in high risk APL 78 . With the ATRA plus arsenic trioxide regimens, the CR rate is 90+% and the cure rates 80+%. Induction mortality from DIC is low (about 5%). Resistant disease is extremely rare, except in molecular variant-APL (translocations between chromosome 11 and 17 [ PLZF-RAR alpha ], or between chromosome 5 and 17).

I mportant considerations in APL management are: (1) Granulocyte-colony stimulating growth factors (filgrastim, pegfilgrastim) should never be used in APL, as it is the one leukemia where granulocyte growth factors may induce a drastic increase in APL progression, and trigger fatal DIC 79 . (2) Watch for fluid overload (often confused with “differentiation syndrome”). This is related to ATRA and arsenic trioxide, as well as the use of high-volume blood product transfusions (fresh frozen plasma) to prevent the complication of consumptive coagulopathy. These complications are best managed by holding ATRA-arsenic trioxide therapy briefly and with aggressive diuresis 80 . (3) The development of a “differentiation syndrome” with possible multi-organ failure; this requires the use of prophylactic steroids during induction (together with antibiotics and antifungal prophylaxis). (4) Among patients with CNS bleeding at diagnosis, the risk of CNS leukemia may increase; two intrathecal cytarabine injections in CR may eliminate this rare complication.

The MRC comparative trial investigated a lower dose schedule of arsenic trioxide 0.3 mg/kg on Days 1–5 during week 1, then 0.25 mg/kg twice weekly in weeks 2–8 of Course 1 followed by 4 consolidations courses (63 arsenic trioxide doses) 77 .

Oral formulations of arsenic trioxide are under investigation; these would render the treatment of APL more convenient, particularly during the longer term consolidation 81 , 82

Figure 2 shows the MD Anderson results in APL, and the significant outcome improvement in the era of ATRA and arsenic trioxide.

Survival of acute promyelocytic leukemia at MD Anderson (1970–2020).

Core-binding factor acute myeloid leukemia

The CBF AMLs include the subsets with chromosomal abnormalities involving inversion 16/t (16; 16) or t (8; 21). These constitute 10–15% of adult AML cases.

The use of established chemotherapy drugs in optimized combinations has gradually improved the cure rates in CBF AML from <50% to about 75% 13 , 14 , 15 , 16 , 17 . Historically, CBF AML was treated with cytarabine plus anthracycline induction chemotherapy followed by 1–4 high-dose cytarabine consolidations. The cure rates were 30–40% with one consolidation versus 50+% with 3–4 consolidations 83 , 84 . Using induction- consolidation courses of high-dose cytarabine combinations with fludarabine and idarubicin, and the addition of GO 3 mg/m 2  × 1 during induction and consolidation (comparative SWOG and MRC studies) resulted in estimated 5-year survival rates of 75+% in CBF AML 13 , 14 , 15 , 16 , 17 . At MD Anderson, we currently use fludarabine, high-dose cytarabine and GO (i.e., FLAG-GO) during induction and consolidations, for a total of up to six courses, and modify therapy with the addition of maintenance for persistent MRD at the completion of therapy. The results were better when GO replaced idarubicin. The 5-year survival rates were 80% in both inversion 16 and t (8; 21) AML (Fig. 3 ) 3 , 14 . The MRC trials using the fludarabine, high-dose cytarabine and idarubicin combination (FLAG- IDA regimen) +/− GO also reported cure rates of 80+% in CBF AML 15 . In a meta-analysis of five studies, adding GO to standard induction-consolidation therapy improved survival from 50 to 75% 17 .

Survival of core-binding factor acute myeloid leukemia at MD Anderson (1970–2020).

Today, GO should always be added to the standard chemotherapy in CBFAML. The new regimens utilizing fludarabine, high-dose cytarabine and GO, with or without idarubicin, may be better, producing cure rates of 75–80+% 14 , 15 .

The CBF AML often exhibits co-occurrence of mutations in FLT3 (15–20%), c-KIT (29–30%), RAS (30–50%), and others. Some studies report c-KIT or multiple mutations to be associated with worse prognosis 47 , 48 , 49 . This has not been our experience with the FLAG-GO/idarubicin regimen where the efficacy of the regimen may have overcome the adverse effects of these mutations. Recent studies suggest an adverse impact of epigenetic mutations ( ASXL2 or cohesin/spliceosome mutations). Older patients with CBF AML are treated with lower adjusted dose FLAG-GO/IDA. Patients who cannot tolerate FLAG-GO/IDA or who have persistence molecular MRD positivity may be offered HMA therapy (decitabine, azacitidine) with venetoclax/GO, the treatment duration adjusted according to the MRD results or for 12+ months. Targeted therapies may also be considered (avapritinib or dasatinib for c-KIT mutations; FLT3 inhibitors for FLT3 mutations) 50 , 51 .

Figure 3 shows the MD Anderson outcomes in CBF AML over the decades.

Younger patients with acute myeloid leukemia (and/or older patients fit for intensive chemotherapy)

The median age in AML is 68 years 85 . Most of the research with 3 + 7 and other intensive chemotherapy regimens was conducted in younger patients (usual upper age limit 60–65 years). The published results of these trials may not reflect the actual results in the community practice (discussed later) 85 .

The “3 + 7” anthracyclines-cytarabine regimens; high-dose cytarabine consolidations

The discovery of the anti-AML activity of cytarabine and anthracyclines in the 1970s led to a series of randomized trials evaluating different doses and schedules of cytarabine (5 versus 7 versus 10 days; 100 mg/m 2 versus 200 mg/m 2 ) in combination with anthracyclines, and the addition of other agents (etoposide, 6-mercaptopurine, 6-thioguanine, others) to induction-maintenance therapy. These studies established the 3 + 7 regimen as a standard of care over the next 40 years. The 3 + 7 refers to 3 days of anthracyclines (daunorubicin 30–60 mg/m² intravenously [IV] daily × 3; idarubicin 12 mg/m² IV daily × 3 days) and cytarabine (100–200 mg/m² IV as a continuous infusion daily for 7 days). Consolidation strategies have investigated multiple courses of chemotherapy with cytarabine and anthracyclines, as well as high-dose cytarabine. A randomized trial by Meyer and the Cancer and Acute Leukemia Group B (CALGB) reported significantly superior survival using high-dose cytarabine consolidation therapy (3 g/m² IV over 2–3 h every 12 h on Days 1, 3, and 5) for four courses, compared with lower cytarabine dose schedules 86 . In the CALGB study, high-dose cytarabine consolidations were followed by four additional courses of 2 + 5 chemotherapy. The latter addition was omitted from the subsequent comparative trials, which may be important (later studies using this regimen reported 5-year survival rates of 20–30% rather than 40%) 7 . High-dose cytarabine then became the consolidation standard of care in AML. Other studies investigated lower doses of high-dose cytarabine (1.5 g/m 2 ), 4–5 courses versus lower numbers of consolidation courses, and the possible benefits of using allogeneic or autologous SCT in first CR 87 .

Better regimens than 3 + 7

An increasing body of research suggests that there are better induction-consolidation regimens than 3 + 7. Modifications of frontline AML therapy include: (1) The use high-dose cytarabine combination during induction. (2) Optimization of the dose of daunorubicin (60 mg/m 2 daily × 3, versus 45 mg/m 2 or 90 mg/m 2 daily × 3) and the use of other anthracyclines (idarubicin, mitoxantrone). (3) The addition of adenosine nucleoside analogs (fludarabine, clofarabine, cladribine) to cytarabine-anthracyclines. (4) The addition of the CD33-targeted monoclonal antibody (GO). (5) The addition of targeted therapies such as FLT3 and IDH inhibitors in appropriate patients. (6) The addition of the BCL-2 inhibitor venetoclax to induction therapy on investigational trials. (7) The use of maintenance therapy with oral azacitidine.

High-dose cytarabine induction

High-dose cytarabine (1–3 g/m 2 twice daily on Days 1, 3 and 5 or daily × 5) in AML consolidation is an established standard of care 86 , 88 , 89 . Several studies evaluated high-dose cytarabine during induction. A SWOG trial randomizing younger patients (<65 years) to standard-dose cytarabine (200 mg/m 2 daily × 7) versus high-dose cytarabine (2 g/m 2 every 12 h × 12) during induction (both with daunorubicin) showed a higher 4-year relapse-free survival (RFS) rate with high-dose cytarabine among younger (<50 years; 33% versus 21%) and older patients (50 to 64 years; 21% versus 9%; p  = 0.049) 88 . An Australian study randomizing 301 younger patients (60 years or less) to high-dose cytarabine (3 g/m 2 every 12 h × 8) or standard-dose cytarabine (both with daunorubicin and etoposide induction) reported significant improvements in CR duration (median 45 versus 12 months; p  = 0.0004) and 5-year RFS rate (49% versus 24%) with high-dose cytarabine 89 . A meta-analysis of three trials in 1691 patients randomized to induction therapy with high-dose versus standard- dose cytarabine reported improved 4-year rates of RFS ( p  = 0.03), overall survival ( p  = 0.0005) and EFS ( p  < 0.0001) with high-dose cytarabine 90 .

Lowenberg and colleagues 91 randomized 858 younger patients (median age 49 years; range 18 to 60 years) to induction therapy with high-dose cytarabine 1 g/m 2 every 12 h × 10 versus standard-dose cytarabine 200 mg/m 2 daily × 7, both in combination with idarubicin. They reported similar CR, EFS, and survival rates in the two study arms. This study results may have been confounded by the study design, in which all patients received high-dose cytarabine during induction Course 2 (either 2 g/m 2 every 12 h × 8—total dose 16 g/m 2 —for patients randomized to high-dose cytarabine during Course 1; or cytarabine 1 g/m 2 every 12 h × 6 days—total dose 12 g/m 2 —for patients randomized to standard-dose cytarabine during Course 1). Thus, all patients received high- dose cytarabine during the two induction courses.

Willemze and colleagues 92 (EORTC-GIMEMA) conducted a randomized trial in which 1942 younger patients (60 years or less) received daunorubicin plus etoposide and high-dose cytarabine 3 g/m 2 every 12 h × 8 versus standard-dose cytarabine 100 mg/m 2 daily × 10. High-dose cytarabine was associated with significantly higher CR rates (82% versus 76%; p  = 0.01), 6-year EFS rates (44% versus 35%; p  = 0.003), and 6-year survival rates (52% versus 43%; p  = 0.009) among patients 15–45 years old. Among patients 45–60 years, high-dose cytarabine was also associated with significant improvements in CR and 6-year EFS rates, as well as a trend for better survival among patients with FLT3- ITD AML or poor prognosis karyotypes.

Bassan and colleagues 93 randomized 574 patients (median age 52 years; range 16 to 73 years) to ICE (idarubicin-cytarabine-etoposide) or idarubicin plus sequential high-dose cytarabine (2-weekly 3-day blocks of cytarabine 2 g/m 2 twice daily × 2 days). Sequential high-dose cytarabine induction was associated with a significantly higher CR rate post Course 1(81% versus 69%; p  = 0.02), and significantly better rates of 5-year survival (49% versus 39%; p  = 0.045) and RFS (48% versus 36%; p  = 0.028).

A recent SWOG trial (SWOG-1203) randomized patients to: (1) 3 + 7 induction followed by four consolidations with high-dose cytarabine (3 g/m 2 twice daily on Days 1, 3, and 5—total cytarabine 18 g/m 2 /course x 4 = 72 g/m 2 ), (2) IA regimen:Idarubicin plus continuous high-dose cytarabine (1.5 g/m 2 continuous infusion daily × 4) followed by IA consolidations with cytarabine 0.75 g/m 2 continuous infusion daily × 3 days ( = 2.25 g/m 2 /course) × 4 (total cytarabine 15 g/m 2 ); (3) IA + vorinostat 94 . While the latter two arms were presumably testing the benefit of high-dose cytarabine induction, the total dose of cytarabine was 4.5 times higher with the 3 + 7 regimen compared with the IA regimen. As expected, the 3 + 7 regimen, delivering more total high-dose cytarabine, was superior in the CBF AML. However, despite the lower total cytarabine dose given in IA, the results of 3 + 7 and IA were similar among patients with intermediate or adverse karyotypes. The design of this trial unfortunately did not allow a real testing of the benefit of high-dose cytarabine added to induction.

Addition of nucleoside analogs

A combination regimen of fludarabine, high-dose cytarabine and idarubicin combination (FLAG-IDA or FAI), was developed at MD Anderson based the preclinical studies of Plunkett et al. 95 , 96 , 97 , 98 . The Medical research Council (MRC) AML 15 randomized trial compared the FLAG-IDA in younger patients with AML to 3 + 7 regimens without or with etoposide. The FLAG-IDA regimen consists of cytarabine 2 g/m 2 daily for 5 days, fludarabine 30 mg/m 2 daily for 5 days, and idarubicin 8–10 mg/m 2 daily for 3 days. Among patients who tolerated four courses on the FLAG-IDA arm (2 FLAG-IDA + 2 high-dose cytarabine), the 8-year survival rate was 66% versus 47% in the standard arm 15 , 87 , 98 . The FLAG-IDA/FAI is intensive and difficult to deliver due to side effects related to myelosuppression, but likely not more than allogeneic SCT, and possibly worth a 20% difference in 8-year survival. The FLAG-IDA/FAI is not a simple exploration of high-dose cytarabine, but a multi-faceted strategy (addition of fludarabine, idarubicin instead of daunorubicin, high-dose cytarabine induction) that may be better than 3 + 7 when administered at AML centers of excellence. Improved leukemia management expertise (supportive care; antibiotics and antifungal prophylaxis; timely transfusions support, management of toxicity and treatment of infections/sepsis) would allow safe and full delivery of this regimen.

The optimal dose of high-dose cytarabine is unknown even after 30+ years of research of different high-dose cytarabine schedules. Cytarabine 3 g/m 2 may be beyond the dose required to maximize the anti-AML effect, and may increase toxicity. High-dose cytarabine 1.5–2 g/m 2 may be equally effective and less toxic. The MRC studies compared high-dose cytarabine 1.5 g/m 2 versus 3 g/m 2 during consolidation, and four versus five courses, reporting equivalent results 87 . A study from Korea showed that high-dose cytarabine 1.5 g/m 2 or more during consolidation was associated with better RFS and survival rates compared with cytarabine 1 g/m 2 99 . At MD Anderson, we use high-dose cytarabine 1.5–2 g/m 2 daily × 5 (total 7.5–10 g/m 2 per course) during induction and consolidations.

Other adenosine nucleoside analogs (clofarabine, cladribine) have also been explored in combinations with standard chemotherapy.

The Polish investigators added cladribine to frontline 3 + 7 induction chemotherapy in two sequential randomized trials. In the first study, they randomized 400 patients to induction with 3 + 7 + /− cladribine, and reported that adding cladribine produced higher CR (64% versus 46%; p  = 0.0009) and leukemia-free survival rates (44% versus 28%; p  = 0.05) 100 . In the subsequent study, they compared three arms, two of them adding cladribine or fludarabine. They showed again that the addition of cladribine (but not fludarabine) resulted in higher CR (67.5% versus 56%; p  = 0.001) and 3-year survival rates (45% versus 33%; p  = 0.02) 101 .

At MD Anderson, we continue to use AML regimens that add adenosine nucleoside analogs like fludarabine (FAI, FLAG-IDA regimens), clofarabine (CIA regimen) and cladribine (CLIA regimen) to idarubicin and high-dose cytarabine as frontline induction therapy in younger patients with AML 102 . All patients with FLT3- mutated AML now receive gilteritinib or quizartinib during induction and consolidation. Based on the positive experiences of combining FLT3 inhibitors (midostaurin, sorafenib, gilteritinib) with chemotherapy from pilot studies and from the German and Intergroup randomized trials (discussed later), this approach may become a standard of care in FLT3- mutated AML, but also perhaps in all patients with AML regardless of FLT3 mutation status.

Choice of anthracycline

The better anthracycline and its optimal dose have been the subject of several randomized trials. Historically, daunorubicin 30–60 mg/m 2 daily × 3 was used for induction therapy. Two studies compared higher-dose daunorubicin 90 mg/m 2 daily × 3 to daunorubicin 45 mg/m 2 daily × 3 (in combination with cytarabine) in younger (age <60 years) and older patients (age 60+ years) 6 , 7 . In younger patients, high-dose daunorubicin was associated with a significantly higher CR rate (71% versus 57%; p  < 0.001) and longer survival (median 24 versus 16 months; p  = 0.003). However, the benefit was observed only in patients younger than 50 years and those with normal karyotypes 7 . In older patients, high-dose daunorubicin was associated with a higher CR rate (64% versus 54%; p  = 0.002) but not with improved survival, although a survival benefit was observed in the subset of patients 60 to 65 years old 6 . Daunorubicin 45 mg/m 2 daily × 3 is sub-standard. Daunorubicin 60 mg/m 2 daily × 3 may be as effective and less toxic than 90 mg/m 2 daily × 3. A French study analyzed 402 patients (median age 49 years) who received daunorubicin 60 mg/m 2 versus 90 mg/m 2 as part of 3 + 7 induction, and reported no difference in CR, induction mortality, RFS or overall survival 103 . A MRC study compared daunorubicin 60/m 2 versus 90 mg/m 2 during induction and reported no difference in the longer term outcome (2-year survival 60% versus 59%; p 0.14), but a higher early mortality with daunorubicin 90 mg/m 2   104 . These studies helped establish daunorubicin 60 mg/m 2 daily × 3 as the likely optimal dose schedule of daunorubicin.

Studies comparing idarubicin to daunorubicin, including a meta-analysis of five randomized trials, indicated that idarubicin may be associated with higher CR and survival rates 105 . Pautas and colleagues 106 randomized 468 patients to induction therapy of standard-dose cytarabine in combination with daunorubicin 80 mg/m 2 daily × 3 versus idarubicin 12 mg/m 2 daily × 3 or 4 days. Idarubicin for 3 days resulted in a higher CR rate (83% versus 70%; p  = 0.007) and a trend for better 4-year EFS (21% versus 12%) and survival (32% versus 23%) rates. A four-day schedule of idarubicin was not better. A retrospective analysis of two large French trials comparing idarubicin to daunorubicin in 727 patients reported that idarubicin 12 mg/m 2 daily for 3 days resulted in significantly higher CR (69% versus 61%; p  = 0.03) and cure rates (16.6% versus 9.8%; p  = 0.018) compared with daunorubicin 107 . Mandelli and the Italian colleagues 108 randomized 2157 patients to daunorubicin (50 mg/m 2 daily × 3), idarubicin (10 mg/m 2 daily × 3), or mitroxantrone (12 mg/m 2 daily × 3), in combination with standard-dose cytarabine. Both idarubicin and mitroxantrone were associated with higher 5-year RFS (37% versus 29%; p  = 0.02) and survival rates (43% versus 45% versus 36%; p  = 0.01) among patients who did not receive allogeneic SCT. At MD Anderson, we use idarubicin 8–10 mg/m 2 daily × 3 as part of the FAI/CLIA AML frontline regimens.

Gemtuzumab ozogamicin

Antibody-targeting therapy is a major success story in hematologic malignancies, particularly in lymphoid malignancies (antibodies targeting CD20, CD19, and CD22 in lymphomas, chronic lymphocytic leukemia, acute lymphoblastic leukemia). The development of GO, a CD33 monoclonal antibody bound to calicheamicin, has had a rough journey in AML. The Food and Drug Administration (FDA) originally granted accelerated approval of GO (9 mg/m 2 on Days 1 and 15) in the US in May 2000 for the treatment of older patients (60 years or older) in first relapse who are not candidates for cytotoxic chemotherapy. This approval was based on three phase 2 studies in 142 patients with relapsed AML (response rate 30%; CR rate 16%) 109 . The approval was conditional on a future demonstration of the GO benefit in randomized trials. Several studies then explored lower and fractionated dose GO schedules in frontline randomized trials (3 mg/m 2  × 1 during induction and consolidation; 3 mg/m 2 on Days 1, 4, and 7 during induction). The pivotal trial in the US 16 randomized patients to standard 3 + 7 with daunorubicin 60 mg/m 2 daily × 3, versus the addition of GO 6 mg/m 2 on Day 4 to 3 + 7, but with daunorubicin 45 mg/m 2 daily × 3 (equitoxic but suboptimal dose in retrospect). They reported a higher induction mortality rate with GO (5% versus 1%), which resulted in the withdrawal of GO from the US market in 2010 16 . This study had an unusually low mortality rate in the standard arm (usually about 3–7%), which suggested that GO may have increased mortality. The dose of daunorubicin in the GO arm was suboptimal, as confirmed today by several studies (discussed earlier). Four other randomized trials later matured, all demonstrating the benefit of adding GO, either overall or in subsets of patients 15 , 98 , 110 , 111 . A meta-analysis of the five randomized trials involving 3,325 patients showed that the addition of GO did not increase the CR rate, reduced the risk of relapse ( p  = 0.0001), and improved the 5-year survival rate ( p  = 0.01). The GO effect was most pronounced in AML with favorable cytogenetics (increased 5-year survival rate from 50 to 75%; p  = 0.0006) and intermediate cytogenetics ( p  = 0.005). Gemtuzumab 3 mg/m 2 was associated with fewer early deaths than 6 mg/m 2 and provided equal efficacy 17 . This resulted in the FDA re-approval of GO at the lower dose schedules for AML therapy in 2017 112 , 113 .

French experience with lomustine in older AML on 3 + 7

In three French studies involving 847 older patients (>60 years), the investigators reported that the addition of lomustine (alkylating agent) 200 mg/m 2 orally on Day 1 to idarubicin + cytarabine ( n  = 508), compared with idarubicin + cytarabine ( n  = 339), was associated with a higher CR rate (68% versus 58%; p  = 0.002), a similar rate of toxic deaths, and a longer survival (median 12.7 versus 8.7 months; p  = 0.004). By multivariate analysis, lomustine was an independent favorable treatment variable for achievement of CR ( p  = 0.002) and for survival prolongation ( p  = 0.002) 114 .

The MD Anderson approach in 2020

To summarize, the optimal frontline therapy for younger patients with AML is evolving. While many AML experts (and community oncologists) favor 3 + 7 as the standard of care, better regimens may have emerged. These incorporate high-dose cytarabine during induction and consolidations, include nucleoside analogs into the regimens, may incorporate lower-dose GO as part of induction-consolidation in CBF and intermediate-karyotype AML, may add other targeted therapies, particularly FLT3 inhibitors (e.g., gilteritinib, midostaurin, sorafenib) in FLT3 -mutated AML, and may add venetoclax to regimens in non FLT3- mutated AML (discussed later).

AT MD Anderson, younger patients with AML referred today are treated with a combination of idarubicin, high-dose cytarabine and an adenosine nucleoside analog (fludarabine—FAI/FLAG-IDA; cladribine—CLIA). FLT3 inhibitors (gilteritinib, quizartinib) are added to the regimen in patients with FLT3- mutated AML. Venetoclax shorter courses (7–14 days) are under investigation in combination with FAI or CLIA in the other AML subsets 115 , 116 . Once in CR, and based on availability of donors, patient age and co-morbidities, pretreatment AML characteristics (cytogenetics, molecular profiles) and MRD status in CR, patients may be offered allogeneic SCT. On average, patients are considered for allogeneic SCT in first CR if they have high-risk disease based on adverse cytogenetic abnormalities, high FLT3- mutation AR, or persistent MRD >0.1% in CR post first consolidation. Otherwise, they complete 4–6 courses of consolidation and are then offered maintenance therapy with azacitidine and venetoclax for 2+years, with or without the addition of targeted inhibitors (e.g., FLT3 inhibitors if FLT3 -mutated AML; IDH inhibitors if IDH -mutated AML). Figure 4 shows the approaches in community practice and at MD Anderson. Patients 50 years or older are offered induction therapy in the protected environment to reduce induction mortality (Table 4 ). In community practice, reasonable isolation procedures could be proposed: laminar air-flow rooms; reverse isolation; gloves, masks, gowns; no plants or flowers; limiting visitors. Intensive supportive care is offered with antibiotic prophylaxis including antifungals (posaconazole or voriconazole) 117 , 118 .

A standard of care; B MD Anderson approach in young/fit patients, and C in older patients.

With this general approach, the CR rate among non-selected younger patients with AML is 70–80%, and the long-term survival rate is 40–50% (Fig. 1 ). With the encouraging data incorporating venetoclax, FLT3 inhibitors, IDH inhibitors, and monoclonal antibodies (GO, novel CD33 monoclonal antibodies), combined modality strategies involving targeted agents and chemotherapy are becoming a reality in the management of all younger and older patients with AML.

Since the 2015 AML review 1 , many of the strategies listed then as investigational are now FDA approved and used as standards of care, either in the FDA approved indications, or in combined modality therapies that synergize their clinical benefits and render them more cost-effective. This is certainly the case for venetoclax, FLT3 inhibitors (gilteritinib), and IDH inhibitors (enasidenib, ivosidenib). Next, we summarize such ongoing studies with intensive chemotherapy in younger patients with AML.

Regimens with venetoclax

At MD Anderson, the frontline regimens, FLAG/IDA and CLIA, are now combined with venetoclax for 7–14 days during induction and for 5–7 days in maintenance, as tolerated 115 . The preliminary data are encouraging. Among 28 patients treated with FLAG/idarubicin-venetoclax, the overall response rate is 93%, and the MRD negativity rate in CR 92% 115 . Among 31 patients treated with CLIA-venetoclax, the overall response rate is 90%, and the estimated 1-year survival 78% 116 . The regimens are myelosuppressive as expected, but tolerable with very low rates of induction mortality. Growth factors and prophylactic antibiotics/antifungals are essential to reduce the risk and morbidity of opportunistic infections.

Regimens with IDH inhibitors

Stein and colleagues 119 treated 134 patients with de novo AML and IDH mutations using a combination of 3 + 7 and ivosidenib (IDH1 mutation; n  = 60) or enasidenib (IDH2 mutation; n  = 91). With 3 + 7 + ivosidenib the overall response rate was 93% and the estimated 1-year survival rate 79%. With 3 + 7 + enasidenib the overall response rate was 73% and the estimated 1-year survival rate 75% 119 . The HOVON and German study groups are currently evaluating 7 + 3 with either ivosidenib or enasidenib (versus placebo) in a large Phase III randomized study (NCT03839771).

Regimens with FLT3 inhibitors

Stone and colleagues 120 conducted a randomized phase III RATIFY trial (CALGB 10603) in 717 patients <60 years of age with newly diagnosed FLT3 -mutated AML ( FLT3- ITD and/or FLT3- TKD; median age 48 years; range 18 to 60 years) with the combination of 3 + 7 with or without midostaurin. Seventy-seven percent of patients had a FLT3- ITD mutation and 23% had a FLT3- TKD mutation. The addition of midostaurin improved the CR rate (59% versus 54%, p  = 0.045) and the survival (median survival 74.7 versus 25.6 months, p  = 0.009; estimated 5-year survival rate 50% versus 42%). The benefit was noted in FLT3- ITD low AR (AR less or equal 0.70), FLT3- ITD high AR (AR >0.70) and TKD - mutated AML. At MD Anderson, a matched-cohort analysis similarly showed the benefit of adding sorafenib to idarubicin-cytarabine in FLT3 -mutated AML 41 . In our study of CLIA + FLT3 inhibitor (sorafenib/midostaurin), the CR rate was 86% and the estimated 1-year survival 70% 121 .

Several studies are now underway evaluating newer generation FLT3 inhibitors (gilteritinib, quizartinib, crenolanib) in combination with intensive chemotherapy. Pratz and colleagues 122 treated 33 patients with newly diagnosed AML with 3 + 7 plus gilteritinib, reporting a marrow CR rate of 80+% and an estimated 2-year survival rate of 70%. These encouraging data have led to two randomized studies of 3 + 7 + gilteritinib versus 3 + 7 + midostaurin in Europe (HOVON 156ML; NCT04027309) and the US (NCT03836209). A phase III, randomized study of 3 + 7 + quizartinib versus 3 + 7 in frontline FLT3- ITD AML completed enrollment; the results are expected in 2021 (QUANTUM-First, NCT02668653)

Sorafenib has been used as maintenance therapy post allogeneic SCT in FLT3 -mutated AML in single arm and randomized trials, all showing survival and/or RFS benefits for the addition of sorafenib maintenance 123 , 124 . A randomized study of gilteritinib versus placebo administered after allogeneic SCT in FLT3 -mutated AML may help address more definitively the benefit and optimal use of FLT3 inhibitors in this setting. (BMT CTN 1506; ClinicalTrials.gov identifier: NCT02997202).

While FLT3 inhibitors are now established therapies in combination regimens in FLT3 -mutated AML, it is of interest that several non-targeted chemotherapy strategies have also shown selective benefits in FLT3 -mutated AML, including induction regimens containing high-dose cytarabine, cladribine and high-dose daunorubicin 92 , 125 , 126 .

Older patients with acute myeloid leukemia (or younger patients not fit for intensive chemotherapy)

Intensive chemotherapy.

The median age of patients with AML is 68 years, but most of the experience with 3 + 7 and intensive chemotherapy regimens is in younger patients, usually 60 years or younger. Older patients with AML tolerate intensive chemotherapy poorly. In the study by Lowenberg and colleagues 6 evaluating 3 + 7 with daunorubicin 45 mg/m 2 versus 90 mg/m 2 daily × 3, among 813 selected patients 60 years and older (median age 67 years), the median survival was 7 to 8 months and the estimated 3-year survival rate was 20%. The study reported an acceptable low early mortality rate of 11–12%. Whether this mortality rate is replicable in unselected patients in oncology community practice is questionable.

The treatment of older patients with AML remains challenging. Acute myeloid leukemia in older patients carries a distinctly different disease biology associated with high risk and often complex karyotype, a high incidence of cytogenetic abnormalities involving monosomies 5 and 7 and chromosome 17 abnormalities, a high incidence of multiple mutations including TP53 (20+%), and a high incidence of secondary/therapy-related AML (20 to 30%). Older patients have multiple co-morbidities (hypertension; diabetes; organ dysfunctions including cardiac, pulmonary and renal abnormalities) that result in poor tolerance to intensive chemotherapy and high early (4- to 8-week) mortality rates. In community practice (SEER data; 2010–2017) treating unselected older patients, the 4-week mortality is 24% among patients 60–69 years old and the 5-year survival 18%. Among patients 70 years and older (45% of all AML), the 4-week mortality is 44% and the 5-year survival 4%. Clearly neither intensive chemotherapy nor supportive/hospice care are acceptable options in older AML.

At MD Anderson, historical studies using intensive chemotherapy in older patients with AML (age 60–65 years or older) showed CR rates of 40–50%, 4–8-week mortality rates of 26–36%, median survivals of 4–6 months, and one -year survival rates of <30% 127 , 128 . By multivariate analysis, independent adverse factors predictive of early mortality with intensive chemotherapy were: age 75 years and older; adverse karyotype with three or more chromosomal abnormalities; presence of an antecedent hematologic disorder; poor performance status (ECOG 2–4); creatinine level 1.3 mg/dl or higher; and treatment outside a protected environment. The expected 8-week mortality was 10–19% with the presence of 0–1 adverse factors, and 36–65% with the presence of 2–5 adverse factors 127 .

Epigenetic and low-intensity therapy

Faced with the poor results with intensive chemotherapy, investigators began in the 1990’s evaluating lower-intensity strategies in patients unfit for intensive chemotherapy (expected high-early mortality). These included low-dose cytarabine, HMA therapy, and targeted therapies (monoclonal antibodies; more recently FLT3 inhibitors and IDH 1/2 inhibitors). This raised the question of how to select patients unfit for intensive chemotherapy. At our institution, we use the above model to select such patients, based on an estimated early mortality rate in excess of 10%. Over time and over several investigational studies since 2000, we have shown that lower-dose chemotherapy/HMA therapy combinations now provide, since 2015, overall response rates as high as with intensive chemotherapy, significantly lower rates of early mortality and myelosuppression-associated complications, and survival equivalent or superior to intensive chemotherapy 129 , 130 .

In clinical practice, leukemia experts often base the decision of intensive versus low-intensity therapy on the “oculometer” (looking at the patient and deciding by intuition and experience). The approach is subjective and based on the oncologist’s experience and perception of the patient’s condition (performance, co-morbidities, infections at presentation, tolerance to intensive chemotherapy). This may be better replaced by more objective prediction models such as the one used at our institution. Patients are then categorized according to their predicted early mortality (based on the multivariate prognostic models) 127 , 128 . If the expected 4–8-week mortality is <10%, they are offered intensive chemotherapy. If it is >10–20%, they are offered low-intensity approaches. Of interest, a third of patients who present as afebrile with normal chest radiographs may have significant abnormalities detected by computerized tomography (CT) scans (infections, nodular lesions suggestive of early fungal pneumonia, bleeding, other) 131 . Patients with AML and pneumonia at diagnosis have a significantly higher risk of early mortality with intensive chemotherapy (4–8-week mortality 15–30%; Sasaki-unpublished). Future studies should investigate incorporating pretreatment routine CT of chest findings into predictive models of early mortality in AML.

Historically, many older patients (age 70 or older) with AML were offered supportive palliative or hospice care 132 . The MRC AML14 study randomized 217 older patients to low-dose cytarabine 20 mg subcutaneously twice daily × 10 days versus supportive care and hydroxurea 133 . Low-dose cytarabine was associated with a higher CR rate (18% versus 1%; p  = 0.00006) and with longer survival (odds ratio: 0.60; p  = 0.0009). This study drove home an important message: that an active tolerable treatment would have a significant effect on improving early mortality and overall survival, even among patients deemed suitable only for supportive care at the time of diagnosis. In the 2000s, studies with HMAs demonstrated the benefits of decitabine and azacitidine for the treatment of older patients unfit for intensive chemotherapy. A phase 3 study randomized 485 patients 65 years or older to decitabine 20 mg/m 2 IV daily × 5 every month versus supportive care or low-dose cytarabine. In a final analysis, the median survival was 7.7 with decitabine versus 5 months with supportive care or low-dose cytarabine ( p  = 0.036). This led to the European Medicines Agency (EMA) approval of decitabine for the treatment of older patients with AML 26 . A similar study (AZA-AML-001) randomized 488 older patients to azacitidine ( n  = 241) versus three predetermined conventional care regimens ( n  = 247; low-dose cytarabine, intensive chemotherapy, supportive care). Azacitidine therapy was associated with longer survival (median 10.4 versus 6.5 months; p  = 0.06; hazard ratio 0.85) 30% blasts. Blood 126, 291–299 (2015)." href="/articles/s41408-021-00425-3#ref-CR28" id="ref-link-section-d52434916e3213">28 .

Studies have also evaluated longer durations of decitabine schedules (20 mg/m 2 daily × 10) 134 in combinations (venetoclax, FLT3 and IDH inhibitors, others). The FDA approved recently a 100% absorbable oral formulation of decitabine plus oral cedazuridine (cytosine deaminase inhibitor; oral combination bioequivalent to intravenous decitabine) 135 , 136 . This opens research into potentially highly effective oral therapies in older AML (oral decitabine-cedazuridine plus venetoclax), which may improve tolerance and quality of life, and offer safe and effective outpatient therapy.

At MD Anderson, prior to the discovery of the role of venetoclax in AML, we had evaluated sequential three-drug low-intensity therapy combining an adenosine nucleoside analog (clofarabine or cladribine) with low-dose cytarabine, and alternating this with decitabine over a period of 18 months 137 , 138 . Among 248 patients (median age 69; range 48–85 years) treated with the two regimens, the overall response rate was 66%, the CR rate 59%, the early (4-week) mortality rate 2%, the median survival 12.5 months, and the estimated 2-year survival rate 29%. Among patients with normal karyotype, the median survival was 19.9 months and the estimated 2-year survival rate 45% 137 , 138 . At that time, compared to single-agent HMAs, which were standard therapy, the triple-nucleoside analog (cladribine-cytarabine-HMA) low-intensity therapy showed better results. It also represented a novel, well-tolerated, effective new backbone therapy upon which to build combination approaches. Deriving from the success of HMA + venetoclax combinations, we are evaluating the combination of cladribine-low-dose cytarabine-azacitidine with venetoclax in older AML.

Regimens with hypomethylating agents and venetoclax (ABT-199)

One therapeutic strategy to target AML involves activation of the intrinsic or mitochondrial pathway of apoptosis. This pathway is regulated by the BCL2-family of proteins. It involves a dynamic balance of pro-apoptotic effectors (Bak, Bax) and anti-apoptotic proteins (BCL-2, BCL-XL, MCL-1). In a balanced state, the anti-apoptotic proteins bind to and sequester the pro-apoptotic proteins and prevent them from triggering apoptosis. Anti-apoptotic proteins are overexpressed in many tumors including AML. Small molecule “BH3 –mimetics” were developed that bind to the anti-apoptotic proteins in the BH3 domain and liberate pro-apoptotic proteins that subsequently trigger apoptosis. The earlier generation of BH3 mimetics bound efficiently to multiple anti-apoptotic proteins, including BCL-2, BCL-XL, and MCL-1, and thus were associated with unacceptable on- target toxicities, including thrombocytopenia.

Venetoclax (ABT-199; BCL2 inhibitor) was developed over many years as a more advanced BH3 mimetic molecule designed to retain specificity for BCL-2, but without affinity for BCL-XL or MCL-1. Venetoclax has already revolutionized the treatment of chronic lymphocytic leukemia and may have a role in other cancers (acute lymphoblastic leukemia, myelodysplastic syndrome, lymphoma and myeloma subsets). The AML blasts and AML stem cells depend on BCL-2 for survival, but normal hematopoietic stem cells depend on MCL-1. This presented the rationale for investigating venetoclax in AML. Preclinical studies confirmed its activity in AML cell lines, in murine primary xenografts, and in AML samples 139 . A phase 2 single-agent study in AML investigated venetoclax (800 mg daily) in 32 patients with refractory-relapsed AML. The overall response rate was 15%, with another 19% of patients having reductions of blasts 140 . Responses appeared to be more frequent among patients with IDH mutations, a clinical observation that confirms preclinical studies, suggesting BCL-2 to be a synthetic lethal partner AML with IDH1/2 mutations 53 , 140 .

Based on the encouraging preclinical data of venetoclax in combination with HMAs and low-dose cytarabine, single-arm trials evaluated these combinations in newly diagnosed patients with AML who were older than 75 years or unfit to receive intensive chemotherapy. The positive results (overall response rates 67%; estimated median survival 17.5 months; 2-year survival rate 40%) led to the FDA accelerated approval of venetoclax in combination with epigenetic therapy or low-dose cytarabine for the treatment of these patients 141 , 142 .

The subsequent VIALE-A pivotal trial randomized such patients (75 + years; or unfit for intensive chemotherapy) to therapy with azacitidine alone or in combination with venetoclax. Among 431 patients randomized on a 2:1 basis to azacitidine plus venetoclax ( n  = 286) or azacitidine ( n  = 145), the addition of venetoclax resulted in a significantly longer survival (median survival 14.7 versus 9.6 months; p  < 0.001). The overall response rate (66.4% versus 28.3%; p  < 0.001) and CR rate (29.7% versus 17.9%; p  < 0.001) were also higher 143 . A similar randomized study (211 patients; 2:1 randomization) of low-dose cytarabine with venetoclax versus low-dose cytarabine alone showed a median survival of 8.4 versus 4.1 months ( p  = 0.04), an overall response rate of 48% versus 13% ( p  < 0.001), and a CR rate of 27% versus 7% ( p  < 0.001) 144 .

A single-arm trial from our institution investigated the use of decitabine for a 10-day induction with venetoclax (followed by maintenance with monthly decitabine for 5 days and venetoclax for 14–21 days). Among 70 older patients (median age 72 years; range 70–78 years) with newly diagnosed de novo AML treated with the regimen, the overall response rate (CR + CRi) was 84%, the CR rate 67%, the 4-week mortality rate 0%, and the median survival 18.1 months 145 .

Experience with low-intensity chemotherapy combination and venetoclax

One of the current frontline trials in older AML at MD Anderson explores the combination of cladribine-cytarabine-venetoclax alternating with azacitidine-venetoclax 146 . Among 48 patients treated so far (median age 68 years; range 57–84 years), the CR rate was 77%, the overall response rate 94%, the MRD negativity rate 80%, the 4-week mortality rate 0%, and the estimated 1-year survival rate 70%.

Hypomethylating agents with FLT3 inhibitors

The combination of azacitidine and sorafenib in older patients with FLT3-ITD AML resulted in a CR-CRi rate of 78% and a median survival of 8.3 months 147 .

Gilteritinib was combined with azacitidine in the frontline setting in the ongoing phase III LACEWING trial. The initial safety run-in data from this study showed an encouraging marrow CR rate of 67% among the first 15 patients treated prior to the beginning of the randomization 148 . A gilteritinib dose of 120 mg daily was selected with standard-dose azacitidine (NCT02752035).

Older patients (age 65 years or older) and patients not fit for intensive chemotherapy (based on predicted high early mortality) are now offered low-intensity strategies using combinations of cladribine and low-dose cytarabine alternating with decitabine or azacitidine together with venetoclax; decitabine (10-day induction, 5-day maintenance) combined with venetoclax, and other HMAs (e.g., oral decitabine) plus venetoclax-based combinations that also incorporate FLT3 inhibitors (if FLT3 -mutated AML), IDH inhibitors (if IDH -mutated AML), or APR246 or magrolimab (if TP53 -mutated AML). (Table 4 ).

CPX-351 in older AML

CPX-351 is a nano-scale liposome, which contains a fixed 5:1 molar ratio of cytarabine and daunorubicin 149 . Following the encouraging preclinical and phase 1–2 trials in the subset of secondary AML,a pivotal phase 3 randomized trial in newly diagnosed secondary AML accrued 309 patients randomized to CPX-351 versus 3 + 7. Therapy with CPX-351 was associated with a significantly longer survival (hazard ratio 0.69; p  = 0.005). The CR rate was 38% with CPX-351 versus 26% with 3 + 7 ( p  = 0.035); the CR + CRi rate was 48% versus 33% ( p  = 0.016). CPX-351 was associated with a longer duration of myelosuppression. More of the patients achieving CR post CPX-351 were able to undergo later allogeneic SCT (20% versus 12%); their survival was also longer post SCT. The study findings resulted in the FDA approval of CPX-351 as frontline therapy of secondary AML 150 , 151 . Ongoing studies are combining CPX-351 with venetoclax, GO, and other targeted therapies.

The Hedgehog (Hh) signaling pathway plays critical roles in embryogenesis and stem cell maintenance. Dysregulations in the Hh pathway can result in the development, maintenance and expansion of the leukemic stem cells, which play a critical role in AML pathogenesis, persistence and progression 152 .

Glasdegib, a cyclopamine derivative, is a selective inhibitor of Smoothened (SMO), a component of the Hh signaling pathway. Following encouraging preclinical and phase 1–2 trials, a phase 2 study investigated low-dose cytarabine alone versus low-dose cytarabine plus glasdegib 100 mg daily. The addition of glasdegib was associated with a significant prolongation of survival (median survival 8.8 months versus 4.9 months; 12-month survival 59.8% versus 38.2%) 153 . This led to the approval of glasdegib for the treatment of newly diagnosed AML in patients 75+ years old or unsuitable for intensive induction chemotherapy 154 . Ongoing studies are evaluating glasdegib combination with azacitidine and with intensive chemotherapy.

The potential roles of APR-246 and magrolimab in TP53 -mutated AML

TP53 - mutated AML is associated with older age, therapy-related disease, complex (adverse) cytogenetics, and very poor prognosis. Even with the advent of HMAs plus venetoclax, older patients with TP53 -mutated AML ineligible for induction therapy continue to do poorly: response rates 50% but median survival only 3–6 months 145 .

APR-246 is a novel agent that may restore the transcriptional activity of unfolded wild-type or mutant p53 , leading to induction of apoptosis in cancer cells with mutant p53 155 . In two parallel ongoing studies in France and the US, the combination of azacitidine with APR-246 produced CR/CRi rates of 60–80%; >60% of responders had undetectable TP53 mutation by next-generation sequencing 156 , 157 . A phase III randomized study of azacitidine with or without APR-246 in frontline MDS and AML with 20 to 30% blasts has recently completed enrollment (NCT03745716), and reported not to have met the study primary endpoint of significantly higher CR rate (December 28, 2020).

CD47 functions as a macrophage checkpoint, providing a potent “do not eat me” signal that allows tumor cell evasion and immune destruction by macrophages. CD47 is upregulated in AML, and CD47 upregulation was independently associated with a poor prognosis 158 , 159 , 160 . Hu5F9-G4 (magrolimab) is a humanized monoclonal antibody that binds CD47 and blocks it from interacting with its ligand SIRPα on phagocytic cells, leading to phagocytic elimination of cancer cells. The combination of magrolimab plus azacitidine was evaluated in patients with newly diagnosed AML who were unfit for intensive chemotherapy or who had MDS intermediate-higher risk (Revised International Prognostic Scoring System [IPSS-R]). In 34 evaluable patients with AML, the objective response rate was 65%, (CR 40%, CRi 12%). The median time to response was 2.0 months. Among patients who had abnormal cytogenetics at baseline, 47% achieved complete cytogenetic response. In patients harboring TP53 mutations, the overall response rate was 71% (15 of 21 patients) and the CR rate 48 % (5 of 12 patients). The median survival in TP53 -mutant AML was 12.9 months and in TP53 wild-type 18.9 months 161 .

Maintenance therapy in acute myeloid leukemia

Maintenance therapy is an established positive approach in many cancers, including acute lymphocytic leukemia. However, studies in AML could not confirm a clear benefit of maintenance therapy, until the recent positive results reported with oral azacitidine (CC-486). The oral drug is poorly absorbed (AUC 10–30% of intravenous azacitidine). In an international multi-center trial (QUAZAR AML-001), 472 patients 55 years and older (median age 68 years) with AML in first CR for <4 months were randomized to oral azacitidine (CC-486) 300 mg orally daily × 14 every month ( n  = 238), or placebo ( n  = 234). The median survival was 24.7 months with CC486 versus 14.8 months with placebo (hazard ratio 0.69, p  = 0.0009). The median RFSs were 10.2 and 4.8 months. The FDA approved CC-486 as oral maintenance therapy for this indication in September 2020 162 .

A second study (HOVON97) randomized 116 patients 60 years and older with AML who were in CR post two courses of intensive chemotherapy to azacitidine 50 mg/m 2 subcutaneously daily × 5 every month for 12 courses ( n  = 56) versus observation ( n  = 60). The 12-month disease-free survival (DFS) was 64% with azacitidine versus 42% with observation ( p  = 0.04) 163

In the context of post-SCT, maintenance therapy has also been of benefit. Buchert and colleagues 124 reported on 83 patients (median age 54 years) with FLT3- ITD AML post allogeneic SCT who were randomized to sorafenib 200–400 mg twice daily for two years versus placebo. The 2-year PFS rate was 85% with sorafenib versus 53% with placebo ( p  = 0.04). Survival was also better (hazard ratio 0.447; p  = 0.03). In the pivotal gilteritinib versus salvage chemotherapy (ADMIRAL) trial in 371 patients with FLT3- mutated AML, Perl and colleagues 164 reported on 51 patients achieving a response post gilteritinib and undergoing allogeneic SCT who either resumed gilteritinib post SCT ( n  = 35) or did not ( n  = 16). The median survival was longer with gilteritinib resumption (16.2 months versus 8.4 months; hazard ratio 0.387; p  = 0.024).

Translating the published literature into real-world experience

Here a word of caution—an analysis of the SEER data (more reflective of the reality on the ground and of general oncology community practice) in about 29,000 patients with AML showed results substantially worse than those reported from single institutions and from cooperative trials. In the SEER data, the results have improved since 2000 in APL (5-year survival about 60 + %) and CBF AML (5-year survival 50%), mostly in patients younger than 60 years. However, even restricting the analysis to the Years 2000–2017, the 4-week mortality among patients 40–59 years old with de novo AML (excluding APL and CBF AML) is 27% and the 5-year survival rate 40%. Among patients 70+ years old, the 4-week mortality rate is 45–50% and the 5-year survival rate <5% 85 .

Therapy of AML is difficult and requires long-term expertise. This is because AML is rare, and often affects older patients who require chemotherapy in the setting of a compromised marrow by the disease; this results in severe cytopenias at diagnosis and throughout therapy. All these conditions require also the use of antibiotics prophylaxis and the prompt availability of optimal supportive care (platelets and blood transfusions; skilled emergency centers and facilities to deliver the support needed, recognize infections and sepsis, implement proper broad-spectrum IV antibiotics, and offer timely intensive care unit care when needed). Thus, the risks of serious morbidities, mortality and treatment abandonment are high.

For a long time, it was assumed that AML care may be equally optimal in the community practice as it is in published data from cooperative trials. This, however, may not be the case. In several AML cooperative trials, the early (4-week) mortality with intensive chemotherapy in younger patients with AML ranges from 1 to 10% 91 , 165 . At our institution, the early mortality with intensive chemotherapy is <5%; the early mortality with low-intensity regimens in older AML is 1–2%.

Two recent studies reported significantly higher early mortality rates among patients treated in non-academic versus academic centers, and in non-NCI-designated versus NCI-designated cancer centers 166 , 167 . In a National Cancer data Base of 60,738 patients with AML, the 1-month mortality was 16% in academic centers and 29% in non-academic centers ( p  < 0.001), and the 5-year survival rate was 25% versus 15 % ( p  < 0.001) 166 , 167 . The second study from California in 7007 patients with AML reported an early mortality rate in AML of 12% in NCI-designated cancer centers versus 24% in non-NCI-designated cancer center 167 .

Perhaps AML, being rare and requiring intensive chemotherapy and supportive care in the setting of a compromised marrow, is better treated in specialized leukemia centers, rather than in the community practice.

Allogeneic and autologous stem cell transplantation

A meta-analysis combining data of multiple randomized trials demonstrated the significant benefit, on average, of allogeneic SCT in first CR 168 . The value of allogeneic SCT in AML first CR was difficult to confirm in earlier randomized trials because of: (1) the limited number of patients in each study (may not detect modest but clinically significant benefits); (2) the lead time bias to allogeneic SCT; (3) many patients allocated to allogeneic SCT could not undergo the SCT (infections, organ dysfunction, new chemotherapy related morbidities, AML relapse, others); (4) patients allocated to chemotherapy in first CR may have benefited from an allogeneic SCT in second CR. A study by the MRC reported that the benefits of chemotherapy versus allogeneic SCT in first CR were similar when the benefit of allogeneic SCT in second CR was factored in 169 .

Allogeneic SCT is an accepted standard of care in first CR, and based on several patient, AML and treatment-associated factors: (1) the presence of an adverse AML karyotype or high FLT3- mutated AR at diagnosis; (2) persistent MRD in CR; (3) low-risk of SCT-associated mortality based on the patient’s age and co-morbidities, donor availability and degree of matching. With the FDA approval and availability of venetoclax and FLT3 and IDH inhibitors, the role of allogeneic SCT in first CR needs to be continuously evaluated.

Allogeneic SCT should not be considered as a one-time independent procedure, but part of the total strategy of chemotherapy-targeted therapy-SCT. Investigations of post allogeneic SCTmaintenance strategy to reduce the risk of relapse should be incorporated into this continuum, including azacitidine-decitabine (parenteral and oral), FLT3 inhibitors, IDH inhibitors, venetoclax, and others.

Autologous SCT has been largely abandoned in the United States because of the lack of a definite benefit. European AML experts still advocate for its role in first CR based on randomized trials showing that autologous SCT provides equivalent results to multiple chemotherapy consolidations (usually fewer than 4). With the knowledge concerning persistence of MRD in CR, it is possible that historical studies may have reinfused autologous marrows with significant persistent AML disease burden, thus perhaps increasing the relapse rates. This may have abrogated the potential benefit of this approach. Future studies may evaluate again the benefit of autologous SCT using collected MRD-negative marrows. At our institution, autologous SCT is still considered occasionally in the setting of APL and CBF AML in second CR and with negative molecular MRD in collected stem cells.

Salvage therapy

The choice of salvage therapy in AML depends on multiple factors: patient age and wishes, co-morbidities, salvage status, prior therapies, duration of prior response, exposure to allogeneic SCT, leukemia characteristics, and availability of investigational therapies. Guidelines of salvage therapies offered at our institution are detailed below.

In young/fit patients with AML and failure or progression on 3 + 7 regimens, therapies that include high-dose cytarabine provide good results. Using the FLAG-IDA plus venetoclax regimen in 25 patients in Salvage 1, the marrow CR rate was 65% and 1-year survival 52% 115 . The combination of HMA therapy (azacitidine, decitabine) plus venetoclax may help patients not previously exposed to either agent. For patients post frontline high-dose cytarabine-based regimens (FAI-FLAG/IDA, CLIA) who are in first relapse with a first CR duration of 12 months or longer, we still offer the high-dose cytarabine-based regimens (FLAG-IDA, CIA, CLIA, twice daily fludarabine + cytarabine) 170 in combination with novel targeted therapies as indicated (venetoclax, FLT3 or IDH inhibitors). In salvage situations, repeating the molecular studies for FLT3, IDH 1–2 , and TP53 mutations may identify the emergence of resistant clones with these mutations. Patients may then become candidates for targeted inhibitors-based therapies. Patients in second salvage or beyond are offered phase 1–2 investigational approaches.

Patients achieving subsequent CR should be considered for allogeneic SCT immediately, provided they understand the procedure risks, expected mortality rates, and expected (low) rate of long-term survival. Along these lines, we are investigating a regimen of sequential intensive chemotherapy, with the application of allogeneic SCT at the time of marrow aplasia (Day 21–35 of chemotherapy) rather than after achievement of CR (which is of low probability; <10–20% in most such situations).

FLT3 inhibitors in AML salvage

Gilteritinib (SP 2215) is a potent type-1 FLT3 inhibitor (dual FLT3-AXL inhibitor) with excellent selectivity against FLT3 mutations (both FLT3- ITD and FLT3-TKD mutations). Gilteritinib 120 mg daily produced CRc (composite CR) rates of 45–50% as a single agent in relapsed/refractory FLT3- mutated AML patients 171 . The phase 3 pivotal ADMIRAL trial randomized (2:1) 371 patients with relapsed FLT3 -mutated AML to gilteritinib 120 mg daily ( n  = 247) or investigator choice salvage chemotherapy (both high- and low-dose chemotherapy) ( n  = 124) 164 . Gilteritinib therapy resulted in a significantly longer survival (median survival 9.3 versus 5.6 months; hazard ratio 0.637; p  = 0.0007). It was also associated with a higher rates of CR (21% versus 11%; p  = 0.013), CR/CRh rate (34% versus 15%), and CRc rate (54% vesus 22%) 164 . This led to the FDA approval of single-agent gilteritinib as salvage therapy of FLT3 -mutated AML. Ongoing studies are combining gilteritinib with HMA therapy and with intensive chemotherapy, as well as with venetoclax in frontline, salvage, and maintenance strategies in AML.

Combination therapy with agents that induce apoptosis may enhance cytotoxicity against FLT3- mutated and wild-type clones and potentially delay or prevent drug resistance to FLT3 inhibitor-based therapies. Preclinical data indicated strong synergism between venetoclax and FLT3 inhibitors. An ongoing phase IB study is evaluating the combination of venetoclax and gilteritinib (NCT03625505) in refractory-relapsed AML (most patients with prior exposure to FLT3 inhibitors). Currently, 31 of 37 patients (84%) treated achieved marrow CR; the median duration of response has not been reached 172 . A triplet-therapy combining azacitidine,venetoclax and gilteritinib in older AML is ongoing.

Isocitrate dehydrogenase inhibitors in AML salvage

The IDH 1–2 mutations induce neomorphic IDH enzyme activity, which results in aberrant production of the onco-metabolite 2-hydroxyglutarate (2-HG). The 2-HG competitively inhibits alpha-ketoglutarate (αKG), and leads to dyregulated epigenetic function, a hypermethylated phenotype, and a block in maturation, leading to AML tumorigenesis 173 .

Enasidenib, formerly AG221, is an orally bioavailable small molecule inhibitor of mutant IDH2 , which is FDA approved for the treatment of relapsed-refractory IDH2 -mutated AML at a dose of 100 mg orally continuously daily. The FDA approval was based on the results of the Phase1–2 trial in 176 patients with relapsed-refractory IDH2 -mutated AML. Enasidenib therapy resulted in an overall response rate of 41%, a CR/CRh rate of 23%, a median response duration of 5.8 months, and a median survival of 9.3 months. When used as monotherapy, patients with RAS pathway co-mutations and/or high mutational burden (>6 mutations) were less likely to respond 173 , 174 , suggesting the importance of combination therapy (under evaluation in both newly diagnosed and relapsed IDH2 -mutated AML). In a randomized Phase 2 study in newly diagnosed IDH2 -mutated AML of azacitidine + enasidenib compared with enasidenib alone, the combination resulted in a significantly higher CR rate (53% versus 12%) and overall response rate (71% versus 42%), and a trend for improved EFS (17 months versus 11 months). The overall median survival was impressive, 22 months, but similar in both arms, likely because of the availability of effective salvage 175 .

Ivosidenib, formerly AG120, is a selective small molecule inhibitor of IDH1 . Ivosidenib 500 mg daily was approved by the FDA for the treatment of relapsed-refractory IDH1 -mutated AML (as well frontline therapy of IDH1 -mutated AML in patients unfit for intensive chemotherapy) based on the results of the Phase 1–2 clinical trial evaluating 179 patients. In this study, ivosidenib produced an overall response rate of 42%, a CR/CRh of 30%, a CR of 22%, and a median survival of 8.8 months 176 . Similar to enasidenib, mutations in the RTK pathway (i.e., RAS, PTPN11 and FLT3 mutations) were associated with a lower response rate to ivosidenib monotherapy 177 . A trial of ivosidenib + venetoclax + azacitidine is currently ongoing in newly diagnosed and relapsed IDH1- mutated AML.

Expanding on topics of interest in AML

Polo-like-1 kinase inhibitors.

Polo-like kinase-1 (PLK-1) belongs to a family of serine-threonine kinases and plays an important role in centrosome maturation, spindle formation, and cytokinesis during mitosis. It is highly expressed in leukemic cells. Volasertib, a small molecule serine-threonine inhibitor, binds competitively to the kinase ATP-binding pocket and inhibits its enzymatic activity at low nanomolar concentrations. It also inhibits two related PLKs, PLK-2, and PLK-3. The encouraging data from preclinical and phase 1–2 trials led to a phase 2 randomized study of low-dose cytarabine with and without volasertib in patients with AML not suitable for frontline intensive chemotherapy. Among 87 patients randomized (median age 75 years), the addition of volasertib led to a higher overall response rate (31% versus 13.3%; p  = 0.052) and a longer median survival (8.0 versus 5.2 months; hazard ratio 0.63; p  = 0.047) 178 . Unfortunately, the phase 3 pivotal trial comparing low-dose cytarabine with or without volasertib in older patients with newly diagnosed AML not eligible for intensive chemotherapy (NCT 01721876) did not meet the study endpoints. The status of volasertib is uncertain, but other presumably better PLK1 inhibitors (such as onvansertib) 179 are under development.

Antibodies targeting AML surface molecules

Monoclonal antibodies targeting cluster designation (CD) surface molecules CD33, CD123, CD70, CLL1 (or CLEC12a), TIM3, WT1 and others, may result in important anti-AML efficacy. These antibodies may be unconjugated, conjugated to immunotoxins, or bispecific antibodies (BiTEs) directing killer CD3 T-cells (linking to T-cell CD3) to the AML CD surface molecules.

Unconjugated monoclonal antibodies have so far had little success in AML, as shown with CD33 unconjugated antibodies. A pilot study of azacitidine plus cusatuzumab (monoclonal unconjugated antibody-targeting CD70) was promising 180 . Studies of cusatuzumab combination with azacitidine and/or venetoclax are ongoing.

Monoclonal antibodies conjugated to immunotoxins have had some success, as shown by the experience with GO. Some studies with CD33 and CD123 monoclonal antibodies (e.g., SGN-33A [vadastuxumab], a humanized anti-CD33 monoclonal antibody conjugated to pyrrolo-benzodiazepine) have shown excessive myelosuppression and mortality, resulting in abandoning the drug development. IMGN632 is a CD123 antibody conjugated to an alkyl-benzodiazepine. As a single-agent, IMGN632 was evaluated in 74 patients (67 AML, 7 blastic plasma-dendritic cell neoplasm [BPDCN]). Among 66 evaluable patients with AML, 55% had a reduction in bone marrow blasts, and 20% achieved a CR/CRi across a range of IMGN632 doses (0.045 to 0.3 mg/kg per course). Among seven patients with BPDCN, three (43%) achieved a CR/CRi. IMGN632 monotherapy is being evaluated in patients with relapsed-refractory BPDCN and MRD-positive AML. Combinations of IMGN632 with azacitidine and/or venetoclax are under evaluation in AML (NCT04086264) 181 .

Ongoing studies are evaluating the delivery of radioisotopes using AML surface antigen-targeting antibodies. The clinically most advanced among these is the use of CD45-targeted antibodies (e.g., Iomab-B or 90Y-BC8-DOTA) 182 , 183 . As CD45 is ubiquitously expressed in the hematopoietic system, CD45-targeting may lead to significant myeloablation and such approaches are studied as part of pre-SCT conditioning in transplant-eligible patients. A randomized phase III study evaluating this approach with Iomab-B versus investigator choice salvage therapy prior to SCT in patients with relapsed-refractory AML is ongoing (NCT02665065).

The bispecific T-cell engaging antibody (BITE) technology utilizes bispecific antibody constructs that recruit CD3-effector T cells to target tumor cells (CD33, CD123, and also CD70 in the case of AML). Several AML-targeted BiTEs are under development in AML, including flotetuzumab, AMG-330, AMG673, AMG 427, XmAb14045, AMV564. Several have shown modest activity (response rates 20 to 30%) and were associated with the predicted toxicities (fever, hypotension, cytokine release syndrome). A potential area of research interest is exploring their efficacy in the setting of AML in CR with MRD-positive disease (as was done with blinatumomab in ALL).

CAR-T cellular therapy in AML

The success of immunotherapy in cancer led to renewed interest in developing immune-based strategies in AML, including antibody-based (discussed earlier) and cellular therapy. Trials of chimeric antigen receptor (CAR)-T cells are ongoing including autologous and allogeneic CART cells (targeting CD123, CD33, and CLL1) followed by allogeneic SCT.

Many of the hopeful predictions outlined in the AML summary of 2016 are now therapeutic realities: GO, venetoclax, FLT3 inhibitors (midostaurin, gilteritib), IDH inhibitors (ivosidenib, enasidenib), CPX-351, glasdegib, oral decitabine, and oral azacitidine. Others may soon be (quizartinib, APR246, magrolimab, menin inhibitors). The wealth of positive data allows reconsideration of what might soon be new standards of care during induction-consolidation-SCT-maintenance in younger and older patients with AML.

Kantarjian, H. Acute myeloid leukemia–major progress over four decades and glimpses into the future. Am. J. Hematol. 91 , 131–145 (2016).

Article   PubMed   Google Scholar  

Short, N. J., Rytting, M. E. & Cortes, J. E. Acute myeloid leukaemia. Lancet 392 , 593–606 (2018).

Kadia, T. M., Ravandi, F., Cortes, J. & Kantarjian, H. Toward individualized therapy in acute myeloid leukemia: a contemporary review. JAMA Oncol . 1 , 820–828 (2015).

Kadia, T. M., Ravandi, F., O’Brien, S., Cortes, J. & Kantarjian, H. M. Progress in acute myeloid leukemia. Clin. Lymphoma Myeloma Leuk. 15 , 139–151 (2015).

Dohner, H., Weisdorf, D. J. & Bloomfield, C. D. Acute myeloid leukemia. N. Engl. J. Med. 373 , 1136–1152 (2015).

Article   CAS   PubMed   Google Scholar  

Lowenberg, B. et al. High-dose daunorubicin in older patients with acute myeloid leukemia. N. Engl. J. Med. 361 , 1235–1248 (2009).

Fernandez, H. F. et al. Anthracycline dose intensification in acute myeloid leukemia. N. Engl. J. Med. 361 , 1249–1259 (2009).

Article   CAS   PubMed   PubMed Central   Google Scholar  

Ravandi, F. et al. Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J. Clin. Oncol. 27 , 504–510 (2009).

Lo-Coco, F. et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N. Engl. J. Med. 369 , 111–121 (2013).

Abaza, Y. et al. Long-term outcome of acute promyelocytic leukemia treated with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab. Blood 129 , 1275–1283 (2017).

Platzbecker, U. et al. Improved outcomes with retinoic acid and arsenic trioxide compared with retinoic acid and chemotherapy in non-high-risk acute promyelocytic leukemia: final results of the randomized Italian-German APL0406 trial. J. Clin. Oncol. 35 , 605–612 (2017).

Burnett, A. K. et al. Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial. Lancet Oncol. 16 , 1295–1305 (2015).

Borthakur, G. et al. Gemtuzumab ozogamicin with fludarabine, cytarabine, and granulocyte colony stimulating factor (FLAG-GO) as front-line regimen in patients with core binding factor acute myelogenous leukemia. Am. J. Hematol. 89 , 964–968 (2014).

Borthakur, G., Cortes, J. & Ravandi, F. Fludarabine, cytarabine, G-CSF and gemtuzumab ozogamicin (FLAG-GO) regimen results in better molecular response and relapse-free survival in core binding factor acute myeloid leukemia than FLAG and idarubicin (FLAG-Ida). Blood 134 , 290 (2019).

Article   Google Scholar  

Burnett, A. K. et al. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J. Clin. Oncol. 29 , 369–377 (2011).

Petersdorf, S. H. et al. A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. Blood 121 , 4854–4860 (2013).

Hills, R. K. et al. Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials. Lancet Oncol . 15 , 986–996 (2014).

Patel, J. P. et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N. Engl. J. Med. 366 , 1079–1089 (2012).

Cancer Genome Atlas Research Network. et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N. Engl. J. Med. 368 , 2059–2074 (2013).

Article   CAS   Google Scholar  

Ding, L. et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature 481 , 506–510 (2012).

Papaemmanuil, E. et al. Genomic classification and prognosis in acute myeloid leukemia. N. Engl. J. Med. 374 , 2209–2221 (2016).

Grimwade, D. et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood 116 , 354–365 (2010).

Pastore, F. et al. Combined molecular and clinical prognostic index for relapse and survival in cytogenetically normal acute myeloid leukemia. J. Clin. Oncol. 32 , 1586–1594 (2014).

Article   PubMed   PubMed Central   Google Scholar  

Richard-Carpentier, G. & DiNardo, C. D. Single-agent and combination biologics in acute myeloid leukemia. Hematol. Am. Soc. Hematol. Educ. Program 2019 , 548–556 (2019).

Short, N. J. et al. Advances in the treatment of acute myeloid leukemia: new drugs and new challenges. Cancer Discov. 10 , 506–525 (2020).

Kantarjian, H. M. et al. 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. J. Clin. Oncol. 30 , 2670–2677 (2012).

Tuma, R. Withdrawl will have major impact on patients, some leukemia experts say. Oncol. Times 22 , 11–13 (2010).

Dombret, H. et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood 126 , 291–299 (2015).

Ravandi, F. et al. Vosaroxin plus cytarabine versus placebo plus cytarabine in patients with first relapsed or refractory acute myeloid leukaemia (VALOR): a randomised, controlled, double-blind, multinational, phase 3 study. Lancet Oncol. 16 , 1025–1036 (2015).

Dohner, H. et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 129 , 424–447 (2017).

Article   PubMed   PubMed Central   CAS   Google Scholar  

Tallman, M. S. et al. Acute Myeloid Leukemia, Version 3.2019, NCCN Clinical Practice Guidelines in Oncology. J. Natl. Compr. Canc. Netw. 17 , 721–749 (2019).

DiNardo, C. D. et al. Characteristics, clinical outcome, and prognostic significance of IDH mutations in AML. Am. J. Hematol. 90 , 732–736 (2015).

Santos, F. P. et al. Prognostic value of FLT3 mutations among different cytogenetic subgroups in acute myeloid leukemia. Cancer 117 , 2145–2155 (2011).

Pratcorona, M. et al. Favorable outcome of patients with acute myeloid leukemia harboring a low-allelic burden FLT3-ITD mutation and concomitant NPM1 mutation: relevance to post-remission therapy. Blood 121 , 2734–2738 (2013).

Schlenk, R. F. et al. Differential impact of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic transplantation. Blood 124 , 3441–3449 (2014).

Ho, A. D. et al. Allogeneic stem cell transplantation improves survival in patients with acute myeloid leukemia characterized by a high allelic ratio of mutant FLT3-ITD. Biol. Blood Marrow Transplant 22 , 462–469 (2016).

Schlenk, R. F. et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N. Engl. J. Med. 358 , 1909–1918 (2008).

Seifert, H. et al. The prognostic impact of 17p (p53) deletion in 2272 adults with acute myeloid leukemia. Leukemia 23 , 656–663 (2009).

Kadia, T. M. et al. TP53 mutations in newly diagnosed acute myeloid leukemia: Clinicomolecular characteristics, response to therapy, and outcomes. Cancer 122 , 3484–3491 (2016).

Boddu, P. et al. Outcomes with lower intensity therapy in TP53-mutated acute myeloid leukemia. Leuk. Lymphoma 59 , 2238–2241 (2018).

Sasaki, K. et al. Impact of the variant allele frequency of ASXL1, DNMT3A, JAK2, TET2, TP53, and NPM1 on the outcomes of patients with newly diagnosed acute myeloid leukemia. Cancer 126 , 765–774 (2020).

Thol, F. et al. Incidence and prognostic influence of DNMT3A mutations in acute myeloid leukemia. J. Clin. Oncol. 29 , 2889–2896 (2011).

Ley, T. J. et al. DNMT3A mutations in acute myeloid leukemia. N. Engl. J. Med. 363 , 2424–2433 (2010).

Mendler, J. H. et al. RUNX1 mutations are associated with poor outcome in younger and older patients with cytogenetically normal acute myeloid leukemia and with distinct gene and MicroRNA expression signatures. J. Clin. Oncol. 30 , 3109–3118 (2012).

Gaidzik, V. I. et al. RUNX1 mutations in acute myeloid leukemia: results from a comprehensive genetic and clinical analysis from the AML study group. J. Clin. Oncol. 29 , 1364–1372 (2011).

Groschel, S. et al. Deregulated expression of EVI1 defines a poor prognostic subset of MLL-rearranged acute myeloid leukemias: a study of the German-Austrian Acute Myeloid Leukemia Study Group and the Dutch-Belgian-Swiss HOVON/SAKK Cooperative Group. J. Clin. Oncol. 31 , 95–103 (2013).

Cairoli, R. et al. Prognostic impact of c-KIT mutations in core binding factor leukemias: an Italian retrospective study. Blood 107 , 3463–3468 (2006).

Paschka, P. et al. Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv(16) and t(8;21): a Cancer and Leukemia Group B Study. J. Clin. Oncol. 24 , 3904–3911 (2006).

Schnittger, S. et al. KIT-D816 mutations in AML1-ETO-positive AML are associated with impaired event-free and overall survival. Blood 107 , 1791–1799 (2006).

Marcucci, G. et al. Adding the KIT inhibitor dasatinib (DAS) to standard induction and consolidation therapy for newly diagnosed patients (pts) with core binding factor (CBF) acute myeloid leukemia (AML): initial results of the CALGB 10801 (Alliance) Study. Blood 124 , 8, https://doi.org/10.1182/blood.V124.21.8.8 (2014).

Gotlib, J. et al. Avapritinib induces responses in patients (PTS) with advanced systemic mastocytosis (ADVSM), regardless of prior midostaurin therapy. EHA Abstract EP1079, (2020).

Angenendt, L. et al. Chromosomal abnormalities and prognosis in NPM1-mutated acute myeloid leukemia: a pooled analysis of individual patient data from nine international cohorts. J. Clin. Oncol. 37 , 2632–2642 (2019).

Chan, S. M. et al. Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nat. Med. 21 , 178–184 (2015).

Welch, J. S. et al. TP53 and decitabine in acute myeloid leukemia and myelodysplastic syndromes. N. Engl. J. Med. 375 , 2023–2036 (2016).

Klossowski, S. et al. Menin inhibitor MI-3454 induces remission in MLL1-rearranged and NPM1-mutated models of leukemia. J. Clin. Invest. 130 , 981–997 (2020).

Jongen-Lavrencic, M. et al. Molecular minimal residual disease in acute myeloid leukemia. N. Engl. J. Med. 378 , 1189–1199 (2018).

Grimwade, D. & Freeman, S. D. Defining minimal residual disease in acute myeloid leukemia: which platforms are ready for “prime time”? Blood 124 , 3345–3355 (2014).

Pastore, F. & Levine, R. L. Next-Generation sequencing and detection of minimal residual disease in acute myeloid leukemia: ready for clinical practice? JAMA 314 , 778–780 (2015).

Klco, J. M. et al. Association between mutation clearance after induction therapy and outcomes in acute myeloid leukemia. JAMA 314 , 811–822 (2015).

Ravandi, F. et al. Persistence of minimal residual disease assessed by multiparameter flow cytometry is highly prognostic in younger patients with acute myeloid leukemia. Cancer 123 , 426–435 (2017).

Short, N. J. et al. Association of measurable residual disease with survival outcomes in patients with acute myeloid leukemia: a systematic review and meta-analysis. JAMA Oncol. 6 , 1890–1899 (2020).

Hourigan, C. S. et al. Impact of conditioning intensity of allogeneic transplantation for acute myeloid leukemia with genomic evidence of residual disease. J. Clin. Oncol. 38 , 1273–1283 (2020).

Grimwade, D. et al. Prospective minimal residual disease monitoring to predict relapse of acute promyelocytic leukemia and to direct pre-emptive arsenic trioxide therapy. J. Clin. Oncol. 27 , 3650–3658 (2009).

Yin, J. A. et al. Minimal residual disease monitoring by quantitative RT-PCR in core binding factor AML allows risk stratification and predicts relapse: results of the United Kingdom MRC AML-15 trial. Blood 120 , 2826–2835 (2012).

Zhu, H. H. et al. MRD-directed risk stratification treatment may improve outcomes of t(8;21) AML in the first complete remission: results from the AML05 multicenter trial. Blood 121 , 4056–4062 (2013).

Kronke, J. et al. Monitoring of minimal residual disease in NPM1-mutated acute myeloid leukemia: a study from the German-Austrian acute myeloid leukemia study group. J. Clin. Oncol. 29 , 2709–2716 (2011).

Schnittger, S. et al. Minimal residual disease levels assessed by NPM1 mutation-specific RQ-PCR provide important prognostic information in AML. Blood 114 , 2220–2231 (2009).

Kantarjian, H. M. et al. Acute promyelocytic leukemia. M.D. Anderson Hospital experience. Am. J. Med. 80 , 789–797 (1986).

Kantarjian, H. M. et al. Role of maintenance chemotherapy in acute promyelocytic leukemia. Cancer 59 , 1258–1263 (1987).

Lo-Coco, F. et al. Gemtuzumab ozogamicin (Mylotarg) as a single agent for molecularly relapsed acute promyelocytic leukemia. Blood 104 , 1995–1999 (2004).

Soignet, S. L. et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J. Clin. Oncol. 19 , 3852–3860 (2001).

Fenaux, P. et al. A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood 94 , 1192–1200 (1999).

Sanz, M. A. et al. A modified AIDA protocol with anthracycline-based consolidation results in high antileukemic efficacy and reduced toxicity in newly diagnosed PML/RARalpha-positive acute promyelocytic leukemia. PETHEMA group. Blood 94 , 3015–3021 (1999).

CAS   PubMed   Google Scholar  

Tallman, M. S. et al. All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol. Blood 100 , 4298–4302 (2002).

Powell, B. L. et al. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood 116 , 3751–3757 (2010).

Avvisati, G. et al. AIDA 0493 protocol for newly diagnosed acute promyelocytic leukemia: very long-term results and role of maintenance. Blood 117 , 4716–4725 (2011).

Russell, N. et al. Attenuated arsenic trioxide plus ATRA therapy for newly diagnosed and relapsed APL: long-term follow-up of the AML17 trial. Blood 132 , 1452–1454 (2018).

Lancet, J. E. et al. A phase 2 study of ATRA, arsenic trioxide, and gemtuzumab ozogamicin in patients with high-risk APL (SWOG 0535). Blood Adv. 4 , 1683–1689 (2020).

Tsimberidou, A. M. et al. Granulocyte colony stimulating factor administration associated with cerebral hemorrhage in acute promyelocytic leukemia. Leukemia 20 , 1452–1453 (2006).

Chamoun, K. et al. Unrecognized fluid overload during induction therapy increases morbidity in patients with acute promyelocytic leukemia. Cancer 125 , 3219–3224 (2019).

Ravandi, F. et al. Oral arsenic trioxide ORH-2014 pharmacokinetic and safety profile in patients with advanced hematologic disorders. Haematologica 105 , 1567–1574 (2021).

Zhu, H. H. et al. Oral arsenic plus retinoic acid versus intravenous arsenic plus retinoic acid for non-high-risk acute promyelocytic leukaemia: a non-inferiority, randomised phase 3 trial. Lancet Oncol. 19 , 871–879 (2018).

Byrd, J. C. et al. Repetitive cycles of high-dose cytarabine benefit patients with acute myeloid leukemia and inv(16)(p13q22) or t(16;16)(p13;q22): results from CALGB 8461. J. Clin. Oncol. 22 , 1087–1094 (2004).

Paschka, P. et al. Secondary genetic lesions in acute myeloid leukemia with inv(16) or t(16;16): a study of the German-Austrian AML Study Group (AMLSG). Blood 121 , 170–177 (2013).

Sasaki, K. et al. De novo acute myeloid leukemia: a population- based study of outcome in the united states based on the surveillance, epidemiology, and end results (SEER) database, 1980-2017. Cancer (in press) (2021).

Mayer, R. J. et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B. N. Engl. J. Med. 331 , 896–903 (1994).

Burnett, A. K. et al. Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the medical research council AML15 trial. J. Clin. Oncol. 31 , 3360–3368 (2013).

Weick, J. K. et al. A randomized investigation of high-dose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study. Blood 88 , 2841–2851 (1996).

Bishop, J. F. et al. A randomized study of high-dose cytarabine in induction in acute myeloid leukemia. Blood 87 , 1710–1717 (1996).

Kern, W. & Estey, E. H. High-dose cytosine arabinoside in the treatment of acute myeloid leukemia: Review of three randomized trials. Cancer 107 , 116–124 (2006).

Lowenberg, B. et al. Cytarabine dose for acute myeloid leukemia. N. Engl. J. Med. 364 , 1027–1036 (2011).

Willemze, R. et al. High-dose cytarabine in induction treatment improves the outcome of adult patients younger than age 46 years with acute myeloid leukemia: results of the EORTC-GIMEMA AML-12 trial. J. Clin. Oncol. 32 , 219–228 (2014).

Bassan, R. et al. Randomized trial comparing standard vs sequential high-dose chemotherapy for inducing early CR in adult AML. Blood Adv. 3 , 1103–1117 (2019).

Garcia-Manero, G. et al. Standard versus high-dose cytarabine with or without vorinostat in acute myelogenous leukemia: results of SWOG 1203. Leukemia (in press), (2021).

Plunkett, W. et al. Saturation of 1-beta-D-arabinofuranosylcytosine 5’-triphosphate accumulation in leukemia cells during high-dose 1-beta-D-arabinofuranosylcytosine therapy. Cancer Res . 47 , 3005–3011 (1987).

Plunkett, W., Liliemark, J. O., Estey, E. & Keating, M. J. Saturation of ara-CTP accumulation during high-dose ara-C therapy: pharmacologic rationale for intermediate-dose ara-C. Semin. Oncol. 14 , 159–166 (1987).

Estey, E. H. et al. Randomized phase II study of fludarabine + cytosine arabinoside + idarubicin + /- granulocyte colony-stimulating factor in poor prognosis newly diagnosed acute myeloid leukemia and myelodysplastic syndrome. Blood 93 , 2478–2484 (1999).

Burnett, A. K. et al. Addition of gemtuzumab ozogamicin to induction chemotherapy improves survival in older patients with acute myeloid leukemia. J. Clin. Oncol . 30 , 3924–3931 (2012).

Park, Y. et al. High-dose cytarabine consolidation (≥1.5 g/m2) might have shown a better outcomes than intermediate-dose cytarabine (1.0 g/m2) combined with anthracyclines in AML patients who had achieved complete remissions in the first induction by standard 3 + 7 regimen. Blood 122 , 2692 (2013).

Holowiecki, J. et al. Addition of cladribine to daunorubicin and cytarabine increases complete remission rate after a single course of induction treatment in acute myeloid leukemia. Multicenter, phase III study. Leukemia 18 , 989–997 (2004).

Holowiecki, J. et al. Cladribine, but not fludarabine, added to daunorubicin and cytarabine during induction prolongs survival of patients with acute myeloid leukemia: a multicenter, randomized phase III study. J. Clin. Oncol. 30 , 2441–2448 (2012).

Jabbour, E. et al. A randomized phase 2 study of idarubicin and cytarabine with clofarabine or fludarabine in patients with newly diagnosed acute myeloid leukemia. Cancer 123 , 4430–4439 (2017).

Devillier, R., Bertoli, S. & Prebet, T. Induction therapy for AML patients with daunorubicin dose of 60 mg/m 2 and 90 mg/m 2 results in similar complete response rate, relapse-free and overall survival. Blood 122 , 66 (2013).

Burnett, A. K. et al. A randomized comparison of daunorubicin 90 mg/m2 vs 60 mg/m2 in AML induction: results from the UK NCRI AML17 trial in 1206 patients. Blood 125 , 3878–3885 (2015).

A systematic collaborative overview of randomized trials comparing idarubicin with daunorubicin (or other anthracyclines) as induction therapy for acute myeloid leukaemia. AML Collaborative Group. Br. J. Haematol. 103 , 100–109 (1998).

Pautas, C. et al. Randomized study of intensified anthracycline doses for induction and recombinant interleukin-2 for maintenance in patients with acute myeloid leukemia age 50 to 70 years: results of the ALFA-9801 study. J. Clin. Oncol. 28 , 808–814 (2010).

Gardin, C. et al. Superior long-term outcome with idarubicin compared with high-dose daunorubicin in patients with acute myeloid leukemia age 50 years and older. J. Clin. Oncol . 31 , 321–327 (2013).

Mandelli, F. et al. Daunorubicin versus mitoxantrone versus idarubicin as induction and consolidation chemotherapy for adults with acute myeloid leukemia: the EORTC and GIMEMA Groups Study AML-10. J. Clin. Oncol. 27 , 5397–5403 (2009).

Bross, P. F. et al. Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin. Cancer Res. 7 , 1490–1496 (2001).

Castaigne, S. et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet 379 , 1508–1516 (2012).

Delaunay, J. et al. Addition of gemtuzumab ozogamycin to chemotherapy improves event-free survival but not overall survival of AML patients with intermediate cytogenetics not eligible for allogeneic transplantation. Results of the GOELAMS AML 2006 IR Study. Blood 118 , 79 (2011).

Kharfan-Dabaja, M. A. A new dawn for gemtuzumab ozogamicin? Lancet Oncol . 15 , 913–914 (2014).

Ravandi, F. et al. Gemtuzumab ozogamicin: time to resurrect? J. Clin. Oncol. 30 , 3921–3923 (2012).

Pigneux, A. et al. Addition of lomustine to idarubicin and cytarabine improves the outcome of elderly patients with de novo acute myeloid leukemia: a report from the GOELAMS. J. Clin. Oncol. 28 , 3028–3034 (2010).

Lachowiez, C. et al. Interim analysis of the Phase 1b/2 study of the BCL-2 inhibitor venetoclax in combination with standard intensive AML induction/consolidation therapy with FLAG-IDA in patients with newly diagnosed or relapsed/refractory AML. Blood 136 , 332 (2020).

Reville, P. K., Kantarjian, H. & Borthakur, G. Cladribine, idarubicin, cytarabine (ara-C), and venetoclax in treating patients with acute myeloid leukemia and high-risk myelodysplastic syndrome. Blood 136 , 2854 (2020).

Google Scholar  

Halpern, A. B., Lyman, G. H., Walsh, T. J., Kontoyiannis, D. P. & Walter, R. B. Primary antifungal prophylaxis during curative-intent therapy for acute myeloid leukemia. Blood 126 , 2790–2797 (2015).

Cornely, O. A. et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N. Engl. J. Med. 356 , 348–359 (2007).

Stein, E. M. et al. Ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed AML: a phase 1 study. Blood 2020007233, https://doi.org/10.1182/blood.2020007233 . (2020). Epub ahead of print.

Stone, R. M. et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N. Engl. J. Med. 377 , 454–464 (2017).

Alfayez, M. et al. Outcomes with subsequent FLT3-inhibitor (FLT3i) based therapies in FLT3-mutated (mu) patients (pts) refractory/relapsed (R/R) to one or more prior FLT3 inhibitor based therapies: a single center experience. Blood 132 , 633 (2018).

Pratz, K. W. et al. A Phase 1 Study of Gilteritinib in Combination with Induction and Consolidation Chemotherapy in Patients with Newly Diagnosed AML: Final Results. Blood 136 , abst 24 (2020).

Xuan, L. et al. Sorafenib maintenance in patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic haematopoietic stem-cell transplantation: an open-label, multicentre, randomised phase 3 trial. Lancet Oncol. 21 , 1201–1212 (2020).

Burchert, A. et al. Sorafenib maintenance after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia With FLT3-internal tandem duplication mutation (SORMAIN). J. Clin. Oncol. 38 , 2993–3002 (2020).

Libura, M. et al. Cladribine added to daunorubicin-cytarabine induction prolongs survival of FLT3-ITD + normal karyotype AML patients. Blood 127 , 360–362 (2016).

Choi, E. J. et al. Comparison of anthracyclines used for induction chemotherapy in patients with FLT3-ITD-mutated acute myeloid leukemia. Leuk. Res. 68 , 51–56 (2018).

Kantarjian, H. et al. Results of intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome: predictive prognostic models for outcome. Cancer 106 , 1090–1098 (2006).

Kantarjian, H. et al. Intensive chemotherapy does not benefit most older patients (age 70 years or older) with acute myeloid leukemia. Blood 116 , 4422–4429 (2010).

Quintas-Cardama, A. et al. Epigenetic therapy is associated with similar survival compared with intensive chemotherapy in older patients with newly diagnosed acute myeloid leukemia. Blood 120 , 4840–4845 (2012).

Takahashi, K. et al. Clofarabine plus low-dose cytarabine is as effective as and less toxic than intensive chemotherapy in elderly AML patients. Clin. Lymphoma Myeloma Leuk. 16 , 163–8 e1-2 (2016).

Bitterman, R. et al. Baseline chest computed tomography for early diagnosis of invasive pulmonary aspergillosis in hemato-oncological patients: a prospective cohort study. Clin. Infect. Dis. 69 , 1805–1808 (2019).

Lang, K. et al. Trends in the treatment of acute myeloid leukaemia in the elderly. Drugs Aging 22 , 943–955 (2005).

Burnett, A. K. et al. A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer 109 , 1114–1124 (2007).

Blum, W. et al. Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine. Proc. Natl Acad. Sci. USA 107 , 7473–7478 (2010).

Savona, M. R. et al. An oral fixed-dose combination of decitabine and cedazuridine in myelodysplastic syndromes: a multicentre, open-label, dose-escalation, phase 1 study. Lancet Haematol. 6 , e194–e203 (2019).

Garcia-Manero, G. et al. Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. Blood 136 , 674–683 (2020).

Kadia, T. M. et al. Cladribine and low-dose cytarabine alternating with decitabine as front-line therapy for elderly patients with acute myeloid leukaemia: a phase 2 single-arm trial. Lancet Haematol . 5 , e411–e421 (2018).

Kadia, T. M. et al. Final results of a phase 2 trial of clofarabine and low-dose cytarabine alternating with decitabine in older patients with newly diagnosed acute myeloid leukemia. Cancer 121 , 2375–2382 (2015).

Pan, R. et al. Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia. Cancer Discov. 4 , 362–375 (2014).

Konopleva, M. et al. Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov. 6 , 1106–1117 (2016).

Wei, A. H. et al. Venetoclax combined with low-dose cytarabine for previously untreated patients with acute myeloid leukemia: results from a phase Ib/II study. J. Clin. Oncol. 37 , 1277–1284 (2019).

DiNardo, C. D. et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood 133 , 7–17 (2019).

DiNardo, C. D. et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N. Engl. J. Med. 383 , 617–629 (2020).

Wei, A. H. et al. Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. Blood 135 , 2137–2145 (2020).

DiNardo, C. D. et al. 10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial. Lancet Haematol. 7 , e724–e736 (2020).

Kadia, T. et al. Phase II study of venetoclax added to cladribine + low dose AraC (LDAC) alternating with 5-azacytidine demonstrates high rates of minimal residual disease (MRD) negative complete remissions (CR) and excellent tolerability in older patients with newly diagnosed acute myeloid leukemia (AML). Blood 136 , 25 (2020).

Ohanian, M. et al. Sorafenib combined with 5-azacytidine in older patients with untreated FLT3-ITD mutated acute myeloid leukemia. Am. J. Hematol. 93 , 1136–1141 (2018).

Esteve, J. et al. Multicenter, open-label, 3-arm study of gilteritinib, gilteritinib plus azacitidine, or azacitidine alone in newly diagnosed FLT3 mutated (FLT3mut+) acute myeloid leukemia (AML) patients ineligible for intensive induction chemotherapy: findings from the safety cohort. Blood 132 (Supplement 1), 2736, https://doi.org/10.1182/blood-2018-99-110976 (2018).

Feldman, E. J. et al. First-in-man study of CPX-351: a liposomal carrier containing cytarabine and daunorubicin in a fixed 5:1 molar ratio for the treatment of relapsed and refractory acute myeloid leukemia. J. Clin. Oncol. 29 , 979–985 (2011).

Lancet, J. E. et al. Phase 2 trial of CPX-351, a fixed 5:1 molar ratio of cytarabine/daunorubicin, vs cytarabine/daunorubicin in older adults with untreated AML. Blood 123 , 3239–3246 (2014).

Lancet, J. E. et al. CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J. Clin. Oncol. 36 , 2684–2692 (2018).

Jamieson, C., Martinelli, G., Papayannidis, C. & Cortes, J. E. Hedgehog pathway inhibitors: a new therapeutic class for the treatment of acute myeloid leukemia. Blood Cancer Discov. 1 , 134–145 (2020).

Cortes, J. E. et al. Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. Leukemia 33 , 379–389 (2019).

Norsworthy, K. J. et al. FDA Approval summary: glasdegib for newly diagnosed acute myeloid leukemia. Clin. Cancer Res . 25 , 6021–6025 (2019).

Lehmann, S. et al. Targeting p53 in vivo: a first-in-human study with p53-targeting compound APR-246 in refractory hematologic malignancies and prostate cancer. J. Clin. Oncol. 30 , 3633–3639 (2012).

Sallman, D. A. et al. Phase 2 results of APR-246 and azacitidine (AZA) in patients with TP53 mutant myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia (AML). Blood 134 , 676 (2019).

Cluzeau, T. et al. APR-246 combined with azacitidine in TP53 mutated myelodysplastic syndromes (MDS) and acute myeloid leukemia. A phase 2 study by the Groupe FrancoPhone des Myelodysplasies (GFM) A. Blood 134 , 677 (2020).

Jaiswal, S. et al. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell 138 , 271–285 (2009).

Majeti, R. et al. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell 138 , 286–299 (2009).

Advani, R. et al. CD47 blockade by Hu5F9-G4 and rituximab in non-hodgkin’s lymphoma. N. Engl. J. Med. 379 , 1711–1721 (2018).

Sallman, D. A. et al. The first-in-class anti-CD47 antibody magrolimab in combination with azacitidine is effective in AML patients: phase 1b results. Blood 134 , 330 (2020).

Wei, A. et al. Maintenance Therapy with CC-486 for acute myeloid leukemia in first remission. N. Engl. J. Med. 383 , 2526–2537, https://doi.org/10.1056/NEJMoa2004444 (2020).

Huls, G. et al. Azacitidine maintenance after intensive chemotherapy improves DFS in older AML patients. Blood 133 , 1457–1464 (2019).

Perl, A. E. et al. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N. Engl. J. Med. 381 , 1728–1740 (2019).

Derolf, A. et al. Decreasing early mortality in acute myeloid leukaemia in Sweden 1997-2014: improving performance status is a major contributing factor. Br. J. Haematol. 188 , 187–191 (2020).

Bhatt, V. R. et al. Early mortality and overall survival of acute myeloid leukemia based on facility type. Am. J. Hematol. 92 , 764–771 (2017).

Ho, G. et al. Decreased early mortality associated with the treatment of acute myeloid leukemia at National Cancer Institute-designated cancer centers in California. Cancer 124 , 1938–1945 (2018).

Koreth, J. et al. Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta-analysis of prospective clinical trials. JAMA 301 , 2349–2361 (2009).

Burnett, A. K. et al. The value of allogeneic bone marrow transplant in patients with acute myeloid leukaemia at differing risk of relapse: results of the UK MRC AML 10 trial. Br. J. Haematol. 118 , 385–400 (2002).

Jabbour, E. et al. Twice-daily fludarabine and cytarabine combination with or without gentuzumab ozogamicin is effective in patients with relapsed/refractory acute myeloid leukemia, high-risk myelodysplastic syndrome, and blast- phase chronic myeloid leukemia. Clin. Lymphoma Myeloma Leuk. 12 , 244–251 (2012).

Perl, A. E. et al. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study. Lancet Oncol. 18 , 1061–1075 (2017).

Daver, N. et al. Efficacy and safety of venetoclax in combination with gilteritinib for relapsed/refractory FLT3-mutated acute myeloid leukemia in the expansion cohort of a phase 1b study. Blood 134 , 333 (2020). (Abstract).

Amatangelo, M. D. et al. Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response. Blood 130 , 732–741 (2017).

Stein, E. M. et al. Safety and efficacy of AG-221, a potent inhibitor of mutant IDH2 that promotes differentiation of myeloid cells in patients with advanced hematologic malignancies: results of a phase 1/2 trial. Blood 126 , 323 (2015).

DiNardo, C. D. et al. Enasidenib plus azacitidine significantly improves complete remission and overall response compared with azacitidine alone in patients with newly diagnosed acute myeloid leukemia (AML) with isocitrate dehydrogenase 2 (IDH2) mutations: interim phase II results from an ongoing, randomized study. Blood 134 , 643 (2019).

DiNardo, C. D. et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N. Engl. J. Med. 378 , 2386–2398 (2018).

Choe, S. et al. Molecular mechanisms mediating relapse following ivosidenib monotherapy in IDH1-mutant relapsed or refractory AML. Blood Adv. 4 , 1894–1905 (2020).

Dohner, H. et al. Randomized, phase 2 trial of low-dose cytarabine with or without volasertib in AML patients not suitable for induction therapy. Blood 124 , 1426–1433 (2014).

Zeidan, A. M. et al. Safety, efficacy and biomarker analysis of a phase 1b/2 study of onvansertib (ONV), a polo-like kinase 1 (PLK1) inhibitor, in combination with low-dose cytarabine (LDAC) or decitabine (DEC) in patients (pts) with relapsed/refractory acute myeloid leukemia (R/R AML). Blood 134 , 230 (2019).

Riether, C. et al. Targeting CD70 with cusatuzumab eliminates acute myeloid leukemia stem cells in patients treated with hypomethylating agents. Nat. Med. 26 , 1459–1467 (2020).

Daver, N. G. et al. A phase Ib/II study of the CD123-targeting antibody-drug conjugate IMGN632 as monotherapy or in combination with venetoclax and/or azacitidine for patients with CD123-positive acute myeloid leukemia. Blood 134 (Supplement_1), 2601, https://doi.org/10.1182/blood-2019-128501 (2019).

Agura, E., Gyurkocza, B. & Nath, R. Targeted conditioning of Iomab-B (131I-anti-CD45) prior to allogeneic hematopoietic cell transplantation versus conventional care in relapsed or refractory acute myeloid leukemia (AML): preliminary feasibility and safety results from the prospective, randomized phase 3 sierra trial. Blood 132 , 1017 (2018).

Vo, P. T. et al. Safety and efficacy of yttrium-90-labeled anti-CD45 antibody (90Y-DOTA-BC8) followed by a standard reduced-intensity hematopoietic stem cell transplant (HCT) regimen for patients with refractory/relapsed leukemia or high-risk myelodysplastic syndrome (MDS). Blood 132 , 1018- (2018).

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This research is supported in part by the MD Anderson Cancer Center Leukemia SPORE CA100632, the Cancer Center Support Grant (CCSG) P30CA016672, and the Charif Souki Cancer Research Grant.

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Hagop Kantarjian, Tapan Kadia, Courtney DiNardo, Naval Daver, Gautam Borthakur, Elias Jabbour, Guillermo Garcia-Manero, Marina Konopleva & Farhad Ravandi

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Dr. H.K. reports research grants and honoraria from AbbVie, Amgen, Ascentage, BMS, Daiichi-Sankyo, Immunogen, Jazz, Novartis, Pfizer, and Sanofi; honoraria from Actinium (Advisory Board), Adaptive Biotechnologies, Aptitude Health, BioAscend, Delta Fly, Janssen Global, Oxford Biomedical, and Takeda. Dr. T.K. reports grant or research support from BMS, Celgene, Pfizer, Amgen, Jazz, AstraZeneca, and Genetech; consultant fees from Agios, Jazz, Genetech, and Novartis. Dr. C.D. reports research support to institution from Abbvie, Agios, Bayer, Calithera, Cleave, BMS/Celgene, Daiichi-Sankyo and ImmuneOnc; consultant/advisory boards with Abbvie, Agios, Celgene/BMS, Daiichi-Sankyo, ImmuneOnc, Novartis, Takeda and Notable Labs. Dr. N.D. reports research funding from Daiichi-Sankyo, Bristol-Myers Squibb, Pfizer, Gilead, Sevier, Genentech, Astellas, Daiichi-Sankyo, Abbvie, Hanmi, Trovagene, FATE, Amgen, Novimmune, Glycomimetics, and ImmunoGen and has served in a consulting or advisory role for Daiichi-Sankyo, Bristol-Myers Squibb, Pfizer, Novartis, Celgene, AbbVie, Astellas, Genentech, Immunogen, Servier, Syndax, Trillium, Gilead, Amgen, and Agios. G.B. reports research funding from Bristol‐Myers Squibb, GlaxoSmithKline, Janssen Scientific Affairs, Eli Lilly and Company, Cyclacel, AstraZeneca, AbbVie, Oncoceutics, Arvinas, Cantargia, PTC Therapeutics, Argenx, BioTheryX, and Bioline and personal fees from PTC Therapeutics, Argenx, BioTheryX, and Bioline. Dr. E.J. reports research grants and advisory rolls with AbbVie, Adaptive Biotechnologies, Amgen, BMS, Pfizer and Takeda, and advisory roll with Genetech. Dr. M.K. reports grants and other from AbbVie, Genentech, F. Hoffman La-Roche, Stemline Therapeutics, Amgen, and Forty-Seven. G.G.‐M. has received grants from and acted in an advisory role for Celgene; has received grants and personal fees from Amphivena Therapeutics and Astex; and has received grants from Helsinn, Novartis, AbbVie, Onconova, H3 Biomedicine, and Merck for work performed outside of the current study. Dr. M.K. reports grants from Kisoji, Eli Lilly, Cellectis, Calithera, Ablynx, Agios, Ascentage, Astra Zeneca, other from Reata Pharmaceutical, Rafael Pharmaceutical, Sanofi. In addition, Dr. M.K. has US patents wityh Reara and Eli Lilly (US 7,795,305 B2 and a patent 62/993,166). Dr. F.R. reports research funding from BMS, Amgen, Xencor, Macrogenics, Orsenix, Abbvie, Prelude, Astex; consultancy and honoraria from Celgene, BMS, Amgen, Astellas, Xencor, Agios, AstraZeneca, and Orsenix.

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Kantarjian, H., Kadia, T., DiNardo, C. et al. Acute myeloid leukemia: current progress and future directions. Blood Cancer J. 11 , 41 (2021). https://doi.org/10.1038/s41408-021-00425-3

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Published By: Elsevier Ltd.

Abbreviation: Leuk. Res. Rep.

Impact Score The impact Score or journal impact score (JIS) is equivalent to Impact Factor. The impact factor (IF) or journal impact factor (JIF) of an academic journal is a scientometric index calculated by Clarivate that reflects the yearly mean number of citations of articles published in the last two years in a given journal, as indexed by Clarivate's Web of Science. On the other hand, Impact Score is based on Scopus data.

Important details.

About Leukemia Research Reports

Leukemia Research Reports is a journal published by Elsevier Ltd. . This journal covers the area[s] related to Hematology, Oncology, etc . The coverage history of this journal is as follows: 2012-2022. The rank of this journal is 14147 . This journal's impact score, h-index, and SJR are 1.01, 14, and 0.333, respectively. The ISSN of this journal is/are as follows: 22130489 . The best quartile of Leukemia Research Reports is Q3 . This journal has received a total of 108 citations during the last three years (Preceding 2022).

Leukemia Research Reports Impact Score 2022-2023

The impact score (IS), also denoted as the Journal impact score (JIS), of an academic journal is a measure of the yearly average number of citations to recent articles published in that journal. It is based on Scopus data.

Prediction of Leukemia Research Reports Impact Score 2023

Impact Score 2022 of Leukemia Research Reports is 1.01 . If a similar upward trend continues, IS may increase in 2023 as well.

Impact Score Graph

Check below the impact score trends of leukemia research reports. this is based on scopus data..

Leukemia Research Reports h-index

The h-index of Leukemia Research Reports is 14 . By definition of the h-index, this journal has at least 14 published articles with more than 14 citations.

What is h-index?

The h-index (also known as the Hirsch index or Hirsh index) is a scientometric parameter used to evaluate the scientific impact of the publications and journals. It is defined as the maximum value of h such that the given Journal has published at least h papers and each has at least h citations.

Leukemia Research Reports ISSN

The International Standard Serial Number (ISSN) of Leukemia Research Reports is/are as follows: 22130489 .

The ISSN is a unique 8-digit identifier for a specific publication like Magazine or Journal. The ISSN is used in the postal system and in the publishing world to identify the articles that are published in journals, magazines, newsletters, etc. This is the number assigned to your article by the publisher, and it is the one you will use to reference your article within the library catalogues.

ISSN code (also called as "ISSN structure" or "ISSN syntax") can be expressed as follows: NNNN-NNNC Here, N is in the set {0,1,2,3...,9}, a digit character, and C is in {0,1,2,3,...,9,X}

Leukemia Research Reports Ranking and SCImago Journal Rank (SJR)

SCImago Journal Rank is an indicator, which measures the scientific influence of journals. It considers the number of citations received by a journal and the importance of the journals from where these citations come.

Leukemia Research Reports Publisher

The publisher of Leukemia Research Reports is Elsevier Ltd. . The publishing house of this journal is located in the United Kingdom . Its coverage history is as follows: 2012-2022 .

Call For Papers (CFPs)

Please check the official website of this journal to find out the complete details and Call For Papers (CFPs).

Abbreviation

The International Organization for Standardization 4 (ISO 4) abbreviation of Leukemia Research Reports is Leuk. Res. Rep. . ISO 4 is an international standard which defines a uniform and consistent system for the abbreviation of serial publication titles, which are published regularly. The primary use of ISO 4 is to abbreviate or shorten the names of scientific journals using the technique of List of Title Word Abbreviations (LTWA).

As ISO 4 is an international standard, the abbreviation ('Leuk. Res. Rep.') can be used for citing, indexing, abstraction, and referencing purposes.

How to publish in Leukemia Research Reports

If your area of research or discipline is related to Hematology, Oncology, etc. , please check the journal's official website to understand the complete publication process.

Acceptance Rate

• Interest/demand of researchers/scientists for publishing in a specific journal/conference.
• The complexity of the peer review process and timeline.
• Time taken from draft submission to final publication.
• Number of submissions received and acceptance slots
• And Many More.

The simplest way to find out the acceptance rate or rejection rate of a Journal/Conference is to check with the journal's/conference's editorial team through emails or through the official website.

Frequently Asked Questions (FAQ)

What is the impact score of leukemia research reports.

The latest impact score of Leukemia Research Reports is 1.01. It is computed in the year 2023.

What is the h-index of Leukemia Research Reports?

The latest h-index of Leukemia Research Reports is 14. It is evaluated in the year 2023.

What is the SCImago Journal Rank (SJR) of Leukemia Research Reports?

The latest SCImago Journal Rank (SJR) of Leukemia Research Reports is 0.333. It is calculated in the year 2023.

What is the ranking of Leukemia Research Reports?

The latest ranking of Leukemia Research Reports is 14147. This ranking is among 27955 Journals, Conferences, and Book Series. It is computed in the year 2023.

Who is the publisher of Leukemia Research Reports?

Leukemia Research Reports is published by Elsevier Ltd.. The publication country of this journal is United Kingdom.

What is the abbreviation of Leukemia Research Reports?

This standard abbreviation of Leukemia Research Reports is Leuk. Res. Rep..

Is "Leukemia Research Reports" a Journal, Conference or Book Series?

Leukemia Research Reports is a journal published by Elsevier Ltd..

What is the scope of Leukemia Research Reports?

For detailed scope of Leukemia Research Reports, check the official website of this journal.

What is the ISSN of Leukemia Research Reports?

The International Standard Serial Number (ISSN) of Leukemia Research Reports is/are as follows: 22130489.

What is the best quartile for Leukemia Research Reports?

The best quartile for Leukemia Research Reports is Q3.

What is the coverage history of Leukemia Research Reports?

The coverage history of Leukemia Research Reports is as follows 2012-2022.

Credits and Sources

• Scimago Journal & Country Rank (SJR), https://www.scimagojr.com/
• Journal Impact Factor, https://clarivate.com/
• Issn.org, https://www.issn.org/
• Scopus, https://www.scopus.com/

Note: The impact score shown here is equivalent to the average number of times documents published in a journal/conference in the past two years have been cited in the current year (i.e., Cites / Doc. (2 years)). It is based on Scopus data and can be a little higher or different compared to the impact factor (IF) produced by Journal Citation Report. Please refer to the Web of Science data source to check the exact journal impact factor ™ (Thomson Reuters) metric.

Impact Score, SJR, h-Index, and Other Important metrics of These Journals, Conferences, and Book Series

Check complete list

Leukemia Research Reports Impact Score (IS) Trend

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Annals of hematology, british journal of haematology, leukemia research, frontiers in oncology, journal of clinical oncology, international journal of hematology.

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Leukemia research reports scite analysis.

452 articles received 1.6K citations see all

• 52 Supporting
• 1,467 Mentioning
• 4 Contrasting

Leukemia Research Reports Editorial notices

• 0 Retractions
• 1 Withdrawals
• 0 Corrections
• 0 Expression of Concern

FAQs on Leukemia Research Reports

How many articles did leukemia research reports publish last year.

In 2023, Leukemia Research Reports publsihed 43 articles.

Who is the publisher of Leukemia Research Reports?

Elsevier is the publisher of Leukemia Research Reports.

Copyright 2024 Cactus Communications. All rights reserved.

Advances in Leukemia Research

Human cells with acute myelocytic leukemia.

NCI-funded researchers are working to advance our understanding of how to treat leukemia. With progress in both targeted therapies and immunotherapies, leukemia treatment has the potential to become more effective and less toxic.

This page highlights some of the latest research in leukemia, including clinical advances that may soon translate into improved care, NCI-supported programs that are fueling progress, and research findings from recent studies.

Leukemia Treatment for Adults

The mainstays of leukemia treatment for adults have been chemotherapy , radiation therapy , and stem cell transplantation . Over the last two decades, targeted therapies have also become part of the standard of care for some types of leukemia. These treatments target proteins that control how cancer cells grow, divide, and spread. Different types of leukemia require different combinations of therapies.  For a complete list of all currently approved drugs, see Drugs Approved for Leukemia.

Although much progress has been made against some types of leukemia, others still have relatively poor rates of survival. And, as the population ages, there is a greater need for treatment regimens that are less toxic .

Acute Lymphoblastic Leukemia (ALL) Treatment

Adult acute lymphoblastic leukemia (ALL) is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell). It usually gets worse quickly and needs rapid treatment. Some recent research includes:

Combining less-toxic therapies

The intensive chemotherapy treatments used for ALL have serious side effects that many older patients cannot tolerate. Targeted therapies may have fewer side effects than chemotherapy. Clinical trials, including one at NCI , are now testing whether combinations of these types of therapies can be used instead of chemotherapy for older patients with a form of ALL called B-cell ALL.

Immunotherapy

Immunotherapies are treatments that help the body’s immune system fight cancer more effectively. Immunotherapy strategies being used or tested in ALL include:

CAR T-cell therapy

CAR T-cell therapy is a type of treatment in which a patient’s own immune cells are genetically modified to treat their cancer.

• Currently, one type of CAR T cell therapy is  approved for the treatment of some children and young adults with ALL. They are now being explored for use in older adults with B-cell ALL. 
• A second CAR T-cell therapy has been approved for adults with a type of ALL called B-cell precursor ALL that has not responded to treatment or has returned after previous treatment.

CAR T cell therapies are now being explored for other uses in ALL. For example, scientists hope that it will be possible to use CAR T-cell therapy to delay—or even replace—stem-cell transplantation in older, frailer patients.

Bispecific T-cell engagers

Another immunotherapy being tested in ALL is bispecific T-cell engagers (BiTEs). These drugs attach to immune cells and cancer cells, enabling the immune cells to easily find and destroy the cancer cell by bringing them closer together.

Once such BiTE, called blinatumomab (Blincyto) , was recently shown to improve survival for people with ALL who are in remission after chemotherapy, even when there is no trace of their disease.

Improving treatment for adolescents and young adults (AYAs)

An intensive treatment regimen developed for children with ALL has been found to also improve outcomes for newly diagnosed AYA patients . The pediatric regimen more than doubled the median length of time people lived without their cancer returning compared with an adult treatment regimen. Further studies are now testing the addition of targeted therapies to the combination .

Acute Myeloid Leukemia (AML) Treatment

Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. It can cause a buildup of abnormal red blood cells, white blood cells, or platelets.

AML tends to be aggressive and is harder to treat than ALL. However, AML cells sometimes have gene changes that cause the tumors to grow but can be targeted with new drugs. Researchers are starting to look at whether genomic sequencing of tumor cells can help doctors choose the best treatment (such as chemotherapy, targeted therapy, stem-cell transplant, or a combination of therapies) for each patient. Scientists are also testing other ways to treat AML.

New Treatment Option for Some People with AML

Combining ivosidenib with chemo is effective for AML with an IDH1 gene mutation.

Targeted therapies

Targeted therapies recently approved to treat AML with certain gene changes include  Enasidenib (Idhifa) ,  Olutasidenib (Rezlidhia) ,  Ivosidenib (Tibsovo) ,  Venetoclax (Venclexta) ,  Gemtuzumab ozogamicin (Mylotarg) ,  Midostaurin (Rydapt) ,  Gilteritinib (Xospata) ,  Glasdegib (Daurismo) , and  Quizartinib (Vanflyta) . 

Other ways to treat AML

• Testing newer targeted therapies.  Researchers continue to develop new drugs to shut down proteins that some leukemias need to grow. For example, new drugs called menin inhibitors stop cancer-promoting genes from being expressed. 
• Studying ways to target AML cells indirectly. These include testing ways to make cancer cells more vulnerable to new and existing treatments.
• Targeting AML and related conditions. A type of less-aggressive cancer called myelodysplastic syndrome (MDS) can eventually progress to AML. Researchers are testing HDAC inhibitors and other drugs that alter how genes are switched on and off in both MDS and AML.
• Reducing side effects. Some older adults cannot tolerate the intensive treatments most commonly used for AML. Studies have recently found that several drug combinations can help older people with AML live longer while avoiding many serious side effects. New treatments to relieve symptoms of MDS have also been developed.
• Immunotherapy. CAR T-cells and BiTEs are being tested in people with AML.

Chronic Myelogenous Leukemia (CML) Treatment

Chronic myelogenous leukemia (CML) is a type of cancer in which the bone marrow makes too many granulocytes (a type of white blood cell). These granulocytes are abnormal and can build up in the blood and bone marrow so there is less room for healthy white blood cells, red blood cells, and platelets. CML usually gets worse slowly over time.

Blocking an abnormal protein

Most people with CML have a specific chromosome alteration called the Philadelphia chromosome , which produces an abnormal protein that drives the growth of leukemia cells. Targeted therapies that block this abnormal protein— imatinib (Gleevec) , nilotinib (Tasigna) , dasatinib (Sprycel) , and ponatinib (Iclusig) —have radically changed the outlook for people with CML, who now have close to a normal life expectancy.

Testing new combination therapies

Some people with CML continue to have detectable cancer cells in their body even after long-term treatment with drugs that target the protein produced by the Philadelphia chromosome. NCI-sponsored trials are testing whether the addition of immunotherapy or other targeted therapies to these drugs can reduce the number of CML cells in such patients.

Looking at whether patients can stop taking therapy

Researchers have found that some drugs that target the protein produced by the Philadelphia chromosome can be safely stopped in some CML patients rather than taken for life. These patients must undergo regular testing to ensure the disease has not come back.

Chronic Lymphocytic Leukemia (CLL) Treatment

Like ALL, chronic lymphocytic leukemia (CLL) is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell). But unlike ALL, CLL is slow growing and worsens over time.

Targeted therapy

Ibrutinib (Imbruvica) . The targeted therapy ibrutinib (Imbruvica) was the first non-chemotherapy drug approved to treat CLL. It shuts down a signaling pathway called the B-cell receptor signaling pathway, which is commonly overactive in CLL cells. Depending on people’s age , ibrutinib may be given in combination with another targeted drug, rituximab (Rituxan) .

Clinical trials have shown that ibrutinib benefits both younger and older patients with CLL.

Venetoclax (Venclexta) and obinutuzumab (Gazyva) . In 2019, the Food and Drug Administration (FDA) approved the second chemotherapy-free initial treatment regimen for CLL , containing the targeted therapies venetoclax (Venclexta) and obinutuzumab (Gazyva) .

Other combinations of these drugs plus ibrutinib are now being used or tested for CLL, including •    ibrutinib and venetoclax in people with newly diagnosed CLL •    ibrutinib, obinutuzumab, and venetoclax in older adults with newly diagnosed CLL •    ibrutinib and obinutuzumab with or without venetoclax in younger adults with newly diagnosed CLL

An ongoing trial at NCI is also testing whether giving the combination of venetoclax and obinutuzumab to some people with CLL before symptoms develop can help them live longer overall.

Zanubrutinib (Brukinsa) . In early 2023, the FDA approved a drug that works in a similar manner to ibrutinib, called zanubrutinib (Brukinsa) , for people with CLL. A large study showed that zanubrutinib alone has fewer side effects and is more effective than ibrutinib for people whose leukemia has returned after initial treatment. More research is now needed to understand how to best combine zanubrutinib with other newer therapies, such as venetoclax.

CAR T-cell therapy is also being tested in adults with CLL. Researchers would like to know if using this type of immunotherapy early in the course of treatment would be more effective than waiting until the cancer recurs.

Hairy Cell Leukemia (HCL) Treatment

Hairy cell leukemia (HCL) is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell). The disease is called hairy cell leukemia because the abnormal lymphocytes look "hairy" when viewed under a microscope. This rare type of leukemia gets worse slowly, or sometimes does not get worse at all.

Combinations of drugs

Researchers are studying combinations of drugs to treat HCL. For example, in a recent small study, a combination of two targeted therapies— vemurafenib (Zelboraf) and rituximab (Rituxan) — led to long-lasting remissions for most participants with HCL that had come back after previous treatments. More drug combinations are currently being tested in clinical trials.

Leukemia Treatment for Children

For the two most common types of leukemia, AML and ALL, standard leukemia treatments for children have been chemotherapy, radiation therapy, and stem-cell transplant. Despite great improvements in survival for children with many types of leukemia, some treatments don't always work. Also, some children later experience a relapse of their disease. Others live with the side effects of chemotherapy and radiation therapy for the rest of their lives, highlighting the need for less toxic treatments.

Now researchers are focusing on targeted drugs and immunotherapies for the treatment of leukemia in children. Newer chemotherapy drugs are also being tested.

Targeted Therapies

Targeted therapies that have been approved or are being studied for children with leukemia include:

• imatinib (Gleevec) and dasatinib (Sprycel), which are  approved for the treatment of children with CML  as well as those with a specific type of ALL. The approvals are for children whose cancer cells have the Philadelphia chromosome. 
• sorafenib (Nexavar) , which has been studied in combination with standard chemotherapy for children with AML whose leukemia has changes in a gene called FLT3. The addition of sorafenib to standard treatment was safe, and its addition may improve survival time free from leukemia. Other ongoing clinical trials are testing drugs that target FLT3 more specifically than sorafenib (such as gilteritinib).
• larotrectinib (Vitrakvi) , which is being tested in children with leukemia that has a specific change in a gene called NTRK . 

More possible targets for the treatment of childhood cancers are discovered every year, and many new drugs that could potentially be used to treat cancers that have these targets are being tested through the Pediatric Preclinical In Vivo Testing Consortium (PIVOT) .

CAR T-cell therapy has recently generated great excitement for the treatment of children with relapsed ALL. One CAR T-cell therapy, tisagenlecleucel (Kymriah) , was approved in 2017 for some children with relapsed ALL.

Researchers continue to address remaining challenges about the use of CAR T-cell therapy in children with leukemia:

• Sometimes, leukemia can become resistant to tisagenlecleucel. Researchers in NCI’s Pediatric Oncology Branch have developed CAR T cells that target leukemia cells in a different way. An  ongoing clinical trial is testing whether the combination of these two types of CAR T cells can provide longer-lasting remissions.
• CAR T cells are currently only approved for use in leukemia that has relapsed or proved resistant to standard treatment. A clinical trial from COG is now testing tisagenlecleucel as part of first-line therapy in children with ALL at high risk of relapse.
• More research is needed to understand which children who receive CAR T cells are at high risk of developing resistance to treatment. Researchers also plan to test whether strategies such as combining CAR T-cell therapy with other immunotherapies may help prevent resistance from developing. 
• Other research, both in NCI’s Pediatric Oncology Branch and at other institutions, is focused on creating CAR T-cell therapies that work for children with other types of childhood leukemia, such as AML. Several clinical trials of these treatments, including one led by NCI researchers , are now under way.

Two other drugs that use the body’s immune system to fight cancer have shown promise for children with leukemia:

• In clinical trials, the drug was shown to be more effective than chemotherapy in treating ALL that has relapsed in children and young adults.
• An NCI-sponsored trial is now testing the drug as part of treatment for newly diagnosed ALL in children, adolescents, and young adults .
• A drug called inotuzumab ozogamicin (Besponsa)  is being tested in children with relapsed B-cell ALL. This drug consists of an antibody that can bind to cancer cells linked to a drug that can kill those cells. An NCI-sponsored trial is also testing the drug as part of treatment for newly diagnosed ALL in children and adolescents at higher risk of relapse.

Chemotherapy

In addition to targeted therapies and immunotherapies, researchers are also working to develop new chemotherapy drugs for leukemia and find better ways to use existing drugs. In 2018, a large clinical trial showed that adding the drug nelarabine (Arranon) to standard chemotherapy improves survival for children and young adults newly diagnosed with T-cell ALL.

Other drugs are being tested that may make standard chemotherapy drugs more effective. These drugs include venetoclax , which has been approved for older adults with some types of leukemia and is now being tested in children .

Survivorship

Children’s developing brains and bodies can be particularly sensitive to the harmful effects of cancer treatment. Because many children treated for cancer go on to live long lives, they may be dealing with these late effects for decades to come.

The NCI-funded Childhood Cancer Survivor Study , ongoing since 1994, tracks the long-term harmful effects of treatments for childhood cancer and studies ways to minimize these effects. NCI also funds research into addressing ways to help cancer survivors cope with and manage health issues stemming from cancer treatment, as well into altering existing treatment regimens to make them less toxic in the long term.

For example, one study found that, in children with ALL, radiation therapy to prevent the cancer from returning in the brain is likely unnecessary . The study found that radiation can even be omitted for children at the highest risk of the cancer coming back, reducing the risk of future problems with thinking and memory, hormone dysfunction, and other side effects of radiation to the brain.

Preventing and Treating Graft Versus Host Disease

Many people with leukemia—both adults and children—have a stem-cell transplant as part of their treatment. If the new stem cells come from a donor, the immune cells they produce may be able to attack any cancer cells that remain in the body.

But sometimes, immune cells produced by donor stem cells attack healthy tissues of the body instead. This condition, called graft versus host disease ( GVHD ), can affect nearly every organ and can cause many painful and debilitating symptoms. 

In recent years, several drugs have been approved by the FDA for the treatment of GVHD, including:

•    ibrutinib, which is also used as a treatment for some types of leukemia •     ruxolitinib (Jakafi) •     belumosudil (Rezurock)

Researchers are also testing ways to prevent GVHD from developing in the first place. For example, a recent study found that removing certain immune cells from donated stem cells before they are transplanted may reduce the risk of chronic GVHD without any apparent increase in the likelihood of relapse.

NCI-Supported Research Programs

Many NCI-funded researchers working at the NIH campus and across the United States and the world are seeking ways to address leukemia more effectively. Some research is basic, exploring questions as diverse as the biological underpinnings of cancer. And some is more clinical, seeking to translate this basic information into improving patient outcomes. The programs listed below are a small sampling of NCI’s research efforts in leukemia.

NCI’s Leukemia Specialized Programs of Research Excellence (SPORE) promotes collaborative, interdisciplinary research. SPORE grants involve both basic and clinical/applied scientists working together. They support the efficient movement of basic scientific findings into clinical settings, as well as studies to determine the biological basis for observations made in individuals with cancer or in populations at risk for cancer.

The Pediatric Immunotherapy Discovery and Development Network (PI-DDN) is working to discover and characterize new targets for immunotherapies, design experimental models to test the effectiveness of pediatric immunotherapies, develop new immunotherapy treatments, and improve the understanding of tumor immunity in pediatric cancer patients. The PI-DDN was established as part of the Cancer Moonshot initiative.

The Fusion Oncoproteins in Childhood Cancers (FusOnC2) Consortium is also part of the Cancer Moonshot initiative. The consortium of collaborating research teams will work to advance the understanding of how five important fusion oncoproteins help drive pediatric cancers, including leukemia, and apply this knowledge towards developing drugs that target these proteins.

NCI has also formed partnerships with the pharmaceutical industry, academic institutions, and individual investigators for the early clinical evaluation of innovative cancer therapies. The Experimental Therapeutics Clinical Trials Network (ETCTN) was created to evaluate these therapies using a coordinated, collaborative approach to early-phase clinical trials.

The Pediatric Early-Phase Clinical Trials Network was established to help identify and develop effective new drugs for children and adolescents with cancer. The network’s focus is on phase I and early phase II trials, as well as pilot studies of novel drugs and treatment regimens to determine their tolerability.

NCI’s Pediatric Preclinical In Vivo Testing Consortium (PIVOT) develops mouse models to allow early, rapid testing of new drugs for pediatric cancers, including leukemia. The models are all derived from tissue samples taken from patients’ tumors. The consortium partners both with commercial drug companies and with drug development efforts at universities and cancer centers.

The Therapeutically Applicable Research to Generate Effective Treatments (TARGET) program uses a comprehensive approach to determine the genetic changes that drive childhood cancers. The goal of the program is to use data to guide the development of effective, less toxic therapies. TARGET is organized into disease-specific teams, including those for ALL and AML.

Researchers in NCI’s Division of Cancer Epidemiology and Genetics (DCEG)  investigate novel, molecular biomarkers for leukemia, as well as clarify relationships of established risk factors. Studies include those looking at environmental and workplace exposure, families with multiple leukemia cases, and inherited bone marrow failure syndromes to name a few.

Clinical Trials

NCI funds and oversees both early- and late-phase clinical trials to develop new treatments and improve patient care. Search NCI-Supported Clinical Trials to find leukemia-related trials now accepting patients. 

Leukemia Research Results

The following are some of our latest news articles on leukemia research:

• Quizartinib Approval Adds New Treatment Option for AML, Including in Older Patients
• Blinatumomab Increases Survival for Infants with an Aggressive Type of ALL
• Revumenib Shows Promise in Treating Advanced Acute Myeloid Leukemia
• Help Desk for Oncologists Treating People with a Rare Leukemia Pays Big Dividends
• Zanubrutinib’s Approval Improves Targeted Treatment for CLL
• Trial Suggests Expanded Role for Blinatumomab in Treating ALL

View the full list of Leukemia Research Results and Study Updates .

Leukemia Research Reports impact factor, indexing, ranking (2024)

Aim and Scope

The Leukemia Research Reports is a research journal that publishes research related to Medicine . This journal is published by the Elsevier Ltd.. The ISSN of this journal is 22130489 . Based on the Scopus data, the SCImago Journal Rank (SJR) of leukemia research reports is 0.333 .

Leukemia Research Reports Ranking

The SJR (SCImago Journal Rank) measures citations weighted by prestige. It is useful for comparing journals within the same field, and forms the basis of the subject category ranking. A journal SJR indicator is a numeric value representing the average number of weighted citations received during a selected year per document published in that journal during the previous three years, as indexed by Scopus. Higher SJR indicator values are meant to indicate greater journal prestige. SJR is developed by the Scimago Lab, originated from a research group at University of Granada. Q1 journals are cited more often and by more prestigious journals than those in the other quartiles.

Each subject category of journals is divided into four quartiles: Q1, Q2, Q3, Q4. Q1 is occupied by the top 25% of journals in the list; Q2 is occupied by journals in the 25 to 50% group; Q3 is occupied by journals in the 50 to 75% group and Q4 is occupied by journals in the 75 to 100% group.

CiteScore of an academic journal is a measure reflecting the yearly average number of citations to recent articles published in that journal. This journal evaluation metric was launched in December 2016 by Elsevier as an alternative to the generally used JCR impact factors (calculated by Clarivate). CiteScore is based on the citations recorded in the Scopus database rather than in JCR, and those citations are collected for articles published in the preceding four years instead of two or five.

Source Normalized Impact per Paper (SNIP) is calculated annually from Scopus data. It is a sophisticated metric that intrinsically accounts for field-specific differences in citation practices.

Important Metrics

leukemia research reports Indexing

The leukemia research reports is indexed in:

• Web of Science (ESCI)

An indexed journal means that the journal has gone through and passed a review process of certain requirements done by a journal indexer.

The Web of Science Core Collection includes the Science Citation Index Expanded (SCIE), Social Sciences Citation Index (SSCI), Arts & Humanities Citation Index (AHCI), and Emerging Sources Citation Index (ESCI).

Note: ESCI journals donot come with an impact factor. However, ESCI journals are evaluated every year and those who qualified are transferred to SCIE.

Leukemia Research Reports Quartile

The latest Quartile of leukemia research reports is Q3 .

Publication fee

According to journal website, the publication fee of leukemia research reports is around 880 USD .

The leukemia research reports has also Journal waiver policy (for developing countries, authors etc).

An article processing charge (APC), also known as a publication fee, is a fee which is sometimes charged to authors. Most commonly, it is involved in making a work available as open access (OA), in either a full OA journal or in a hybrid journal.

Journal Publication Time

The Journal Publication Time means the average number of weeks between article submission and publication. According to the journal website, the leukemia research reports publishes research articles in 23 weeks on an average.

Call for Papers

Visit to the official website of the journal/ conference to check the details about call for papers.

How to publish in Leukemia Research Reports?

If your research is related to Medicine, then visit the official website of leukemia research reports and send your manuscript.

Tips for publishing in Leukemia Research Reports:

• Selection of research problem.
• Presenting a solution.
• Designing the paper.
• Make your manuscript publication worthy.
• Write an effective results section.
• Mind your references.

Acceptance Rate

Final summary.

• It is published by Elsevier Ltd. .
• The journal is indexed in UGC CARE, Scopus, ESCI, DOAJ, PubMed .
• It is an open access journal .
• The (SJR) SCImago Journal Rank is 0.333 .
• The publication time (Average number of weeks between article submission and publication) of the journal is 23 weeks .
• The Publication fee (APC) of leukemia research reports 880 USD .

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Gen X is on track to have more cancer than baby boomers—and these 9 cancers are to blame

While cancer deaths have steadily declined over the past 30 years, cancer rates have been on the rise —especially, a new study has found, for members of Generation X.

By the time they turn 60, Gen Xers (born between 1965 and 1980) are projected to see a cancer rate higher than that of baby boomers—and any prior generation born between 1964 and 1908, for that matter. 

The only exception was with Gen X Asian or Pacific Islander males, whose rates of cancer are projected to go down, per the report. 

The findings were published this week in the JAMA Network Open and come out of the National Cancer Institute . The cohort study was led by senior investigator Philip Rosenberg, PhD, who used what’s called an age period cohort model to make the predictions, analyzing data of 3.8 million people (Asian or Pacific Islander, Hispanic, non-Hispanic Black, and non-Hispanic white) with cancer through the institute’s Surveillance, Epidemiology, and End Results Program . 

Rosenberg tells Fortune that for him, understanding how cancer rates vary from one generation to the next is a research passion. “It’s kind of understanding history in a way,” he says. 

And these results, he admits, took him by surprise.  

“Going in, I was anticipating that I may see colon or rectal cancer rates in particular to be as high or higher than the boomers, and that’s because there’s just so much of these studies coming out about early onset colorectal cancer cases,” he says. “But what kind of took me more by surprise was the number of different cancer types that our models project will occur in Generation X compared to baby boomers.”

Gen X women, the research found, will see significant increases over baby boomer women of the following cancers: thyroid, kidney, rectal, corpus uterine, colon, and pancreatic, plus non-Hodgkin’s lymphoma and leukemia. Gen X men, meanwhile, will see increases in thyroid, kidney, rectal, colon, and prostate cancers and leukemia. 

Lung and cervical cancer incidence is on track to decrease among Gen X women, while lung, liver, and gall bladder cancer and non-Hodgkin’s lymphoma incidence will decrease among Gen X men. Breast cancer rates will stay about the same, although Rosenberg and his team are currently looking into breast cancer rates in greater detail. 

The study noted: “Numerous preventable causes of cancer have been identified. Cancer control initiatives have led to substantial declines in tobacco consumption. Screening is well accepted for precancerous lesions of the colon, rectum, cervix, uterus, and breast.” But despite all of that, “other suspected carcinogenic exposures are increasing.”

Among those, the study points out, are PFAs (“ forever chemicals ”), processed food, and “rising obesity rates and increasingly sedentary lifestyles.” 

Another possibility for the rise in cancer rates, the study posits, is that changes in cancer registry policies as well as the rise of medical imaging technology in making diagnoses have led to more cancer cases being counted. 

Rosenberg explains that the primary purpose of a study like this is to “provide clues for other researchers to follow, so when you see the unexpected, that’s where to look to see cancer causes and novel means of prevention.” But a useful takeaway for the public, he says, is to focus on the many recommendations that are out there when it comes to reducing the risk of cancer. 

“Spending some time thinking about those recommendations would be a great exercise for all of us—really saying, ‘Am I doing everything I can?’” That would include eating healthy and staying active, following evidence based advice for specific screenings , “obviously not smoking,” and drinking in moderation. “There’s a lot of advice that people can take to heart,” he says.

The disparity in health care, though, is having a worrisome impact on certain groups. As the study pointed out: “The Black-to-white cancer mortality gap narrowed following passage of the Patient Protection and Affordable Care Act. However, income inequality, underinsurance, food swamps and deserts, deficits in the built environment, and other factors make it difficult for everyone to eat healthy and stay active. Taken together, these findings indicate that for many people in the U.S., a healthy lifestyle remains, to various degrees, an unattainable privilege rather than a fundamental right.”

The researchers had too few data points to produce estimates for millennials (born between 1981 and 1996). “Our results beg the question of what the cancer experience may be like among the 72 million millennials…when they enter their 40s, 50s, and 60s,” the study concluded. “On current trajectories, cancer incidence could remain high for decades.”

It’s why Rosenberg tells Fortune, “I don’t think you have to be a Gen Xer to be concerned” about what’s going on in the world today with all of these issues that may be impacting not only our health, but the future of our children.”

More on cancer:

• 5 lifestyle changes can significantly reduce your cancer risk , from giving up drinking to wearing sunscreen
• Cancer patients face grave financial barriers to care : ‘There is this dramatic loss of income’
• Global cancer rates are expected to rise 77% by 2050 . From aging to alcohol, here’s why
• Olivia Munn’s OB/GYN:  Women dismissed by doctors, leading to devastating consequences for cancer

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June 18, 2024

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Gastroenterologists generally trust and accept use of AI medical tools in clinics and hospitals, finds study

by Nanyang Technological University

Artificial intelligence (AI) has permeated many aspects of medicine, with promises of accurate diagnoses, better management decisions, and improved outcomes for both patients and the health care system. However, to successfully implement AI technology in clinical practice, trust and acceptance among health care providers to use such tools is crucial.

Now, using the treatment of digestive diseases as a case study , an international study led by Nanyang Technological University, Singapore (NTU Singapore) has found that doctors in gastroenterology practice generally trust and accept AI medical tools.

The paper, " Risk Perception, Acceptance, and Trust of Using AI in Gastroenterology Practice in the Asia-Pacific Region: Web-Based Survey Study, " is published in JMIR AI .

Through surveying 165 gastroenterologists and gastrointestinal surgeons in the Asia-Pacific region, the NTU Singapore-led research team found that eight in 10 say they accept and trust the use of AI-powered tools in diagnosing and assessing colorectal polyps (benign growths in the colon that could become cancerous).

When it came to using AI to guide an endoscopist on whether to remove polyps found in the bowel of those undergoing screening colonoscopy, seven in 10 said they accept and trust this AI-assisted application.

The research team found no difference in levels of acceptance between the male and female doctors, between those working in public and private settings, as well as between those working in big hospital units and small group practices.

However, the number of years of experience was a crucial factor. While one would expect young doctors to be more receptive to using technology in clinical decision making, the study found that gastroenterologists with fewer than 10 years of clinical experience perceived a higher risk of these AI-powered medical tools than their colleagues with more than 10 years of experience.

The findings highlight the need for more research into what influences doctors' acceptance of AI in their medical practice, said the team of scientists from Singapore, China, Hong Kong, and Taiwan.

Assistant Professor Wilson Goh from the NTU Lee Kong Chian School of Medicine (LKCMedicine), who led the study, said, "For this study, we zoomed in on the use of AI in the context of gastroenterology because we see that this specialty, with its heavy usage of image-based diagnosis and surgical or endoscopic intervention, will be able to readily use AI technologies in clinical management.

"This is one of the earliest reports of AI risk perception, acceptance, and trust among gastroenterologists, with a unique focus on the Asia-Pacific region."

Asst Prof Goh, also the Co-Director of NTU's Center for Biomedical Informatics, said, "Although the study participants found certain AI technologies risky, most practitioners still trusted and accepted these applications, highlighting the intricate relationship between the complexity of AI technologies and their acceptance.

"AI has the potential to revolutionize the health care sector, but for AI to be integrated into the sector, a better understanding of the factors that underpin clinicians' trust and acceptance towards AI-powered medical tools is necessary."

NTU Senior Vice President (Health & Life Sciences) and Director of Center for AI in Medicine Professor Joseph Sung, one of the study's co-authors and a leading gastroenterologist, said, "The finding that more experienced gastroenterologists have a lower risk perception of AI tools is intriguing.

"Having more clinical experience in managing colorectal polyps among senior gastroenterologists may have given these clinicians greater confidence in their medical expertise and practice, thus generating more confidence in exercising clinical discretion when new technologies are introduced."

On the other hand, a general lack of confidence when there is a discrepancy between AI and the human experience may be one of the reasons why less experienced doctors perceive AI as riskier when it involves invasive operative procedures such as removal of polyps in the colon, said Professor Sung, who is also the Dean of NTU's LKCMedicine.

"A greater emphasis on AI, as we have implemented in NTU LKCMedicine's recently refreshed curriculum, may help mitigate risk aversion and promote responsible AI use in clinical practice ," he added.

Professor May O. Lwin, Chair of the NTU Wee Kim Wee School of Communication, another study co-author whose research interest is in health communication, suggested that future studies could include patients' perspective by assessing the circumstances in which patients would have concerns using AI technology in their health conditions.

She added, "It is important to capture the perspectives of other stakeholders, such as nurses, endoscopy assistants, and the general public, to understand better how their opinions align or conflict with each other. This will help us more realistically navigate complex trust and acceptance issues and create valuable propositions and effective policies."

How the study was conducted

For this study, the scientists developed a questionnaire based on questions or statements adapted from validated frameworks and models.

Participants were asked to rate their level of agreement with the questions or statements designed to assess their level of trust, acceptance, and risk perception of AI use in gastroenterology.

• Participants were also presented with three different medical scenarios in which AI could be applied:
• For detection: to assist in identifying the presence of colorectal polyps and improving the detection rate of polyps that are likely to turn into cancer
• For characterization: to assess the nature of pathology of polyps and predict the risk of a colorectal polyp turning cancerous
• For intervention: to guide the removal of polyps in an endoscopy

For each medical scenario, the participants were asked to rate their agreement with statements that assess their perceived risk and trust in AI tools, including :

• I expect major risks involved with the AI diagnosis.
• I am ready to try the method myself.

They were also asked to rate their belief in statements that assess their acceptance of AI tools, such as:

• Do you believe that machine learning algorithm can, in some cases (such as the ones described above), perform better than human beings?

The scores for each participant were then tabulated and used in statistical analyses to find out how the factors of risk perception, acceptance, and trust may interact with each other.

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