Advances in targeted therapy for acute myeloid leukemia

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Abstract

Acute myeloid leukemia (AML) is a clonal malignancy characterized by genetic heterogeneity due to recurrent gene mutations. Treatment with cytotoxic chemotherapy has been the standard of care for more than half of a century. Although much progress has been made toward improving treatment related mortality rate in the past few decades, long term overall survival has stagnated. Exciting developments of gene mutation-targeted therapeutic agents are now changing the landscape in AML treatment. New agents offer more clinical options for patients and also confer a more promising outcome. Since Midostaurin, a FLT3 inhibitor, was first approved by US FDA in 2017 as the first gene mutation-targeted therapeutic agent, an array of new gene mutation-targeted agents are now available for AML treatment. In this review, we will summarize the recent advances in gene mutation-targeted therapies for patients with AML.

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(R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible.

Julie-Aurore Losman, Ryan Looper, Peppi Koivunen … (2013)

Mutations in IDH1 and IDH2, the genes coding for isocitrate dehydrogenases 1 and 2, are common in several human cancers, including leukemias, and result in overproduction of the (R)-enantiomer of 2-hydroxyglutarate [(R)-2HG]. Elucidation of the role of IDH mutations and (R)-2HG in leukemogenesis has been hampered by a lack of appropriate cell-based models. Here, we show that a canonical IDH1 mutant, IDH1 R132H, promotes cytokine independence and blocks differentiation in hematopoietic cells. These effects can be recapitulated by (R)-2HG, but not (S)-2HG, despite the fact that (S)-2HG more potently inhibits enzymes, such as the 5'-methylcytosine hydroxylase TET2, that have previously been linked to the pathogenesis of IDH mutant tumors. We provide evidence that this paradox relates to the ability of (S)-2HG, but not (R)-2HG, to inhibit the EglN prolyl hydroxylases. Additionally, we show that transformation by (R)-2HG is reversible.

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Acute Myeloid Leukemia, Version 3.2019, NCCN Clinical Practice Guidelines in Oncology

Martin S. Tallman, Eunice S Wang, Jessica Altman … (2019)

Acute myeloid leukemia (AML) is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths due to leukemias in the United States. Recent advances have resulted in an expansion of treatment options for AML, especially concerning targeted therapies and low-intensity regimens. This portion of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for AML focuses on the management of AML and provides recommendations on the workup, diagnostic evaluation and treatment options for younger (age <60 years) and older (age ≥60 years) adult patients.

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Ponatinib efficacy and safety in Philadelphia chromosome–positive leukemia: final 5-year results of the phase 2 PACE trial

Jorge E. Cortes, Dong-Wook Kim, Javier Pinilla-Ibarz … (2018)

Ponatinib continued to provide deep, durable responses in heavily pretreated patients with CP-CML. Tolerability was acceptable in this heavily pretreated population with 5 years of follow-up. Ponatinib has potent activity against native and mutant BCR-ABL1, including BCR-ABL1 T315I . The pivotal phase 2 Ponatinib Ph + ALL and CML Evaluation (PACE) trial evaluated efficacy and safety of ponatinib at a starting dose of 45 mg once daily in 449 patients with chronic myeloid leukemia (CML) or Philadelphia chromosome–positive acute lymphoblastic leukemia (ALL) resistant/intolerant to dasatinib or nilotinib, or with BCR-ABL1 T315I . This analysis focuses on chronic-phase CML (CP-CML) patients (n = 270) with 56.8-month median follow-up. Among 267 evaluable patients, 60%, 40%, and 24% achieved major cytogenetic response (MCyR), major molecular response (MMR), and 4.5-log molecular response, respectively. The probability of maintaining MCyR for 5 years was 82% among responders. Dose reductions were implemented in October 2013 to decrease the risk of arterial occlusive events (AOEs); ≥90% of CP-CML patients who had achieved MCyR or MMR maintained response 40 months after elective dose reductions. Estimated 5-year overall survival was 73%. In CP-CML patients, the most common treatment-emergent adverse events were rash (47%), abdominal pain (46%), thrombocytopenia (46%), headache (43%), dry skin (42%), and constipation (41%). The cumulative incidence of AOEs in CP-CML patients increased over time to 31%, while the exposure-adjusted incidence of new AOEs (15.8 and 4.9 per 100 patient-years in years 1 and 5, respectively) did not increase over time. These final PACE results demonstrate ponatinib provides durable and clinically meaningful responses, irrespective of dose reductions, in this population of heavily pretreated CP-CML patients. This trial was registered at www.clinicaltrials.gov as #NCT01207440.

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Author and article information

Contributors

Jifeng Yu:

ORCID: http://orcid.org/0000-0003-1217-4385

Yujifengzzu@163.com

Yongping Song: Songyongping001@126.com

Journal

Journal ID (nlm-ta): Biomark Res

Journal ID (iso-abbrev): Biomark Res

Title: Biomarker Research

Publisher: BioMed Central (London )

ISSN (Electronic): 2050-7771

Publication date (Electronic): 20 May 2020

Publication date PMC-release: 20 May 2020

Publication date Collection: 2020

Volume: 8

Electronic Location Identifier: 17

Affiliations

[1 ]GRID grid.412633.1, The First Affiliated Hospital of Zhengzhou University, ; #1 East Jianshe Road, Zhengzhou, 450052 China

[2 ]GRID grid.207374.5, ISNI 0000 0001 2189 3846, Academy of Medical and Pharmaceutical Sciences of Zhengzhou University, ; #1 East Jianshe Road, Zhengzhou, 450052 China

[3 ]GRID grid.492859.b, Department of Hematology and Oncology, , The Everett Clinic and Providence Regional Cancer Partnership, ; 1717 13th Street, Everett, WA 98201 USA

[4 ]GRID grid.414008.9, ISNI 0000 0004 1799 4638, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, ; 127 Dongming Road, Zhengzhou, 450008 China

Author information

Jifeng Yu http://orcid.org/0000-0003-1217-4385

Article

Publisher ID: 196

DOI: 10.1186/s40364-020-00196-2

PMC ID: 7238648

PubMed ID: 32477567

SO-VID: f37233ef-5b05-4d45-91da-16f0d3aa5bca

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Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 14 March 2020

Date accepted : 10 May 2020

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100004609, Foundation of Henan Educational Committee;

Award ID: 20A320062

Award ID: 19A320046

Award Recipient : Jifeng Yu Yingmei Li

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: U1804192

Award Recipient : Yingmei Li

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Keywords: targeted therapy,gene mutation,acute myeloid leukemia (aml)

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Keywords: targeted therapy, gene mutation, acute myeloid leukemia (aml)

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Advances in targeted therapy for acute myeloid leukemia

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Neuropharmacology and Therapy

Most cited references 81

(R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible.

Acute Myeloid Leukemia, Version 3.2019, NCCN Clinical Practice Guidelines in Oncology

Ponatinib efficacy and safety in Philadelphia chromosome–positive leukemia: final 5-year results of the phase 2 PACE trial

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Cited by 26

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