Hypomethylating agent-based therapies in older adults with acute myeloid leukemia – A joint review by the Young International Society of Geriatric Oncology and European Society for Blood and Marrow Transplantation Trainee Committee

Neuendorff, Nina Rosa; Gagelmann, Nico; Singhal, Surbhi; Meckstroth, Shelby; Thibaud, Vincent; Zhao, Yue; Mir, Nabiel; Shih, Yung-Yu; Amaro, Danielle M.C.; Roy, Mukul; Lombardo, Joseph S.; Gjærde, Lars Klingen; Loh, Kah Poh

doi:10.1016/j.jgo.2022.11.005

Cited by 2 publications

(2 citation statements)

References 137 publications

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“…A randomised phase 3 clinical trial is currently underway to assess the combination of IDH inhibitors with induction, consolidation and maintenance therapies in newly diagnosed IDH-mutant AML patients that are eligible for intensive chemotherapy (NCT03839771). However, many AML patients are ineligible for standard of care intensive chemotherapy and are instead treated with hypomethylating agents (HMAs), which are well-tolerated and thus improved clinical outcomes are frequently assessed by combining HMAs with targeted AML therapies [ 106 ]. HMAs, including 5-Azacytidine (AZA) and Decitabine, are cytidine analogues that inhibit the DNA methyltransferase activity of DNMT1 which results in DNA hypomethylation [ 106 ].…”

Section: Therapeutic Targeting Of Idh-mutant Amlmentioning

confidence: 99%

“…However, many AML patients are ineligible for standard of care intensive chemotherapy and are instead treated with hypomethylating agents (HMAs), which are well-tolerated and thus improved clinical outcomes are frequently assessed by combining HMAs with targeted AML therapies [ 106 ]. HMAs, including 5-Azacytidine (AZA) and Decitabine, are cytidine analogues that inhibit the DNA methyltransferase activity of DNMT1 which results in DNA hypomethylation [ 106 ]. The AGILE study, a phase 3 clinical trial, reported a significantly longer event-free survival when Ivosidenib was given in combination with AZA, relative to AZA monotherapy, in newly diagnosed IDH1-mutated AML patients that were ineligible for intensive chemotherapy induction [ 107 ].…”

Section: Therapeutic Targeting Of Idh-mutant Amlmentioning

confidence: 99%

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The curious case of IDH mutant acute myeloid leukaemia: biochemistry and therapeutic approaches

Gruber

Kats

2023

Biochemical Society Transactions

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Of the many genetic alterations that occur in cancer, relatively few have proven to be suitable for the development of targeted therapies. Mutations in isocitrate dehydrogenase (IDH) 1 and -2 increase the capacity of cancer cells to produce a normally scarce metabolite, D-2-hydroxyglutarate (2-HG), by several orders of magnitude. The discovery of the unusual biochemistry of IDH mutations spurred a flurry of activity that revealed 2-HG as an ‘oncometabolite’ with pleiotropic effects in malignant cells and consequences for anti-tumour immunity. Over the next decade, we learned that 2-HG dysregulates a wide array of molecular pathways, among them a large family of dioxygenases that utilise the closely related metabolite α-ketoglutarate (α-KG) as an essential co-substrate. 2-HG not only contributes to malignant transformation, but some cancer cells become addicted to it and sensitive to inhibitors that block its synthesis. Moreover, high 2-HG levels and loss of wild-type IDH1 or IDH2 activity gives rise to synthetic lethal vulnerabilities. Herein, we review the biology of IDH mutations with a particular focus on acute myeloid leukaemia (AML), an aggressive disease where selective targeting of IDH-mutant cells is showing significant promise.

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Section: Therapeutic Targeting Of Idh-mutant Amlmentioning

confidence: 99%

Section: Therapeutic Targeting Of Idh-mutant Amlmentioning

confidence: 99%

The curious case of IDH mutant acute myeloid leukaemia: biochemistry and therapeutic approaches

Gruber

Kats

2023

Biochemical Society Transactions

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Decitabine in older patients with AML: quality of life results of the EORTC-GIMEMA-GMDS-SG randomized phase 3 trial

Efficace,

Kicinski,

Coens

et al. 2024

Blood

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We hypothesized that fit older patients with acute myeloid leukemia (AML) treated with decitabine (DEC) would report better health-related quality of life (HRQoL) outcomes compared to those receiving intensive chemotherapy (IC). We conducted a phase 3 randomized trial to compare DEC (10-day schedule) to IC (3+7) in older fit AML patients. HRQoL was a secondary endpoint, and it was assessed with the EORTC QLQ-C30 and the QLQ-ELD14. The following scales were a priori selected for defining the primary endpoint: physical and role functioning, fatigue, pain, and burden of illness. HRQoL was assessed at baseline, at regeneration from cycle 2, and at 6 and 12 months after randomization, and also prior to allo-HSCT and 100 days after transplantation. Overall, 606 patients underwent randomization. At 2 months, the risk of HRQoL deterioration was lower in the DEC arm than in the 3+7 arm (76% [95% CI, 69 to 82] v 88% [95% CI, 82 to 93]; odds ratio, 0.43 [95% CI, 0.24 to 0.76], P=.003). No statistically significant HRQoL differences were observed between treatment arms at the long-term evaluation combining assessments at 6 and 12 months. HRQoL deteriorations between baseline and post-allo-HSCT were observed in both arms. However, these deteriorations were not clinically meaningful in patients randomized to DEC, while this was the case for those in the 3+7 arm, in four out of the five primary HRQoL scales. Our HRQoL findings suggest that lower-intensity treatment with DEC, may be preferable to current standard IC (3+7), in fit older AML patients. ClinicalTrials.gov (NCT02172872).

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Hypomethylating agent-based therapies in older adults with acute myeloid leukemia – A joint review by the Young International Society of Geriatric Oncology and European Society for Blood and Marrow Transplantation Trainee Committee

Cited by 2 publications

References 137 publications

The curious case of IDH mutant acute myeloid leukaemia: biochemistry and therapeutic approaches

The curious case of IDH mutant acute myeloid leukaemia: biochemistry and therapeutic approaches

Decitabine in older patients with AML: quality of life results of the EORTC-GIMEMA-GMDS-SG randomized phase 3 trial

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