Updates on DNA methylation modifiers in acute myeloid leukemia

Contieri, Bruna; Duarte, Bruno; Lazarini, Mariana

doi:10.1007/s00277-020-03938-2

Cited by 19 publications

(16 citation statements)

References 51 publications

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“…The bone marrow aspirate showed 30% myeloid blasts, with relapsed AML. As the patient was not eligible for intensive chemotherapy, due to the altered physical status, the therapeutic options were now chemotherapy with azacytidine (AZA) monotherapy, decitabine monotherapy or low‐dose cytarabine 21‐23 . Taking into consideration the altered physical status of the patients, azacytidine 75 mg/m 2 treatment was started for seven days.…”

Section: Clinical Scenariomentioning

confidence: 99%

Azacytidine plus olaparib for relapsed acute myeloid leukaemia, ineligible for intensive chemotherapy, diagnosed with a synchronous malignancy

Iluta

Pașca

Gafencu

et al. 2021

J Cellular Molecular Medi

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Patients with relapsed/refractory acute myeloid leukaemia (AML), ineligible for intensive chemotherapy and allogeneic stem cell transplantation, have a dismal prognosis. For such cases, hypomethylating agents are a viable alternative, but with limited success. Combination chemotherapy using a hypomethylating agent plus another drug would potentially bring forward new alternatives. In the present manuscript, we present the cell and molecular background for a clinical scenario of a 44‐year‐old patient, diagnosed with high‐grade serous ovarian carcinoma, diagnosed, and treated with a synchronous AML. Once the ovarian carcinoma relapsed, maintenance treatment with olaparib was initiated. Concomitantly, the bone marrow aspirate showed 30% myeloid blasts, consistent with a relapse of the underlying haematological disease. Azacytidine 75 mg/m2 treatment was started for seven days. The patient was administered two regimens of azacytidine monotherapy, additional to the olaparib‐based maintenance therapy. After the second treatment, the patient presented with leucocytosis and 94% myeloid blasts on the bone marrow smear. Later, the patient unfortunately died. Following this clinical scenario, we reproduced in vitro the combination chemotherapy of azacytidine plus olaparib, to accurately assess the basic mechanisms of leukaemia progression, and resistance to treatment. Combination chemotherapy with drugs that theoretically target both malignancies might potentially be of use. Still, further research, both pre‐clinical and clinical, is needed to accurately assess such cases.

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Section: Clinical Scenariomentioning

confidence: 99%

Azacytidine plus olaparib for relapsed acute myeloid leukaemia, ineligible for intensive chemotherapy, diagnosed with a synchronous malignancy

Iluta

Pașca

Gafencu

et al. 2021

J Cellular Molecular Medi

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“…Patients who are not fit to receive standard chemotherapy for AML, or high-risk MDS patients, may be treated with HMAs [96]. HMAs are generally considered effective and safe [97]. Some have already been approved, and others are currently undergoing clinical trials.…”

Section: Dnmt Inhibitorsmentioning

confidence: 99%

The DNA methylation landscape of hematological malignancies: an update

2020

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The rapid advances in high‐throughput sequencing technologies have made it more evident that epigenetic modifications orchestrate a plethora of complex biological processes. During the last decade, we have gained significant knowledge about a wide range of epigenetic changes that crucially contribute to some of the most aggressive forms of leukemia, lymphoma, and myelodysplastic syndromes. DNA methylation is a key epigenetic player in the abnormal initiation, development, and progression of these malignancies, often acting in synergy with other epigenetic alterations. It also contributes to the acquisition of drug resistance. In this review, we summarize the role of DNA methylation in hematological malignancies described in the current literature. We discuss in detail the dual role of DNA methylation in normal and aberrant hematopoiesis, as well as the involvement of this type of epigenetic change in other aspects of the disease. Finally, we present a comprehensive overview of the main clinical implications, including a discussion of the therapeutic strategies that regulate or reverse aberrant DNA methylation patterns in hematological malignancies, including their combination with (chemo)immunotherapy.

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“…Mutant IDH1 and IDH2 which found in about 20% of AML patients, could produce more oncometabolite 2-hydroxyglutarate which interferes with DNA methylation and block cell differentiation. There are already two IDH inhibitors approved, IDH1 inhibitor ivosidenib for the treatment of relapsed or refractory AML with a susceptible IDH1 mutation, and IDH2 inhibitor enasidenib for the treatment of relapsed or refractory AML with an IDH2 mutation (8).…”

Section: Epigenetic Drugs In Hematologic Malignanciesmentioning

confidence: 99%