Hypomethylating Agent-Based Combination Therapies to Treat Post-Hematopoietic Stem Cell Transplant Relapse of Acute Myeloid Leukemia

Ciotti, Giulia; Marconi, Giovanni; Martinelli, Giovanni

doi:10.3389/fonc.2021.810387

Cited by 12 publications

(14 citation statements)

References 91 publications

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“…However, relapse remains the primary cause of mortality in patients receiving allo-HSCT for MDS or AML ( 3 , 4 ). Epigenetic agents, mainly including hypomethylating agents (HMAs) and histone deacetylase inhibitors (HDACi), have become widely used in the pretransplant, transplant, and posttransplant stages for MDS or AML ( 5 – 9 ) and are regarded as candidates to reduce the tumor burden, as they have tolerable toxicity and mitigate graft-versus-host disease (GvHD) without influencing graft versus leukemia (GvL) ( 9 , 10 ). Furthermore, HMAs have been proven effective in exerting an antitumor effect by promoting cell differentiation and apoptosis in leukemia cells ( 11 , 12 ) and by reactivating silent tumor suppressor antigens like MAGE-1 and WT-1 to improve the response to other therapeutic hematologic malignancies ( 10 , 13 , 14 ).…”

Section: Introductionmentioning

confidence: 99%

Generalist in allogeneic hematopoietic stem cell transplantation for MDS or AML: Epigenetic therapy

et al. 2022

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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative treatment for patients with myeloid malignancies such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). However, relapse and graft-versus-host disease (GvHD) still affect the survival of patients who receive allo-HSCT, and more appropriate therapeutic strategies should be applied at all stages of transplantation to prevent these adverse events. The use of epigenetics agents, such as hypomethylating agents (HMAs), has been explored to decrease the risk of relapse by epigenetic modulation, which is especially effective among AML patients with poor mutations in epigenetic regulators. Furthermore, epigenetic agents have also been regarded as prophylactic methods for GvHD management without abrogating graft versus leukemia (GvL) effects. Therefore, the combination of epigenetic therapy and HSCT may optimize the transplantation process and prevent treatment failure. Existing studies have investigated the feasibility and effectiveness of using HMAs in the pretransplant, transplant and posttransplant stages among MDS and AML patients. This review examines the application of HMAs as a bridge treatment to reduce the tumor burden and the determine appropriate dose during allo-HSCT. Within this review, we also examine the efficacy and safety of HMAs alone or HMA-based strategies in posttransplant settings for MDS and AML. Finally, we provide an overview of other epigenetic candidates, which have been discussed in the nontransplant setting.

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Section: Introductionmentioning

confidence: 99%

Generalist in allogeneic hematopoietic stem cell transplantation for MDS or AML: Epigenetic therapy

et al. 2022

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“…This mechanism may crucially contribute to the development of drug resistance [ 94 ]. In summary, their immunomodulatory properties make them an interesting backbone for combination therapies [ 95 ]. Especially since combination therapies might comprise the possibility to bypass drug resistance mechanisms.…”

Section: Immunomodulation In Amlmentioning

confidence: 99%

“…Combination trials of ivosidenib or enasidenib with AZA in relapsed or refractory AML (NCT03683433) as well as in first-line therapy of IDH mut AML with enasidenib (AML005-trial) or ivosidenib (AGIL-trial) in combination with AZA (NCT02677922) are currently ongoing [ 97 , 98 ]. Even in the posttransplant setting several studies showed the benefit of the combination of DLIs and AZA, further randomized trials are, up to date, still lacking [ 95 ]. Additionally, the therapy with DLIs and AZA can be enhanced with venetoclax in the posttransplant setting [ 95 ].…”

Section: Immunomodulation In Amlmentioning

confidence: 99%

“…Even in the posttransplant setting several studies showed the benefit of the combination of DLIs and AZA, further randomized trials are, up to date, still lacking [ 95 ]. Additionally, the therapy with DLIs and AZA can be enhanced with venetoclax in the posttransplant setting [ 95 ]. Another combination partner with HMAs in the posttransplant setting is lenalidomide [ 95 ].…”

Section: Immunomodulation In Amlmentioning

confidence: 99%

“…Additionally, the therapy with DLIs and AZA can be enhanced with venetoclax in the posttransplant setting [ 95 ]. Another combination partner with HMAs in the posttransplant setting is lenalidomide [ 95 ]. While lenalidomide as a single agent caused high rates of GvHD, there were acceptable side effects and good response rates when combined with HMAs [ 95 ].…”

Section: Immunomodulation In Amlmentioning

confidence: 99%

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Increasing Role of Targeted Immunotherapies in the Treatment of AML

Greiner

Götz

Wais

2022

IJMS

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Acute myeloid leukemia (AML) is the most common acute leukemia in adults. The standard of care in medically and physically fit patients is intensive induction therapy. The majority of these intensively treated patients achieve a complete remission. However, a high number of these patients will experience relapse. In patients older than 60 years, the results are even worse. Therefore, new therapeutic approaches are desperately needed. One promising approach in high-risk leukemia to prevent relapse is the induction of the immune system simultaneously or after reduction of the initial tumor burden. Different immunotherapeutic approaches such as allogenic stem cell transplantation or donor lymphocyte infusions are already standard therapies, but other options for AML treatment are in the pipeline. Moreover, the therapeutic landscape in AML is rapidly changing, and in the last years, a number of immunogenic targets structures eligible for specific therapy, risk assessment or evaluation of disease course were determined. For example, leukemia-associated antigens (LAA) showed to be critical as biomarkers of disease state and survival, as well as markers of minimal residual disease (MRD). Yet many mechanisms and properties are still insufficiently understood, which also represents a great potential for this form of therapy. Therefore, targeted therapy as immunotherapy could turn into an efficient tool to clear residual disease, improve the outcome of AML patients and reduce the relapse risk. In this review, established but also emerging immunotherapeutic approaches for AML patients will be discussed.

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AVALON: The Italian cohort study on real‐life efficacy of hypomethylating agents plus venetoclax in newly diagnosed or relapsed/refractory patients with acute myeloid leukemia

Todisco

Papayannidis

Fracchiolla

et al. 2023

Cancer

Self Cite

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Background: Venetoclax in combination with hypomethylating agents (HMA) is revolutionizing the therapy of acute myeloid leukemia (AML). However, evidence on large sets of patients is lacking, especially in relapsed or refractory leukemia. Methods:AVALON is a multicentric cohort study that was conducted in Italy on patients with AML who received venetoclax-based therapies from 2015 to 2020.The study was approved by the ethics committee of the participating institution and was conducted in accordance with the Declaration of Helsinki. The effectiveness and toxicity of venetoclax + HMA in 190 (43 newly diagnosed, 68 refractory, and 79 relapsed) patients with AML are reported here. Results:In the newly diagnosed AML, the overall response rate and survival confirmed the brilliant results demonstrated in VIALE-A. In the relapsed or refractory AML, the combination demonstrated a surprisingly complete remission rate (44.1% in refractory and 39.7% in relapsed evaluable patients) and conferred to treated patients a good expectation of survival. Toxicities were overall manageable, and most incidents occurred in the first 60 days of therapy. Infections were confirmed as the most common nonhematologic adverse event.Conclusions: Real-life data show that the combination of venetoclax and HMA offers an expectation of remission and long-term survival to elderly, newly diagnosed patients, and to relapsed or chemoresistant AML, increasing the chance of cure through a TODISCO ET AL.-993 different mechanism of action. The venetoclax + HMA combination is expected to constitute the base for triplet combinations and integration of target therapies. Our data contribute to ameliorate the understanding of venetoclax + HMA effectiveness and toxicities in real life.

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Hypomethylating Agent-Based Combination Therapies to Treat Post-Hematopoietic Stem Cell Transplant Relapse of Acute Myeloid Leukemia

Cited by 12 publications

References 91 publications

Generalist in allogeneic hematopoietic stem cell transplantation for MDS or AML: Epigenetic therapy

Generalist in allogeneic hematopoietic stem cell transplantation for MDS or AML: Epigenetic therapy

Increasing Role of Targeted Immunotherapies in the Treatment of AML

AVALON: The Italian cohort study on real‐life efficacy of hypomethylating agents plus venetoclax in newly diagnosed or relapsed/refractory patients with acute myeloid leukemia

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