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      Decitabine as epigenetic priming with CLAG induce improved outcome of relapsed or refractory acute myeloid leukemia in children

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          Abstract

          Background

          Decitabine (DAC), a DNA methyltransferase inhibitor, has shown efficacy combined with chemotherapy for relapsed or refractory (R/R) acute myeloid leukemia (AML) in adults, but less is known about its efficacy in children. Accordingly, we conducted a study which involved a priming regimen consisting of DAC with cladribine, cytarabine, and granulocyte-stimulating factor (DAC-CLAG) and compared the efficacy and safety of this regimen with CLAG alone.

          Methods

          A total of 39 R/R AML children who received the CLAG or DAC-CLAG regimen in Shanghai Children’s Hospital were retrospectively enrolled in this non-randomized study. These regimens were studied sequentially over time. Twenty-two patients received CLAG from 2015, while 17 patients were administered epigenetic priming with DAC before CLAG from 2020. Patients were subsequently bridged to stem cell transplantation (SCT) or consolidation chemotherapy. Complete remission (CR) and adverse effects were analyzed by Fisher’s exact test, and survival was analyzed by the Kaplan–Meier method.

          Results

          DAC-CLAG conferred a numerically higher CR compared to CLAG (70.59% vs 63.64%; P = 0.740). High CR rates occurred in patients with good cytogenetics ( P = 0.029) and prior induction without cladribine ( P = 0.099). The 1-year event-free survival (EFS) was 64.71% ± 11.59% and 63.31% ± 10.35% in the DAC-CLAG and CLAG group ( P = 0.595), and 1-year overall survival (OS) was 81.45% ± 9.72% and 77.01% ± 9.04%, respectively ( P = 0.265). The 1-year OS and EFS after SCT were higher in the DAC-CLAG than in the CLAG cohort (100% vs 92.31% ± 7.39%, P = 0.072; 92.31% ± 7.39% vs 85.71% ± 9.35%, P = 0.158). Univariate analysis revealed that a good prognosis included good cytogenetics ( P = 0.002), non-complex karyotype ( P = 0.056), CR on reinduction ( P < 0.0001), and bridging to SCT ( P = 0.0007). Use of a hypomethylating agent ( P = 0.049) and bridging to SCT ( P = 0.011) were independent prognostic factors. Grade 3/4 hematologic toxicity and infection were the main adverse events.

          Conclusions

          DAC prior to the CLAG regimen improved remission in pediatric R/R AML, and was feasible and well tolerated. CLAG ± DAC as a salvage therapy prior to SCT induced improved survival.

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s13148-024-01677-z.

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          Most cited references35

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          Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel.

          Hartmut Döhner, Elihu Estey, David Grimwade … (2017)
          The first edition of the European LeukemiaNet (ELN) recommendations for diagnosis and management of acute myeloid leukemia (AML) in adults, published in 2010, has found broad acceptance by physicians and investigators caring for patients with AML. Recent advances, for example, in the discovery of the genomic landscape of the disease, in the development of assays for genetic testing and for detecting minimal residual disease (MRD), as well as in the development of novel antileukemic agents, prompted an international panel to provide updated evidence- and expert opinion-based recommendations. The recommendations include a revised version of the ELN genetic categories, a proposal for a response category based on MRD status, and criteria for progressive disease.
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            A Comparison of Azacitidine and Decitabine Activities in Acute Myeloid Leukemia Cell Lines

            Paul W Hollenbach, Aaron Nguyen, Helen Brady … (2010)
            Background The cytidine nucleoside analogs azacitidine (AZA) and decitabine (DAC) are used for the treatment of patients with myelodysplastic syndromes and acute myeloid leukemia (AML). Few non-clinical studies have directly compared the mechanisms of action of these agents in a head-to-head fashion, and the agents are often viewed as mechanistically similar DNA hypomethylating agents. To better understand the similarities and differences in mechanisms of these drugs, we compared their in vitro effects on several end points in human AML cell lines. Methodology/Principal Findings Both drugs effected DNA methyltransferase 1 depletion, DNA hypomethylation, and DNA damage induction, with DAC showing equivalent activity at concentrations 2- to 10-fold lower than AZA. At concentrations above 1 µM, AZA had a greater effect than DAC on reducing cell viability. Both drugs increased the sub-G1 fraction and apoptosis markers, with AZA decreasing all cell cycle phases and DAC causing an increase in G2-M. Total protein synthesis was reduced only by AZA, and drug-modulated gene expression profiles were largely non-overlapping. Conclusions/Significance These data demonstrate shared mechanisms of action of AZA and DAC on DNA-mediated markers of activity, but distinctly different effects in their actions on cell viability, protein synthesis, cell cycle, and gene expression. The differential effects of AZA may be mediated by RNA incorporation, as the distribution of AZA in nucleic acid of KG-1a cells was 65∶35, RNA∶DNA.
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              Treatment, risk factors, and outcome of adults with relapsed AML after reduced intensity conditioning for allogeneic stem cell transplantation.

              Vanderson Rocha, Emmanuelle Polge, Jürgen Kuball … (2012)
              Because information on management and outcome of AML relapse after allogeneic hematopoietic stem cell transplantation (HSCT) with reduced intensity conditioning (RIC) is scarce, a retrospective registry study was performed by the Acute Leukemia Working Party of EBMT. Among 2815 RIC transplants performed for AML in complete remission (CR) between 1999 and 2008, cumulative incidence of relapse was 32% ± 1%. Relapsed patients (263) were included into a detailed analysis of risk factors for overall survival (OS) and building of a prognostic score. CR was reinduced in 32%; remission duration after transplantation was the only prognostic factor for response (P = .003). Estimated 2-year OS from relapse was 14%, thereby resembling results of AML relapse after standard conditioning. Among variables available at the time of relapse, remission after HSCT > 5 months (hazard ratio [HR] = 0.50, 95% confidence interval [CI], 0.37-0.67, P < .001), bone marrow blasts less than 27% (HR = 0.53, 95% CI, 0.40-0.72, P < .001), and absence of acute GVHD after HSCT (HR = 0.67, 95% CI, 0.49-0.93, P = .017) were associated with better OS. Based on these factors, 3 prognostic groups could be discriminated, showing OS of 32% ± 7%, 19% ± 4%, and 4% ± 2% at 2 years (P < .0001). Long-term survival was achieved almost exclusively after successful induction of CR by cytoreductive therapy, followed either by donor lymphocyte infusion or second HSCT for consolidation.
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                Author and article information

                Contributors
                Hui Jiang: jhui0111@126.com
                Jing-Bo Shao: shaojb@shchildren.com.cn
                Cheng Cai: caicheng2004@163.com
                Journal
                Journal ID (nlm-ta): Clin Epigenetics
                Journal ID (iso-abbrev): Clin Epigenetics
                Title: Clinical Epigenetics
                Publisher: BioMed Central (London )
                ISSN (Print): 1868-7075
                ISSN (Electronic): 1868-7083
                Publication date (Electronic): 9 May 2024
                Publication date PMC-release: 9 May 2024
                Publication date Collection: 2024
                Volume: 16
                Electronic Location Identifier: 63
                Affiliations
                [1 ]GRID grid.16821.3c, ISNI 0000 0004 0368 8293, Department of Hematology and Oncology, Shanghai Children’s Hospital, School of Medicine, , Shanghai Jiao Tong University, ; No. 1400, West Beijing Road, Shanghai, 200040 China
                [2 ]GRID grid.16821.3c, ISNI 0000 0004 0368 8293, Department of Neonatology, Shanghai Children’s Hospital, School of Medicine, , Shanghai Jiao Tong University, ; No. 355, Luding Road, Shanghai, 200062 China
                Author information
                https://orcid.org/0000-0002-1962-0897
                Article
                Publisher ID: 1677
                DOI: 10.1186/s13148-024-01677-z
                PMC ID: 11080195
                PubMed ID: 38725010
                SO-VID: 1f2f3cac-5915-45cc-a645-d4c4b2f6feeb
                Copyright © © The Author(s) 2024
                License:

                Open Access This 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 : 27 February 2024
                Date accepted : 1 May 2024
                Funding
                Funded by: Shanghai Children’s Hospital
                Award ID: No. 2020YLYM09
                Award Recipient :
                Categories
                Subject: Research
                Custom metadata
                issue-copyright-statement © BioMed Central Ltd., part of Springer Nature 2024

                ScienceOpen disciplines: Genetics
                Keywords: acute myeloid leukemia,children,cladribine,decitabine,refractory,relapsed
                Data availability:
                ScienceOpen disciplines: Genetics
                Keywords: acute myeloid leukemia, children, cladribine, decitabine, refractory, relapsed

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