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      Venetoclax-Azacitidine Bridging PTCy-haplo-PBSCT for Refractory Acute Myeloid Leukemia with IDH2 Mutations

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          Abstract

          Venetoclax and azacitidine combination therapy (VEN+AZA) is a promising novel therapy for elderly or unfit patients with acute myeloid leukemia (AML). Recently, VEN+AZA with subsequent allo-hematopoietic stem cell transplantation has been reported, and human leukocyte antigen-haploidentical peripheral blood stem cell transplantation using posttransplant cyclophosphamide (PTCy-haplo-PBSCT) from related donors appears to be a suitable option. Here, we report two elderly patients with refractory AML harboring an IDH2 mutation, who were successfully treated with VEN+AZA bridged to PTCy-haplo-PBSCT. This report suggests the efficacy and safety of VEN+AZA as a bridging treatment for PTCy-haplo-PBSCT in refractory AML.

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          Most cited references11

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

          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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            Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia

            Older patients with acute myeloid leukemia (AML) have a dismal prognosis, even after treatment with a hypomethylating agent. Azacitidine added to venetoclax had promising efficacy in a previous phase 1b study.
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              Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML

              The BCL-2 inhibitor venetoclax combined with hypomethylating agents or low-dose cytarabine represents an important new therapy for older or unfit patients with acute myeloid leukemia (AML). We analyzed 81 patients receiving these venetoclax-based combinations to identify molecular correlates of durable remission, response followed by relapse (adaptive resistance), or refractory disease (primary resistance). High response rates and durable remissions were typically associated with NPM1 or IDH2 mutations, with prolonged molecular remissions prevalent for NPM1 mutations. Primary and adaptive resistance to venetoclax-based combinations was most commonly characterized by acquisition or enrichment of clones activating signaling pathways such as FLT3 or RAS or biallelically perturbing TP53. Single-cell studies highlighted the polyclonal nature of intratumoral resistance mechanisms in some cases. Among cases that were primary refractory, we identified heterogeneous and sometimes divergent interval changes in leukemic clones within a single cycle of therapy, highlighting the dynamic and rapid occurrence of therapeutic selection in AML. In functional studies, FLT3 internal tandem duplication gain or TP53 loss conferred cross-resistance to both venetoclax and cytotoxic-based therapies. Collectively, we highlight molecular determinants of outcome with clinical relevance to patients with AML receiving venetoclax-based combination therapies.
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                Author and article information

                Journal
                Case Rep Oncol
                Case Rep Oncol
                CRO
                CRO
                Case Reports in Oncology
                S. Karger AG (Basel, Switzerland )
                1662-6575
                22 September 2023
                Jan-Dec 2023
                22 September 2023
                : 16
                : 1
                : 999-1006
                Affiliations
                [a ]Department of Hematology, Chugoku Central Hospital of Japan Mutual Aid Association of Public School Teachers, Hiroshima, Japan
                [b ]Division of Hematopoietic Disease Control, Advanced Clinical Research Center, Department of Hematology/Oncology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
                [c ]Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan
                Author notes
                Correspondence to: Hiroyuki Sugiura, hiroyuki.sugiura0715@ 123456gmail.com
                Article
                533749
                10.1159/000533749
                10601807
                37900854
                81bc1ca7-eab4-4446-911b-20d585e986f3
                © 2023 The Author(s). Published by S. Karger AG, Basel

                This article is licensed under the Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC) ( http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.

                History
                : 15 June 2023
                : 3 August 2023
                : 2023
                Page count
                Figures: 2, Tables: 2, References: 11, Pages: 8
                Funding
                No funding was received for this study.
                Categories
                Case Report

                Oncology & Radiotherapy
                acute myeloid leukemia,venetoclax-azacitidine,ptcy-haplo-pbsct, idh2 mutation

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