Emerging agents and regimens for AML

(2021) 14:49 Liu J Hematol Oncol https://doi.org/10.1186/s13045-021-01062-w Open Access REVIEW Emerging agents and regimens for AML Hongtao Liu* Abstract Until recently, acute myeloid leukemia (AML) patients used to have limited treatment options, depending solely on cytarabine + anthracycline (7 + 3) intensive chemotherapy and hypomethylating agents. Allogeneic stem cell transplantation (Allo-SCT) played an important role to improve the survival of eligible AML patients in the past several decades. The exploration of the genomic and molecular landscape of AML, identification of mutations associated with the pathogenesis of AML, and the understanding of the mechanisms of resistance to treatment from excellent translational research helped to expand the treatment options of AML quickly in the past few years, resulting in noteworthy breakthroughs and FDA approvals of new therapeutic treatments in AML patients. Targeted therapies and combinations of different classes of therapeutic agents to overcome treatment resistance further expanded the treatment options and improved survival. Immunotherapy, including antibody-based treatment, inhibition of immune negative regulators, and possible CAR T cells might further expand the therapeutic armamentarium for AML. This review is intended to summarize the recent developments in the treatment of AML. Keywords: AML, Targeted therapy, Novel treatment Introduction AML is a heterogeneous disease, defined by a broad spectrum of genomic changes and molecular mutations that influence clinical outcomes and provide potential targets for drug development. The updated 2017 European LeukemiaNet (ELN) risk stratification guidelines combining cytogenetic abnormalities and genetic mutations have been widely used to predict the prognosis of AML patients [1], while others have been exploring to incorporate additional prognostic factors into ELN-2017 guidelines to improve the risk stratification models [2]. Advanced by basic and translational research, especially through large scale genomic analysis to understand the molecular landscape of AML, the development of targeted therapies, such as targeting fms-like tyrosine kinase 3 (FLT3) and isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) mutations, the treatment of AML landscape changed significantly with FDA approvals for several *Correspondence: Section of Hematology/Oncology, Department of Medicine, The University of Chicago Medical Center, 5841 S. Maryland Ave, MC 2115, Chicago, IL 60637‑1470, USA new drugs in the past several years. Even with all these improvements, primary resistance to initial treatment and disease relapse remain huge unmet need in the treatment of AML. The majority of AML patients still eventually succumb to the disease. We still have a long way to further improve the survival of the AML patients, thus many investigational drugs have been explored to target the primary and secondary treatment resistance in AML patients. This review will provide updates of the emerging therapeutic approaches for the treatment of AML, including combinations with mutation driven targeted treatments, novel immunotherapies in the myeloid disease. Targeted therapies: alone or combination BCL‑2 inhibitor: venetoclax BCL-2 is a member of the BCL-2 family of anti- and proapoptotic proteins. BCL-2 protects cells against apoptosis. BCL-2 expression in AML has been associated with decreased sensitivity to cytotoxic chemotherapy and a higher rate of relapse [3]. Venetoclax is an orally bioavailable selective inhibitor of BCL-2, promoting intrinsic apoptotic pathway activation resulting in mitochondrial © The Author(s) 2021. 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://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Liu J Hematol Oncol (2021) 14:49 Page 2 of 20 outer membrane permeability through dissociation of BCL-2 mediated sequestration of BH3 proteins BIM and BID and effector proteins BAX and BAK. Venetoclax was initially approved by U. S. Food and Drug Administration (FDA) in 2016 to treat individuals with chronic lymphocytic leukemia (CLL) with deletion (17p). Venetoclax + hypomethylating agents or low dose cytarabine Early studies using venetoclax as monotherapy in AML demonstrated only modest efficacy in high-risk relapsed/ refractory (R/R) AML patients with an overall response rate (ORR) of 38% and complete remission/complete remission with incomplete hematologic recovery (CR/ CRi) of 19%. The responses were short lived, with overall survival (OS) of only 4.7 months [4]. Based on promising results from two large Phase 1b/II trials using combination of a hypomethylating agent (HMA) or low-dose cytarabine (LDAC) with venetoclax in untreated older AML patients [5, 6], FDA granted accelerated approval to venetoclax in combination with azacitidine (AZA) or decitabine (DEC) or LDAC for the treatment of newlydiagnosed (ND) AML in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapies in 2018. Recently published Phase III randomized studies confirmed the results from these early single arm trials, and demonstrated a significant survival benefit from adding venetoclax to azacitidine and to LDAC [7, 8]. The major findings from the VIALE-A and VIALE-C trials are summarized in Table 1. In summary, the VIALE-A trial included 431 patients without history of exposure to azacitidine. At a median follow-up of 20.5 months, the median OS was 14.7 months in the azacitidine-venetoclax group and 9.6 months in the control group. The incidence of CR and composite complete remission rate (cCR) (CR + CRi) were significantly higher with azacitidine-venetoclax than with the control regimen. However, there were higher rates in key adverse events in the azacitidine-venetoclax group than those in the control group, but they were manageable [7]. The VIALE-C study assigned 211 patients to either venetoclax (n = 143) or placebo (n = 68) in 28-day cycles, plus LDAC on days 1 to 10. In contrast to VIA (...truncated)