Advances in targeted therapy for acute myeloid leukaemia.
ABSTRACT: In the past few years, research in the underlying pathogenic mechanisms of acute myeloid leukaemia (AML) has led to remarkable advances in our understanding of the disease. Cytogenetic and molecular aberrations are the most important factors in determining response to chemotherapy as well as long-term outcome, but beyond prognostication are potential therapeutic targets. Our increased understanding of the pathogenesis of AML, facilitated by next-generation sequencing, has spurred the development of new compounds in the treatment of AML, particularly the creation of small molecules that target the disease on a molecular level. Various new agents, such as tyrosine kinase inhibitors, immune checkpoint inhibitors, monoclonal or bispecific T-cell engager antibodies, metabolic and pro-apoptotic agents are currently investigated within clinical trials. The highest response rates are often achieved when new molecularly targeted therapies are combined with standard chemotherapy. Presented here is an overview of novel therapies currently being evaluated in AML.
Project description:Although acute myeloid leukaemia (AML) has long been recognized for its morphological and cytogenetic heterogeneity, recent high-resolution genomic profiling has demonstrated a complexity even greater than previously imagined. This complexity can be seen in the number and diversity of genetic alterations, epigenetic modifications, and characteristics of the leukaemic stem cells. The broad range of abnormalities across different AML subtypes suggests that improvements in clinical outcome will require the development of targeted therapies for each subtype of disease and the design of novel clinical trials to test these strategies. It is highly unlikely that further gains in long-term survival rates will be possible by mere intensification of conventional chemotherapy. In this review, we summarize recent studies that provide new insight into the genetics and biology of AML, discuss risk stratification and therapy for this disease, and profile some of the therapeutic agents currently under investigation.
Project description:Approximately two-thirds of children with acute myeloid leukemia (AML) are cured with intensive multi-agent chemotherapy. However, refractory and relapsed AML remains a significant source of childhood cancer mortality, highlighting the need for new therapies. Further therapy intensification with traditional cytotoxic chemotherapy in pediatric AML is not feasible given the risks of both short-term and long-term organ dysfunction. Substantial emphasis has been placed upon the development of molecularly targeted therapeutic approaches for adults and children with high-risk subtypes of AML with the goal of improving remission induction and minimizing relapse. Several promising agents are currently in clinical testing or late preclinical development for AML, including monoclonal antibodies against leukemia cell surface proteins, kinase inhibitors, proteasome inhibitors, epigenetic agents, and chimeric antigen receptor engineered T cell immunotherapies. Many of these therapies have been specifically tested in children with relapsed/refractory AML in Phase 1 and 2 trials with a smaller number of new agents under Phase 3 evaluation for children with de novo AML. Although successful identification and implementation of new drugs for children with AML remain a formidable challenge, enthusiasm for novel molecular therapeutic approaches is great given the potential for significant clinical benefit for children who do not have other curative options.
Project description:Acute myeloid leukaemia (AML) is a malignant disorder of the myeloid blood lineage characterized by impaired differentiation and increased proliferation of hematopoietic precursor cells. Recent technological advances have led to an improved understanding of AML biology but also uncovered the enormous cytogenetic and molecular heterogeneity of the disease. Despite this heterogeneity, AML is mostly managed by a 'one-size-fits-all' approach consisting of intensive, highly toxic induction and consolidation chemotherapy. These treatment protocols have remained largely unchanged for the past several decades and only lead to a cure in approximately 30-35% of cases. The advent of targeted therapies in chronic myeloid leukaemia and other malignancies has sparked hope to improve patient outcome in AML. However, the implementation of targeted agents in AML therapy has been unexpectedly cumbersome and remains a difficult task due to a variety of disease- and patient-specific factors. In this review, we describe current standard and investigational therapeutic strategies with a focus on targeted agents and highlight potential tools that might facilitate the development of targeted therapies for this fatal disease. The classes of agents described in this review include constitutively activated signalling pathway inhibitors, surface receptor targets, epigenetic modifiers, drugs targeting the interaction of the hematopoietic progenitor cell with the stroma and drugs that target the apoptotic machinery. The clinical context and outcome with these agents will be examined to gain insight about their optimal utilization.
Project description:The heterogeneity of acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS) has led to a multiplicity of treatments, from cytotoxic agents to signal transduction modulators, cell-cycle inhibitors and epigenetic therapies. While some have shown promising initial results, the outlook for AML patients, particularly older and relapsed patients, as well as patients whose cells exhibit certain adverse chromosomal abnormalities or mutant oncoproteins, continues to be grim. Combination chemotherapy using new agents that act at a number of different levels may provide the greatest potential for successful future therapies. A select number of new agents, approaches and combinations are reviewed here.
Project description:Acute myeloid leukaemia (AML) is a haematopoietic stem cell disorder, that is characterized by the clonal expansion of myeloid blasts and suppression of normal haematopoiesis. The 3 + 7 regimen is the backbone of standard first-line induction therapy among young/fit patients. However, in elderly and/or unfit patients with newly diagnosed AML, who cannot receive intensive chemotherapy, low-dose cytarabine or hypomethylating agents (azacitidine or decitabine) are the treatment options, which generally cannot induce durable responses. Among young/fit patients, for high-risk disease in first remission, or in cases with relapsed/refractory AML, allogeneic stem cell transplantation should be performed when complete remission is achieved. However, since AML is primarily a disease of the elderly, neither intensive chemotherapy nor allogeneic stem cell transplantation can be generally tolerated in most cases. There is clearly a need for new treatment options in elderly and young/unfit patients who cannot receive intensive chemotherapy. The discovery of novel molecular genetic markers (e.g. FMS-like tyrosine kinase 3, isocitrate dehydrogenase 1 and 2) resulted in the development of new therapeutic options in AML. This review mainly focuses on 4 targeted therapy agents; glasdegib and venetoclax used in combination treatment with low-dose cytarabine or hypomethylating agents among newly diagnosed cases with AML; and ivosidenib and gilteritinib as monotherapy in the treatment of relapsed/refractory AML, which were all approved by the US Food and Drug Administration in 2018.
Project description:Epigenetics refers to the regulation of gene expression mainly by changes in DNA methylation and modifications of histone proteins without altering the actual DNA sequence. While epigenetic modifications are essential for normal cell differentiation, several driver mutations in leukemic pathogenesis have been identified in genes that affect epigenetic processes, such as DNA methylation and histone acetylation. Several therapeutic options to target epigenetic alterations in acute myeloid leukemia (AML) have been successfully tested in preclinical studies and various drugs have already been approved for use in clinical practice. Among these already approved therapeutics are hypomethylating agents (azacitidine and decitabine) and isocitrate dehydrogenase inhibitors (ivosidenib, enasidenib). Other agents such as bromodomain-containing epigenetic reader proteins and histone methylation (e.g. DOT1L) inhibitors are currently in advanced clinical testing. As several epigenetic therapies have only limited efficacy when used as single agents, combination therapies that target AML pathogenesis at different levels and exploit synergistic mechanisms are also in clinical trials. Combinations of either epigenetic therapies with conventional chemotherapy, different forms of epigenetic therapies, or epigenetic therapies with immunotherapy are showing promising early results. In this review we summarize the underlying pathophysiology and rationale for epigenetically-based combination therapies, review current preclinical and clinical data and discuss the future directions of epigenetic therapy combinations in AML.
Project description:The prognosis of adult acute myeloid leukemia (AML) remains poor, with the long-term survival rate less than 50%. However, the current paradigms of treatment are changing through a better understanding of the disease genetics and pathophysiology. Since 2017, eight new drugs have been approved by the U.S. Food and Drug Administration for the treatment of AML, including the FLT3 inhibitors midostaurin and gilteritinib, the IDH inhibitors ivosidenib and enasidenib, the anti-CD33 monoclonal antibody gemtuzumab ozogamicin, liposomal daunorubicin and cytarabine, the hedgehog pathway inhibitor glasdegib and the BCL-2 inhibitor venetoclax. Preclinical data demonstrated the anti-leukemic efficacy of venetoclax in AML and its synergy when combined with hypomethylating agents or chemotherapy agents. Clinical trials have demonstrated the clinical benefit of venetoclax-based therapies in newly diagnosed AML, leading to the recent FDA approval of venetoclax in combination with hypomethylating agents or low-dose cytarabine for older adults with newly diagnosed AML. Herein, we focus on the role of single-agent BCL-2 inhibition in AML and review the clinical studies of venetoclax-based combination regimens and the evolving mechanisms of resistance.
Project description:Acute myeloid leukemia (AML) is a complex hematological disease characterized by genetic and clinical heterogeneity. Recent advances in the understanding of AML pathogenesis have paved the way for the development of new agents targeting specific molecules or mechanisms that contribute to finally move beyond the current standard of care, which is "3 + 7" regimen. In particular, new therapeutic options such as targeted therapies (midostaurin and enasidenib), monoclonal antibodies (gemtuzumab ozogamicin), and a novel liposomal formulation of cytarabine and daunorubicin (CPX-351) have been recently approved, and will be soon available for the treatment of adult patients with AML. In this review, we will present and describe these recently approved drugs as well as selected novel agents against AML that are currently under investigation, and show the most promising results as monotherapy or in combination with chemotherapy. The selection of these emerging treatments is based on the authors' opinion.
Project description:Acute myeloid leukemia (AML) is a debilitating and life-threatening condition, especially for elderly patients who account for over 50% of diagnoses. For over four decades, standard induction therapy with intensive cytotoxic chemotherapy for AML had remained unchanged. However, for most patients, standard therapy continues to have its shortcomings, especially for elderly patients who may not be able to tolerate the complications from intensive cytotoxic chemotherapy. New research into the development of targeted and alternative therapies has led to a new era in AML therapy. For the nearly 20% of diagnoses harboring a mutation in isocitrate dehydrogenase 1 or 2 (IDH1/2), potential treatment options have undergone a paradigm shift away from intensive cytotoxic chemotherapy and towards targeted therapy alone or in combination with lower intensity chemotherapy. The first FDA approved IDH2 inhibitor was enasidenib in 2017. In addition, IDH1 inhibitors are in ongoing clinical studies, and the oral BCL-2 inhibitor venetoclax shows preliminary efficacy in this subset of patients. These new tools aim to improve outcomes and change the treatment paradigm for elderly patients with IDH mutant AML. However, the challenge of how to best incorporate these agents into standard practice remains.
Project description:Acute myeloid leukemia (AML) in patients over the age of 60 carries a poor prognosis, mainly due to unsatisfactory control of leukemia with chemotherapy alone. Allogeneic hemopoietic stem cell transplantation (HSCT) would provide significant anti-leukemic effect but is associated with morbidity and mortality, especially in older patients with comorbidities. Reduced-intensity conditioning (RIC) and non-myeloablative (NMA) conditioning regimens have been designed and have led to improved outcomes in this older patient population. New targeted agents, such as Flt3 inhibitors, are currently being used to improve the control of AML further and may be incorporated in a transplant approach. The increasing knowledge of AML in the elderly is currently being associated with a multidimensional approach to identify eligibility and design tailored transplant platforms.