Browse
Submit Data
Databases
API
Help

Dataset Information

28 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Personalizing initial therapy in acute myeloid leukemia: incorporating novel agents into clinical practice.

ABSTRACT: While the past decade has seen a revolution in understanding of the genetic and molecular etiology of the disease, in clinical practice, initial therapy for acute myeloid leukemia (AML) patients has been a relatively straightforward choice between intensive combination cytotoxic induction therapy as used for decades or less-intensive hypomethylating therapy. The year 2017, however, witnessed US Food and Drug Administration approvals of midostaurin, enasidenib, gemtuzumab ozogamicin and CPX-351 for AML patients, with many other promising agents currently in clinical trials. This review discusses these options, highlights unanswered questions regarding optimal combinations and proposes some suggested approaches for the personalization of initial therapy for AML patients.

SUBMITTER: DeStefano CB

PROVIDER: S-EPMC5900827 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Personalizing initial therapy in acute myeloid leukemia: incorporating novel agents into clinical practice.

DeStefano Christin B CB Hourigan Christopher S CS

Therapeutic advances in hematology 20180327 5

While the past decade has seen a revolution in understanding of the genetic and molecular etiology of the disease, in clinical practice, initial therapy for acute myeloid leukemia (AML) patients has been a relatively straightforward choice between intensive combination cytotoxic induction therapy as used for decades or less-intensive hypomethylating therapy. The year 2017, however, witnessed US Food and Drug Administration approvals of midostaurin, enasidenib, gemtuzumab ozogamicin and CPX-351 f ...[more]

PMID: 29713444

Similar Datasets

Personalizing therapy for older adults with acute myeloid leukemia: Role of geriatric assessment and genetic profiling.

Project description:Acute myeloid leukemia (AML) presents therapeutic challenges in older adults because of high-risk leukemia biology conferring chemoresistance, and poor functional status resulting in increased therapy-related toxicities. Recent FDA approval of 8 new drugs for AML has increased therapeutic armamentarium and also provides effective low-intensity treatment options. Rational therapy selection strategies that consider individual's risk of therapy-related toxicities and probability of disease control can maximize benefits of available treatments. Studies have demonstrated that fitness level, measured by geriatric assessment can predict therapy-related toxicities, whereas cytogenetic and mutation results correlate with the probability of responses to standard chemotherapy. We are approaching an era when we move from "one size fits all" approach to personalized therapy selection based on geriatric assessment, genetic and molecular profiling.

| S-EPMC6481658 | biostudies-literature

Novel Agents for Acute Myeloid Leukemia.

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.

| S-EPMC6267447 | biostudies-literature

New agents in acute myeloid leukemia (AML).

Project description:Despite expanding knowledge in the molecular landscape of acute myeloid leukemia (AML) and an increasing understanding of leukemogenic pathways, little has changed in the treatment of AML in the last 40 years. Since introduction in the 1970s, combination chemotherapy consisting of anthracycline and cytarabine has been the mainstay of treatment, with major therapeutic advances based on improving supportive care rather than the introduction of novel therapeutics. Over the last decades, there have been extensive efforts to identify specific target mutations or pathways with the aim of improving clinical outcomes. Finally, after a prolonged wait, we are witnessing the next wave of AML treatment, characterized by a more "precise" and "personalized" understanding of the unique molecular or genetic mapping of individual patients. This new trend has since been further facilitated, with four new FDA approvals granted in 2017 in AML therapeutics. Currently, a total of eight targeted agents have been approved since 2017 (as of Jan. 2020). In this review, we will briefly discuss these newer agents in the context of their indication and the basis of their approval.

| S-EPMC7386889 | biostudies-literature

Hypomethylating Chemotherapeutic Agents as Therapy for Myelodysplastic Syndromes and Prevention of Acute Myeloid Leukemia.

Project description:Myelodysplastic Syndromes (MDSs) affect the elderly and can progress to Acute Myeloid Leukemia (AML). Epigenetic alterations including DNA methylation and chromatin modification may contribute to the initiation and progression of these malignancies. DNA hypomethylating agents such as decitabine and azacitidine are used as therapeutic treatments and have shown to promote expression of genes involved in tumor suppression, apoptosis, and immune response. Another anti-cancer drug, the proteasome inhibitor bortezomib, is used as a chemotherapeutic treatment for multiple myeloma (MM). Phase III clinical trials of decitabine and azacitidine used alone and in combination with other chemotherapeutics demonstrated their capacity to treat hematological malignancies and prolong the survival of MDS and AML patients. Although phase III clinical trials examining bortezomib's role in MDS and AML patients are limited, its underlying mechanisms in MM highlight its potential as a chemotherapeutic for such malignancies. Further research is needed to better understand how the epigenetic mechanisms mediated by these chemotherapeutic agents and their targeted gene networks are associated with the development and progression of MDS into AML. This review discusses the mechanisms by which decitabine, azacitidine, and bortezomib alter epigenetic programs and their results from phase III clinical trials.

| S-EPMC8308509 | biostudies-literature

Precision therapy for acute myeloid leukemia.

Project description:Acute myeloid leukemia (AML) is a molecularly and clinically heterogeneous disease. Despite advances in understanding the pathogenesis of AML, the standard therapy remained nearly unchanged over the past three decades. With the poor survival for older patients and high relapse rate, multiple studies are ongoing to address this important issue. Novel therapies for AML, including the refinements of conventional cytotoxic chemotherapies and genetic and epigenetic targeted drugs, as well as immunotherapies, have been developed in recent years. Here, we present a mechanism-based review of some promising new drugs with clinical efficacy, focus on targeted drugs that are most potential to pave the road to success, and put forward the major challenges in promoting the precision therapy for AML.

| S-EPMC5755341 | biostudies-literature

Pre-clinical evaluation of Minnelide as a therapy for acute myeloid leukemia.

Project description:BackgroundThere is an urgent need for novel and effective treatment options for acute myeloid leukemia (AML). Triptolide, a diterpenoid tri-epoxide compound isolated from the herb Tripterygium wilfordii and its water-soluble pro-drug-Minnelide have shown promising anti-cancer activity. A recent clinical trial for patients with solid tumors confirmed the safety and efficacy at biologically equivalent doses of 0.2 mg/kg/day and lower.MethodsCell viability of multiple AML cell lines as well as patient apheresis samples were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) based assay. Apoptosis was evaluated by estimating the amount of cleaved caspase. AML cell line (THP1-Luc) was implanted in immunocompromised mice and treated with indicated doses of Minnelide. Leukemic burden before and after treatment was evaluated by imaging in an In Vivo Imaging System (IVIS).ResultsIn the current study, we show that Minnelide, at doses below maximum tolerated dose (MTD) demonstrates leukemic clearance of both primary AML blasts and luciferase expressing THP-1 cells in mice. In vitro, multiple primary AML apheresis samples and AML cell lines (THP-1, KG1, Kasumi-1, HL-60) were sensitive to triptolide mediated cell death and apoptosis in low doses. Treatment with triptolide led to a significant decrease in the colony forming ability of AML cell lines as well as in the expression of stem cell markers. Additionally, it resulted in the cell cycle arrest in the G1/S phase with significant downregulation of c-Myc, a major transcriptional regulator mediating cancer cell growth and stemness.ConclusionOur results suggest that Minnelide, with confirmed safety and activity in the clinic, exerts a potent anti-leukemic effect in multiple models of AML at doses easily achievable in patients.

| S-EPMC6528210 | biostudies-literature

Targeting CD33 for acute myeloid leukemia therapy.

Project description:BackgroundThe aim of this study was to analyze the level of CD33 expression in patients with newly diagnosed AML and determine its correlation with clinical characteristics.MethodsSamples were collected for analysis from AML patients at diagnosis. We evaluated the level of CD33 expression by flow cytometry analysis of bone marrow. Chi-square or t- tests were used to assess the association between the high and low CD33 expression groups. Survival curves were generated by the Kaplan-Meier and Cox regression model method.ResultsIn this study we evaluated the level of CD33 expression in de novo patients diagnosed from November 2013 until January 2019. The mean value of 73.4% was used as the cutoff for the two groups. Statistical analysis revealed that 53 of the 86 (61.2%) AML patients were above the mean. Although there was no statistical significance between CD33 expression level and gene mutation, FLT3 mutation (P = 0.002) and NPM1 mutation (P = 0.001) were more likely to be seen in the high CD33 group. The overall survival (OS) was worse in the high CD33 group (39.0 m vs. 16.7 m, x2 = 13.06, P < 0.001). The Cox survival regression display that the CD33 is independent prognostic marker (HR =0.233,p = 0.008). Univariate analysis showed that the high expression of CD33 was an unfavorable prognostic factor. Of the 86 patients, CD33-high was closely related to the patients with normal karyotype (x2 = 4.891,P = 0.027), high white blood cell count (WBC, t = 2.804, P = 0.007), and a high ratio of primitive cells (t = 2.851, P = 0.005).ConclusionsThese findings provide a strong rationale for targeting CD33 in combination with chemotherapy, which can be considered a promising therapeutic strategy for AML.

| S-EPMC8722076 | biostudies-literature

New agents in acute myeloid leukemia: beyond cytarabine and anthracyclines.

Project description:The standard therapeutic approaches for acute myeloid leukemia (AML) continue to be based on anthracyclines and cytarabine. However, the prognosis for AML remains poor, especially for patients with high-risk disease. During the past decade, promising novel agents that target DNA replication and repair, as well as cell cycling and apoptosis, have been developed and are being actively investigated in AML. Among these agents is flavopiridol, which interferes with key steps of the cell cycle and effectively promotes cell death, and voreloxin, an intercalating agent that also targets topoisomerase II. Also under clinical study in AML are oligonucleotide antisense constructs, which suppress the translation of proteins essential for leukemic blast survival and proliferation, and agents that target antiapoptotic cascades. In summary, it is hoped that novel therapies such as these will augment and/or supplant our current cytarabine- and anthracycline-based approaches, overcome active drug-resistance pathways, and eventually improve outcomes for patients with AML.

| S-EPMC3066101 | biostudies-literature

Immune therapy: a new therapy for acute myeloid leukemia.

Project description:Although complete remission could be achieved in about 60%-70% of acute myeloid leukemia (AML) patients after conventional chemotherapy, relapse and the state of being refractory to treatment remain the main cause of death. In addition, there is a great need for less intensive regimens for all medically frail patients (both due to age/comorbidity and treatment-related). Immune therapy anticipates improved prognosis and reduced toxicities, which may offer novel therapeutic rationales. However, one of the major difficulties in developing immune therapies against AML is that the target antigens are also significantly expressed on healthy hematopoietic stem cells; B-cell malignancies are different because CD20/CD19/healthy B-cells are readily replaceable. Only the anti-CD33 antibody-drug conjugate gemtuzumab-ozogamicin is approved by the FDA for AML. Thus, drug development remains extremely active, although it is still in its infancy. This review summarizes the clinical results of immune therapeutic agents for AML, such as antibody-based drugs, chimeric antigen receptor therapy, checkpoint inhibitors, and vaccines.

| S-EPMC9891447 | biostudies-literature

Evaluation of reporting quality in clinical practice guidelines for acute myeloid leukemia using the RIGHT checklist.

Project description:BackgroundAcute myeloid leukemia (AML) is an aggressive hematologic malignancy. Clinical practice guidelines (CPGs) on the management of AML have great value in clinical practice. However, the reporting quality of CPGs for AML has not yet been evaluated. This is the first study aiming to evaluate the reporting quality of the most recent AML CPGs published worldwide using the Reporting Items for Practice Guidelines in Healthcare (RIGHT) checklist.MethodsWe systematically searched PubMed, Chinese National Knowledge Infrastructure (CNKI), Wanfang, and Chinese Biomedical Literature (CBM) to extract CPGs for AML published between January 2016 and December 2020. Websites for guideline development organizations and medical associations were also searched. Two independent researchers assessed compliance of the guidelines to each of the 35 checklist items and summarized reporting rates for the 7 domains of the RIGHT checklist.ResultsWe identified 16 guidelines, of which 3 (18.8%) were written in Chinese and 13 (81.3%) were written in English. The average overall reporting rate of the 16 guidelines was 52.9%, and only 7 CPGs (43.8%) had a reporting rate >50%. The average reporting rates of the 7 domains (basic information; background; evidence; recommendations; review and quality assurance; funding, declaration, and management of interests; and other information) were 79.2%, 62.5%, 38.8%, 53.6%, 21.9%, 32.8%, and 43.8%, respectively. For the 35 checklist items, the average reporting rate was 52.9%, and only 16 items had a reporting rate >50%, of which 5 items were reported by all the guidelines. There was 1 item which was not reported by any of the guidelines.ConclusionsThe reporting quality of recently published AML guidelines remains poor. While the recommendations of CPGs have great value in clinical practice, the reporting quality of CPGs for AML still needs to be improved.

| S-EPMC8506773 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data