Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The development of cancer vaccines directed against myeloid leukaemias has been a research area of intense interest in the past decade. Both human studies in vitro and mouse models in vivo have demonstrated that leukaemia-associated antigens (LAAs), such as the fusion protein BCR-ABL, Wilms' tumour protein and proteinase 3, may serve as effective targets for cellular immunotherapy. Peptide-based vaccines are able to induce cytotoxic T-lymphocyte responses that kill leukaemia cells. Based on these results, pilot clinical trials have been initiated in chronic and acute myeloid leukaemia and other haematological malignancies, which include vaccination of patients with synthetic peptides derived from these LAAs. Results from these trials show that peptide vaccines are able to induce immune responses that are sometimes associated with clinical benefit. These early clinical results are promising and provide valuable information for future improvement of the vaccines. This chapter will focus mainly on discussing the preclinical studies of peptide vaccines in human systems, the results from clinical trials and the future prospects for vaccine therapy for myeloid leukaemia.
Best Pract Res Clin Haematol 2008 Sep
PMID:Peptide vaccines for myeloid leukaemias. 1879 Apr 45

The success of donor lymphocyte infusion (DLI) in treating chronic myeloid leukaemia that had recurred after allogeneic haematopoietic stem cell transplantation provided direct evidence for the existence of an immunologically mediated graft-vs-leukaemia effect and led to the development of non-myeloablative transplantation. For patients with acute myeloid leukaemia (AML), DLI has been less effective, both as a result of its rapid growth kinetics and its decreased susceptibility to alloimmune-mediated effects. This chapter reviews the historical experience with DLI for AML, both as treatment for and prophylaxis of relapse. New approaches aimed at improving the efficacy of DLI are discussed, including administration of chemotherapy prior to DLI, use of immunomodulatory cytokines to bolster the cytotoxic effector response, priming of donor lymphocytes to recipient tumour antigens ex vivo, and infusions of alloreactive natural killer cells.
Best Pract Res Clin Haematol 2008 Sep
PMID:Donor lymphocyte infusions for acute myeloid leukaemia. 1879 Apr 49

The graft-versus-leukaemia effect is one of the most important biological effects to influence outcome in patients with acute leukaemia. The recognition of this modality over the past three decades has led to far-reaching changes in the concept and conduct of allogeneic transplantation in acute myeloid leukaemia, and in the infusion of donor lymphocytes as a therapeutic modality. Despite these conceptual advances, there is a considerable need for more structured prospective studies to optimally define the role of reduced-intensity transplantation in both acute myeloid and acute lymphoblastic leukaemia.
Best Pract Res Clin Haematol 2008 Sep
PMID:Graft-versus-disease effect following allogeneic transplantation for acute leukaemia. 1879 Apr 51

Although there have been several major laboratory advances which have been helpful diagnostically and in the general classification of risk groups, they have not resulted in improvement in the overall outcome for patients with AML and, with occasional exceptions, have not provided clues about new therapeutic directions. Gene expression profiling and the identification of a number of unique mutations in leukemia cells may help discriminate among the heterogeneous outcomes observed both in patients with the same karyotypic abnormality and in patients with normal cytogenetics. However, the mechanism(s) by which these new molecular markers affect prognosis are poorly understood, and as more mutations and other patient subgroups are discovered, identifying new, non-empiric therapies and designing efficient clinical trials, becomes even more complicated.
Best Pract Res Clin Haematol 2008 Dec
PMID:Molecular characterization of AML: a significant advance or just another prognostic factor? 1904 1

The concept of combining targeted agents for the treatment of acute myeloid leukemia (AML) is a relatively new but potentially promising area of investigation. A number of targeted agents may have limited single-agent activity but could show significant promise when used in conjunction with other types of similar compounds. Combinations of targeted agents may effectively interrupt multiple pathways in either a linear or parallel fashion. There are currently numerous combination regimens under investigation at either the preclinical or clinical levels, including histone deacetylase (HDAC) and CDK inhibitors; HDAC and proteasome inhibitors; HDAC and NF-kappaB (IKKbeta) inhibitors; CHK1 and MEK1/2 inhibitors; and BCL-2 antagonists and CDK inhibitors. Although combinations of targeted agents will not displace conventional cytotoxic regimens in AML or related disorders in the foreseeable future, these combinations clearly warrant further attention.
Best Pract Res Clin Haematol 2008 Dec
PMID:Is the focus moving toward a combination of targeted drugs? 1904 2

Acute promyelocytic leukemia (APL), a highly curable subtype of acute myeloid leukemia (AML) is characterized by the chromosomal translocation t(15;17) and, consequently, the presence of the PML-RARalpha fusion transcript. Most patients are treated with all-trans retinoic acid (ATRA), which targets the RAR-alpha moiety of the PML/RAR-alpha fusion transcript, and anthracycline-based chemotherapy. Arsenic trioxide (ATO) targets the PML moiety and has different mechanisms of action at different concentrations, and induces differentiation and apoptosis. Several clinical trials have tested the combination of ATRA and ATO with outstanding results. Furthermore, other trials have explored ATO as a single agent in newly diagnosed patients. ATRA plus ATO has emerged as a promising strategy, even for those with high-risk disease. Future studies will compare ATRA and ATO to conventional ATRA and anthracycline-based chemotherapy.
Best Pract Res Clin Haematol 2008 Dec
PMID:What is the role of arsenic in newly diagnosed APL? 1904 5

Acute myeloid leukemia (AML) patients over the age of 55 years are generally more difficult to treat than younger patients due to intrinsic drug resistance and diminished tolerance to treatment. The unfortunate result is that conventional chemotherapy is toxic and rarely curative. Recent studies suggest a better outcome for older AML patients treated with reduced-intensity conditioning (RIC) hematopoietic cell transplantation (HCT) than those treated with conventional chemotherapy. However, there are major limitations to RIC HCT. Some of these limitations may be able to be overcome, broadening the impact of allogeneic RIC HCT for older patients with AML. Ways to improve RIC HCT include making more patients eligible for RIC HCT by improving initial complete response rates using novel agents or combinations; finding a way to more rapidly identify alternative stem cell sources, such as by using donors that have already undergone HLA profiling or by using unrelated cord blood; eliminating the requirement for a complete response prior to transplant; and educating patients and physicians about the chances of survival after RIC HCT when compared to conventional chemotherapy.
Best Pract Res Clin Haematol 2008 Dec
PMID:What is the impact of hematopoietic cell transplantation (HCT) for older adults with acute myeloid leukemia (AML)? 1904 6

Since the initial description of the disease, the life-threatening coagulopathy associated with acute promyelocytic leukaemia (APL) has been the defining clinical characteristic. Historically, this uncommon subtype of acute myeloid leukaemia has been associated with a high mortality rate during induction therapy, most frequently attributable to haemorrhage. Since the introduction of all-trans retinoic acid (ATRA) into the therapy of all patients with APL, disease-free survival and overall survival have improved dramatically, such that the disease is now highly curable. However, induction mortality remains a major problem and haemorrhage still accounts for the majority of such early deaths. Pathogenesis of the coagulopathy is complex and includes disseminated intravascular coagulation (DIC), fibrinolysis and proteolysis. As a result, while the predominant clinical manifestation of the coagulopathy is haemorrhage, thromboembolic events may occur both at presentation and during therapy. A major recent finding is the high expression of annexin II in the leukaemic cells from patients with APL. Annexin II is a protein with high affinity for plasminogen and tissue-type plasminogen activator (tPA), and also acts as a cofactor for plasminogen activation by tPA. As a result, both plasminogen and tPA are increased on the cell surface of the leukaemic cell, increasing plasmin activity. Annexin II is expressed in high amounts in cerebral microvascular endothelial cells, perhaps accounting for the relatively high incidence of intracranial haemorrhage in APL compared with other sites. Microparticles are cell-derived membrane fragments originating from normal cells or released from malignant cells involved in activating coagulation. Recent studies have found that microparticles containing tissue factor, tPA, plasminogen activator inhibitor-1 and annexin II have been found in the plasma of APL patients, suggesting a role in pathogenesis of the coagulopathy. Treatment of the coagulopathy remains primarily supportive. Aggressive transfusions of platelets and cryoprecipitate appear to be important. There is no clear role for the routine use of heparin or antifibrinolytic therapy. The most important factor may be the early introduction of ATRA at the first suspicion of a diagnosis of APL, before it is confirmed genetically.
Best Pract Res Clin Haematol 2009 Mar
PMID:The coagulopathy of acute promyelocytic leukaemia revisited. 1928 82

In view of the genetic heterogeneity of acute myeloid leukaemia (AML), gene expression profiling (GEP) with the possibility of investigating the expression of tens of thousands of genes in parallel represents a promising approach to facilitate and improve the diagnostic process in this complex disorder. In the last decade, following the introduction of this methodology in leukaemia research, various studies have demonstrated that classification of the majority of known genetic subclasses in AML can be performed with high accuracy by GEP. Further, GEP allowed for detecting new biologically and prognostically relevant subclasses within the defined subgroups, mainly in the normal karyotype AML. These new classifiers cross the borders of traditionally defined prognostic parameters, and some of these gene expression signatures were independently validated by different study groups. The development of treatment-specific sensitivity assays being able to predict the individual patient's response to targeted therapy is another interesting perspective. With respect to molecular mutations in genes such as FLT3 or NPM1, future studies must outline the definite position of GEP. International multicentre studies such as the MILE study (Microarray Innovations in LEukemia) pave the way to a standardised workflow of GEP in routine diagnostics in AML.
Best Pract Res Clin Haematol 2009 Jun
PMID:Gene expression profiling in acute myeloid leukaemia (AML). 1969 26

Altered expression of microRNAs, a new class of noncoding RNAs that regulate messenger RNA and protein expression of target genes, has been recently demonstrated to have an essential role in the process of leukaemogenesis. Distinctive patterns of activation and/or silencing of multiple microRNAs (microRNA signatures) associated with certain cytogenetic and molecular subsets of leukaemia have been identified using genome-wide high-throughput profiling assays. This has led not only to the discovery of new molecular pathways implicated in leukaemogenesis, but also supplied prognostic information complementing that gained from cytogenetics, gene mutations and altered gene expression in acute and chronic leukaemias. We review herein results of current studies analysing changes of microRNA expression in acute myeloid leukaemia and chronic lymphocytic leukaemia, and discuss their potential biologic, diagnostic and prognostic relevance.
Best Pract Res Clin Haematol 2009 Jun
PMID:MicroRNA expression profiling in acute myeloid and chronic lymphocytic leukaemias. 1969 31


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