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)

Current investigations have revealed that angiogenesis plays a role in the pathogenesis of high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia, and in the mechanisms of disease progression. Secretion of cytokines and growth factors modulates angiogenesis in the marrow leading to increased vascularity and sustenance of the clonal population. For high-risk MDS patients older than 60 years who are not eligible for aggressive chemotherapy or stem cell transplant, there are few therapeutic options other than supportive treatment. Recent delineation of the pathobiology of MDS has resulted in the development of new agents and treatment modalities that impact on these mechanisms. One of the features of bone marrow pathology is the presence of new vessels, which appear to sustain growth and the hypercellularity of the marrow. Blocking angiogenesis may reduce the microvessel density of the marrow, cellularity, and disease progression. Angiogenesis can be targeted by inhibition of vascular endothelial growth factor (VEGF), which modulates new vessel growth, by the use of antibodies aimed at VEGF and its receptors, as well as receptor tyrosine kinases that block VEGF signaling. Other agents include inhibitors of farnesyl transferase and protein kinase C, which affect upstream modulators of growth factors and their receptor interactions; matrix metalloproteinases, which disrupt matrices and adhesion function promoting vessel growth; and other inhibitors with broader function, such as endostatin, thalidomide, and related analogues.
Best Pract Res Clin Haematol 2004 Dec
PMID:Modulation of angiogenesis in patients with myelodysplastic syndrome. 1549 99

Resistance to chemotherapy is an obstacle to the successful treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The failure of therapeutic treatment may be due to the development of multidrug resistance (MDR), mechanisms of which include upregulation of membrane-resident transporters which efflux chemotherapeutic drugs from tumor cells, and failure of the cancer cell to undergo apoptosis in response to chemotherapy. Membrane transporter-based drug efflux transporters have been extensively studied, and agents that block drug efflux have been found and investigated. Presence of P-glycoprotein (Pgp, MDR1, ABCB1), a member of the ATP-binding cassette (ABC) transporter family, has been reported to correlate with poor prognosis in AML and MDS. In MDS, Pgp expression increases as the disease progresses. Overexpression of other transporters, such as the multidrug resistance protein (MRP1, ABCC1), and the vault-associated transporter lung resistance protein have been shown as well in both MDS and AML, but their prognostic relevance is not clear. Recently, a novel ABC half-transporter, the breast cancer resistance protein (ABCG2) has been found in approximately 30% of AML cases, and may play a role in resistance to chemotherapy. In clinical trials in MDS, first-generation Pgp blockers, such as cyclosporin-A and verapamil, were minimally effective, non-specific, and toxic. However, another first-generation blocker, quinine, was used in MDS and may specifically benefit MDS patients overexpressing Pgp. A second-generation drug, the non-immunosuppressive cyclosporine analog valspodar (PSC833), was studied in AML and MDS, and was highly toxic, resulting in the need to reduce the dosage of the chemotherapeutic drugs as a result of valspodar reducing the clearance of the chemotherapeutic agents. Third-generation drugs, which are highly specific for Pgp and which seem to have only modest effects on drug clearance, include tariquidar, zosuquidar, laniquidar, and ONT-093. These are all in phase I/II trials and show promise for future treatment.
Best Pract Res Clin Haematol 2004 Dec
PMID:Modulation of drug resistance transporters as a strategy for treating myelodysplastic syndrome. 1549

Recent progress in understanding the pathobiology of the myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) have led to the development of various immunologically oriented therapies for these diseases. The existence of elevated levels of tumor necrosis factor-alpha (TNF-alpha) in bone marrow during early stages of MDS, and the possibility that TNF- proportional, variant suppresses normal hematopoiesis led to studies of attempts to block the activity of TNF-alpha. An anti-TNF monoclonal antibody and an antibody comprised of the soluble extracellular ligand-binding portion of the TNF receptor have both been evaluated recently in several small pilot studies. The recognition that marrow suppression in MDS may, in part, be a T-cell mediated autoimmune process has stimulated various trials of antithymocyte globulin and other similar agents. Gemtuzumab ozogamicin, an antibody against CD33 conjugated to the cytotoxic agent calicheamicin, is approved for use in AML and is currently being investigated as a potential therapeutic agent in MDS. Clinical trials were conducted as either monotherapy or in combination with cytokines such as IL-11 and chemotherapeutic agents including idarubicin, fludarabine, and/or cytarabine. Other antibodies are being developed as immunoconjugates with radioisotopes as part of conditioning regimens prior to bone marrow transplantation for AML or MDS. These include (131)I-anti-CD45 antibody (BC8), (131)I anti-CD33 antibody (p67), (213)Bi-M195 antibody, and (188)Re-labeled anti-CD66 antibody. The clearest example of successful immunotherapy for MDS (and AML) is the use of the graft-versus-tumor effect associated with allogeneic hematopoietic cell transplantation. Recently, nonmyeloablative transplants have been explored with encouraging results. Vaccines using overexposed self-antigens such as WT1 and PR1 are other attempts to induce a T-cell mediated response against MDS.
Best Pract Res Clin Haematol 2004 Dec
PMID:Immunobiologic therapies for myelodysplastic syndrome. 1549 1

Natural-killer-cell-mediated, donor-vs-recipient alloresponses occur following transplantation of human-leukocyte-antigen (HLA)-haplotype-mismatched haematopoietic stem cells. Natural killer (NK) cell alloreactivity reduces the risk of relapse in acute myeloid leukaemia patients, while improving engraftment and protecting against graft-vs-host disease. NK cells are primed to kill by several activating receptors. NK cell killing of autologous cells is prevented as NK cells co-express inhibitory receptors (killer cell Ig-like receptors, KIR) that recognize groups of (self) major histocompatibility complex class I alleles. As KIRs are distributed clonally, the NK cell population in any individual constitutes a repertoire with different allospecificities. NK cells in the repertoire mediate alloreactions when the allogeneic targets do not express class I alleles that block them. High-resolution molecular HLA typing of recipient and donor, positive identification of donor KIR genes and, in some cases, functional assessment of donor NK clones will identify haplo-identical donors who are able to mount donor-vs-recipient NK alloreactions.
Best Pract Res Clin Haematol 2004 Sep
PMID:Natural killer cells as a therapeutic tool in mismatched transplantation. 1549 14

Adoptive immunotherapy with transfusion of donor lymphocytes in allogeneic stem cell chimeras has been successful in the treatment of recurrent chronic myelogenous leukaemia (CML) and some patients with acute myeloid leukaemia (AML). The hypothesis that the graft-vs-leukaemia effect (GVL) is promoted by leukaemia-derived dendritic cells has been supported by the concurrent treatment of patients with cytokines that are known to induce differentiation of leukaemia cells towards dendritic cells. In combination with donor lymphocyte transfusions, treatment with interferon-alpha and granulocyte-macrophage colony-stimulating factor has been studied in patients with recurrent CML and AML, and pre-emptively in patients with high-risk AML. Long-term remissions have been observed in cytokine-treated patients, indicating the beneficial effect of cytokine stimulation of GVL reactions. This is likely to be due to differentiation of leukaemia progenitor cells towards dendritic cells in vivo.
Best Pract Res Clin Haematol 2004 Sep
PMID:In-vivo generation of leukaemia-derived dendritic cells. 1549 15

The graft-versus-leukemia effect following allogeneic stem cell transplantation (SCT) reduces the incidence of leukemic relapse and establishes that effector cells can eliminate or at least contain resistant leukemic stem cells. Natural killer cells also appear to play a role in directly lowering the rate of relapse following allogeneic SCT in patients with acute myeloid leukemia. To date, however, effective prevention of leukemic relapse by autologous immune effector cells has not been demonstrated. This article examines some of the challenges that limit autologous antileukemia immunity as well as some possible immunotherapeutic approaches that may help control leukemic relapse following autologous SCT.
Best Pract Res Clin Haematol 2006
PMID:Autologous immune strategies to reduce the risk of leukemic relapse: consideration for IL-15. 1651 25

Myelodysplastic syndrome (MDS) is a disorder of hematopoietic stem cells characterized by ineffective hematopoiesis. The result is pancytopenia leading to transfusion-dependent anemia, an increased risk of infection or bleeding, and a potential to progress to acute myeloid leukemia (AML). MDS is most prevalent among older individuals, many of whom also suffer from other medical conditions. MDS is classified according to World Health Organization criteria and the International Prognostic Scoring System. Supportive care remains the mainstay of therapy. Those with low-risk MDS can often be monitored for an extended period of time without specific therapy, whereas those with intermediate- or high-risk MDS benefit from treatment. Currently, only azacitidine is approved for the treatment of MDS. Several new agents are being tested, including inhibitors of angiogenesis (thalidomide, lenalidomide), farnesyl transferase inhibitors (lonafarnib, tipifarnib), and DNA methyltransferase inhibitors (azacitidine, decitabine). Lenalidomide appears particularly effective in patients with low-risk MDS with the deletion of chromosome 5q31. Allogeneic stem cell transplantation is an alternative for high-risk MDS. With advances in transplantation techniques, this treatment can be offered to an increasing number of patients. However, it is necessary to assess each patient's disease individually and to evaluate prognostic factors, other treatment options, and the appropriateness and timing of transplantation.
Best Pract Res Clin Haematol 2006
PMID:Myelodysplasia: when to treat and how. 1651 26

The heterogeneity of acute myeloid leukemia (AML) has been established by many new insights into the diagnosis, pathogenesis, clinical manifestations, treatment, and prognosis of patients with AML. Morphology remains the foundation for the diagnosis. However, additional diagnostic studies, including immunophenotyping, cytogenetic evaluation, and molecular genetic studies, are necessary to develop treatments because specific subtypes of AML can now be approached with targeted therapy. Acute promyelocytic leukemia (APL), defined by a single molecular abnormality, is now treated with specific targeted therapy, all-trans retinoic acid (ATRA), and this subtype of AML is now highly curable. Currently, a number of agents have been explored in AML, including anti-CD33 antibodies and immunoconjugate drugs, inhibitors of multidrug resistance proteins, farnesyl transferase inhibitors, tyrosine kinase inhibitors, anti-Bcl-2 transcription agents, and inhibitors of mammalian target of rapamycin (mTOR). New alkylating agents, and purine analogs such as Cloretazine and clofarabine, affect DNA and ribonucleoside reductases, respectively. These agents have shown promise in small studies. Large phase III studies will address whether these are effective in inducing complete responses. Combining targeted agents with chemotherapy may improve the response rates. The plan for the future is to find therapeutic strategies that are specific for patients based on the specific biology of the disease. Future studies will investigate combinations of targeted therapies with each other and with chemotherapies to maximize the inhibition of multiple pathways present in AML. Additionally, evaluation of the identified prognostic factors and gene mutations will enable further pathologic classification of patients with AML.
Best Pract Res Clin Haematol 2006
PMID:New agents for the treatment of acute myeloid leukemia. 1651 28

There has been controversy about the optimal consolidation therapy for patients with acute myeloid leukemia (AML) in first remission. Hematopoietic stem cell transplantation from human leukocyte antigen (HLA)-identical siblings has improved the survival of patients with unfavorable cytogenetics, but has not improved the survival of intermediate- or favorable-risk patients. If an HLA-identical sibling donor is not available, alternative sources of stem cells may be sought. HLA mismatched transplants are associated with an increased risk of graft rejection and graft-versus-host disease, and lower survival. Since large registries of HLA-typed volunteer donors have been established and the newer and more sensitive tissue typing technology can more clearly differentiate between matched and unmatched donors, some AML patients without an HLA-matched sibling have received transplants from an HLA-matched unrelated donor while in first remission. Data from the Center for International Blood and Marrow Transplant Research indicate that survival of patients with unfavorable cytogenetics appears at least as good with unrelated donor grafts as previously reported for matched sibling grafts, and better than consolidation chemotherapy. AML patients in first remission with unfavorable cytogenetics without a matched family donor should be offered an unrelated donor transplant.
Best Pract Res Clin Haematol 2006
PMID:Are matched unrelated donor transplants justified for AML in CR1? 1651 29

Patients with acute myeloid leukemia (AML) may differ significantly in their response to therapy and long-term outcome. A number of risk factors have been identified that characterize patients at diagnosis as well as during their clinical course. At diagnosis these parameters include age, cytogenetic configuration, hemopoietic elements, and a previous history of myelodysplasia or cytoreductive therapy for a preexisting malignancy. They are complemented by the response to induction therapy and subsequent treatments as well as by the duration of response. More recently, gene expression profiling of leukemic cells has added a new dimension to simultaneously assess biological risk factors that may ultimately lead to individualization of therapy. This presentation will review data to address the question of whether or not allogeneic transplants are effective in the management of patients with AML presenting with adverse cytogenetics and older age, showing a poor response to induction therapy, and relapsing after achieving a remission.
Best Pract Res Clin Haematol 2006
PMID:How good is allogeneic transplantation for high-risk patients with AML? 1651 30


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