Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute graft-versus-host disease (GVHD) is a primary T-cell-mediated complication of allogeneic hematopoietic stem cell transplantation (HSCT), occurring when donor-derived T cells are stimulated by host antigen-presenting cells (APCs), enhanced by proinflammatory cytokines such as interleukin (IL)-1, IL-6, IL-8, and tumor necrosis factor (TNF)-alpha. Recent data indicate that besides differences in major histocompatibility and minor histocompatibility antigens, cytokine gene polymorphisms have a predictive value for the complication of GVHD. Patients with a high anti-inflammatory IL-10 production have been demonstrated to be protected from GVHD while patients with high TNF-alpha serum levels were more at risk for GVHD. Pharmacological immunosuppression for GVHD prophylaxis and therapy, including unspecific approaches with corticosteroids or methotrexate (MTX), as well as more specific therapy with cyclosporin A (CsA), tacrolimus (FK506), sirolimus, mycophenolate mofetil (MMF), antithymocyte globulin (ATG), and monoclonal antibodies (MAbs) directed against CD3, CD25, CD52, cytotoxic T-lymphocyte antigen (CTLA)-4, CD40 ligand, or TNF-alpha, have been proven to be effective. Recent data on novel techniques to selectively deplete alloreactive T cells by removal, destruction, or anergy induction while preserving leukemia-specific T-cell clones suggest a clinical benefit from these approaches. Gene-modified T cells that can selectively be depleted and CD4(+)CD25(+) regulatory T cells are under investigation for their ability to modulate alloreactivity after HSCT. With a better understanding of the immunopathogenesis of acute GVHD and the technical improvement of recently described therapeutic approaches, such as removal of naive T cells, selection of Th2 cells, suicide gene transduced T cells, and adoptive transfer of regulatory T cells, the use of alloreactivity as a treatment modality may be expanded to nonhematological disease entities such as solid tumors or autoimmune disorders.
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PMID:Immunopathogenesis of acute graft-versus-host disease: implications for novel preventive and therapeutic strategies. 1544 32

Alemtuzumab is a humanized therapeutic monoclonal antibody (MAb) that recognizes the CD52 antigen, expressed on normal and neoplastic lymphocytes, monocytes, and natural killer cells. In 2001, alemtuzumab was approved in the US and Europe to treat B-cell chronic lymphocytic leukemia (CLL) that had been treated previously with alkylating agents and was refractory to fludarabine. In heavily pretreated patients this MAb is able to produce response rates of about 40%, and in symptomatic, previously untreated patients response rates of more than 80% can be achieved. Alemtuzumab can also be used in patients with CLL as a preparative regimen for stem cell transplantation (SCT) and to prevent graft versus host disease. Moreover its in vivo use before or after SCT may also potentially result in depletion of residual leukemia cells, especially in the autologous setting. Adverse events associated with alemtuzumab include acute first-dose reaction, hematologic toxicity, and infectious complications. Usually they are predictable, manageable, and acceptable in the context of CLL. However, in a significant percentage of patients, cytomegalovirus reactivation occurs during alemtuzumab therapy, and routine weekly monitoring with the polymerase chain reaction methodology is indicated. Moreover, antiviral and antibacterial prophylaxis is mandatory.
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PMID:Alemtuzumab in the treatment of chronic lymphocytic leukemia. 1569 Dec 13

B-cell chronic lymphocytic leukemia (CLL) is a clonal hematopoietic disorder characterized by proliferation and accumulation of small lymphocytes. It is the most common form of leukemia in North America and Europe. The management of CLL is determined by the stage and activity of the disease. Several randomized studies indicate that cytotoxic therapy based on alkylating agents in the indolent phase of disease, does not prolong the survival time of CLL patients. Chlorambucil, with or without steroids, has been for many years the drug of choice in previously untreated patients with this leukemia. Alternative treatment approaches, including new purine nucleoside analogs (PNA), such as fludarabine and 2-chlorodeoxyadenosine (cladribine) have also shown activity in CLL. The randomized studies have indicated a higher overall response, complete remission rates and longer response duration in patients treated initially with PNA than with chlorambucil or cyclophosphamide based combination regimens. These agents alone or in combinations, seem to be the treatment of choice for patients failing standard therapies. The monoclonal antibodies directed against CD52 antigen (alemtuzumab, Campath-1H) and CD20 antigen (rituximab) demonstrate also significant activity in CLL patients. These agents have significant single-agent activity, distinct mechanism of action and generally, favorable toxicity profiles. Both antibodies achieved the most promising results in the treatment of patients with relapsed or refractory CLL. More recently the effect of alemtuzumab in previously untreated patients has been also investigated and results are very encouraging. A multicenter prospective randomized study comparing alemtuzumab and chlorambucil as first line therapies are ongoing and preliminary results show acceptable toxicity profile of monoclonal antibody.
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PMID:Therapy of chronic lymphocytic leukemia with purine analogs and monoclonal antibodies. 1573 72

Alemtuzumab (anti-CD52; Campath-1H) is effective in fludarabine-refractory chronic lymphocytic leukemia (CLL), but is associated with infection and early onset neutropenia. To reduce toxicity, filgrastim (G-CSF) was administered concurrently with alemtuzumab. In total, 14 CLL patients (median age 59) with a median of 3.5 prior regimens (range 1--12) received i.v. alemtuzumab, stepped up from 3 to 30 mg the first week, then 30 mg thrice weekly for 12 weeks. Filgrastim 5 microg/kg was administered daily 5 days before and throughout alemtuzumab therapy. Six patients developed cytomegalovirus (CMV) reactivation 3--6 weeks into treatment; six patients developed fever, three neutropenia, and one pneumonia. The patient with CMV pneumonia died; ganciclovir cleared CMV in the other patients. Five patients developed early neutropenia (weeks 2--5). Four patients developed delayed neutropenia (weeks 10--13) unassociated with CMV reactivation. Nine patients ceased therapy because of infectious and hematologic toxicity. Five partial responses were noted, all in patients with lymph nodes>cm, lasting a median of 6.5 months (range 5--13). Filgrastim and alemtuzumab were given concurrently with manageable infusion toxicity and clinical activity, but the efficacy of this regimen was limited by delayed neutropenia of unclear etiology and CMV reactivation. Filgrastrim should not be administered prophylactically during alemtuzumab therapy outside clinical trials.
Leukemia 2005 Jul
PMID:Filgrastim and alemtuzumab (Campath-1H) for refractory chronic lymphocytic leukemia. 1585 11

Few reports on the successful treatment of T-cell large granular lymphocyte (LGL) leukemia with the humanized anti-CD52 monoclonal antibody alemtuzumab are emerging in the literature. The expression of CD52 by LGLs has not been previously investigated. Using semi-quantitative 2- and 3-color flow cytometry, we documented the expression of CD52 in 100% of abnormal cells in T-cell LGL leukemia (n = 11) and natural killer (NK) cell LGL leukemia (n = 2), and showed no significant difference in CD52 expression between T-cell prolymphocytic leukemia (PLL) and T-cell LGL leukemia. Higher CD52 expression has been noted in responders to alemtuzumab in T-cell PLL and in chronic lymphocytic leukemia (CLL), a B-cell disorder. The strong and consistent expression of CD52 shown here highlights the potential role of alemtuzumab in the treatment of refractory T-cell LGL leukemia and possibly aggressive NK cell leukemia.
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PMID:CD52 expression in T-cell large granular lymphocyte leukemia--implications for treatment with alemtuzumab. 1601 10

Two patients with pure red cell aplasia (PRCA) refractory to anti-thymocyte globulin, prednisolone, cyclophosphamide, fludarabine, mitoxantrone, dexamethasone and cyclosporine, were treated with alemtuzumab (anti-CD52 antibody). Case 1, a 35-year-old man with idiopathic PRCA, remitted completely with 130 mg of alemtuzumab. Case 2, a 42-year-old man with PRCA due to T-cell large granular lymphocyte (T-LGL) leukaemia, achieved complete remission of the PRCA with 490 mg of alemtuzumab, although the T-LGL leukaemia responded only transiently. There were no significant side effects, and normalization of erythropoiesis was durable. Alemtuzumab is active in PRCA that is idiopathic or secondary to T-cell lymphoproliferative diseases.
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PMID:Alemtuzumab induced complete remission of therapy-resistant pure red cell aplasia. 1611 36

Alemtuzumab is an exciting targeted therapy for patients with CD52-sensitive malignancies. The drug is being used in a variety of hematologic malignancies in different dosing schedules and different routes of administration. The Cancer and Leukemia Group B is conducting a study using alemtuzumab as consolidation treatment for patients with B-CLL. The group also is conducting a phase I and II dose-escalation study using alemtuzumab during intensification therapy in adults with untreated acute lymphoblastic leukemia. A national pharmaceutical protocol is actively accruing participants for a trial in which alemtuzumab is used in combination with fludarabine for relapsed and refractory B-CLL. The SQ route of administration is gaining popularity because it is highly effective with fewer side effects than IV infusions. Nurses administering alemtuzumab are in a unique position to ensure patient safety and tolerance of the therapy. By understanding the mechanism of action and the potential complications associated with alemtuzumab, nurses will be better able to provide optimal care to patients as the use of targeted monoclonal therapy continues to progress.
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PMID:Alemtuzumab (Campath 1-H). 1623 92

Alemtuzumab is a humanized IgG1 kappa antibody directed against CD52, a glycosyl-phosphatidylinositol linked cell-membrane protein of unknown function. Herein, we demonstrate that alemtuzumab promotes rapid death of chronic lymphocytic leukemia (CLL) cells in vitro, in a complement and accessory cell free system. Using minimal detergent solubilization of CLL membranes, we found that CD52 colocalizes with ganglioside GM-1, a marker of membrane rafts. Fluorescence microscopy revealed that upon crosslinking CD52 with alemtuzumab+anti-Fc IgG, large patches, and in many cases caps, enriched in CD52 and GM-1 formed upon the CLL cell plasma membrane. Depletion of membrane cholesterol or inhibition of actin polymerization significantly diminished the formation of alemtuzumab-induced caps and reduced alemtuzumab-mediated CLL cell death. We compared alemtuzumab-induced direct cytotoxicity, effector cell-mediated toxicity and complement-mediated cytotoxicity of CLL cells to normal T cells. The direct cytotoxicity and observed capping was significantly greater for CLL cells as compared to normal T cells. Cell-mediated and complement-mediated cytotoxicity did not significantly differ between the two cell types. In summary, our data support the hypothesis that alemtuzumab can initiate CLL cell death by crosslinking CD52-enriched lipid rafts. Furthermore, the differential direct cytotoxic effect suggests that CD52 directed antibodies could possibly be engineered to more specifically target CLL cells.
Leukemia 2006 Feb
PMID:Alemtuzumab induces caspase-independent cell death in human chronic lymphocytic leukemia cells through a lipid raft-dependent mechanism. 1634 Oct 49

Despite recent success in the treatment of early-stage disease, blastic phase (BP) of chronic myeloid leukemia (CML) that is characterized by rapid expansion of therapy-refractory and differentiation-arrested blasts, remains a therapeutic challenge. The development of resistance upon continuous administration of imatinib mesylate is associated with poor prognosis pointing to the need for alternative therapeutic strategies and a better understanding of the molecular mechanisms underlying disease progression. To identify transcriptional signatures that may explain pathological characteristics and aggressive behavior of BP blasts, we performed comparative gene expression profiling on CD34+ Ph+ cells purified from patients with untreated newly diagnosed chronic phase CML (CP, n=11) and from patients in BP (n=9) using Affymetrix oligonucleotide arrays. Supervised microarray data analysis revealed 114 differentially expressed genes (P<10(-4)), 34 genes displaying more than two-fold transcriptional changes when comparing CP and BP groups. While 24 of these genes were downregulated, 10 genes, especially suppressor of cytokine signalling 2 (SOCS2), CAMPATH-1 antigen (CD52), and four human leukocyte antigen-related genes were strongly overexpressed in BP. Expression of selected genes was validated by real-time-polymerase chain reaction and flow cytometry. Our data suggest the existence of a common gene expression profile of CML-BP and provide new insight into the molecular phenotype of blasts associated with disease progression and high malignancy.
Leukemia 2006 Jun
PMID:Gene expression profiling of CD34+ cells identifies a molecular signature of chronic myeloid leukemia blast crisis. 1661 18

Nonmyeloablative stem cell transplants provide a viable therapeutic option for older patients or patients with comorbid conditions, who were previously deemed to be ineligible for transplantation. Despite improvements in clinical outcomes, graft-versus-host disease (GVHD) remains a significant and potentially lethal complication. One approach by which GVHD has been managed is through introduction of new agents, such as alemtuzumab, into the conditioning regimen. Alemtuzumab is a humanized monoclonal antibody that targets the CD52 antigen, which is highly expressed on both B and T lymphocytes. By depleting T cells in both the donor and the recipient, alemtuzumab has been shown to prevent development of both acute and chronic GVHD, without inhibiting the benefits associated with the graft-versus-leukemia effect. Clinical trials have shown that alemtuzumab is able to decrease the incidence of acute and chronic GVHD without impairing engraftment. Furthermore, in chronic lymphocytic leukemia therapy, alemtuzumab has been shown to purge malignant cells from the host to allow for harvesting for the purpose of autologous transplantation. Despite results showing that alemtuzumab can play an important role in managing GVHD, little information is available regarding a standardized dosing schedule. Greater insight into alemtuzumab's pharmacokinetic activity would assist in developing a schedule that can optimize alemtuzumab-mediated T-cell depletion to prevent GVHD, while retaining sufficient host T-cell activity to encourage the graft-versus-leukemia effect and prevent relapse.
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PMID:The role of alemtuzumab in nonmyeloablative hematopoietic transplantation. 1672 Feb 2


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