Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alemtuzumab is a humanized monoclonal antibody against CD52, a small glycosylphosphatidylinositol-anchored glycoprotein that is highly expressed on normal T- and B-lymphocytes, and on a large proportion of malignant lymphoid cells, but not on hematopoietic progenitor cells. Over the past several years, a number of clinical trials have demonstrated the clinical activity of alemtuzumab in treating patients with chronic lymphocytic leukemia, T-cell malignancies such as T-prolymphocytic leukemia and cutaneous T-cell lymphoma, as well as in the prevention and therapy of graft-versus-host disease in the setting of allogeneic stem cell transplantation. Its application in a number of autoimmune disorders is currently under investigation. The most significant side effect of alemtuzumab is predisposition to infections related to the associated profound lymphopenia. Despite this, and with appropriate and more effective antibiotic prophylaxis, it is likely that we will witness an expansion of the role of alemtuzumab in the future.
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PMID:Alemtuzumab. 1575 37

Alemtuzumab (Campath 1H -MabCampath), initially used for prophylaxis of graft versus host disease in allogenic transplantaion, is now increasingly used for refractory chronic lymphatic leukaemia (CLL). Its efficacy has been well documented in this--the commonest form of leukaemia. Alemtuzumab is associated with severe immunosuppression, allergic reactions and thrombocytopenia. Data sheet and information supplied by the manufacturer confirm the rare occurrence of serious immune thrombocytopenia, recommending discontinuation of therapy when platelet counts fall below 50x10(9)/l. We report a patient with refractory CLL in which relentless progressive cytopenia occurred despite the discontinuation of alemtuzumab therapy while the platelet count was over 97x10(9)/l. Marrow biopsy showed increased megakaryocytes, the patient bleed uncontrollably and died of cerebral haemorrhage with a platelet count <10x10(9)/l. Data on the predictive factors underlying this complication are few and deserve further study as this drug is increasingly used the treatment of CLL.
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PMID:Fatal thrombocytopaenia temporally related to the administration of alemtuzumab (MabCampath) for refractory CLL despite early discontinuation of therapy. 1576 82

The incidence of Epstein-Barr virus (EBV) viraemia and lymphoproliferative disease (LPD) was studied in a consecutive cohort of 128 paediatric patients undergoing stem cell transplantation (SCT) with reduced-intensity conditioning (RIC; n = 65) or conventional-intensity conditioning (CIC; n = 68). Following CIC, six of 68 (8%) developed viraemia; all remained asymptomatic. EBV viraemia (23 of 65 patients = 35%, P < 0.001) and LPD (10 of 65 = 15%, P < 0.001) were significantly more frequent following RIC. Of the 23 RIC patients who developed viraemia, eight remained asymptomatic, five had symptomatic viraemia (fever +/- rash), and 10 patients developed LPD, two of whom died. An absolute lymphocyte count of <0.3 x 10(9)/l at the time of onset of viraemia was strongly predictive of development of LPD (P < 0.05) in this group. The incidence of viraemia was significantly higher in patients receiving serotherapy with antithymocyte globulin (ATG; 15 of 43, 35%) than Campath (12 of 73, 16.4%, P < 0.05). Primary immunodeficiency and acute graft-versus-host disease were associated with EBV viraemia in univariate analysis, but were not independent risk factors. In conclusion, EBV viraemia and LPD appear to be significantly more common in children following RIC SCT, particularly with selective depletion of recipient T cells relative to B cells following the use of ATG. This probably reflects the profound immunosuppression following RIC SCT, together with the incomplete ablation of recipient-derived B cells.
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PMID:Increased incidence of EBV-related disease following paediatric stem cell transplantation with reduced-intensity conditioning. 1581 51

A 10-year-old girl diagnosed with acute myeloid leukemia FAB M4 failed to achieve remission following several courses of induction chemotherapy. From the first course of chemotherapy the patient had continuous marrow aplasia, managed by a total of 57 granulocyte transfusions. After reinduction and reduced-intensity conditioning including fludarabine, Campath-1H, and melphalan, the patient received unmanipulated marrow from an HLA-matched unrelated donor. Leukocyte and platelet engraftment was observed on day +18 and +50, respectively. Graft-versus-host disease did not occur. The patient is alive and well in complete remission 18 months after transplantation with complete donor chimerism.
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PMID:Five-month marrow aplasia in a child with refractory acute myeloid leukemia: successful management with continuous granulocyte support and reduced-intensity conditioning followed by matched unrelated bone marrow transplantation. 1583 1

We compared antithymocyte globulin (ATG) with alemtuzumab in 73 patients with multiple myeloma, who underwent reduced conditioning with melphalan/fludarabine, followed by allogeneic stem cell transplantation from human leucocyte antigen-matched or -mismatched unrelated donors. The ATG group had more prior high-dose chemotherapies (P < 0.001), while bone marrow was used more as the stem cell source in the alemtuzumab group (P < 0.001). Alemtuzumab resulted in faster engraftment of leucocytes (P = 0.03) and platelets (P = 0.02) and in a lower incidence of acute graft versus host disease (GvHD) grades II-IV (24% vs. 47%, P = 0.06). More cytomegalovirus (CMV) seropositive patients in the alemtuzumab group experienced CMV reactivation (100% vs. 47%, P = 0.001). The cumulative incidence of treatment-related mortality at 2 years was 26% [95% confidence interval (CI) = 12-37%] for ATG vs. 28% (95% CI = 15-55%) for alemtuzumab, P = 0.7. There was no significant difference in the estimated 2-year overall and progression-free survival between ATG and alemtuzumab: 54% (95% CI: 39-75%) vs. 45% (95% CI: 28-73%) and 30% (95% CI: 16-55%) vs. 36% (95% CI: 20-62%) respectively. In multivariate analysis, treatment with alemtuzumab had a higher risk for relapse (hazard ratio: 2.37; P = 0.05) while killer immunoglobulin-like receptor (KIR)-ligand mismatch was protective for relapse (P < 0.0001). We conclude that alemtuzumab produced less acute GvHD, but higher probability of relapse. The data implicated a major role of KIR-ligand mismatched transplantation in multiple myeloma.
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PMID:Comparison between antithymocyte globulin and alemtuzumab and the possible impact of KIR-ligand mismatch after dose-reduced conditioning and unrelated stem cell transplantation in patients with multiple myeloma. 1591 86

Alemtuzumab is a humanized monoclonal antibody directed against human CD52 with a strong lympholytic effect. We have performed unmanipulated hematopoietic stem cell transplantation (HSCT) from 2- or 3-locus-mismatched family donors in 14 patients using in vivo alemtuzumab. All achieved complete donor cell engraftment and grade III-IV acute graft-versus-host disease was observed in only one patient. However, eight of the 14 patients developed grade II-IV cardiac complications according to Bearman's criteria. Next, we retrospectively analyzed the records of 142 adult patients who underwent allogeneic HSCT from 1995 to 2004 to evaluate whether the use of alemtuzumab was an independent risk factor for cardiac complications. Among several factors that increased the incidence of grade II-IV cardiac complications with at least borderline significance, a multivariate analysis identified the cumulative dose of anthracyclines (P=0.0016) and the use of alemtuzumab (P=0.0001) as independent significant risk factors. All of the cardiac complications in the alemtuzumab group were successfully treated with diuretics and/or catecholamines. Patient selection and close monitoring of cardiac function may be important in HLA-mismatched HSCT using in vivo alemtuzumab.
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PMID:Cardiac complications after haploidentical HLA-mismatched hematopoietic stem cell transplantation using in vivo alemtuzumab. 1611 61

The study comprised 37 consecutive patients who underwent transplantation with a Campath-1H in vitro T cell-depleted granulocyte colony-stimulating factor-mobilized peripheral blood stem cell graft from an HLA-identical sibling, followed 24 hours later by an unmanipulated graft. Acute graft-versus-host disease (GVHD) was limited to grade I to II, whereas chronic graft-versus-host disease occurred in 9 patients, mostly (n = 7) with limited disease. Molecular relapses (8 chronic myeloid leukemia [CML] and 1 non-Hodgkin lymphoma) that occurred not earlier than the sixth month after transplantation were treated with donor lymphocyte infusion (DLI), which induced complete remission in all but 1 CML patient with persistent very low BCR-ABL molecular levels. With a median follow-up of 54 months (range, 29-84 months), the actuarial 5-year overall survival, disease-free survival, and transplant-related mortality are 78% (95% confidence interval [CI], 52%-88%), 78% (95% CI, 52%-86%), and 6% (95% CI, 1.5%-32%), respectively. All CML patients are alive and free of disease. The results of this prospective, nonrandomized study show that incomplete T-cell depletion in vitro with Campath-1H (in combination with DLI for molecular relapses in CML) may decrease the incidence of GVHD and transplant-related mortality with no adverse effect on disease-free survival. The described method decreases the number of T cells to an extent that severe GVHD is prevented while relapse is postponed to a time when the patient can be treated with DLI without severe side effects.
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PMID:Can only partial T-cell depletion of the graft before hematopoietic stem cell transplantation mitigate graft-versus-host disease while preserving a graft-versus-leukemia reaction? A prospective phase II study. 1639 74

Alemtuzumab (Campath-1H)-based conditioning regimens are effective in preventing GVHD, but are associated with very high rates of cytomegalovirus (CMV) infection, a major limitation to their use. We evaluated 85 patients receiving conditioning with fludarabine 30 mg/m2/day (day -7 to day -3), alemtuzumab 20 mg/day (day -7 to day -3), and melphalan 140 mg/m2 on day -2. The initial patients received post transplant CMV prophylaxis with high-dose acyclovir. A very high incidence of CMV viremia was observed as has been commonly reported after alemtuzumab-based conditioning. Sixty-seven subsequent patients received pre-transplant ganciclovir and high-dose valacyclovir after engraftment. The cumulative incidence of CMV infection in the valacyclovir cohort was 29%. This compared favorably to the cumulative incidence of 53% in patients receiving only acyclovir (P = 0.004) and to literature data. CMV prophylaxis with pre-transplant ganciclovir and high-dose valacyclovir after engraftment appears effective in preventing the excessive incidence of CMV infection after alemtuzumab-based conditioning regimens.
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PMID:Pre-transplant ganciclovir and post transplant high-dose valacyclovir reduce CMV infections after alemtuzumab-based conditioning. 1640 Mar 39

For decades, chemotherapy was the only available approach for patients with advanced lymphoid malignancies. Treatment paradigms were dramatically altered by the availability of novel and active targeted agents, particularly the monoclonal antibodies, alemtuzumab and rituximab. These agents are now playing an increasingly important role in the treatment of lymphoid malignancies. Alemtuzumab is being used earlier in the course of chronic lymphocytic leukemia in patients with a more intact immune system, when it is likely to have its greatest activity. The immunosuppressive properties of monoclonal antibodies are also being explored in the stem cell transplant setting, including in vivo purging and, with alemtuzumab, for the management of graft-versus-host disease. Rituximab has become ubiquitous in the treatment of most B-cell malignancies. Further research with this antibody is focused on optimizing its use and determining its role in each of the relevant disease states. In addition, newer antibodies are in development for treating chronic lymphocytic leukemia and other B-cell malignancies. New treatment regimens, including combinations of monoclonal antibodies, could enhance complete response rates and prolong progression-free survival, perhaps eventually improving our ability to cure patients with lymphoid malignancies.
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PMID:Monoclonal antibody therapy for B-cell malignancies. 1672 Jan 98

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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