Evaluation of efficacy of alemtuzumab in 5 patients with aplastic anemia and/or myelodysplastic neoplasm
Wolfgang FürederSabine Cerny‐ReitererWolfgang R. SperrLeonhard MüllauerEva JägerIlse SchwarzingerKlaus GeißlerPeter Valent
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Abstract:
Patients with aplastic anemia or hypoplastic myelodysplastic syndrome (MDS) may respond to immunosuppressive therapy, including the anti-CD52 antibody alemtuzumab. We analyzed treatment responses to alemtuzumab in 5 patients with MDS or aplastic anemia (AA) evolving to MDS. Two patients with hypoplastic MDS (hMDS) showed a partial response (PR) to alemtuzumab. In both responding patients, a concomitant paroxysmal nocturnal hemoglobinuria (PNH) clone was detected before therapy. One responder relapsed after 15 months and underwent successful allogeneic stem cell transplantation. Both patients are still alive and in remission after 40 and 20 months, respectively. The other patients showed no response to alemtuzumab. One patient died from pneumonia 4 months after treatment. In summary, our data confirm that alemtuzumab is an effective treatment option for a subset of patients with MDS, even in the presence of a PNH clone.Keywords:
Paroxysmal nocturnal hemoglobinuria
Aplastic anemia
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The CD52 antigen is a glycoprotein anchored on the cell membrane of mature B and T lymphocytes, monocytes, and eosinophils. Alemtuzumab (CAMPATH-1H; anti-CD52) is currently approved for the treatment of patients with refractory chronic lymphocytic leukemia (CLL). The authors investigated the possibility that CD52 may be shed from cells and, once soluble, may bind to injected alemtuzumab, forming immune complexes.The authors used Western blot analysis, immunoprecipitation, and enzyme-linked immunoadsorbent assay to investigate the presence of soluble CD52 (sCD52) in the plasma specimens of 117 patients with CLL. They also used in vitro mixing experiments to examine the ability of sCD52 to compete with cells and sequester therapeutic alemtuzumab.The authors detected high levels of sCD52 in the plasma specimens of patients with CLL. sCD52 can compete with cells in vitro for binding to alemtuzumab, and can form complexes in patients receiving alemtuzumab. Plasma levels of sCD52 were found to be correlated (r)with Rai stage (P = 0.0001), beta-2-microglobulin (beta-2M) levels (P = 0.00002), soluble CD23 levels (r = 0.42, P < 0.001), and immunoglobulin mutation status (P = 0.003). In the multivariate analysis adjusted for beta-2M level, patients with sCD52 levels > 2336 nM/L had a nearly 4-fold increase in risk of death. Higher levels of plasma alemtuzumab were achieved when levels of sCD52 were lower.These data not only demonstrated that sCD52 was detectable and useful in the staging and monitoring of patients with CLL, but also showed that sCD52 formed immune complexes with alemtuzumab and may influence the efficacy and toxicity of alemtuzumab therapy.
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Alemtuzumab has been proposed as a therapeutic agent in myeloma. CD52 was detected on plasma cells in 46/106 patients but levels were 30-fold lower than on alemtuzumab-responsive cells (n=138) and 8-fold lower than on alemtuzumab-resistant cells (n=57). The data suggest that myeloma plasma cells are unlikely to be depleted by alemtuzumab in most patients.
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The pathogenesis of multiple sclerosis (MS) is thought to involve peripheral activation of immune cells against central nervous system (CNS) antigens and their migration across the blood-brain barrier, leading to CNS inflammation and neurodegeneration. Alemtuzumab, a humanized anti-CD52 monoclonal antibody that rapidly depletes CD52-expressing cells from the circulation, is being investigated as a new treatment option in relapsing-remitting MS (RRMS). Clinical and radiologic results indicate robust suppression of inflammation related to the depletion of T and B lymphocytes during each treatment course of alemtuzumab. Furthermore, several lines of evidence suggest that the long-term clinical effects of alemtuzumab are attributable to qualitative changes in repopulating lymphocyte subsets potentially leading to a rebalancing of the immune system. Here, we review the contribution of data from animal models, ex vivo human studies, and clinical trials to the understanding of the mechanisms underlying the therapeutic effect of alemtuzumab in patients with RRMS.
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CD52, an antigen expressed on immune cells including mature T lymphocytes, is thought to be involved in immunomodulatory mechanisms. Alemtuzumab is a humanized monoclonal antibody against CD52, which causes a marked and long-term decrease in immune cells, especially CD4-positive T lymphocytes. A few randomized clinical trials have revealed the efficacy of alemtuzumab to be much greater than that of interferon-β in patients with relapsing-remitting multiple sclerosis. However, the development of other autoimmune disorders, including autoimmune thyroid disorders and thrombocytic purpura, because of alemtuzumab application has been considered an obstacle in its widespread use.
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Successful attenuation of allograft rejection rate is a major clinical aspect in transplant. The CD52 binding monoclonal antibody CAMPATH1 or alemtuzumab, in this aspect, shows a promise as an effective immunomodifier. This humanized monoclonal antibody efficiently depletes CD52-bearing mature B- and T lymphocytes from circulation and thereby causes transient lymphopenia, a condition for generalized immunosuppression. Alemtuzumab is an approved drug for the treatment of B cell chronic lymphocytic leukemia. However, its implication in transplant as nonsteroidal drug is a growing area of investigation. Here, we provided a brief account on alemtuzumab as an immunomodifier in allotransplant.
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The antibody alemtuzumab (anti-CD52) is effective in preventing acute graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (aHSCT). As well as depleting donor T cells, alemtuzumab may also work by targeting host dendritic cells (DC). To determine whether this second mechanism of action is significant, we investigated the effects of intravenous alemtuzumab by comparing skin and blood DC numbers of patients with chronic lymphocytic leukemia, before and after a 4-week course of alemtuzumab treatment. Although skin DC express CD52, the epitope is only weakly detectable and their numbers were not consistently reduced by alemtuzumab. In contrast, circulating blood DC, with stronger CD52 expression, were invariably diminished by alemtuzumab. Because DC depletion in the transplant recipient remains a promising approach for GvHD prophylaxis and therapy, more potent techniques, such as an antibody of different specificity, may be required for effective DC eradication in GvHD target organs.
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Alemtuzumab is a humanized monoclonal antibody against CD52, an antigen found on lymphocytes and monocytes. Pulsed administration causes prolonged T-cell depletion and has been shown to be effective in early relapsing–remitting multiple sclerosis, reducing relapse rate and risk of acquiring disability in comparison with the standard therapy IFN-β. Alemtuzumab is currently approved for the treatment of B-cell chronic lymphocytic leukemia but not for multiple sclerosis. The most significant complication of treatment is the late development of autoimmunity, which occurs in 30% of patients. Serious infections are rare. Phase III trials are ongoing and it is possible that alemtuzumab will have a place among the range of emerging disease-modifying therapies for multiple sclerosis.
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Meeting abstracts Alemtuzumab, a humanised CD52 monoclonal antibody, is routinely used as treatment for patients with refractory chronic lymphocytic leukaemia (CLL). Although alemtuzumab has been evaluated in numerous prospective clinical trials, little is known about its safety and efficacy in the
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